Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:19])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C=O)C>[CH:1]1([NH:6][C:7](=[O:19])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:60][O:59][CH:54]3[CH2:55][CH2:56][CH2:57][CH2:58][O:53]3)=[O:18])=[CH:13][CH:12]=2)[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOC1CCCCO1
Reactant: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NOC2CCCCO2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(1-(3-cyclopentylureido)ethyl)thiophene-2-carboxylic acid obtained in step 2 in DMF (1 mL) was added HATU (62 mg, 0.165 mmol) and N,N-diisopropylethylamine (130 μL, 0.75 mmol) was added a solution of O-(tetrahydropyran-2-yl)hydroxylamine (19.3 mg, 0.165 mmol) in N,N-dimethylformamide (1.0 mL). The reaction was stirred at room temperature for 12 hours. The solution was evaporated to dryness and to the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give crude 5-(1-(3-cyclopentylureido)ethyl)-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide. LC-MS: (FA) ES+ 382.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)=[O:20]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1

Procedure:
1-(t-Butoxycarbonyl)piperazine (1.86 g, 10 mmol), p-fluorobenzaldehyde 27 (1.24 g, 10 mmol), and K2CO3 (1.74 g, 11 mmol) in dry pyridine (10 mL) are stirred at reflux under a nitrogen atmosphere for 24 h. Most of the solvent is removed under vacuum and the residue is partitioned between EtOAc (150 mL) and water (100 mL). The aqueous layer is washed with EtOAc (2×50 mL) and the combined organic layers are sequentially washed with 3% aq. citric acid (2×100 mL), water (100 mL), brine (100 mL), and dried (MgSO4). The solvent is removed under vacuum and the residue washed with hexanes and dried under vacuum. The product can be used as such, or further purified by silica gel column chromatography (dichloromethane-MeOH gradient).
Reaction SMILES: [C:1]([NH:18][C:19]1[C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:25])[CH:24]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[ClH:27]>C(OCC)(=O)C>[C:1]([NH:18][C:19]1[C:20](=[O:26])[CH:21]=[C:22]([Cl:27])[C:23](=[O:25])[CH:24]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)NC1=CC(=O)C=CC1=O
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)NC1=CC(=O)C(Cl)=CC1=O
Reaction time: 2 h
Yield: 64 %

Procedure:
To 100 g of 2-palmitoylamino-1,4-benzoquinone were added 500 ml of ethyl acetate was stirring. The system was then allowed to undergo reaction at room temperature with hydrogen chloride gas blown thereinto for 2 hours. After completion of the reaction, the reaction system was washed with 1,000 ml of iced water. 50 ml of concentrated nitric acid was then added to the system which was then allowed to undergo reaction at room temperature for 30 minutes. After completion of the reaction, the reaction system was washed with 500 ml of water and then with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. To the resulting ethyl acetate solution was added 1,500 ml of acetonitrile. The reaction system was then cooled for crystallization. The resulting crystal was filtered off, and then dried to obtain 70 g of 2-palmitoylamino-5-chloro-1,4-benzoquinone. (Yield: 64%)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si](O[C:27]1[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[CH:31][CH:30]=[C:29]([O:47][Si](C(C)(C)C)(C)C)[C:28]=1[O:55][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C(O)(=[O:65])C.O>C1COCC1>[OH:65][C:30]1[C:29]([OH:47])=[C:28]([OH:55])[CH:27]=[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:31]=1
Reactant: CC(=O)O
Reactant: COc1cc(/C=C\c2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C\c2cc(O)c(O)c(O)c2)cc(OC)c1OC
Temperature: 25 °C
Yield: 122.9 %

Procedure:
Tetrabutylammonium fluoride (1.37 mL, 1.37 mmol, 1M in THF) was added to a solution of 32 (0.45 g, 0.69 mmol) and glacial acetic acid (78 μL, 1.37 mmol) in THF (6 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was partitioned between CH3CN and cyclohexane and the CH3CN layer was separated and concentrated in vacuo to give the crude product (0.27 g). Purification by column chromatography (SiO2 1:1 EtOAc:cyclohexane) gave ZSB-79 (0.127 g, 58%) as a 86:14 mixture of Z:E isomers:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])=[O:8].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23])=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1OC(=O)N1CCOCC1
Yield: 92.1 %

Procedure:
Using 5-chloro-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.O.S(=O)(=O)(O)[OH:23]>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Yield: 78.5 %

Procedure:
56.2 g of p-cyanobenzylamine, 59.6 g of hexamethylenetetramine, 46 ml of water, 320 ml of acetic acid and 46.0 g of 98% sulfuric acid were mixed and reacted at 100° C. for 2 hours while stirring. The reaction solution was concentrated to about a half amount in an evaporator and 400 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 43.8 g (yield: 78%) of p-cyanobenzaldehyde. The purity was 99.8% or more.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Imidazole 1 g (0.015 mol) was dissolved in dry DMF 50 mL under argon atmosphere. After a NaH mineral oil dispersion (60%) 0.68 g (0.017 mol) was added, the mixture was heated at 80° C. for 70 min. After cooling to room temperature, 1-Bromo-2-(2-methoxyethoxy)-ethane (1), 2.75 g (0.015 mol), was added, then stirred overnight. The reaction was poured into water, extracted by CHCl3, washed by water, dried over Na2SO4, then dried (Rotavap) until an oily residue remained. The crude product was purified with silica gel flash column chromatography with an eluant of CHCl3: CH3OH=20:1. 1.69 g (70% yield) of the product (2) was obtained as a colorless oil. As an alternative to column chromatography, product (2) is purified by vacuum distillation.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>CN(C1C=CN=CC=1)C.C1COCC1>[C:12]([O:11][C:9]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])=[O:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1ccc[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.1 %

Procedure:
A mixture of pyrrole-2-carboxaldehyde (9.5 g, 0.1 mol), (BOC)2O (24.0 g, 0.11 mol) and DMAP (0.25 g) in THF (150 ml) was stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue dissolved in CH2Cl2 (200 ml) and washed with 10% citric add, water and brine. The organic layer was dried (Na2SO4) and evaporated to give the desired product (20.9 g, 95%); δ (360 MHz, CDCl3) 1.65 (9H, s, 3 of CH3), 6.28-6.30 (1H, m, Ar--H), 7.18-7.19 (1H, m, Ar--H), 7.43-7.45 (1H, m, Ar--H). 2. trans-Methyl-2-N-tert-butyloxycarbonylpyrrol-2-yl)acrylate Prepared from the preceding aldehyde and methyl diethylphosphonoacetate as described for Intermediate 4 (step 3). The product (98%) was obtained as a pale yellow oil; δ (360 MHz, CDCl3) 1.63 (9H, s, 3 of CH3), 3.78 (3H, s, CH3), 6.21 (1H, d, J=16.0 Hz, vinyl CH), 6.21-6.22 (1H, m, Ar--H), 6.69-6.71 (1H, m, Ar--H), 7.38-7.39 (1H, m, Ar--H), 8.30 (1H, d, J=16.0 Hz, vinyl CH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:20])[CH:10]([CH3:21])[N:9]=1.[Cu][C:23]#[N:24].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:23]#[N:24])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:20])[CH:10]([CH3:21])[N:9]=1
Reactant: CC1N=C(c2ccccc2F)c2cc(I)ccc2NC1=O
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CC1N=C(c2ccccc2F)c2cc(C#N)ccc2NC1=O

Procedure:
23.2 g (58.8 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-iodo-3-methyl-2H-1,4-benzodiazepin-2-one and 10 g (0.11 mol) of copper (I) cyanide in 250 ml of dimethylformamide are heated at 150° for 2 hours under argon. After cooling, 700 ml of water are added to the mixture and the resulting precipitate is filtered off. This is dissolved in 1 l of water/ethylenediamine (1:1) and extracted with 1 l of methylene chloride; the separated aqueous phase is extracted a further twice with methylene chloride. The combined organic extracts are washed with water, dried and evaporated. The residue gives, from cyclohexane, 5-(o-fluorophenyl)-2,3-dihydro-3-methyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile of melting point 216°.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[CH:26]=[N:25]1>>[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:2]3[C:3]4[C:10]5[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:30][CH:31]=2)[CH:26]=[N:25]1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2C1

Procedure:
In analogy to Example 22A, ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (100 mg, 0.35 mmol) and 1-(3-fluorobenzyl)-1H-indazol-5-amine from Example 8A (89 mg, 0.37 mmol) were reacted to the title compound to yield 120 mg (68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Periodinane (26.9 g, 63.5 mmol) was added to a solution of 1-tert-butoxycarbonyl-piperidine-4-methanol (10.5 g, 48.8 mmol) in methylene chloride (200 mL) and the mixture was stirred for 90 min. Diethyl ether was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 300 mL). The organic layer was washed with 0.5 M NaOH and brine, dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 8:2) gave 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (8.5 g, 81%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27]([N:6]4[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]4)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2C[C@@H](C)N[C@@H](C)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials cis-2,6 dimethylpiperazine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.03 (d, 6H), 2.28 (s, 3H), 2.40 (t, 2H), 2.79 (m, 3H), 3.94 (d, 2H), 7.05 (m, 2H), 7.28 (d, 1H), 7.55 (d, 1H), 8.01 (m, 2H), 8.36 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[S:11][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1ccc(-c2ccccn2)s1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccn4)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-(2-pyridinyl)-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 420.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:34]1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)(=[O:40])=[O:39])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Product: Cn1cc(S(=O)(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cn1

Procedure:
Prepared from 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 1-methyl-1H-pyrazole-4-sulfonyl chloride. Off-white solid; EI-HRMS m/e calculated for C27H26FN7O4S (M+) 563.1751, found 563.1752.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1.C(C1NC=CN=1)(C1[NH:33]C=CN=1)=O.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21]([NH2:33])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c2C1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(N)=O)c2C1
Temperature: 70 °C

Procedure:
A suspension of 4-[2-(5-Chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid (25 mg, 60.56 μmol) and carbonyl-diimidazole (20 mg, 121.11 μmol) in dry DMF (3 mL) was heated at 70° C. for 1 h and then cooled to r.t. A stream of NH3 gas was passed through the solution for 30 min., giving clean conversion to the amide product. Evaporation of the solution, followed by HPLC purification gave, after lyophilization, the pure amide of formula (62) as the TFA salt (20 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5]2.[Br:19][C:20]1[CH:21]=[C:22]([C:32](O)=O)[N:23]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:24]=1>>[Br:19][C:20]1[CH:21]=[C:22]([C:32]2[O:13][C:12](=[O:14])[C:11]3[C:2](=[CH:3][C:4]4[C:9]([CH:10]=3)=[N:8][C:7]([C:15]([F:18])([F:16])[F:17])=[CH:6][CH:5]=4)[N:1]=2)[N:23]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:24]=1
Reactant: Nc1cc2ccc(C(F)(F)F)nc2cc1C(=O)O
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2cc3ccc(C(F)(F)F)nc3cc12

Procedure:
Prepared from 6-Amino-2-trifluoromethyl-quinoline-7-carboxylic acid and 5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid analogously to the procedure described in step h) of example H-18. This gives the title compound as orange crystals.
Reaction SMILES: [BH4-].[Li+].[O:3]=[S:4]1(=[O:38])[C:8]([C:9]2[CH:36]=[CH:35][C:12]([CH2:13][O:14][CH2:15][C:16]3[CH:34]=[CH:33][C:19]([O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:22]=4[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:7][C:6](=[O:37])[NH:5]1>O1CCCC1>[O:3]=[S:4]1(=[O:38])[CH:8]([C:9]2[CH:36]=[CH:35][C:12]([CH2:13][O:14][CH2:15][C:16]3[CH:34]=[CH:33][C:19]([O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:22]=4[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:37])[NH:5]1
Reactant: COC(=O)c1c(OC)cccc1Oc1ccc(COCc2ccc(C3=CC(=O)NS3(=O)=O)cc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(OC)cccc1Oc1ccc(COCc2ccc(C3CC(=O)NS3(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
2 M Lithium borohydride in tetrahydrofuran (0.045 mL, 0.090 mmol) was added to methyl 2-[4-([4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)benzyl]oxymethyl)phenoxy]-6-methoxybenzoate (8 mg, 0.02 mmol) in tetrahydrofuran (1 mL). After stirring at ambient temperature for one hour, the reaction was quenched with saturated aqueous ammonium chloride. The product was purified on a 50 mm Luna C18 column using a 20–100% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The major product was lyophilized to give a white powder (7 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J=7.1 Hz, 2H), 7.42 (d, J=7.1 Hz, 2H), 7.31 (m, 4H), 6.68 (d, J=8.6 Hz, 1H), 6.48 (d, J=8.6 Hz, 1H), 4.98 (t, J=8.4 Hz, 1H), 4.56 (m, 4H), 3.87 (s, 3H), 3.85 (s, 3H), 3.37 (m, 2H); LCMS found for C26H25NNaO8S (M+Na)+: m/z=534.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14]([C:15]=1[O:16]C(=O)C)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].CCCCO.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Reaction time: 4 h

Procedure:
A mixture of 4-acetoxy-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester (671 mg, 2 mmol; can be obtained according to D. A. Walsh et al. in J. Med. Chem. 1978, 21, 582-585), n-BuOH (60 ml) and concentrated H2SO4 (1.7 ml) was refluxed with stirring for 4 h before the reaction mixture was added to concentrated aqueous NaHCO3 solution (60 ml) with stirring. Then EtOAc (120 ml) was added and the mixture was stirred vigorously for 15 min. Subsequently, the organic phase was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=95:5 as the eluent gave the title compound as a solid (126 mg); 1H NMR (CDCl3): δ=11.96 (s, 1H), 8.44 to 8.49 (m, 1H), 8.01 to 8.05 (m, 1H), 7.43 to 7.80 (m, 7H), 4.56 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:3].[Mg].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl.[Cl-].[NH4+]>C(OCC)C>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=1)[OH:15])[CH3:1]
Reactant: CN(C)CC1CCc2ccccc2C1=O
Reactant: COc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(CC2(O)c3ccccc3CCC2CN(C)C)c1

Procedure:
A solution of 8.13 g 2-dimethylaminomethyl-3,4-dihydro-naphthalen-1-one in 20 ml dry diethyl ether was added dropwise to a freshly prepared Grignard reagent of 1.46 g magnesium filings and 8.8 ml 3-methoxybenzyl chloride in 50 ml dry diethyl ether at 20° C., while stirring. The reaction mixture was heated under reflux for 3 hours, decomposed by dropwise addition of 30 ml of a saturated ammonium chloride solution and, after dilution with distilled water, extracted three times with 50 ml diethyl ether each time. The extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography with ethyl acetate/methanol=20/1 as the eluting agent. 9.41 g (72.3% of th.) of the title compound were obtained here as a diastereomer mixture.