Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH2:20][O:21]CC3C=CC=CC=3)=[CH:8][C:7]([C:29]([NH2:31])=[O:30])=[CH:6][N:5]2[C:32]=1[CH3:33].C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH2:20][OH:21])=[CH:8][C:7]([C:29]([NH2:31])=[O:30])=[CH:6][N:5]2[C:32]=1[CH3:33]
Reactant: Cc1cccc(CCOCc2ccccc2)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cccc(CCO)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 97.8 %

Procedure:
2,3-dimethyl-8-(2-(2-(benzyloxy)ethyl)-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide (0.13 g, 0.29 mmol), cyclohexene (1 ml), Pd(OH)2 cat. (25 mg) were added to ethanol (5 ml) and the mixture was refluxed overnight. An additional amount of cyclohexene (1 ml) and Pd(OH)2 cat. (25 mg) were added and the mixture was refluxed for 4 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Treating the residue with chloroform and filtration gave 0.1 g (99%) of the title compound.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].C(O)C.[CH2:22](I)[CH2:23][CH2:24][CH3:25].[C:27](=[S:29])=[S:28]>>[CH2:22]([S:29][C:27]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:28])[CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: CCCCI
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O

Procedure:
In the same manner as described in Example 6, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (96%, 1.75 g), 50% ethanol (65 ml), carbon disulfide (0.91 ml) and n-butyl iodide (3.3 g) are reacted and treated. The product is crystallized from chloroform to give the title compound (1.9 g) as pale yellow crystals, m.p. 163°-164° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[C:42]([CH3:68])[CH:43]=[C:44]([S:47]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56](=[O:67])[NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=O)[CH:51]=4)(=[O:49])=[O:48])[CH:45]=3)[N:40]=[CH:39][C:38]=2[C:69]([NH2:71])=[O:70])[CH:33]=[CH:34][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:9]([O:8][C@H:7]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[CH2:6][NH:5][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][NH:57][C:56]([C:52]1[CH:51]=[C:50]([S:47]([C:44]2[CH:45]=[C:46]3[C:41](=[C:42]([CH3:68])[CH:43]=2)[N:40]=[CH:39][C:38]([C:69]([NH2:71])=[O:70])=[C:37]3[NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=2)(=[O:48])=[O:49])[CH:55]=[CH:54][CH:53]=1)=[O:67])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Glacial acetic acid (0.005 mL, 0.089 mmol) and Intermediate 2 (50 mg, 0.149 mmol) were added to a stirring solution of Intermediate 112 (55 mg, 0.089 mmol) in DMF (2 mL) at rt. The resulting solution was stirred for 3 h, then NaBH(OAc)3 (57 mg, 0.267 mmol) was added in portions. The reaction mixture was stirred over night then poured into said. NaHCO3 (40 mL). The precipitate was filtered, washed with H2O (50 mL), and dried to give the title compound (76 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C50H63N6O8SSi+ 935.4. Found m/z=935.4 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: ClCCCBr
Product: Cc1ccc(OCCCCl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using p-cresol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=[O:3])[CH3:2].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3N=CC=C[C:15]3=2)[CH:10]=[CH:9]1.N1[CH:26]=[CH:25][CH:24]=[CH:23]C=1>>[C:1]([O:4][CH2:5][CH:25]1[CH2:24][CH2:23][N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[CH2:26]1)=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: c1cnc2ccc3cc[nH]c3c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC1CCn2c(cc3ccccc32)C1
Reaction time: 18 h

Procedure:
11.4 g of acetic anhydride were added to a solution of 11.0 g of the pyridoindole from c) in 100 ml of pyridine and the resulting solution was stirred under a nitrogen atmosphere for 18 hours. The majority of the pyridine was removed by evaporation and the residue was acidified with 2M hydrochloric acid. The mixture was extracted with diethyl ether and the combined extracts were washed with sodium bicarbonate solution and with water. The extracts were dried and evaporated to dryness to give 11.25 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole of melting point 63°-64° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example were carried out by using 4.16 g (25 mM) of.4-n-butylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 7 ml of benzene. 5-n-Butyl-2,2-dimethyl 1,3 benzodioxol was obtained in the yield of 4.74 g (23 mM) as colorless transparent liquid having a boiling point of 74°-75° C./1 mmHg.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].C1(C)C=CC=CC=1.C(O)CCC>C(O[Ti](OCCCC)(OCCCC)OCCCC)CCC.O>[CH3:11][CH2:10][N:12]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)=[O:9])[CH2:13][CH3:14]
Reactant: CCNCC
Reactant: O=C(O)c1cccnc1
Agent: CCCCO[Ti](OCCCC)(OCCCC)OCCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CCN(CC)C(=O)c1cccnc1

Procedure:
Nicotinic acid (0.5 mole), diethylamine (0.5 mole), toluene (35 ml), n-butanol (60 ml) and tetra n-butoxy titanium were heated until all water was removed by azeotropic distillation from the reaction mixture. The volatile solvents were then distilled off and the remaining product fractionally distilled under vacuum to give nikethamide identified both by its boiling point and its infra-red spectrum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][OH:11].[C:12](Cl)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[OH:11][CH2:10][CH2:9][N:8]([C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:7][CH2:6][CH2:5][N:4]([C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:2][OH:1].[OH:11][CH2:10][CH2:9][N:8]([C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][N:4]([C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:2][OH:1]
Reactant: OCCNCCCNCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCO)CCCN(CCO)C(=O)CCCCCCC/C=C\CCCCCCCC
Product: CCCCCCCCCCCCCCCC(=O)N(CCO)CCCN(CCO)C(=O)CCCCCCCCCCCCCCC
Yield: 222.5 %

Procedure:
The procedure described in Example 33 was followed by employing 7.3 g of N,N'-bis(2-hydroxyethyl)-1,3-diaminopropane prepared in Example 33 and 20.9 g of oleoyl chloride, instead of palmitoyl chloride of Example 33, to give 26.7 g of the title compound as viscous oil, which was identified by IR and NMR. The results are shown in Table 3.
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[CH2:7]([O:9][C:10](=[O:26])[C:11]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1)[CH3:8]>ClCCl>[CH2:7]([O:9][C:10](=[O:26])[C:11]1[CH:23]=[C:22]([CH2:24][O:25][CH:3]([CH3:4])[CH3:2])[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1)[CH3:8]
Reactant: c1ccncc1
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(COC(C)C)cc(C(=O)OCC)c1
Reaction time: 0.08 h

Procedure:
Mix dichloromethane (1.8 mL), pyridine (56 mL, 0.7 mmol), and trifluomethanesulfonic anhydride (97 μL, 0.58 mmol) to a flask at −35 to 45° C. Add premixed 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (65 mg, 0.23 mmol) in dichloromethane (4 mL) dropwise at 40° C. Stir for 5 min and quench with isopropyl alcohol (2 mL). Dilute the reaction mixture with dichloromethane (10 mL), wash with water (2×10 mL), and concentrate to give the title compound and used directly in the next step without further purification.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18]1([CH3:29])[CH:23]=[CH:22][C:21]([S:24](C#N)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:29][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:12]2[N:11]3[C:7](=[N:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=43)[S:6][N:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2nsc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (10.0 g, 40.4 mmole) and p-toluenesulfonyl cyanide (14.7 g, 81.0 mmole) in 120 mL of dichloromethane was stirred at room temperature for 20 h. The precipitate was filtered and washed with dichloromethane to yield 12.2 g (91%) of 3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as white powder: mp 231°-234° C.; 1H NMR (CDCl3) δ8.53 (d, 1H), 8.04 (d, 2H), 7.82 (d, 1H), 7.56-7.44 (m, 4H), 2.53 (s, 3H) ppm; 13C NMR (CDCl3) δ163.72, 150.38, 147.97, 147.54, 132.48, 130.30(2C), 129.97(2C), 128.49, 126.14, 123.06, 119.70, 114.67, 21.93 ppm; IR (KBr) ν1592, 1525, 1444, 1337, 1151, 1081, 735 cm-1 ; HRMS calcd for C15H11N3O2S2 : 329.0293, found: 329.0300. Anal. Calcd for C15H11N3 O2S2 : C, 54.70; H, 3.37; N, 12.76. Found: C, 54.29; H, 3.14; N, 14.59.
Reaction SMILES: [NH:1]([CH:3]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]([OH:6])[CH3:5])[NH2:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](OC)=[C:26]([C:29]#[N:30])[C:27]#[N:28]>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[NH2:30][C:29]1[N:1]([CH:3]([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:4]([OH:6])[CH3:5])[N:2]=[C:25]([O:24][CH3:23])[C:26]=1[C:27]#[N:28]
Reactant: CC(O)C(CCCc1ccccc1)NN
Reactant: COC(OC)=C(C#N)C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C#N
Temperature: 20 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
4.2 g of 3-hydrazino-2-hydroxy-6-phenylhexane are are dissolved in 20 ml of methanol, and 1.38 ml of triethylamine are added. Then, 1.38 g of 1,1-dimethoxy-2,2-dicyano-ethylene are added. The reaction solution is stirred for 2 hours at approx. 20° C. For work-up, the mixture is diluted with citric acid solution and ethyl acetate and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried with magnesium sulphate and evaporated in vacuo. The evaporation residue is chromatographed on silica gel (Merck Si 60 0.04-0.063 mm) with a cyclohexane/ethyl acetate mixture in a ratio of 4:1 to 1:1. This gives a fraction which, after evaporation in vacuo, affords 0.959 g (=30.5% of theory) of 5-amino-4-cyano-3-methoxy-1-[2-hydroxy-6-phenyl-hex-3-yl]-pyrazole as diastereomer mixture.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[CH3:9][O-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[N:17][CH:18]=1.O>C(O)C>[CH2:8]([O:7][C:1](=[O:6])[C:2](=[O:4])[CH2:20][C:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][N:17]=1)=[O:21])[CH3:9]
Reactant: C[O-]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cn1
Reaction time: 0.08 h

Procedure:
Dimethyl oxalate (5 g) was added to sodium methoxide (2.26 g) in ethanol (100 mL), and the mixture was stirred for 5 minutes. 1-(5-Chloro-2-pyridyl)ethanone (3.26 g) was added to the mixture, followed by stirring at room temperature for 45 minutes. Water was added to the reaction mixture, and the resultant mixture was washed with diethyl ether. The aqueous layer was acidified with aqueous 1N hydrochloric acid, and chloroform was added thereto to partition the mixture. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(5-chloro-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester as a solid (4.12 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH2:24][C:23]1=[O:32].N1C2C(=CC=CC=2)NCC1=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]([CH3:21])[C:23](=[O:32])[CH2:24]2)[CH:7]=1
Reactant: CN1C(=O)CNc2ccccc21
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: O=C([O-])O
Agent: O=C1CNc2ccccc2N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(=O)N(C)c2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (98.8 mg) and 1-methyl-3,4-dihydro-1H-quinoxalin-2-one (prepared as the minor regioisomer following a similar procedure described for 3,4-dihydro-1H-quinoxalin-2-one; R. E. TenBrink et al., J. Med. Chem., 1994, 37, pp. 758-768) (165 mg) in dimethylformamide (0.75 mL) was heated at 140° C. for 60 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted twice with diethyl ether. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 20% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (16.2 mg), m.p. 132° C.-134° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=O.Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1COCC1>[NH2:24][C:16]1[CH:15]=[C:14]([F:13])[C:22]([F:23])=[CH:21][C:17]=1[C:18]([NH:34][O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20]
Reactant: NOCc1ccccc1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(F)c(F)cc1C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
Carbonyldiimidazole (6.1 g, 37 mmol) was added to a suspension of 4,5-difluoroanthranilic acid (5.40 g, 31 mmol) in 250 mL of THF, and the mixture was stirred for 24 hours at 25° C. O-benzylhydroxylamine hydrochloride (4.95 g, 31 mmol) and triethylamine (5.2 mL, 37 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 6.0 g of the title compound as a solid, mp 125-126° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:41])=[C:11]([CH3:40])[C:12]=1[C:13]([C:15]1[CH:34]=[CH:33][C:18]([O:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:32])[CH:24]=2)(=[O:22])=[O:21])=[C:17]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43].[I-].[Mg+2].[I-]>CCOCC>[C:42]([O:32][C:25]1[CH:24]=[C:23]([S:20]([O:19][C:18]2[CH:33]=[CH:34][C:15]([C:13]([C:12]3[C:11]([CH3:40])=[C:10]([CH3:41])[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:16][C:17]=2[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A stirred solution containing 4-[4-(2-benzyl-4,5-dimethyl-furan-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.235 g, 0.409 mmol), acetic anhydride (3.3 mL) and magnesium iodide (0.113 g, 0.409 mmol) in ether (8 mL) was refluxed for 0.5 h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. The mixed anhydride/product was dissolved in THF (6 mL), treated with H2O (6 mL) and refluxed for 0.5h. The reaction was allowed to cool to ambient temperature, quenched with H2O (100 mL), extracted with ether and concentrated. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 18 & 25% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.201 g (80%) of the title compound as an off white solid, mp 55-90° C. 1H NMR (DMSO-d6) δ 1.23-1.32 (m, 2H), 1.50-1.53 (m, 2H), 1.64-1.72 (m, 4H), 1.76 (s, 3H), 2.17 (s, 3H), 2.23 (s, 3H), 2.92 (quintet, 1H), 3.79 (s, 2H), 6.98-7.00 (m, 2H), 7.15-7.23 (m, 4H), 7.53 (dd, 1H), 7.58 (d, 1H), 7.84 (d, 1H), 7.88 (dd, 1 H), 8.12 (d, 1H) 13.7 (br s, 1H). mass spectrum (−ESI) m/z 615 (M−H). Anal. Calcd. for C34H32O9S.0.5H2O: C, 65.27; H, 5.32; N, 0.00. Found: C, 65.33; H, 5.30; N, 0.03.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19].Cl>C(Cl)Cl.C(Cl)(Cl)Cl>[C:18]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
6-Aminohexanoic acid methyl ester hydrochloride (5 g) is dissolved in methylene chloride (20 ml) and thereto are added pyridine (4.5 ml) and acetyl chloride (2 ml), and the mixture is stirred at room temperature for 1 hour and 45 minutes. To the reaction solution are added a 1N-hydrochloric acid and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-acetylamino-hexanoate (5.19 g) as a crude product. MS (m/z): 188 [M+H]+
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH:21]=O)[N:16]=2)[N:11]=1)(=[O:8])[CH3:7].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.B.CNC>C(O)(=O)C>[C:6]([NH:9][C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:16]=2)[CH2:21][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)[N:11]=1)(=[O:8])[CH3:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)Nc1nc(O)c2nc(C=O)cnc2n1
Agent: B
Agent: CNC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCc2cnc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.07 g (10 m ole) of the dimethylformamide solvate of 2-acetamido-4-hydroxypteridine-6-aldehyde, 3.30 g (20 mmole) of ethyl p-aminobenzoate and 50 ml of glacial acetic acid is stirred at ambient temperature for 30 minutes. To the resulting suspension is added dropwise 1.00 g of dimethylamine borane in 15 ml of acetic acid. The mixture is stirred for an additional 20 minutes, heated to 60° C for 10 minutes and cooled to 25° C. The precipitate is collected by filtration, washed with acetic acid and ether and then dried. The crude product is crystallized from 50 ml of dimethylformamide, with dilution by 20 ml ether, to yield ethyl N2 -acetylpteroate.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[C:27]([NH2:33])=[N:28][CH:29]=[C:30]([F:32])[CH:31]=3)[O:23][N:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>>[NH2:33][C:27]1[C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][C:19]3[CH:34]=[CH:35][C:16]([OH:15])=[CH:17][CH:18]=3)[CH:25]=2)=[CH:31][C:30]([F:32])=[CH:29][N:28]=1
Reactant: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a trifluoroacetic acid (5 mL) solution of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-5-fluoro-pyridin-2-ylamine (180 mg, 0.48 mmol) described in Example 173 was added thioanisole (225 μL, 1.92 mmol), which was stirred for 6 hours at room temperature. A saturated sodium hydrogencarbonate aqueous solution was added to this reaction solution at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2 ethyl acetate) to obtain the title compound (134.0 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, 1.81 g (6 mmol) of 2-[2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 0.845 g (6 mmol) of glycine ethyl ester hydrochloride (98%), and 0.919 g (6 mmol) of hydroxybenzotriazole, hydrate, are added to 100 ml of dimethylformamide and the mixture is cooled to -10° C. under agitation. Then 0.607 g (6 mmol) of triethylamine is added thereto, the mixture is agitated for 10 minutes and combined with 1.24 g (6 mmol) of dicyclohexylcarbodiimide. The mixture is stirred for another hour at the low temperature and then overnight without cooling. The mixture is suctioned off from the solid matter, the solution is concentrated to dryness under vacuum, and the residue is distributed between sodium bicarbonate solution and ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/hexane, thus obtaining 1.72 g (74.1% of theory) of the title compound.