Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.NCC1CCN(CC2C=CC(Cl)=C(Cl)C=2)C1.[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[CH2:33]1>>[CH2:45]1[O:44][C:41]2[CH:42]=[CH:43][C:38]([CH2:37][N:34]3[CH2:35][CH2:36][CH:32]([CH2:31][NH:30][C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][C:8]5[O:9][CH2:1][O:2][C:3]=5[CH:4]=4)[CH2:33]3)=[CH:39][C:40]=2[O:46]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: NCC1CCN(Cc2ccc3c(c2)OCO3)C1
Agent: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Product: O=C(Cc1ccc2c(c1)OCO2)NCC1CCN(Cc2ccc3c(c2)OCO3)C1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3,4-methylenedioxyphenyl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-aminomethyl-1-(3,4-methylenedioxybenzyl)pyrrolidine gave N-[1-(3,4-methylenedioxybenzyl)pyrrolidin-3-(RS)-ylmethyl]-2-(3,4-methylenedioxyphenyl)acetamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>ClCCl>[N+:26]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:1][CH2:2][C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1)=[CH:24][CH:23]=[CH:22][CH:21]=2)([O-:28])=[O:27]
Reactant: NCC1(O)CCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a solution of 1-(aminomethyl)cyclobutanol (62.5 mmol) in dichloromethane (312 mL) was added triethylamine (8.71 mL, 62.5 mmol) and 4-chloro-3-nitroquinoline (13.04 g, 62.5 mmol). More triethylamine (3 mL) was added almost immediately. The reaction was stirred under N2 for 10 d at rt, then was diluted with dichloromethane and washed with 1 M aqueous NaOH. A solid formed and was isolated by filtration. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to a solid that was crystallized from isopropanol. The resulting crystals were combined with the solid that was isolated from the extraction and the mixture was triturated with hot isopropanol. The solid was isolated by filtration, washed with diethyl ether, and air dried to yield 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as yellow crystals. (12.83 g, 75%).
Reaction SMILES: [O:1]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:7][CH2:6]1.[H][H]>[Pd].C(O)C>[OH:1][CH:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(O)c2ccccc2)CC1

Procedure:
A mixture of 1 g of trans-2-[4-(2-oxo-2-phenyl-ethoxy)-cyclohexyl]-isoindole-1,3-dione and 0.1 g of 10% palladium on carbon in 100 mL of ethanol was stirred under 1 atm. of hydrogen overnight. The catalyst was filtered off and the filtrate concentrated to dryness under reduced pressure. Drying under vacuum gave 1.0 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.65 (t, 1H), 7.4-7.2 (m, 5H), 4.82 (d, 1H), 4.1 (m, 1H), 3.65 (m, 2H), 3.4 (m, 2H), 2.3 (dd, 2H), 2.2 (m, 2H), 1.8 (d, 2H), 1.4 (dd, 2H).
Reaction SMILES: [CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>COCCOC>[CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:27][CH:26]=[CH2:25])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCBr
Reactant: CCC(=C(c1ccccc1)c1ccc(O)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCOc1ccc(C(=C(CC)C2CCCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.92 g (10 mmol) of pure E- or Z-isomer of 2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenyl-1-butene in dry DME was added under nitrogen atmosphere to a stirred suspension of sodium hydride in DME (0.6 g of 50-60% dispersion from which the oil had been removed by washing with dry DME). After stirring for 30 minutes at room temperature, 1.44 g (12 mmol) of allyl bromide was added. The mixture was refluxed for 3 hours. Ice water was added. The water layer was extracted with ether and the combined organic layers washed with diluted sodium hydroxide and water and dried. After evaporation of the solvent the residue was 3.1 g. In the case of the E-isomer the semisolid product was purified by chromatography over silica gel using methylene chloride as eluent. The Z-isomer was purified by recrystallization from methanol, mp. 82°-84° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Mg]Cl)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](Cl)(=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.[Cu]I>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH:18]1[CH:19]=[CH:20][N:15]([C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[CH:16]=[CH:17]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Clc1cccc(Br)c1Cl
Reactant: c1ccncc1
Agent: [Cu]I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C=CC(c2cccc(Cl)c2Cl)C=C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a −30° C. solution of 1-bromo-2,3-dichlorobenzene (10 g, 44 mmol) in THF (120 mL) was added i-PrMgCl (2.0 M in THF, 35 mL, 70 mmol) at a rate such that the temperature <−20° C. Meanwhile, to a −10° C. solution of CuI (420 mg, 2.2 mmol) in THF (120 mL) was added pyridine (7.1 mL, 88 mmol) and then benzyl carbonochloridate (9.7 mL, 68 mmol) such that the temperature <0° C. To this heterogeneous mixture was added the initially formed Grignard at a rate such that the temperature <0° C. The resulting solution was stirred at 0° C. for 30 min and then allowed to warm to rt. The reaction was then quenched with 10% aq NH4Cl. EtOAc was added and the blue aq layer was removed. The organic layer was washed with 10% aq NH4Cl, 1 N HCl, and a 20% aq NaCl solution. The organic layer was then concentrated and the residue was dissolved and crystallized from MeOH. The slurry was filtered and the filtercake washed with MeOH to give benzyl 4-(2,3-dichlorophenyl)pyridine-1(4H)-carboxylate (intermediate 45) (12 g, 76%) as an off-white solid. HPLC: 99%, RT 4.118 min. MS (ESI) m/z 382.0 [M+Na]+. mp: 69-70° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:24][N:23]([CH3:25])[C:21]1[N:20]=[CH:19][C:18]2[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][NH:16][C:17]=2[CH:22]=1
Reactant: CN(C)c1cc2[nH]cc(C3CCN(C(=O)OC(C)(C)C)CC3)c2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2[nH]cc(C3CCNCC3)c2cn1
Yield: 100.7 %

Procedure:
The 4-(6-dimethylamino-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (135 mg, 0.39 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated. The residue was dissolved in MeOH (10 mL) and neutralized with DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to give 96 mg (100%) of a yellow solid. MS (electrospray): exact mass calculated for C14H20N4, 244.17; m/z found, 245.2 [M++H]. 1H NMR (CDCl3, 400 MHz): 9.23 (br s, 1H), 8.54 (s, 1H), 6.67 (s, 1H), 6.31 (d, J=0.98 Hz, 1H), 3.15 (d, J=2.13 Hz, 2H), 3.02 (s, 6H), 2.91-2.81 (m, 1H), 2.81-2.72 (m, 2H), 2.01 (d, J=12.52 Hz, 2H), 1.69-1.52 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9]([S:12]([OH:15])(=[O:14])=[O:13])=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH:16]1[CH:21]=[C:20]2[CH:22]=[C:23]([S:27]([OH:30])(=[O:29])=[O:28])[CH:24]=[C:25]([OH:26])[C:19]2=[CH:18][CH:17]=1.C1C=C(O)C2C=CC=C(S(O)(=O)=O)C=2C=1.C1C=C(N)C2C=CC(S(O)(=O)=O)=CC=2C=1>>[CH:8]1[CH:9]=[C:10]([OH:11])[C:4]2[C:3]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:2][CH:1]=[CH:6][C:5]=2[CH:7]=1.[CH:16]1[CH:17]=[C:18]([S:12]([OH:15])(=[O:14])=[O:13])[C:19]2[C:20](=[CH:22][C:23]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:24][C:25]=2[OH:26])[CH:21]=1
Reactant: O=S(=O)(O)c1ccc2ccccc2c1O
Reactant: O=S(=O)(O)c1cc(O)c2ccccc2c1
Agent: Nc1cccc2cc(S(=O)(=O)O)ccc12
Agent: O=S(=O)(O)c1cccc2c(O)cccc12
Product: O=S(=O)(O)c1cc(O)c2c(S(=O)(=O)O)cccc2c1
Product: O=S(=O)(O)c1cccc2cccc(O)c12

Procedure:
Examples of suitable starting materials for these syntheses are 1-naphthol-2-sulfonic acid, 1-naphthol-3-sulfonic acid, 1-naphthol-5-sulfonic acid, 1-naphthol-6-sulfonic acid, 1-naphthylamine-6-sulfonic acid, from which 1-chloro-1-naphthol-6-sulfonic acid may be obtained by chlorination in the course of a Bucherer synthesis, 1-naphthol-7-sulfonic acid, 1-naphthol-8-sulfonic acid, 1-naphthol-3,8-disulfonic acid, 7-acetylamino-1-naphthol-3-sulfonic acid, 8-acetylamino-2-chloro-1-naphthol-5-sulfonic acid, 8-acetylamino-1-naphthol-5-sulfonic acid, 8-benzoylamino-1-naphthol-5-sulfonic acid, 8-acetylamino-1-naphthol-2,5-disulfonic acid and 5-acetylamino-1-naphthol-3-sulfonic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(C)c2)cc1
Yield: 71.6 %

Procedure:
The title compound (D24) (48 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-methylbenzyl bromide (0.046 ml, 0.34 mmol). (Na2CO3: 2.5 eq; reaction time: 3 hrs; 60° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(Cc1ccccc1)c1ccccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
Methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (4.433 g, 16 mmol, 1 eq) is dissolved in 100 mL of a 1:1 (v:v) mixture of THF and methanol. Sodium hydroxide (3.28 g, 82 mmol, 5 eq) is added and the reaction mixture is stirred 18 hours at room temperature. The reaction is then poured into H2O and the pH is adjusted to 2 via addition of 1N HCl. A white precipitate forms which is removed by filtration. The resulting solution is extracted with 3 portion of diethyl ether. The extracts are pooled, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified over silica to afford 2.107 g (51%) of the desired compound. ESI− MS 255 (M−1), 211 (M-CO2H).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.Cl.[OH-].[Na+].CCOCC>C1COCC1.C(Cl)Cl>[NH2:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][C:2]([OH:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: N#CCCN1CCC(O)(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: NCCCN1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 3-(4-hydroxy-4-phenylpiperidin-1-yl)propionitrile (3.71 g, 16.1 mmol, 1.00 equiv) in THF (15 mL) at room temperature was added boranetetrahydrofuran complex (1.0 M in THF, 56.3 mL, 56.3 mmol, 3.50 equiv) dropwise. The mixture was stirred at reflux for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 85 mL) was added and the mixture was stirred at 50-70° C. for 2 hours. The mixture was basified to pH 9-10 by addition of 6 N aqueous NaOH and extracted with EtOAc (75 mL) and CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (75 mL) was added HCl in Et2O (1.0 M, 38 mL, 2.3 equiv). After removal of the solvents, the residue was triturated with Et2O (185 mL). The resulting white solid was collected by filtration and washed with Et2O. Water (50 mL) was added to this solid, and the mixture was basified to pH 10-11 by addition of 1 N aqueous NaOH and extracted with CH2Cl2 (150 mL+2×75 mL). The combined CH2Cl2 solutions were dried over MgSO4 and concentrated to give 3.12 g (83%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [OH2:1].[O:2]1[C@H:4]2[CH2:5][C@H:6]3[C@:19]([CH3:21])([CH2:20][C@@H:3]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([OH:22])[C@@H:12]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:11]2)[CH2:8][CH2:7]3>N1CCOCC1>[N:23]1([C@H:3]2[CH2:20][C@@:19]3([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@H:12]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[C@@H:13]3[OH:22])[CH2:5][C@@H:4]2[OH:2])[CH2:24][CH2:25][O:1][CH2:11][CH2:12]1
Reactant: O
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: C1COCCN1
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
Water (50 ml) was added to a solution of (2α,3α,5α,16β,17β)2,3-epoxy-16-(1-pyrrolidinyl)-androstan-17-ol (85.2 g) in morpholine (500 ml) and the reaction mixture was heated at reflux temperature for 3 d. Evaporation of the reaction mixture gave a crude product, which was crystallised from acetone. Recrystallisation from methanol gave pure (2β,3α,5α,16β,17β)-2(4-morpholinyl)-16-(1-pyrro lidinyl)-androstane-3,17-diol (71.2 g), m.p. 212°-219° C.; [α]D20=+87.9° (c 1.02 in CHCl3).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]([CH:12]=O)C>O>[CH2:1]([NH:8][C:9]1[CH:4]=[CH:3][C:2]([C:1]#[N:8])=[CH:12][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(NCc2ccccc2)nc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Heat 6-chloroniconitrile (0.58 g, 4.2 mmol) and benzylamine (4.6 mL, 42 mmol) in anhydrous DMF (3 mL) at 120° C. for 4.5 h. Cool at room temperature. Dilute with water and extract with EtOAc. Wash the organic phase with brine, dry over MgSO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1, 2:1, 1:2) to give the desired intermediate as a white solid (840 mg, 96%). MS (ES+) m/z: 210 (4+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:12]1)#[N:9].[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH:53]([NH2:55])[CH3:54])[CH2:49][CH2:48]1>>[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:12][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:55][CH:53]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH3:54])=[O:21])=[CH:17][CH:16]=2)[CH2:14]1)#[N:9]
Reactant: CC(N)C1CCN(C)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1)C1CCN(C)CC1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 19, Step 3 started from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}benzoic acid and 1-(1-methylpiperidin-4-yl)ethanamine (ChemBridge: Cat. #4019769). LCMS (M+H)+: m/z=524.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Reaction time: 1 h
Yield: 80.1 %

Procedure:
N-(2-Aminoethyl)(tert-butoxy)carboxamide (17.5 mL, 0.11 mol) [Alfa #L19947] was stirred in dichloromethane (320 mL) and triethylamine (33 mL, 0.24 mol) was added. A solution of methanesulfonyl chloride (8.5 mL, 0.11 mol) in dichloromethane (10 mL) was added. The resulting mixture was stirred for 1 hour and water (30 mL) was added. The product was extracted with dichloromethane (3×30 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (21 g, 81%). LCMS calculated for C3H11N2O2S (M-Boc+H)+: m/z=139.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:23].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][S:9][C:10]2[C:11]([C:12]([NH:23][C:22]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:20]([CH3:19])[CH:21]=3)=[O:14])=[CH:15][CH:16]=[CH:17][N:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(CSc2ncccc2C(=O)O)n1
Reactant: Cc1cc(C)cc(N)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)n2)c1
Yield: 41 %

Procedure:
O-(7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate (110 mg, 0.29 mmol) was added to a solution of 2-(2-aminopyrimidin-4-ylmethylthio)nicotinic acid (60 mg, 0.24 mmol, Reference Compound No. 12-1), 3,5-dimethylaniline (33 μL, 0.27 mmol) and N,N-diisopropylethylamine (0.93 μL, 0.53 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) at room temperature, and the mixture was stirred for 18 hours. Ethyl acetate (30 mL) was added thereto, and then the whole was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and brine (50 mL), then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the precipitated solid was filtered off, and washed with 50% diethylether-ethyl acetate solution. The solid was then dried at 60° C. under reduced pressure to give 35 mg of the target compound as a light brown solid (Yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10]C.[N+:12]([C:15]1[O:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C1C=CC=CC=1.C(OCC)C.FB(F)F>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:19][C:18]1[O:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH:9]=[O:10]
Reactant: O=[N+]([O-])c1ccc(CO)o1
Reactant: COC=Cc1ccccc1Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
4.0 g of 1-(2-chlorophenyl)-2-methoxyethylene are added dropwise within 20 minutes to 9.55 g of 5-nitrofurfurol in 12 cc of dry benzene at room temperature after the addition of one drop of diethyl ether/trifluoroborane. The mixture is stirred at 35°-40° for 1 hour and is then successively washed with a 5% aqueous sodium acetate solution and water, the benzene solution is dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 3 cc of concentrated hydrochloric acid, 17 cc of water and 120 cc of glacial acetic acid, and the mixture is stirred at 80°-85° for 3 hours. The mixture is concentrated in a vacuum, and, after cooling, the title compound is obtained as yellow crystals having a M.P. of 148°-151°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([OH:28])=O.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][NH:36]2)=[CH:32][CH:31]=1>>[NH:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:15]([C:14]3[CH:13]=[CH:12][C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([NH:1][C:26]([C:22]6[N:21]([CH3:20])[CH:25]=[CH:24][CH:23]=6)=[O:28])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:19][CH:18]=3)=[O:17])[CH:38]=2)[CH:34]=[CH:35]1
Reactant: Cn1cccc1C(=O)O
Reactant: Nc1ccc2c(-c3ccc(C(=O)O)cc3)c[nH]c2c1
Reactant: Nc1ccc2cc[nH]c2c1
Product: Cn1cccc1C(=O)Nc1ccc2c(-c3ccc(C(=O)Nc4ccc5cc[nH]c5c4)cc3)c[nH]c2c1

Procedure:
Compound 979 was prepared according to the procedure described in Scheme IV from 4-(6-amino-1H-indol-3-yl)benzoic acid, 1-methylpyrrole-2-carboxylic acid, and 6-aminoindole. [M+H]+ calcd for C29H23N5O2: 474.05; found: 474.02.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10]C2CCC(O)=O)=[CH:4][CH:3]=1.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[C:22]([CH:23]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][C:12](=[O:14])[NH:11][CH2:10]1)([OH:20])=[O:24]
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C1CC(c2ccc(F)cc2)C(C(=O)O)CN1
Reaction time: 2.5 h

Procedure:
A solution of 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (2.0 g, 0.0075 mol) in ethanol (10 ml) was added to a solution of sodium hydroxide (0.4 g, 0.01 mol) in 95% ethanol and the mixture brought to reflux and stirred for 2.5 hours. The solvent was then removed by evaporation at reduced pressure, and the residue neutralized with 10% aqueous hydrochloric acid (25 ml) and extracted with ethyl acetate (3×20 ml). After separation, the combined organic phases were dried with anhydrous sodium sulphate, filtered. and evaporated to give only 0.1 g of a white solid. The aqueous phase was therefore lyophilized and the residue extracted with hot methanol. The residue, consisting of inorganic salts, was discarded while the methanol extracts were combined and evaporated at reduced pressure to give the title compound (1.34 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH3:28]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole from step 3 (1.81 g, 4.3 mmol) and ethyl iodide (0.86 g, 5.5 mmol) were stirred vigorously in 20 mL dry dimethylformamide (DMF) with finely powdered potassium carbonate (0.58 g, 4.2 mmol) under nitrogen at 25° C. for 18 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole was isolated by chromatography on silica gel using ethyl acetate/toluene (10/90) as the eluant, giving 0.65 g (69%) of a white solid: mp 133-135.5° C.