Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:26][CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=2)[C:28]1=[O:39].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:38][O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:39])[CH:27]([NH:26][C:16]([C:10]1[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=1[C:12]([F:13])([F:14])[F:15])=[O:18])[CH2:36][CH2:35]2
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: COc1ccc2c(c1)CCC(N)C2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 300 mg, 1.167 mmol) in dichloromethane (4 mL) at 0° C. was added oxalyl chloride (0.204 mL, 2.333 mmol) and a few drops of N,N-dimethylformamide, and the mixture was stirred at the same temperature for 20 min. Next, the reaction mixture was stirred for 5 min at room temperature, and the solvent and excess oxalyl chloride were evaporated off. The residue was dissolved in anhydrous dichloromethane and evaporated to give an oily residue which became solid upon drying under vacuum. The solid material was dissolved in 5 mL of dichloromethane and 2-amino-6-methoxy-3,4-dihydronaphthalen-1(2H)-one hydrochloride (223 mg, 1.167 mmol, J. Heterocyclic Chem., 29:1245 (1992)), diisopropylethylamine (0.61 mL, 3.50 mmol), and 4-(dimethylamino)pyridine (7.13 mg, 0.058 mmol) were added. The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate, washed with 1N HCl, saturated sodium bicarbonate and brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to give a dark green solid residue. The product was crystallized from ethyl acetate and hexane to give 317 mg of the desired N-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide. The mother liquor was purified by Combiflash (40 g silica gel) eluting with 2:8 ethyl acetate-hexane to give additional 119 mg of the product (87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, d, J=8.80 Hz), 7.82 (1H, br. s.), 7.61 (2H, d, J=6.82 Hz), 7.47-7.58 (3H, m), 6.89 (1H, dd, J=8.80, 2.42 Hz), 6.75 (1H, d, J=2.20 Hz), 4.77 (1H, ddd, J=13.31, 4.84, 4.73 Hz), 3.90 (3H, s), 3.23-3.36 (1H, m), 3.02-3.10 (1H, m), 2.94-3.02 (1H, m), 1.96-2.10 (1H, m).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csnn1
Yield: 61.2 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer)(1.0 g.) and 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.16 g.) were reacted according to similar manners to those of Examples 1(b) and 8 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.68 g.), mp 104° to 115° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.CCO[C:23]([S-:25])=[S:24].[K+].Cl>CN(C)C=O>[Cl:18][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:23]([SH:25])[S:24][C:3]=2[CH:4]=1
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2Cl)c(=O)n1C(F)F
Temperature: 140 °C
Yield: 68 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-2,4-dichlorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. Then, 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 5 h, cooled, and poured into 100 mL ice water. Then, the mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solids crushed out. The title compound was obtained in a 68% yield as a white solid after filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[C:2]1([NH:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1

Procedure:
A reaction tube having a diameter of 32 mm and a length of 80 cm was used for reacting aniline and cyclohexanone to give diphenylamine. 200 ml (175.4 g) of catalyst were used which had been prepared according to German Offenlegungsschrift 3,801,754, Example 2, from spherical (2-6 mm) γ-Al2O3 by impregnating this support with 1% of Cr, 1.1% of Mn, 0.5% of Rh, 0.5% of Pt, 2.7% of NaOH and 2.7% of K2SO4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:24])=[CH:33][C:34]#[N:35])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(OC)c2OC)c1
Yield: 97.6 %

Procedure:
(3,5-Dimethoxyphenyl)-(2,3,4-trimethoxyphenyl)methanone (11.15 g, 3.46 mmol), cyanomethylphosphonic acid diethyl ester (1.09 ml, 6.92 mmol) in anhydrous THF (8 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 6.92 ml, 6.92 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give 3(3,5-dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile as a pink oil (1.20 g, 98%): 1HNMR (DMSO-d6) δ 7.00-6.84 (m, 2H, Ar), 6.62-6.59 (m, 1H, Ar), 6.45 (d, J=2 Hz, 2H, Ar), 6.01 (s, 0.51H, double bond proton), 3.87-3.44 (multiple singlets, 15H, 50CH3); 13C NMR (CDCl3) δ 160.9, 160.8, 160.7, 160.2, 155.5, 155.4, 152.5, 151.8, 142.7, 142.6, 141.4, 140.5, 126.2, 125.8, 125.4, 124.1, 118.0, 117.8, 107.2, 107.0, 105.7, 102.0, 101.9, 96.8, 96.6, 61.1, 61.0, 60.9, 56.2, 55.7, 55.6; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.53; H, 5.84; N, 3.88.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=1[Cl:55]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=3[Cl:55])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(C(F)(F)F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene and isolated as light-yellow solid. MS (m/e): 475.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[N:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[N:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ncc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-quinazoline.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=1)=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:10]=1)=[O:7]
Reactant: O=C(Nc1ncn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (500 mg, 1.09 mmol, 1.00 equiv) in methanol (20 mL). The solution was treated with Pd/C (500 mg) and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 450 mg (96%) of product as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:14]([O-])=O)[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(C)c(F)c1
Yield: 96.7 %

Procedure:
3-Fluoro-4-methyl-5-nitro-benzoic acid, ethyl ester (Example 169a, 1.43 g) in ethanol (30 mL) was pumped continously through a Pd/C cartridge for 4 h under an atmosphere of hydrogen. The solvents were removed to give the subtitle product (1.20 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8](C3CCC(=O)CC3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(OC(N1CCCCC1)=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)N1CCCCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
In a similar manner to the previous Example, 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (0.4 g from 1.0 g of 40% pure material) and 1-ethoxycarbonyl-piperidine (158 mg) were reacted together in the presence of sodium triacetoxyborohydride (296 mg) in dichloromethane (15 ml) containing glacial acetic acid (60 mg) to give after workup and chromatography cis-7-(4-N-ethoxycarbonyl)piperazin-1-ylcyclohexyl)-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N-ethoxycarbonyl)-piperazin-1-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[Br:19][CH2:20][C:21]([NH:1][C@H:2]([CH2:3][OH:4])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)N[C@H](CO)Cc1ccccc1
Reaction time: 1.25 h
Yield: 88.4 %

Procedure:
To a solution of (S)-2-amino-3-phenyl-1-propanol (1.00 g, 6.61 mmol) and triethylamine (1 mL, 7.17 mmol) in THF (70 mL) at -78° C. was added dropwise bromoacetyl bromide (0.60 mL, 6.9 mmol). After 1.25 hours at -78° C., the resultant mixture was partitioned between 1M pH 7 phosphate buffer (100 mL) and hexanes (100 mL). The aqueous layer was extracted with EtOAc:hex (2:1, 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 1.59 g (85%) of 2-bromo-N-(1(S)-hydroxymethyl-2-phenylethyl)acetamide as a solid, mp 83-5° C. 1H NMR (DMSO-d6): δ 8.15 (d, 1H, J=8.1 Hz), 7.32-7.11 (m, 5H), 4.82 (t, 1H, J=5.3 Hz), 3.83-3.74 (m, 3H), 2.80 (dd, 1H, J=5.9, 13.6 Hz), 2.59 (dd, 1H, J=8.9, 13.6 Hz). Anal. Calculated for C11H14NO2Br: C, 48.55; H, 5.19; N, 5.15; Br, 29.36. Found: C, 48.69; H, 5.13; N, 5.13; Br, 29.30.
Reaction SMILES: [CH2:1]=C1CCC2(OCCO2)CC1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=O)[CH2:14][O:13]1.O1C2(CCC(=O)CC2)OCC1>>[CH2:1]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][O:13][CH2:14]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: O=C1COCc2ccccc21
Agent: O=C1CCC2(CC1)OCCO2
Product: C=C1COCc2ccccc21
Yield: 69.8 %

Procedure:
This intermediate was prepared following the procedure described Compound 31a. As starting material isochroman-4-one replaced 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 1:0 to 0:1) to give the title compound as a colorless oil. Yield: 69.8%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(C)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCC(CC(=O)O)CC1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a stirred solution of 92 parts of ethyl 1-acetyl-4-piperidineacetate in 200 parts of ethanol are added dropwise (slowly) 65 parts of sodium hydroxide solution 30%. Upon completion, stirring is continued for 2 hours in a warm water-bath. The reaction mixture is poured onto water and the whole is filtered over hyflo. The clear filtrate is concentrated to a third of its volume and the concentrate is acidified with a diluted hydrochloric acid solution. While cooling, the product is allowed to crystallize. It is filtered off and dried, yielding 29 parts (36.5%) of 1-acetyl-4-piperidineacetic acid; mp. 124.1° C.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH3:14][C:15]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].N1C(C)=CC=CC=1C>C(Cl)Cl.CCOC(C)=O>[CH3:14][C:15]([NH:23][C:8]([C:7]1[CH:6]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=1)=[O:9])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(NC(=O)c1cccc(S(=O)(=O)Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.7 %

Procedure:
3-Chlorosulfonyl-benzoyl chloride (1 g, 4.2 mmol) was dissolved in DCM (10 mL) and cooled in an ice bath. To the solution was added 1-methyl-1-phenyl-ethylamine (0.9 g, 3.8 mmol) and 2,6-lutidine (1 mL, 8.4 mmol). The mixture was allowed to warm up to RT and stirred for 4 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with 1 N HCl (2×75 mL) and brine. The organic layer was dried (MgSO4) and evaporated in vacuo to provide 1.37 g (98%) of 3-(1-methyl-1-phenyl-ethylcarbamoyl)-benzenesulfonyl chloride as a tan solid. 1H-NMR (CDCl3): δ 8.40 (t, 1H, J=1.7 Hz), 8.15-8.18 (m, 2H), 7.72 (t, 1H, J=7.8 Hz), 7.46-7.50 (m, 2H), 7.36-7.41 (m, 2H), 7.27-7.32 (m, 1H), 6.56 (br s, 1H), and 1.87 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([SH:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C(OCC)C.O.C(=O)(O)[O-]>[CH3:23][CH:22]([CH3:24])[CH2:21][CH:16]([S:12][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:10]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(Br)CC(C)C
Reactant: Sc1nnc(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(CC(C)C)Sc1nnc(-c2ccccc2)[nH]1
Reaction time: 0.5 h

Procedure:
5-Phenyl-4H-1,2,4-triazole-3-thiol (296 mg, 1.67 mmoles) in 5 mL of DMF was treated with sodium hydride (67 mg, 60% oil dispersion, 1.76 mmoles) and stirred for 30 minutes. Methyl 2-bromo-4-methylpentanoate (275 μL, 1.67 mmoles) was added in one portion and the reaction was stirred overnight. The reaction was diluted with diethyl ether, water and sat. aq. bicarbonate. The phases were separated and the organic phase was washed with 2 portions of 1.2 N hydrochloric acid and then brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a residue which was purified by flash chromatography to give methyl 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoate.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:20]([C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:23]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:21].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([CH2:20][CH3:21])=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:24]=3)[CH2:28][CH2:29]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: CCc1sc(N2CCNCC2)nc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCc1sc(N2CCN(C(=O)Nc3ccc(NC(C)=O)nc3)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 27.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (263 mg, 0.805 mmol), 1-(5-ethyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.732 mmol) and diisopropylethylamine (0.255 ml, 1.46 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (90.1 mg, 27.3%) as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>>[CH2:36]([NH:38][C:39]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40])[CH3:37]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: CCN=C=O
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available ethyl isocyanate (Aldrich) via the parallel synthesis described above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:17][C:16]([C@@H:18]([NH:28]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[N:15][CH:14]=1)[CH:7]=[CH:6]2>CCOC(C)=O.CO.[Pd]>[NH2:28][C@H:18]([C:16]1[NH:17][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[CH:14][N:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2ccc3cc(OC)ccc3c2)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)CCCCC[C@H](N)c1ncc(-c2ccc3cc(OC)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
E3 was dissolved in EtOAc/MeOH (1:1, 0.1 M) and treated with Pd/C (10% w/w). Mixture was purged with N2 and stirred under H2 atmosphere at room temperature for 16 h. Then, reaction mixture was filtered through a pad of Solka-Floc® and filtrate was concentrated under reduced pressure to give the title compound as pale yellow oil which was used as such in the next step. MS (ES+) C22H28N4O2: 381 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[CH3:19][C:20](O)([CH3:22])[CH3:21]>>[C:20]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])([CH3:22])([CH3:21])[CH3:19]
Reactant: NCCCCCC(=O)O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
In a 10 L reaction flask equipped with N2 inlet, 0.383 Kg of 6-aminocaproic acid (2.92 mol) was slowly added to 3.14 Kg of stirring thionyl chloride (26.28 mol). The maximum temperature during the addition is kept at about 30° C. Upon complete addition, the reaction was allowed to stir at 20-30° C. for 1 h, then concentrated via rotary evaporation (max 40° C. bath). Excess thionyl chloride was chased-off by the addition of toluene (0.843 Kg) and the solution was re-concentrated via rotary evaporation (max 40° C. bath). To the resulting tan solid a suspension of 0.537 Kg of sodium bicarbonate (6.42 mol) was added in 2.97 Kg of t-BuOH (40.3 mol) and reaction allowed to stir at 20-30° C. for 2 h. The excess t-BuOH was removed in vacuo (max 40° C. bath) and residue diluted with 5.17 Kg of ethyl acetate and washed with four portions of 1M NaOH (0.307 Kg in 7.68 Kg water), three portions of H2O (1.92 Kg), one portion of sat. aq. NaCl (0.767 Kg in 1.92 Kg water), dried with anhydrous Na2SO4 (0.383 Kg), filtered via Buchner funnel, rinced with ethyl acetate (1.72 Kg), and concentrated in vacuo (max 50° C. bath). The tan liquid residue was distilled (bp 97-98° C./2 mmHg) to afford 0.290 Kg of t-butyl-6-aminocaproate (53% yld) as a clear colourless to light yellow oil.