Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[NH:25])[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:25]=[C:18]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=N)N2CCOCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(c1cccc2c1CCNC2)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.7 %

Procedure:
5-(Imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 27a (0.24 g, 0.69 mmol) was dissolved to room temperature in 10 mL of 10% trifluoroacetic acid in dichloromethane and stirred to room temperature for 18 h. The volatiles were evaporated, the residue was suspended in toluene and evaporated again. The residue was purified by flash chromatography eluting with 7% methanol in dichloromethane containing 0.7% of ammonium hydroxide to yield 0.179 g of 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline 28a.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)[N:14]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCc2ccc(Cl)cc2)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2ccc(Cl)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.092 g) as an off-white solid (0.082 g). MS (ESI−): 469.0 ([M−H]−).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:15]1[S:16][C:17]([CH3:20])=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][N:19]=2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: Cc1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(C)s2)c(C=O)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
To a solution of 2-formyl-4-methoxyphenylboronic acid (200 mg, 1.11 mmol) in DMF (10 mL) and H2O (2 mL) are added 2-bromo-5-methylthiazole (217 mg, 1.22 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol) and K2CO3 (230 mg, 1.67 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and filtered. The filtrate is washed with H2O (15 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 5-methoxy-2-(5-methyl-thiazol-2-yl)-benzaldehyde (160 mg, 63%) as a white foam.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:19][C:20](=[O:27])[C:21](=[CH:25][CH:26]=3)[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4]1.C1(N=C=NC2CCCCC2)CCCCC1.OCCN(CCO)S(C1C=CC(C2NC(=O)C(=CC=2)C(O[N:63]2[C:67](=[O:68])[CH2:66][CH2:65][C:64]2=[O:69])=O)=CC=1)(=O)=O>CN(C)C=O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[NH:19][C:20](=[O:27])[C:21](=[CH:25][CH:26]=3)[C:22]([O:24][N:63]3[C:67](=[O:68])[CH2:66][CH2:65][C:64]3=[O:69])=[O:23])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:4]1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC(CO)C3)cc2)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC(CO)C3)cc2)[nH]c1=O

Procedure:
From 5.0 g. of 6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 130 ml. of dimethylformamide, and 2.89 g. of N,N'-dicyclohexylcarbodiimide in 10 ml. of dimethylformamide, following the procedure of (a) above, there is obtained 6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 201°-204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:14].[Cs+]>C(OCC)(=O)C.CCCCCCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([OH:14])=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccccc2)cc1
Yield: 90 %

Procedure:
Following general operating mode B, 4-bromobiphenyl (232 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a brown solid with a yield of 90% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[C:28]([O:32][C:33](=[O:44])[NH:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[NH2:43])([CH3:31])([CH3:30])[CH3:29]>CCCCCCC.C(OCC)(=O)C>[C:28]([O:32][C:33](=[O:44])[NH:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[NH:43][C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=510.080 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][NH2:16])[O:8][CH2:7][CH2:6]2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[CH2:17]([NH:16][CH2:15][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][O:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc2c(cc1OC)C(CN)OCC2
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(CNCc1ccccc1)OCC2
Reaction time: 8 h

Procedure:
A mixture of 6,7-dimethoxy-1-isochromanmethylamine (18.0 g), benzaldehyde (9.7 g) and dry benzene (400 ml) is heated under reflux (Dean-Stark) for 18 hr. The solvent is removed under reduced pressure and the residue (27.0 g) is dissolved in ethanol (400 ml). Sodium borohydride (17.0 g) is added portionwise to the stirred solution. When the addition is complete the mixture is stirred and heated under reflux for 1.5 hr. and then left at room temperature overnight. The mixture is concentrated, diluted with water and extracted with ether. The ether extracts are in turn extracted with 10% HCl and these extracts are made alkaline and re-extracted with ether. These extracts are washed with brine, dried and evaporated to give the title compound, λmax EtOH 285 nm (3750) and 281 nm (4000).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: COc1ccc(N)cc1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(OC)cc2)nc(N)n1
Yield: 61 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-methoxy-phenylamine provided the title compound (61% yield). 1H NMR (DMSO-d6) δ 1.34 (t, 3H, J=6.9 Hz, CH3), 3.74 (s, 3H, CH3), 4.10 (q, 2H, J=7.0 Hz, CH2), 6.18 (s, 2H, NH2), 6.71 (s, 1H, Ar), 6.89 (d, 2H, J=8.6 Hz, Ar), 7.12 (d, 1H, J=8.9 Hz, Ar), 7.39 (dd, 1H, J=8.8 Hz, 2.9 Hz, Ar), 7.53 (d, 2H, J=8.6 Hz, Ar), 7.94 (d, 1H, J=2.8 Hz, Ar), 8.93 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[O:20])[CH2:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(SC2=CCNCC2)cc1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(CCCN1CC=C(Sc2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 98 °C
Yield: 84.1 %

Procedure:
A mixture of 11.2 g of 4-[(4-chlorophenyl)thio]-1,2,3,6-tetrahydropyridine, 10.0 g of 4-chloro-p-fluorobutyrophenone and 6.9 g of potassium carbonate is heated at 98° C. for 1 hour. The mixture is taken up in benzene and filtered. Evaporation of the filtrate gives a brown oil which is treated with a large excess of 1 N hydrochloric acid. The resulting precipitate is collected to afford 8.9 g (46%) of tan powder, m.p. 208°-210° C. Recrystallization from acetonitrile yields off-white crystals, m.p. 220°-222° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])=O.[NH2:13][C:14]([NH2:16])=[S:15].C(=O)([O-])O.[Na+]>C(O)C>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=2[OH:12])[N:13]=1
Reactant: O=C(CBr)c1cc(Cl)ccc1O
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cc(Cl)ccc2O)cs1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethanone (156.9 mg, 0.63 mmol), thiourea (47.9 mg, 0.63 mmol) and ethanol (3 mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (98.6 mg, 64.5%) as a light yellowish white powder.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH:4]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C(=N)N(C)C.[CH:42]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][CH:48]=[CH:47]2)=O>ClCCl>[CH2:7]([O:6][C:5](=[O:14])/[C:4](/[O:3][CH3:2])=[CH:42]/[C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][CH:48]=[CH:47]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: COC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CO/C(=C\c1ccc2[nH]ccc2c1)C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 3.70 g of (1-methoxy-2-benzyloxy-oxoethyl)triphenyl phosphonium chloride in 60 ml of dichloromethane was added at 0° C. 1.07 ml of tetramethyl guanidine and the mixture was warmed to 22° C. The mixture was treated with 2.25 g of 5-formyl-indole and stirring was continued at 40° C. for 16 h. The mixture was treated again with 3.70 g of the Wittig salt and 1.07 ml of tetramethyl guanidine and stirring was continued at 40° for 24 h after which time the conversion was complete. The mixture was evaporated and the residue partitioned between AcOEt and water. The organic layer was dried, evaporated and the residue chromatographed on silica (n-hexane/AcOEt, 4:1) to give 1.67 g of the title compound as a pale yellow oil. MS: (M+H)+ 308.2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([F:15])=[N:10][C:11]=2[NH2:14])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([CH2:4][C:3]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=3[Cl:1])[N:6]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:11]([NH2:14])[N:10]=1
Reactant: COc1cc(Cl)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2Cl)nc2c(N)nc(F)nc21

Procedure:
A solution of 8-(2-chloro-4,5-dimethoxy-benzyl)-2-fluoroadenine (22 mg, 0.065 mmol), Cs2CO3 (21 mg, 0.065 mmol), pent-4-ynyl tosylate (20 mg, 17.3 L, 0.085 mmol) in anhydrous DMF (170 L) was stirred at 50° C. for 2 h. Following solvent removal, the product (14 mg, 53.8%) was collected through silica gel column purification (CHCl3:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDCl3) 6.91 (s, 1H), 6.67 (s, 1H), 6.01 (bs, 2H), 4.31 (s, 2H), 4.14 (t, J=7.5 Hz, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 2.24-2.20 (m, 2H), 2.01-1.99 (m, 1H), 1.97-1.88 (m, 2H); 13C NMR (100 MHz, CDCl3) 1596, 157.9, 156.3, 152.3, 148.9, 146.0, 124.9, 112.7, 82.3, 69.9, 56.3, 56.2, 42.2, 31.2, 28.1, 15.9; MS m/z 404.1 (M+H)+. HPLC: (a) 95.1% (65% water-35% acetonitrile); (b) 96.7% (35% to 45% acetonitrile).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13]2[O:30][C:31](=[O:33])[CH3:32])(=O)=O)=CC=1.CC(C)=O.[I-:39].[Na+]>O>[I:39][CH2:11][C@H:12]1[O:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: [I-]
Reactant: CC(=O)O[C@@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
6-O-(p-Toluenesulfonyl)-1,2,3,4-tetra-O-acetyl-β-D-glucose (5, 18.5 g, 36.8 mmol) was place in a 500-mL round-bottomed flask. Acetone (200 ml) and sodium iodide (18.5 g, 123 mmol) were added. The resulting mixture was heated at reflux for 20 h. The reaction proceeded gradually. The mixture was poured into 1000 ml of water, and the resulting solid was filtered with a glass filter. Recrystalization from ethanol afforded 6-deoxy-6-iodo-1,2,3,4-tetra-O-acetyl-β-D-glucose (compound 6) in 65% yield (11.0 g, 24.0 mmol).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:19]([P:1]([OH:2])[OH:3])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: O=[PH2]O
Reactant: C=CCCCCCCCCCCCCCC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCP(O)O
Yield: 87.5 %

Procedure:
Example 6 is repeated with 66 g (0.5 mol) of phosphinic acid, 114.5 g (0.5 mol) of hexadecene, 23 mg of tris(dibenzylideneacetone)dipalladium and 32 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 500 g of tetrahydrofuran, passed through a column charged with Deloxan® THP II for purification and freed of solvent in a rotary evaporator. The residue is admixed with 500 g of completely ion-free water and stirred, and then filtered and the residue is washed with cold water and acetone to obtain 127 g (81% of theory) of hexadecylphosphonous acid.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 4,4,5,5,5-pentafluoro-3-oxopentanenitrile (500 mg, 2.66 mmol) and phenylhydrazine hydrochloride (386 mg, 2.66 mmol) in ethanol (5 mL) was heated at 90° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the obtained oil purified by silica gel flash column chromatography (eluting with a gradient of 100% petroleum ether to 10% ethyl acetate in petroleum ether) to afford 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (320 mg, 43%) as a solid. 1H NMR (400 MHz, CDCl3) 87.51-7.60 (m, 4H), 7.45 (m, 1H), 5.91 (s, 1H), 3.96 (brs, 2H); LC-MS (ESI) m/z 278 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14](O)=[O:15].CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14]2=[O:15]
Reactant: COc1cccc(CC(CC(=O)O)c2ccccc2)c1OC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Yield: 76.8 %

Procedure:
4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (13.3 g, 44.3 mmol), from Step 4, was treated with 14 mL (216 mmol) of methanesulfonic acid and 200 mL of trifluoroacetic acid at 60° C. for 1.5 h. After cooling the reaction mixture, the trifluoroacetic acid was removed in vacuo and ice water was added to the residue. Methylene chloride was added and the layers were separated. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized three times from methanol to give 9.6 g (77% yield) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, m.p. 126°-128° C.; 1H NMR spectrum was identical to the spectrum reported for the product of Step 6 of Method A, Example 1.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:44])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:44])[CH2:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNC(=O)N(CCc1ccccc1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCNC(=O)N(CCc1ccccc1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)-N-(2-phenylethyl)-amino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:14]1[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:16][C:10]=2[C:11](=[O:15])[NH:12][CH:13]=1
Reactant: O=c1[nH]ccc2sc(-c3ccccc3)nc12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 2-phenyl-5H-thiazolo[4,5-c]pyridin-4-one 44 (400 mg, 1.75 mmol) in acetic acid (5 mL) at rt was treated with bromine (320 mg, 1.93 mmol) and the resulting mixture was heated at reflux for 30 min. After cooling to rt, water (20 mL) was added to the mixture. The yellow solid which formed was filtered, washed with water and dried in the air to afford 45 (527 mg). 1H NMR (400 MHz, d6-DMSO) δ: 7.57 (m, 3H), 7.70 (s, 1H), 8.05 (m, 2H), MS (EI) m/z (M+H+) 308.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[C:13]([OH:16])(=[O:15])[CH3:14]>C(#N)C.[Zn]>[C:13]([OH:16])(=[O:15])[CH3:14].[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
3,3-Dibromo-7-azaoxindole (2.9 g) was dissolved in a mixture of 20 mL of acetic acid and 30 mL of acetonitrile. To the solution was added 6.5 g of zinc dust. The mixture was stirred for 2 hrs at room temperature. The solid was filtered from the mixture and the solvent evaporated. The residue was slurried with ethyl acetate. The ethyl acetate solution containing insoluble solid was passed through a short column of silica gel. The collected ethyl acetate solution was evaporated and the residue dried under vacuum to give 1.8 g (yield 91%) of 7-azaoxindole acetic acid salt.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[N:37]=[C:38]=[O:39]>O1CCCC1>[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[NH:37][C:38]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:39]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1onc(-c2ccccc2)c1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 5-methyl-3-phenyl-4-isoxazolyl isocyanate (244 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 229 mg (63.3%) of the desired product as a solid.