Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:28]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:29])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCCC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)C2CCCCC2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2S, 4R)-4-aminomethyl-2-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 mmol, Example 39C) in dichloromethane (2 mL) at room temperature was added cyclohexanecarbonyl chloride (0.092 g, 0.65 mmol) and triethylamine (0.10 mL, 0.75 mmol). The mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure and the residue taken up in water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed consecutively with saturated aqueous NaHCO3, 10% KHSO4 (aq), brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-40% ethyl acetate:hexane to provide the title compound. MS (CI) m/z 408 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.40-4.28 (m, 1H), 3.88-3.66 (m, 2H), 3.56-3.25 (m, 4H), 3.22-3.16 (m, 2H), 2.57 (m, 2H), 2.55 (m, 1H), 1.99-1.61, (m, 13H), 1.41 (m, 9H), 1.51 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[CH:31][N:30]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:29]3[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Oc3ncccc3C#N)c2)CC1
Temperature: 60 °C
Yield: 58.1 %

Procedure:
To a solution of 4-(3-hydroxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.0 mmol) in DMSO (5.0 mL) were added Cs2CO3 (660 mg, 2.0 mmol) and 2-chloro-3-pyridinecarbonitrile (172 mg, 1.2 mmol). The mixture was heated at 60° C. for 90 min. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc (3×). The organic layer was separated and dried (Na2SO4). The crude residue was purified (FCC) to give 4-[3-(3-cyano-pyridin-2-yloxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (229 mg, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]2=[O:21])([O-])=O>Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]2=[O:21]
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1Cc1cccnc1
Agent: Cl
Product: Nc1ccc2c(c1)C(=O)N(Cc1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To 200 ml of conc. hydrochloric acid was added 21.1 g of stannous chloride under ice cooling, and 9.0 g of 5-nitro-2-(3-pyridylmethyl)-1H-isoindole-1,3 (2H)-dione was added. The reaction mixture was stirred at room temperature for 15 minutes and stirred at 80° C. for 30 minutes. After cooling, the mixture was filtered, and the resultant solid was mixed with water and made alkaline with aqueous ammonia. To this mixture was added 500 ml of tetrahydrofuran, and the resultant mixture was filtered with celite. The filtrate was shaken with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate and hexane (2:1) to give 7.4 g of the titled compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]2[C:7]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]=3[CH:15]=[CH:16][CH:17]=2)(=[O:4])=[O:3].[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH3:22][CH:21]([N:10]1[C:11]2[C:7]3[C:6](=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]1=[O:14])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=2)[CH3:23]
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2cccc3c(S(C)(=O)=O)ccc1c23

Procedure:
A mixture of 2.5 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3), 0.6 g of sodium hydride and 2.7 ml of 2-bromopropane in 100 ml of N,N-dimethylformamide is reacted for 18 hours under argon using the conditions of Example 4 to yield 2.24 g of the desired product as a yellow solid, m.p. 164°-165° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][NH:6][S:7]([C:10]1[S:11][C:12]([C:15]#[C:16][C:17]2[CH:34]=[N:33][C:20]3[N:21]=[C:22]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:23]=[C:24]([OH:25])[C:19]=3[CH:18]=2)=[CH:13][CH:14]=1)(=[O:9])=[O:8])[CH3:2]>C(O)(=O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][NH:6][S:7]([C:10]1[S:11][C:12]([CH2:15][CH2:16][CH:17]2[CH2:34][NH:33][C:20]3[N:21]=[C:22]([NH:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[N:23]=[C:24]([OH:25])[C:19]=3[CH2:18]2)=[CH:13][CH:14]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CNS(=O)(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)s1
Reaction time: 24 h
Yield: 31.5 %

Procedure:
To a mixture of 150 mg of N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)thien-2-ylsulfonyl]glycine ethyl ester in 25 mL of glacial acetic acid was added 100 mg of platinum oxide. This mixture was stirred under hydrogen for 24 hours and an additional 100 mg of platinum oxide was added. The hydrogenation was resumed for another 24 hours and the reaction mixture was then filtered through Celite® and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel using 3.5% CH3OH and chloroform to give 48 mg of N-{5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]thien-2-ylsulfonyl}glycine ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6, δ1.10 (t, J=7 Hz, 3H), 1.17 (s, 9H), 1.62 (m, 3H), 1.90 (m, 1H), 2.52 (m, 1H), 2.91 (m, 3H), 3.25 (m, 1H), 3.68 (d, J=4.9 Hz, 2H), 3.97 (q, J=7 Hz, 2H), 6.45 (s, 1H), 6.92 (d, J=3.5 Hz, 1H, 7.38 (d, J=3.5 Hz, 1H), 8.31 (t, J=4.9 Hz, 1H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.CO.[NH3:36]>>[NH2:36][CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.9 g, 1.70 mmol, Intermediate B) in 2 M NH3 in MeOH (10 mL, 20.0 mmol) was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. The mixture was concentrated and purified on silica gel [2% MeOH in CH2Cl2 to 2% (2 N NH3-MeOH) in CH2Cl2) to give 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a white foam (500 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]([P:12](=[O:15])([OH:14])[OH:13])([P:8](=[O:11])([OH:10])[OH:9])[OH:7])[CH3:3].[OH-].[Na+:17]>>[Na+:17].[CH3:1][N:2]([CH2:4][CH2:5][C:6]([P:8](=[O:9])([OH:11])[O-:10])([P:12](=[O:13])([OH:14])[OH:15])[OH:7])[CH3:3]
Reactant: CN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O

Procedure:
Add with constant stirring 11,11 kg of (II) to 33.3 l sodium hydroxide (50,7 g/l). Filter if necessary, add 122 l of methanol and dry in an oven with forced air circulation until constant weight. 10.7 kg of (III) is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20](O)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: C1CCNC1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), pyrrolidine (226 μl, 2.73 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (239 μl, 1.37 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at 70° C. under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (155 mg, 89%) as a light brown solid. Mp.: 199-201° C. MS: m/z=383.4 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Cl:29][C:26]1[S:25][C:24]([CH2:23][N:16]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Cn2cc(C3CCNCC3)c3cccnc32)s1
Reaction time: 1 h
Yield: 127.8 %

Procedure:
Over a solution of 2.86 g (6.6 mmol) of 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester in 20 ml of dichloromethane, 5.1 ml of trifluoroacetic acid were added. After 1 hour at room temperature, the solvent was removed under reduced pressure. The crude mixture was dissolved in ethyl acetate and washed with saturated solution of potassium carbonate and brine. The organic phase was dried over magnesium sulphate, filtered and removed under reduced pressure affording 2.8 g of a crude mixture which was pure enough for the next synthetic step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C[CH:13]([C@@H:17]1[CH2:22][CH2:21][NH:20][C@H:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:18]1)[C:14]([O-:16])=[O:15]>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:19]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[N:20]2[CH2:21][CH2:22][C@@H:17]([CH2:13][C:14]([OH:16])=[O:15])[CH2:18][C@H:19]2[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C(=O)[O-])[C@@H]1CCN[C@H](c2ccc(C(F)(F)F)cc2)C1
Product: O=C(O)C[C@@H]1CCN(C(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)[C@H](c2ccc(C(F)(F)F)cc2)C1

Procedure:
The compound was prepared analogously to Example 160 using the Grignard reagent derived from 4-brombenzotrifluoride and starting with the chiral piperidine of Example 114 Step 1. M/Z (ES+) 590 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:27])[C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:16][CH:15]=1)[C:8]([OH:10])=[O:9])=[O:5].[OH-].[Na+:34]>CO>[Na+:34].[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH3:27])[C:21]2[N:22]=[CH:23][CH:24]=[CH:25][N:26]=2)=[CH:18][CH:19]=1)[C:8]([O-:10])=[O:9])=[O:5]
Reactant: CN(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)[O-])cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (10.60 g) in methanol (200 ml), 1N aqueous sodium hydroxide solution (22.5 ml) was added, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid sodium salt (11.08 g). IR(KBr)cm−1: 3385, 1584, 1552, 1486, 1431, 1397, 1315, 1195, 1112, 968, 799.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:13]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1ccc(Br)c2cccnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1c(Cl)cc(Br)c2cccnc12
Temperature: 75 °C

Procedure:
To a solution of 8-amino-5-bromoquinoline (440 mg, 1.97 mmol) in CH3CN (39 mL) was added N-chlorosuccinimide (250 mg, 1.87 mmol). The mixture was stirred at 75° C. until no further conversion of the starting material was observed by LC/MS and TLC analysis. The mixture was allowed to cool to room temperature then concentrated. The residue was dissolved in EtOAc, then washed with water (2×50 mL) then saturated NaCl (aq) (50 mL). The organic phase was dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 15% EtOAc/hexanes to afford the title compound as a solid: 1H NMR (500 MHz, CDCl3): δ 8.81 (dd, J=1.4, 4.1 Hz, 1H) 8.43 (dd, J=1.4, 8.5 Hz, 1H), 7.71 (s, 1H), 7.51 (dd, J=4.1, 8.5 Hz, 1H); LC6: 4.27 min. (M+H) 259.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([N:30]3[CH2:31][CH2:32][CH:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[CH:13][C:12]=2[N:4]2[CH2:9][CH2:8][CH:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCC(Cc4ccccc4)CC3)cc2N2CCC(Cc3ccccc3)CC2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.67 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 8.8 ml of 4-benzylpiperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 4.1 g of the title compound as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH:11]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(N[C@H](C)c2ccc(F)cc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2ccc(F)cc2)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 7.60 g of N-[(R)-1-(4-fluorophenyl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 9.51 g of nickel chloride hexahydrate and 3.03 g of sodium borohydride were reacted, to obtain 1.52 g of isomer A and 1.39 g of isomer B of the title compound, each as a pale yellow oil.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].S(O)(O)(=O)=O.[NH2:17][OH:18].[OH-].[Na+]>C(O)C>[C:6]1([C:2]2[CH:3]=[C:4]([NH2:5])[O:18][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 3-oxo-3-phenylpropanenitrile (5.00 g, 34.4 mmol), hydroxylamine sulfate (3.10 g, 18.9 mmol), ethanol (35 ml) and an aqueous solution (35 ml) of sodium hydroxide (1.66 g, 41.4 mmol) was stirred at 80° C. for 24 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=11 by addition of an aqueous 8N sodium hydroxide solution and then extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (1.09 g, 19.8%) as a solid.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16].[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16]
Reactant: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(CI)C(=O)N1c1ccc(F)cc1
Yield: 92 %

Procedure:
A solution of 15.2 g (0.06 moles) 3-chloromethyl-1-(4-fluorophenyl)-pyrrolidine-2,5-dione (according to Example 1) and 10.7 g (0.066 moles) sodium iodide in acetone were refluxed for 8 hours in acetone. The precipitated sodium chloride was then filtered off, and the filtrate was concentrated, extracted with chloroform and the extract once more concentrated. The desired product was obtained in a yield of 92%. Melting point: 156° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][CH3:30])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].[I-:31].[Na+]>C(C(C)=O)C>[CH2:13]([S:12][CH2:11][CH:10]([O:29][CH3:30])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:31])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Yield: 86.6 %

Procedure:
To a solution of 1.03 g (2.12 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane IIIa2 in 20 ml of methyl ethyl ketone is added 636 mg (4.24 mM) of sodium iodide and the mixture is refluxed or 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent to give 1.06 g (1.835 mM) of 1-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methoxypropane IIa2 as an oil in 87% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:9]([N+:11]([O-])=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:9]([CH:10]=1)[NH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(CC)CSc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: CCCCC(CC)CSc1ccc(C(C)(C)C)cc1N

Procedure:
In a typical example of a specific production method, ferric chloride hexahydrate and an activated carbon are added to a 2-propanol solution of 5-tert-butyl-2-(2-ethylhexylthio)nitrobenzene, and the mixture is refluxed under heating for 10 minutes. To this solution is added, dropwise, an aqueous 80% solution of hydrazine monohydrate. After the addition is finished, the reaction is continued under refluxing until the raw material disappears. Then, the reaction solution is cooled, and the catalyst and the activated carbon are separated by filtration. Toluene is added to the filtrate, and the toluene solution is then washed with water, washed with an acid, neutralized, washed with water, and then concentrated, to obtain 5-tert-butyl-2-(2-ethylhexylthio)aniline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].[CH3:15][O:16][CH2:17]/[CH:18]=[CH:19]/B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C.C(O)CC>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([CH:19]=[CH:18][CH2:17][O:16][CH3:15])=[CH:13][C:6]=1[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NC1CC1)c1cc(Br)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: COCC=Cc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
5-Bromo-2-chloro-N-cyclopropyl-benzamide (19.3 g, 70.5 mmol) was dissolved in a mixture of DMF (350 mL) and 1-propanol (210 mL). Pd(OAc)2(PPh3)3 (2.64 g, 3.53 mmol) was added. (E)-2-(3-Methoxypropenyl)4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15 mL, 70.5 mmol) was added through a syringe, and aq. 2M Na2CO3 (123 mL) was added. The mixture was stirred at 80° C. for 2 h, and allowed to cool to rt. Aq. 10% HCl was added carefully until a pH of 2 was reached. The solvents were partially removed under reduced pressure, and the residue was extracted with Et2O (3×). The combined org. extracts were washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→1:1→EtOAc) yielded the title compound (12.7 g, 68%). LC-MS: tR=0.82 min; ES+: 266.17.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:23][CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14](F)=[C:15]([CH:18]=2)C#N)[CH:5]=[CH:6][N:7]=1.[OH:24]OB(C1C=CC=CC=1)O>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:23][CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([OH:24])=[CH:15][CH:18]=2)[CH:5]=[CH:6][N:7]=1
Reactant: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1F
Reactant: OOB(O)c1ccccc1
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(O)cc3)c12

Procedure:
Prepared according to a Suzuki coupling procedure analogous to that described for synthesis of 5-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-fluorobenzonitrile, except using 4 hydroxyphenylboronic acid. MS (ES+): m/z 281.17 (100)[MH+].