Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:30]=[C:11]2[C:12]([C:16](=[O:29])[NH:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)=[O:7])C>CCO>[C:19]12([CH2:18][NH:17][C:16]([C:12]3[C:11]4[N:10]([N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:30]=4)[CH:15]=[CH:14][CH:13]=3)=[O:29])[CH2:28][CH:23]3[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]3)[CH2:26]1)[CH2:20]2
Reactant: CCOC(=O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 4 h

Procedure:
3 M Aqueous KOH (2.6 mL) is added to a mixture of 4-[(adamantan-1-ylmethyl)carbamoyl]-pyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (503 mg, 1.32 mmol) and EtOH (6.6 mL). After 4 h, the volatiles are removed under reduced pressure. The aqueous residue is diluted with water (2 mL) and then acidified with 1 M aq. HCl to ˜pH 2. The solids are collected by filtration and then dried to afford the title compound as a light yellow powder. 1H NMR (400 MHz, ((CD3)2SO) δ: 8.86 (d, 1H), 8.50 (t, 1H), 7.71 (d, 1H), 7.26 (s, 1H), 7.12 (t, 1H), 3.00 (d, 2H), 1.88-1.98 (m, 3H), 1.48-1.69 (m, 12H). LC-MS m/z (M+H+): 354.09.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[S:54][CH:53]2[CH:48]([CH2:49][N:50]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[Cl:62])[CH2:51][CH2:52]2)[CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44]([C:46]2[S:54][C:53]3[CH2:52][CH2:51][N:50]([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[Cl:62])[CH2:49][C:48]=3[CH:47]=2)=[O:45])[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: O=C(CCl)C1=CC2CN(Cc3ccccc3Cl)CCC2S1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1cc2c(s1)CCN(Cc1ccccc1Cl)C2

Procedure:
5-Benzyloxy-2-{2-[5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl]-2-oxo-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b (in DMSO as solvent; purification via reversed HPLC chromatography) from 500 mg (2.47 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 1.03 g (2.72 mmol) 2-chloro-1-[5-(2-chloro-benzyl)-3a,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridin-2-yl]-ethanone (preparation 24).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C1COCC1>[CH:15]1([NH:18][S:11]([C:6]2[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:13])=[O:12])[CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: NC1CC1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)NC1CC1
Temperature: 25 °C

Procedure:
A solution of 1.28 g of 2-(aminosulfonyl)benzenesulfonyl chloride in 12 ml of dry THF was cooled to -65° C. and a solution of 0.80 ml of cyclopropylamine in 12 ml of dry THF added dropwise. The resulting mixture was allowed to warm to room temperature, filtered, and the filtrate concentrated in vacuo. The solid residue was partitioned between water and ethyl acetate, the organic phase was separated, washed with water, dried (MgSO4), concentrated in vacuo, and the residue triturated with 1-chlorobutane to provide 1.15 g of N-cyclopropyl-1,2-benzenedisulfonamide as a white solid, m.p. 202°-203° C.
Reaction SMILES: Br[CH2:2][CH2:3][C@@H:4]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:5][N:6]([CH3:23])[C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.Cl.[NH:32]1[CH2:37][CH2:36][C:35]2([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[S:39][CH2:38]2)[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C@@H:4]([CH2:5][N:6]([CH3:23])[C:7](=[O:22])[C:8]2[CH:9]=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=2)[CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][C:35]3([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[S:39][CH2:38]3)[CH2:34][CH2:33]2)=[CH:29][CH:28]=1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Reactant: CN(C[C@@H](CCBr)c1ccc(Cl)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CCC2(CC1)CSc1ccccc12)c1ccc(Cl)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as in Example 21 from 4-bromo-2-(S)-(4-chlorophenyl)-1-(N-(3,5-bistrifluoromethylbenzoyl)-methylamino)butane and spiro(2,3-dihydrobenzothiophene-3,4'-piperidine) hydrochloride except that 3 eq. of diisopropylethylamine were used.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.CC(C)CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(F)C=2)(=O)=O)N)=CC=CC=1)=O>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=2)(=[O:32])=[O:31])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)CCNC(=O)c1ccccc1-c1ccccc1C(N)S(=O)(=O)c1cccc(F)c1
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(F)c1

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methyl-butyl)amide (precursor 5c) and 3-fluorophenylsulfonyl chloride, according to the general working procedure 118 mg of 2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained; m.p. 141° C. MS (ES+): m/e=455 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C>C(Cl)(Cl)Cl>[CH2:2]([O:9][N:10]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: c1ccc(COn2c(-c3ccccc3)nc3cnc4ccccc4c32)cc1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
O-Benzylhydroxylamine hydrochloride (10.2 g, 63.7 mmol), N-(4-chloroquinolin-3-yl)benzamide (6.00 g, 21.2 mmol), and isopropanol (200 mL) were combined and heated at 80° C. After 18 hours the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed sequentially with saturated aqueous potassium carbonate and water and then concentrated under reduced pressure. This material was purified by column chromatography (320 g of silica gel, eluting with a gradient of 1-2% methanol in dichloromethane). The resulting solid was triturated with hexanes to provide a tan solid that was isolated by filtration. The solid was mixed with chloroform and isolated by filtration to provide 0.951 g of 1-(benzyloxy)-2-phenyl-1H-imidazo[4,5-c]quinoline as a reddish-brown solid. 2-Phenyl-1H-imidazo[4,5-c]quinolin-1-ol (2.39 g) was recovered from the aqueous washings.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([NH:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=1.[N+](=[CH:46][Si](C)(C)C)=[N-]>C1COCC1.CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]([NH:30][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:16])([F:17])[F:18])[CH:9]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=2)[CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:46])[N:1]=2)=[O:43])=[CH:33][C:34]=1[C:39]([F:40])([F:41])[F:42]
Reactant: O=C(NC(Cc1nn[nH]n1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of N-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (18 mg, 0.029 mmol) in THF (0.4 mL) and MeOH (0.1 mL) at rt was added (diazomethyl)trimethylsilane (0.02 mL, 2.0 M solution). The resulting solution was stirred at rt for 20 min. The solvents were evaporated and resulting residue was purified by ISCO flash chromatography (silica gel, hexane/EtOAc) to give 4-fluoro-N-(2-(2-methyl-2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 281, 11 mg, yield: 60%). LCMS: RT=4.06 min [M+H] 638.23, [M+Na] 661.26 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][N+:22]([O-:9])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(-c2ccncc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.5 g (10.2 mmol) of meta-chloroperbenzoic acid are added to a solution of 1.18 g (6.81 mmol) of 4-(4-fluorophenyl)pyridine in 5 mL of chloroform cooled to 0° C. The suspension is stirred for 30 minutes.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:35]=1)[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:16]=1)[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1cc(Cl)cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cc(Cl)cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([OH:35])=[C:27]([C:32](O)=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[OH:35])=[CH:24][CH:23]=[C:22]([Cl:21])[CH:31]=2)=[O:33]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cnc2cc(Cl)ccc2c1O
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1cnc2cc(Cl)ccc2c1O

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 7-chloro-4-hydroxy-quinoline-3-carboxylic acid. MS: 479.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[C:16]1([N:26]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]3)=[N:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[C:16]1([N:26]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH:31]([NH:35][C:13]([C:12]4[C:2]([F:1])=[CH:3][C:4]5[S:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=5[CH:11]=4)=[O:15])[CH2:32]3)=[N:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CSc2cc(F)c(C(=O)O)cc2N1
Reactant: NC1CCc2nn(-c3cccc4ccccc34)cc2C1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1CSc2cc(F)c(C(=O)NC3CCc4nn(-c5cccc6ccccc56)cc4C3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a solution of 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (17 mg, 0.076 mmol), 2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (18 mg, 0.069 mmol), and HOBT (24.0 mg, 0.103 mmol) in DMF (1 mL) was added EDC (20.0 mg, 0.103 mmol). The reaction mixture was stirred overnight at RT. The reaction was diluted with EtOAc (10 mL) and 1 N NaOH (5 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with 1 N HCl (10 mL), brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude was purified by acidic reverse phase HPLC. The TFA salt of the title compound was diluted in CH3OH (10 mL) and treated with anionic exchange resin (550 Å, OH). The mixture was stirred at RT for 20 min. The mixture was filtered and the filtrate was concentrated to afford 2.8 mg (8%) of the title compound. MS (ESI): exact mass calculated for C26H21FN4O2S, 472.14; m/z found, 473.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.76 (br s, 1H), 7.91-7.84 (m, 4H), 7.54-7.49 (m, 5H), 7.11 (d, J=11.4, 1H), 6.97-6.92 (m, 1H), 4.73-4.71 (m, 1H), 3.46 (s, 2H), 3.20 (dd, J=15.5, 5.0, 1H), 3.08-3.02 (m, 1H), 3.00-2.94 (m, 1H), 2.74 (dd, J=15.5, 7.0, 1H), 2.26-2.22 (m, 1H), 2.17-2.11 (m, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]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]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-n4cncn4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1H-1,2,4-triazol-1-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 404.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.C(N(CC)CC)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:14][N:15]([S:38]([CH:35]4[CH2:37][CH2:36]4)(=[O:40])=[O:39])[CH2:16]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CN(S(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (0.241 g, 0.643 mmol) in 2 mL of dioxane was added 4 M HCl in dioxane (4.0 mL). The reaction was stirred at room temperature for 30 min, then evaporated to dryness. To the resulting crude HCl salt in methylene chloride (5.0 mL) was added triethylamine (0.269 mL, 1.93 mmol) followed by cyclopropanesulfonyl chloride (0.0786 mL, 0.771 mmol). The mixture was stirred at room temperature for 30 min, washed with saturated sodium bicarbonate, dried, and evaporated to dryness. The residue was used directly in next step (229 mg, 94%). LCMS (M+H) 379.0.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[C:21]([C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:25][CH:26]=[C:27]([C:29]([NH:1][C@H:2]([CH2:19][CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=3[CH3:18])=[N:5]2)=[O:30])[N:28]=1)(=[O:23])[CH3:22]
Reactant: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1
Reactant: CC(=O)c1nc(C(=O)O)cs1
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1)NC(=O)c1csc(C(C)=O)n1
Yield: 11.4 %

Procedure:
(R)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-butan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (489 mg, 1.355 mmol) and 2-acetylthiazole-4-carboxylic acid (278 mg, 1.626 mmol). The product was purified by Flash-chromatography. Yield 11.4%. 1H-NMR (400 MHz; CDCl3): δ 1.05 (t, 3H), 1.56-1.67 (m, 2H), 2.53 (s, 3H), 2.53 (s, 3H), 4.36-4.52 (m, 3H), 6.42 (d, 1H), 7.47-7.55 (m, 3H), 7.88 (d, 1H), 8.39 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:15]>C(O)C.[Pd]>[ClH:15].[ClH:15].[NH2:2][CH2:1][C:3]1[C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ncccc1OCC(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ncccc1OCC(F)(F)F

Procedure:
A solution of 0.53 g (2.62 mmol) of 2-cyano-3-(2,2,2-trifluoroethoxy)pyridine and 0.66 mL (7.87 mmol) of conc. HCl in 50 mL of ethanol was hydrogenated over 0.27 g of 10% palladium on carbon at 45 psi for 1.5 h. The catalyst was removed by filtration through a pad of Celite with EtOH. The solvents were removed at reduced pressure to give the title compound: 1H NMR (CD3OD) δ8.36 (d, 1H, 5.0 Hz), 7.73 (d,1H, 8.6 Hz), 7.54 (dd, 1H, 8.4, 5.0 Hz), 4.80 (q, 2H, 8.3 Hz), 4.33 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:43])[NH:34][CH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:43])[NH:34][CH2:35][CH2:36][CH:37]1[CH2:38][CH2:39][N:40]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:9]=2)[CH2:41][CH2:42]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(OCCc3ccccc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(OCCc3ccccc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 58.2 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-phenethyloxy benzoic acid 0.6 g (1.66 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.378 g, 1.66 mmol) were used to afford 0.55 g of the required product. 1H NMR (DMSO-d6): δ 1.05 (3H, m), 1.4 (9H, s), 1.55 (2H, m), 1.7 (1H, m), 2.1 (5H, s), 3.0 (5H, m), 4.2 (2H, t), 4.4 (1H, m), 6.62 (1H, s), 6.78 (2H, s), 7.14 (2H, d), 7.24 (1H, m), 7.3 (4H, d), 7.88 (2H, d).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[N:31]3[CH:32]=[CH:33][C:34]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)=[CH:35][C:30]3=[N:29][CH:28]=2)[CH:22]=1)=[O:19])(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[N:31]3[CH:32]=[CH:33][C:34]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)=[CH:35][C:30]3=[N:29][CH:28]=2)[CH:22]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Yield: 15.1 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a stirred solution of [2-(3-{3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-ureido)-ethyl]-carbamic acid tert-butyl ester (85 mg, 0.17 mmol) in CH2Cl2 (2 ml) at 0° C. After 1 h the volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (10 mg, solid).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:26][C:22]1[N:21]=[C:20]2[N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:17]([CH2:27][CH3:28])=[N:18][C:19]2=[C:24]([CH3:25])[CH:23]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(O)cc1
Yield: 61.3 %

Procedure:
A solution of 1.40 g (3.77 mmol) of the product of Step D dissolved in 38 mL of methanol was placed in a Parr hydrogenation flask and 0.140 g of 10% Pd/C catalyst was added. The reaction mixture was placed in a Parr apparatus and rocked under a hydrogen atmosphere (32 psig) for 2 hours. The reaction mixture was then filtered through a plug of silica gel eluted with 20% methanol/chloroform to remove the catalyst. Evaporation of the filtrate and drying in vacuo afforded 0.650 g (61%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[CH:3]=2)[CH:21]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(N)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Cl)ncn2)c2ccccc2n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
To a solution of 4-amino-2-methylquinoline (107) (1.0 g, 6.7 mmol) in anhydrous DMF (60 mL) was added NaH (60% in mineral oil, 0.32 g, 8.0 mmol). The mixture was stirred for 1 hour followed by the addition of 4,6-dichloropyrimidine (106) (1.0 g, 6.7 mmol). The reaction was heated at 90° C. overnight before it was poured into ice water (100 mL). The mixture was extracted with ether (3×100 mL) and the combined organic layers were dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash chromatrography (SiO2, gradient elution, hexanes to 3:1 hexanes/ethyl acetate to 7:3 CH2Cl2/MeOH) to provide 108 (80 mg, 5%) as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH2:49][CH3:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N1C(C(OCC)=O)=C(C(OCC)=O)N=C1CBr)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH:49]([Br:1])[CH3:50])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nc(CC)n(Cc2ccccc2)c1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(C(C)Br)n(Cc2ccccc2)c1C(=O)OCC
Yield: 97.8 %

Procedure:
3.08 g of N-bromosuccinimide and 0.51 g of benzoyl peroxide were added to a solution of 5.19 g of diethyl 1-benzyl-2-ethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] in 100 ml of carbon tetrachloride, and the resulting mixture was heated under reflux for 1 hour. Following a procedure similar to that described in Preparation 42(ii), 6.29 g of the title compound were obtained as a syrup from the resulting reaction solution.