Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].Cl>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(SC3CCCCC3)ccc2c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2cc(SC3CCCCC3)ccc2c1O
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A mixture of 1-Bromo-7-cyclohexylsulfanyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (686 mg, 1.57 mmol) and CuCN (279 mg, 3.13 mmol) in 3.6 mL of NMP was heated in a 130-135° C. oil bath for 3 h. Reaction mixture was diluted with CH2Cl2 (120 mL) and stirred at room temperature overnight. Then 100 mL of 0.5 N HCl aqueous solution was added and the resultant mixture was stirred vigorously for 30 min Two phases were separated and organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was purified by silica gel chromatography, eluting with 5-60% EtOAc/hexanes, to provide the title compound 470 mg (1.22 mmol) in 78% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 12.36 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.50 (t, J=6.8 Hz, 2H), 3.50 (br m, 1H), 2.10 (m, 2H), 1.87-1.39 (m, 12H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH3:44]>O1CCCC1>[CH:28]1([C:25]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)([O:27][CH3:44])[CH3:26])[CH2:31][CH2:30][CH2:29]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCC1
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclobutylethanol (22 mg; 0.038 mmol) in tetrahydrofuran (1.5 mL) was added sodium hydride (10 mg; 0.25 mmol; 60% dispersion in mineral oil). The reaction was stirred for 10 minutes. Iodomethane (0.05 mL; 0.80 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with water. The mixture was diluted with ethyl acetate and filtered over sodium sulfate and silica get column. After being concentrated under reduced pressure, the residue was taken up in ethyl acetate and washed with water (2×) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50% ethyl acetate in hexanes) to give 18 mg (80% yield) of the title compound as a colorless gum. MS (ES+): Calc: 595.5, Found: 596.5 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.73 (s, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.3 (d, J=8.3 Hz, 1H), 5.09 (s, 2H), 4.8 (q, J=16.18 Hz, 2H), 4.2 (s, 3H), 3.04 (s, 3H), 2.83 (m, 1H) 1.99 (m, 1H), 1.89-1.6 (m, 6H), 1.59 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=4)[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[CH2:35][C:36]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:37]([OH:39])=[O:38])=[CH:15][CH:14]=1.FC(F)(F)C1CCNCC1>>[CH2:40]([C:36]([CH2:35][C:19]1[N:18]([CH2:17][C:16]2[CH:44]=[CH:45][C:13]([N:7]3[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]3)=[CH:14][CH:15]=2)[C:22]2[CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)[CH:25]=[CH:26][C:21]=2[N:20]=1)([CH2:42][CH3:43])[C:37]([OH:39])=[O:38])[CH3:41]
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1)C(=O)O
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCC(C(F)(F)F)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting 4-(trifluoromethyl)piperidine hydrochloride and 2-((1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and 4-(trifluoromethyl)piperidine. MS (ESI): mass calcd. for C32H38F3N5O3, 597.29; m/z found, 598.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.70 (d, J=9.1, 1H), 7.55 (d, J=2.3, 1H), 7.35 (d, J=2.3, 1H), 7.26 (dd, J=9.0, 2.3, 1H), 7.20-7.15 (m, 2H), 7.10-7.02 (m, 2H), 6.31 (d, J=2.3, 1H), 5.68 (s, 2H), 5.07 (s, 2H), 3.85 (s, 3H), 3.83-3.77 (m, 2H), 3.41 (s, 2H), 2.85 (td, J=12.6, 2.6, 2H), 2.46-2.29 (m, 1H), 2.00-1.95 (m, 2H), 1.86-1.60 (m, 6H), 0.87 (t, J=7.4, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B(O)(O)[C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[C:29]([Cl:37])[CH:28]=1>>[CH3:36][O:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:28][C:29]=1[Cl:37])=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1Cl

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 74, step 5) and (3-chloro-4-methoxycarbonyl)benzeneboronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=484.1680 ([M+H]+, 1Cl).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[NH:13]([C:20]1[C:25]([Br:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:35]CCO)=[CH:30][CH:29]=2)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(NCC)C>C(Cl)Cl>[NH:13]([C:20]1[C:25]([Br:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][O:35][CH2:2][CH2:1][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:32][CH:33]=2)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)CCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Triethylamine (33 ml, 0.241 mmol) and methanesulphonyl chloride (19 ml, 0.241 mmol) were added to a solution of 4-anilino-5-bromo-2-[4-(2-hydroxyethoxy)methylanilino]pyrimidine (Example 31; 100 mg, 0.241 mmol) in DCM (5 ml) at 0° C. The solution was warmed to ambient temperature and left to stand for 1 hour. Diethylamine (2 ml) was added, and the mixture was heated at 50° C. for 3 hours. The solvent was removed by evaporation, and the residue was purified by column chromatography, eluting with 0-2% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a cream solid (38 mg, 34%). NMR (CDCl3): 1.03 (t, 6H), 2.58 (q, 4H), 2.69 (t, 2H), 3.54 (t, 2H), 4.48 (s, 2H), 7.06 (d, 2H), 7.17 (t, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.38 (dd, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 8.15 (s, 1H); MS (MH+): 470.4, 472.4.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[NH:33]1[C:34]2[C:30](=[C:29]([CH2:28][NH:27][C:26]([C:19]3[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:39])=[O:2])=[O:16])=[C:21]([C:22]([F:23])([F:25])[F:24])[CH:20]=3)=[O:38])[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-({5-[(1H-Indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (170 mg, 0.29 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (120 mg, 2.94 mmol) in water (8 mL). The mixture was then stirred at room temperature overnight. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 0.1089 g (67%). MS m/e 564.9 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:16][C@@:10]1([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=[C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:3]=[C:4]2[NH:11]1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Reactant: C1COCCN1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Temperature: 120 °C

Procedure:
A mixture of 2.2 g of (2S)-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 60 mL of morpholine is heated to 120° C. After one hour of heating and after monitoring with LC/MS, the reaction is completed. After cooling, the reaction mixture is concentrated under reduced pressure. On the obtained residue, 30 mL of cold water and 150 mL of ethyl acetate are added. The organic phase is then separated, dried on magnesium sulfate, filtered and then concentrated under reduced pressure in order to obtain 2.6 g of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one including the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[N:12]=1.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccccc2N)co1

Procedure:
Combine 5-[4-(2-nitro-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.5 g, 8.2 mmol) with 5% Pd/C (300 mg) and Pd/black (50 mg) in THF and react with hydrogen (init. 39 psi) in a Parr® apparatus. When reduction is complete, filter the mixture through, Celite® and concentrate the filtrate. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 2.05 g (91%) of 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester. MS (ES): (M+1)+ 275.1, 276.2 m/z.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:17]I.[H-].[Na+]>CN(C=O)C>[CH3:17][N:3]1[CH:4]=[N:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:7][CH:2]1[Cl:1]
Reactant: CI
Reactant: Fc1ccc(Nc2ncnc(Cl)n2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C=NC(Nc2ccc(F)c(Cl)c2)=NC1Cl
Reaction time: 3 h

Procedure:
To 2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine (1.7 g, 6.56 mmol) and MeI (1.5 mL) in DMF (20 mL) under a nitrogen atmosphere was added NaH (60% dispersion, 0.53 mg, 13.3 mmol). The mixture was stirred for 3 h. The reaction was quenched by the addition of water and the organic extracts are taken up in EtOAc, dried over anh. MgSO4 and concentrated under reduced pressure. The crude was purified via medium pressure liquid chromatography using CH2Cl2 as the solvent system to give N-methyl-2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH:11][C:12](=[O:18])NCCCC)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([S:8]([N:11]=[C:12]=[O:18])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1cccnc1Cl
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccnc1Cl

Procedure:
To 125 ml of dry xylene were added with stirring 20.7 g of 2-chloro-N-(butylcarbamoyl)-3-pyridinesulfonamide. This solution was heated to reflux, and phosgene added until no further uptake of this gas was observed. It was then cooled, filtered and the solvent was removed in vacuo to yield 2-chloro-3-pyridinesulfonylisocyanate as an oil Bp 108°-110° (0.7 mm Hg). This product showed a sharp absorption peak in the infrared region at 2220 cm-1.
Reaction SMILES: CO.[F:3][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N+:20]([O-:22])=O)=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C[O-].[Li+].C(Cl)[Cl:27]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:3][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([Cl:27])=[N:20][OH:22])=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])CCc1ccc(COc2ncccc2F)cc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: ON=C(Cl)Cc1ccc(COc2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a methanol (10 mL) solution of 3-fluoro-2-(4-(2-nitro-ethyl)-benzyloxy)-pyridine (674 mg, 2.44 mmol) described in Manufacturing Example 149-1-3 was added lithium methoxide (185 mg, 4.87 mmol), which was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (10 mL) and methylene chloride (10 mL) was added titanium (IV) tetrachloride (590 μL, 5.37 mmol) under nitrogen atmosphere at −78° C., which was stirred for 1 hour at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered with neutral silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (629 mg, 88%). This compound was used in the following reaction without any further purification.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:30][CH2:29]2)(=O)=O)=CC=1>C(O)C>[CH2:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:29][CH2:30]1)=[O:35])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC

Procedure:
In 80 ml of ethanol is dissolved 0.95 g of sodium, and 7.2 g of diethyl malonate is added to the solution, followed by stirring. 5-(1-Benzyloxycarbonyl-4-piperidyl)-pentyl p-toluenesulfonate (13.7 g) is added to the mixture, followed by refluxing with stirring for 2 hours. Further, a mixture of 0.25 g of sodium, 25 ml of ethanol and 1.8 g of diethyl malonate is added, and the reaction solution is refluxed with stirring for 2 hours. Ethanol is evaporated off under reduced pressure, and 200 ml of water is added to the residue, which is then extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oily material. This product is dissolved in 30 ml of ethanol, and a solution of 6 g of sodium hydroxide in 50 ml of water is added dropwise to the solution with stirring. After the addition is completed, 150 ml of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is made acidic with conc. hydrochloric acid and extracted with 300 ml of ethyl acetate, and the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oily material. This product is heated at 160° to 165° C. with stirring for 1 hour, and the resulting oily material is purified by silica-gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid as an oily material.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[NH:40])[NH2:39])=[CH:34][CH:33]=1.Cl[C:42]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:43]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH:40][C:42]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:43])=[CH:36][CH:37]=1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Product: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 31 from 1-methyl-2-[(4-amidino-phenyl)-oxymethyl]-5-[N-(methoxycarbonylmethyl)-quinoline-8-sulphonylamino)-benzimidazole and cyclohexyl chloroformate.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[C:34]([F:40])[CH:33]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Br:31])=[CH:33][C:34]=2[F:40])[CH2:19]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Br)cc2F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-bromo-2 fluorobenzaldehyde (0.15 mmol), methanol (1.5 mL), and acetic acid (0.016 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CHOH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature for 5 h and concentrated. The residue was dissolved in methanol, loaded onto Varian™0 SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH. in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate (0.5 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (6 mL), and concentrated to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compound No. 2120) (16.0 mg, 31%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 517.0 (M++H, C21H21BrF4N4O2).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH3:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=1
Reactant: CCCCC[Mg]Br
Reactant: Cc1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CCCCCc1cc(C)ccn1
Temperature: -78 °C
Yield: 44.9 %

Procedure:
A 50 ml reactor under argon was charged with 2-bromo-4-methylpyridine and THF. The reaction was cooled to −78° C. and the Pd(dppf)2Cl2 (dppf being 1,1′-di(diphenylphosphine)-ferrocene) catalyst was added, followed by 3.0 M pentyl magnesium bromide. The reaction was allowed to warm to 0° C. until the starting material was consumed. The reaction was quenched with 20 ml of saturated ammonium chloride solution and extracted with 20 ml of ethylacetate. The ethyl acetate layer was extracted with 20 ml of 1 M aqueous hydrochloric acid to extract the pyridine product from neutral organics. The aqueous acid layer was neutralized with 1 M NaOH and extracted with 20 ml of ethyl acetate. The ethyl acetate layer was washed with brine and dried on anhydrous sodium sulphate. The product phase was filtered and concentrated on the rotary evaporator to give 850 mg of product, a 44.9% yield.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[CH2:5][CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CN1CCCc2ccc(N)cc21
Reaction time: 2 h

Procedure:
A mixture of the 1-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (4.0 g, 20.81 mmol), Pd/C (10% w/w; 2 g) in methanol (100 mL) was hydrogenated at 10 PSI for 2 hours. The catalyst was filtered off, and the filtrate was concentrated under vacuum to give the crude product which was used as such without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(O)c1ccc(C=Nc2ccc(Cl)c(Cl)c2)cc1

Procedure:
Equimolar amounts of 3,4-dichloroaniline and p-carboxybenzaldehyde are stirred together at room temperature to give a nearly quantitative yield of N-(p-carboxybenzylidene)-3,4-dichloroaniline that is recrystallized from ethanol.