Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:36][CH2:35][N:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 8 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalent of ethyl piperazine-1-carboxylate as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78.4 %

Procedure:
As in Example 115, (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid (23.75 g) and 4-nitrophenol (12.7 g) in dichloromethane (250 mL) was treated with 1,3-dicyclohexylcarbodiimide (17.12 g). The mixture was stirred at 0°-5° C. for 60 minutes and then at room temperature for 1 hour. After the usual work up, the crude product was crystallized from 2-propanol to give 26.5 g of (E)-5,5-bis (4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 112°-114° C. Recrystallization of a portion from the same solvent yielded the analytical sample, mp 112.5°-114° C. Anal. Calculated for C23H15F2NO4 :C, 67.81; H, 3.71; N, 3.44; F, 9.33 Found: C, 67.76; H, 3.77; N, 3.48; F, 9.11.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: Brc1ccccc1OC1CCNCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3OC3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)piperidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 8.29 (s, 1H), 7.56 (m, 1H), 7.46-7.31 (m, 4H), 7.20 (d, J=8.4, 1H), 7.05 (m, 1H), 6.86 (s, 2H), 4.62-4.66 (m, 1H), 2.91-2.93 (m, 4H), 2.07-1.96 (m, 2H), 1.77-1.65 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:27])=[O:26])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](OC)=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:26])=[O:27])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:20])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3cccnc23)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
65 mg (0.12 mmol) of (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(quinoline-8-sulfonylamino)-propionic acid tert-butyl ester was dissolved in 1 ml of dimethylformamide and 59 mg (0.6 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 72 mg. MS (ES+): m/e=609.3 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[OH:21][CH:22]([CH2:26][C:27](=[O:40])[N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[C:23](O)=[O:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[OH:21][C@@H:22]([CH2:26][C:27](=[O:40])[N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[C:23]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9](=[O:19])[C@@H:10]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:24]
Reactant: O=C(O)C(O)CC(=O)N1CCN(c2ccncc2)CC1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@@H](O)CC(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.1 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.29 g) and 2-hydroxy-4-oxo-4-(4-pyridin-4-ylpiperazin-1-yl)-butanoic acid (0.30 g) in dimethylformamide (15 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 g) and the solution was stirred for 24 hours at room temperature. The solution was concentrated to remove dimethylformamide and the residue was purified by means of CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution). To the produced tert-butyl ester derivative (0.20 g) was added trifluoroacetic acid (6 ml) and the solution was stirred for 1 hour at room temperature. The reaction solution was concentrated and the residue was dissolved in water (10 ml), which was purified by means of CHP-20 column chromatography (H2O→5% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound(0.08 g) as a white amorphous powdery product.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(c2ccccn2)CCNCC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 μL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL) and washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2 Cl2) to afford ethyl 4-(pyridyl)piperidin-4-yl-carboxylate as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C([Mg]Cl)(C)C.[C:15]1([CH:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[C:23]2=[O:32])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:33]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([OH:31])([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=3[OH:9])[C:23]2=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1ccc(O)cc1C
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a stirred solution of 3,4-dimethylphenol (2.50 g, 20.5 mmol) in tetrahydrofuran (100 mL) was added isopropylmagnesium chloride (10.2 mL, 2.0 M tetrahydrofuran solution, 20.40 mmol) at 0° C. The mixture was allowed to stir for 1 h at 0° C., then the solvent was removed in vacuo. Dichloromethane (200 mL) was added, followed by the addition of 1-(diphenylmethyl)-1H-indole-2,3-dione (5.00 g, 15.95 mmol). The mixture was stirred for 54 h at ambient temperature, quenched with saturated ammonium chloride solution. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, the residue was purified by column chromatography to give 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one (5.10 g, 73%): 1H NMR (300 MHz, CDCl3) δ7.49-7.45 (m, 1H), 7.35-7.27 (m, 10H), 7.08-7.04 (m, 2H), 6.93 (s, 1H), 6.81-6.75 (m, 1H), 6.52 (s, 1H), 6.49-6.46 (m, 1H), 2.15 (s, 3H), 2.02 (s, 3H); MS (ES+) m/z 418.1 (M−17).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]34[CH2:22][NH:21][CH2:20][C@H:19]3[CH2:18][S:17][C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15]4)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:21]2[CH2:20][C@@H:19]3[C@@:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([C:7]5[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=5)[CH:9]=4)([N:15]=[C:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[S:17][CH2:18]3)[CH2:22]2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CNC[C@H]2CS1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(-c4cccnc4F)c3)CN(c3ccc(F)cc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (±)-{(4aR*,7aS*)-7a-[3-(2-fluoropyridin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}carbamate obtained in Preparation Example 18-(9) (72 mg) was mixed with 4-fluorobenzeneboronic acid (24.7 mg), copper (II) acetate (6.1 mg), triethylamine (93.2 μL, specific gravity: 0.73 g/cm3) and molecular sieves 4A (powder) (57.6 mg) in dichloromethane (3 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 11 hours and 30 minutes. 4-Fluorobenzeneboronic acid (23.5 mg) and copper (II) acetate (12 mg) were further added. The atmosphere was changed to an open system, followed by further stirring. After 23 hours and 45 minutes, the reaction suspension was purified by NH-silica gel column chromatography. The resulting product was purified again by pTLC to obtain the title compound (15 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH3:15])=[O:5])[CH3:2].B.CSC.Cl.N.O>O1CCCC1>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])=[O:5])[CH3:18]
Reactant: CCN(CC)C(=O)Oc1cnccc1NC(C)=O
Agent: B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: CCNc1ccncc1OC(=O)N(CC)CC
Reaction time: 0.5 h

Procedure:
4-Acetylamino-3-pyridinol N,N-diethylcarbamate (3.43 g) was dissolved in tetrahydrofuran (75 mL) and then the reaction mixture was chilled in an ice-water bath. Borane/methyl sulfide (BMS) was added (3.25 mL, 2.60 g) and the reaction mixture was stirred in the cold bath for 30 minutes. At the end of this time an additional 3.0 mL of BMS was added and stirring was continued for 3 hours. The reaction mixture was then poured into ice/conc. HCl, stirred for 30 minutes, basified with NH3 /water and then extracted with ethyl acetate. The organic phase was then dried, concentrated and purified by flash chromatography to give 0.86 g of chromatographically pure product. This product was combined with a crop obtained from another run and recrystallized from hexane to give an analytically pure material, m.p. 107°-108° C.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[C:11]([Cl:26])[S:10][C:9]=1[NH2:27])=[O:7])C>C1COCC1.[OH-].[Na+].CO>[Cl:26][C:11]1[S:10][C:9]2[NH:27][C:6](=[O:7])[C:8]([C:9]#[N:27])=[C:6]([OH:7])[C:8]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1
Reactant: CCOC(=O)COc1ccc(-c2c(Cl)sc(N)c2C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(O)c2c(-c3ccc(OCC(=O)O)cc3)c(Cl)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ambient suspension of NaH (235 mg, 5.89 mmol, 60% dispersion in mineral oil, washed with dry hexane) in dry THF (6 mL) was added 2-amino-4-(4-ethoxycarbonylmethoxy-phenyl)-5-chloro-thiophene-3-carboxylic acid ethyl ester (1.06 g, 2.36 mmol) as a solution in THF (6 mL). The reaction was stirred overnight at room temperature and was then diluted with 1N NaOH (10 mL) and MeOH (10 mL). After stirring an additional 1.5 h at room temperature, the reaction was concentrated under reduced pressure to ˜20 mL. The solution was acidified to pH ˜1 with 1N HCl and extracted with EtOAc (3×30 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a beije solid that was used without further purification. MS (ESI) m/e 375 (M−H)−; 1H NMR (300 MHz, BENZENE-d6) δ ppm 4.72 (s, 2H), 6.94 (d, J=8.48 Hz, 2H), 7.26 (d, J=8.48 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[I:35])[NH2:31]>>[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[I:35]
Reactant: CN(C)CCOc1cc(N)ccc1I
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(I)c(OCCN(C)C)c4)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP0533268A1) and 3-(2-dimethylaminoethoxy)-4-iodoaniline (D50) using a similar procedure to Example 20 (0.4 g, 28%). The free-base was converted to the oxalate salt. mp 219°-221° C.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.[ClH:32].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:32].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4R)—N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-fluoroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].C[O-].[Na+].Br[CH2:22][C:23](=[O:39])[CH2:24][C@H:25]1[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>CO>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:22][C:23](=[O:39])[CH2:24][C@H:25]3[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: CSc1cc2c(=O)[nH]cnc2cc1Br
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SC)cc2c1=O

Procedure:
Under a nitrogen atmosphere in a flame dried flask at room temperature and with magnetic stirring, a suspension of 0.43 g (0.00136 mol) of 7-bromo-6-methylthioquinazolin-4(3H)-one formic acid salt in 5 ml of methanol was treated with two equivalents of sodium methoxide in methanol (approximately lN). After 15 minutes 0.53 g (0.0016 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate was added in one portion. After being stirred for an hour, the reaction mixture was evaporated under reduced pressure, and the residue was taken up in about 15 ml of water. The aqueous solution was extracted three times with 15 ml portions of dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford the title compound: yield 0.16 g (86%). 1H-NMR(CDCl3): 1.3-2.0 ppm (multiplet, 4H, , CH3OCHCH2CH2CH2N), 2.6 (singlet, 3H, CH3S), 2.8-3.0 (multipl COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4-(singlet, 3H, CH3O), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad doublet, 2H, CH2CH=CH2), 4.8-5.1 (multiple peaks, 2H, NCH2CO), 5.2-5.4 (multiplet, 2H CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, aromatic H), 7.95 (singlet, 1H, N=CH--N).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10](=[O:23])[C@H:9]1[CH2:24][O:25]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10](=[O:23])[C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN2CCCCC2)C(=O)[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCCN2CCCCC2)C(=O)[C@H]1CO
Yield: 78.1 %

Procedure:
A solution of (R)-2-benzyloxymethyl-3-oxo-4-(3-piperidin-1-yl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (321 mg, 0.72 mmol) in acetic acid (9 ml) was stirred for 18 h at room temperature under a hydrogen atmosphere (3 bar) in the presence of palladium (10% on activated charcoal, 161 mg), then insoluble material was removed by filtration and the filtrate evaporated. The residue was partitioned between ethyl acetate and 2 M aq. sodium carbonate solution. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (200 mg, 78%). Light brown oil, MS (ISP)=356.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH2:12][C:13]1[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:16]=[C:15]([CH2:28][CH3:29])[C:14]=1[O:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>ClCCl.CO.O>[Cl:38][C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([Cl:37])[CH:34]=1)[O:30][C:14]1[C:15]([CH2:28][CH3:29])=[N:16][N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:13]=1[CH2:12][NH:11][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CNCc2ccc(OC)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 68 %

Procedure:
4-Methoxybenzaldehyde (46 μl, 0.380 mmol), the amine of Example 138 (172 mg, 0.400 mmol) and magnesium sulphate (200 mg) were stirred in dichloromethane (4 ml) at room temperature for 4 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to leave a yellow oil. The oil was dissolved in methanol (4 ml) and sodium borohydride (18 mg, 0.480 mmol) was added with vigorous stirring. Once the addition was complete the reaction was stirred for 4 hours and then water (2 ml) was added. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 ml). The resulting solution was washed with 1M aqueous potassium carbonate solution (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) and then dichloromethane:methanol (95:5, by volume) to provide the title compound (142 mg) as a colourless oil.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:45][C:44]([CH3:46])=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:36][CH2:35][C:34]([C:41]3[S:45][C:44]([CH3:46])=[N:43][CH:42]=3)([OH:33])[CH2:39][CH2:38]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc(C2(O)CCC(N[C@@H]3CC[C@@](C(=O)N4CCc5ccc(C(F)(F)F)cc5C4)(C(C)C)C3)CC2)s1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (30.0 mg, 0.0846 mmol) from Step C-2 of Example 1 and 4-hydroxy-4-(2-methyl-1,3-thiazol-5-yl)cyclohexanone (25.1 mg, 0.119 mmol) in dichloromethane (8 mL) was added triethylamine (0.0236 mL, 0.169 mmol) followed by sodium triacetoxyborohydride (42 mg, 0.20 mmol) at room temperature. After being stirred overnight, the mixture was quenched by addition of saturated NaHCO3. The resulting solution was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give two isomers (15 and 12 mg). LC-MS for both isomers: calculated for C29H38F3N3O2S (M+H)+550; found 550.2.