Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].C(Cl)CCl>CN(C=O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([F:40])([F:41])[F:39])[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (0.15 g; 0.45 mmol) and 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (0.14 g; 0.45 mmol) in DMF (3 mL) was stirred overnight at rt. EDC (0.086 g; 0.45 mmol) was added and the mixture was heated to 90° C. for 1 h. The mixture was poured in water, extracted with DCM and the combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1ccc(-c2ncnn2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 9.0 g. of 1-(p-fluorophenyl)-5-(p-nitrophenyl)-1H-1,2,4-triazole, 18.0 g. of sodium hydrosulfite, 40 ml. of water and 150 ml. of acetone is stirred at room temperature for 1/2 hour. The acetone is removed in vacuo and the residue extracted with hot chloroform. Cooling produces 1.1 g. of the desired product as off-white crystals, mp. 128°-130° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH:29]=O)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:22]=[CH:21]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5cc[nH]c45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-7-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-7-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15]O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][Cl:26])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO)no1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCl)no1
Reaction time: 10 h
Yield: 22.3 %

Procedure:
18.64 g of [5-(t-butyldimethylsilanyloxymethyl)isoxazol-3-yl]methanol was dissolved in 80 ml of pyridine, and 16.06 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 10 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.48 g of 5-(t-butyldimethylsilanyloxymethyl)-3-(chloromethyl)isoxazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:22]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH2:23][CH2:24][C:25](OC1C=CC=CC=1)=[O:26].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ccccc23)c1
Reactant: O=C(CCC(=O)Oc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCC(=O)n1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.1 %

Procedure:
A solution of 3-(3-nitrobenzyl)indole (280 mg) in N,N-dimethylforma/nide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 66.6 mg) in N,N-dimethylformamide (10 ml) at 0° C. The mixture was stirred at 25° C. for 40 minutes, and a solution of benZyl phenyl succinate (316 mg) in N,N-dimethylformamide was added at -40° C. After stirred at -40° C. for 20 minutes, the reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over, magnesium sulfate. After evaporation of the solvent, the crude crystals were washed with hot isopropyl ether to give benzyl 4-[3-(3-nitrobenzyl)indol-l-yl]-4-oxobutyrate (364 mg).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].C1C=NC2N([OH:39])N=NC=2C=1.C(Cl)CCl.C[CH2:45][N:46]([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])C>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:52]([C@@H:50]2[CH2:51][CH2:49][CH2:47][N:46]2[CH3:45])=[O:39])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: On1nnc2cccnc21
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN1CCC[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (210 mg, 0.48 mmol), N-methyl S-proline (Hachem Company) (68 mg, 0.53 mmol), HOAT (Aldrich) (65 mg, 0.48 mmol), EDC (Aldrich) (184 mg, 0.96 mmol) and DIEA (Aldrich) (84 μL, 0.48 mmol). Purification by reverse phase preparative HPLC (Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min]provided the title compound as a colorless oil (120 mg). MS (ESI, pos. ion) m/z: 547 (M+1). Calc'd for C27H35ClN4O4S: 546.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6](/[CH:8]=[C:9](\C)/[CH:10]=O)[CH:7]=1.CC1C=CC(S([NH:24][NH2:25])(=O)=O)=CC=1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8]2[CH:9]=[CH:10][NH:25][N:24]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: C/C(C=O)=C\c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Oc1ccc(Cl)cc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (E)-3-(5-chloro-2-hydroxyphenyl)-2-methylacrylaldehyde (40 mg, 0.203 mmol) and 4-methylbenzenesulfonohydrazide (41.7 mg, 0.224 mmol) in Acetonitrile (3 mL) were stirred at room temperature for 3 h and then acetonitrile (2 mL), Sodiumhydroxide (8.95 mg, 0.224 mmol) were added and the mixture was heated at reflux for 16 h. Product was used for further reaction without purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:6]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:20]3[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)c1cccc(-c2csc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(C(F)(F)F)c3)cs2)CC1
Yield: 47.9 %

Procedure:
A solution of 2-bromo-4-[3-(trifluoromethyl)phenyl]-1,3-thiazole (2.88 g, 9.35 mmol), tert-butyl piperazine-1-carboxylate (3.48 g, 18.7 mmol) and potassium carbonate (1.29 g, 9.35 mmol) in dimethylformamide (30 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.85 g (47.9%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[C:28]([NH:31][C:32](=[O:34])[CH3:33])[CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[C:28]([NH:31][C:32](=[O:34])[CH3:33])[CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(Cl)ccc1-2
Product: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Yield: 33 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford tert-butyl((2S)-1-((2-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (290 mg, 0.617 mmol, 33% yield) as a yellow oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.99 min.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][N:5]=[C:4](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][N:5]=[C:4](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1O
Product: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1Cl
Yield: 53 %

Procedure:
Ethyl 3-{4-hydroxy-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (11.6 g, 38.9 mmol) in POCl3 (30 mL) was heated at 120° C. for 4 h. The solvent was removed in vacuo. The crude residue was then purified by column chromatography (silica gel) using an EtOAc/hexanes (30-50%) gradient to yield the desired compound as a yellow solid (6.6 g, 53%). LCMS (ES+) m/z 317 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[CH:38]3[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([N:30]5[CH:38]6[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37]6)[CH2:32][CH2:31]5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCC5CCCCC54)ncn3)CC1)C(=O)N2

Procedure:
705 mg (2.56 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 680 mg (2.56 mmol) (6-chloro-pyrimidin-4-yl)-(octahydro-indol-1-yl)-methanone and 0.871 mL (5 mmol) DIPEA were stirred in 10 mL DMF for 2 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and the ACN was eliminated by rotary evaporation. The aqueous phase was made alkaline with 4M NaOH and extracted with EtOAc. The organic phase was dried, filtered and the filtrate was concentrated to dryness by rotary evaporation. The residue was crystallised from a mixture of MeOH and diethyl ether and the solid was suction filtered and dried.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCN(c2ccccc2)N1
Solvent: Cc1ccccc1
Product: ClC1=NN(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Phenylpyrazolidin-3-one (8.1 g) was suspended in dry toluene (100 ml), followed by addition of phosphoryl chloride (7.0 ml) and the mixture stirred for 1 hour at 85°. When cool the toluene was decanted from the solid and solvent removed in vacuo to give the sub-title compound, (6.9 g), mp 92°-93°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[H-].[Na+].[CH3:40]N(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:40])[C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A mixture of 5-(benzyloxy)-2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-indole obtained in Example 23 (880 mg), iodomethane (0.143 mL), sodium hydride (92 mg, 60% in oil dispersion), and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (860 mg, 95%) as crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17].Br[CH2:25][C:26]([NH2:28])=[O:27]>>[NH3:3].[NH2:28][C:26]([CH2:25][N:21]1[CH2:22][CH2:23][C@H:19]([NH:18][C:16]([C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:17])[CH2:20]1)=[O:27]
Reactant: O=C(N[C@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: NC(=O)CBr
Product: N
Product: NC(=O)CN1CC[C@H](NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C1

Procedure:
The title compound was prepared by a similar method to Example 5 from (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide [see Example 4] and 2-bromoacetamide. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 93:7:1, changing to 90:10:1, by volume, dichloromethane:methanol: 0.88 aqueous ammonia solution to afford (2S)-N2-[(3S)-1-((aminocarbonyl)methyl)pyrrolidin-3-yl]-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20](=[O:22])[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20](=[O:22])[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:29]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(=O)O)c(N)c1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1cc(NC(=O)c2ccccc2OC(C)=O)ccc1C(=O)O

Procedure:
By the procedure similar to that described in Example 23, 2-amino-4-(2'-acetoxybenzamido)-benzoic acid and 2-methoxybenzoylchloride were reacted and treated to obtain crude crystals. Recrystallization from water-ethanol gave 2-(2'-methoxybenzamido)-4-(2'-acetoxybenzamido)-benzoic acid which was identical to that of Example 23.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3]C(C)(C)C)=O.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1C(Cl)=O.C(N(CC)CC)C>ClCCl>[N:8]1([C:1]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:26])([F:25])[F:14])=[O:3])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) as a dichloromethane solution in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a pall yellow solid used for next step reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])=[CH:6][CH:5]=1)[CH3:2].II.C(Cl)CCl.[CH3:23][C:24]([CH3:26])=O>>[CH3:12][C:11]1([CH2:13][CH:14]([CH3:15])[CH3:16])[CH:23]=[C:24]([CH3:26])[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=2)[NH:10]1
Reactant: CCOc1ccc(N=C(C)CC(C)C)cc1
Reactant: CC(C)=O
Agent: II
Solvent: ClCCCl
Product: CCOc1ccc2c(c1)C(C)=CC(C)(CC(C)C)N2

Procedure:
A portion (5.98g) of this material, 4-methyl-2-pentanone p-ethoxyphenylimine, combined with iodine (0.15g), ethylene dichloride (0.5 ml) and acetone (200 ml), was refluxed for about 26 hours in a Soxhlet extractor, which was charged with molecular sieves 3A and fitted with a moisture trap at the condenser outlet. The product was evaporated to dryness in vacuo and then fractionated. Fractions with b.p.≥120° C/0.5 mm were combined and the brown oil (3.26lg) was chromatographed on silica gel (180g, mesh 70-230). Benzene (2 l.) and benzene-chloroform (9:1, 1.5 l.) eluates furnished 1,2-dihydro-2,4-dimethyl-2-isobutyl-6-ethoxyquinoline as a brown oil (1.88g).
Reaction SMILES: NC[C:3]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([OH:9])[CH2:4]1.C[CH2:20][N:21](CC)CC.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C(Cl)Cl>[Cl:18][C:13]1[CH:12]=[C:11]([C:3]2([N:21]([CH3:20])[C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][CH2:7][CH2:6][C:5]([OH:9])([CH3:10])[CH2:4]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CCN(CC)CC
Reactant: CC1(O)CCCC(CN)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1(c2ccc(Cl)c(Cl)c2)CCCC(C)(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.5 g, 1.74 mmoL) in CH2Cl2 (15 mL) was added Et3N (528 mg, 727 mL, 5.22 mmol) and (BOC)2O (567 mg, 2.60 mmol). The reaction mixture was stirred for 2 h at room temperature before being quenched by a saturated NH4Cl solution (10.0 mL). The product was extracted with CH2Cl2 (2×15 mL). The combined extracts were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:5) to afford (±)tert-butyl (1-(3,4-dichlorophenyl)-3-hydroxy-3-methylcyclohexyl)-methylcarbamate (0.61 g, 90%). The enantiomers were separated (chiral AD column with hexane/iso-propanol/DEA=95:5:0.1) to afford the fast moving enantiomer E1 (0.22 g, retention time 4.085 min) and the slow moving enantiomer E2 (0.32 g, retention time 6.051 min). To a solution of the respective enantiomer E1 (200 mg, 0.52 mmol) or E2 (200 mg, 0.52 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL). The reaction mixtures were stirred for 0.5 h before being concentrated. The mixtures were each purified by reverse phase column chromatography (CH3CN/H2O) to give the amines 193 E1 and 193 E2 in each 80% yield. 1H NMR (400 MHz, CDCl3) δ 8.32 (broad, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.37 (dd, J=2.0, 8.4 Hz, 1 H), 3.55 (s, 2 H), 2.15 (m, 2 H) 1.88 (m, 1H), 1.74-1.58 (m, 4 H), 1.40 (m, 1 H), 1.21 (m, 3 H); 13CNMR (100 MHz, CD3OD) δ 146.42, 132.75, 131.01, 130.83, 128.41, 125.97, 69.31, 46.48, 44.85, 40.15, 37.81, 32.81, 32.54, 30.91, 18.17; ESI MS m/z=288.4.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:28][C@H:29]1[CH2:34][CH2:33][Si@H:32]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:30]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:35]([Si@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:28][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:30][CH2:31]1)[CH2:36][CH3:37]
Reactant: CCC[Si@H]1CC[C@H](CBr)CC1
Reactant: FC(F)(F)Oc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
39.7 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-4'-trifluoromethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 23.5 g (0.1 mol) of trans-1-bromomethyl-4-n-propyl-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 43.0 g (yield 88.0%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-trifluoromethoxybiphenyl was obtained.