Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([O:32][C:33]1[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]2)=[C:35]([F:49])[C:34]=1[F:50])[CH3:31].O>C1COCC1>[CH2:30]([O:32][C:33]1[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:49])[C:34]=1[F:50])[CH3:31]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(OCC2CCC(C=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(OCC2CCC(C=COC)CC2)c(F)c1F
Reaction time: 1 h
Yield: 90 %

Procedure:
In a reactor under nitrogen atmosphere, 30 mL of THF was added to 9.7 g of methoxymethyltriphenylphosphonium chloride, and the mixture was cooled to −20° C., to which 3.1 g of t-BuOK was added, followed by stirring for 1 hour. A solution containing 6.6 g of 4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexane carboaldehyde obtained in the seventh step dissolved in 70 mL of THF was added dropwise thereto, followed by stirring for 1 hour. The temperature of the reaction mixture was increased to room temperature, to which 100 mL of water was added, and the mixture was extracted three times with 100 mL toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to about 100 mL, and the concentrated solution was placed in 500 mL of n-hexane, followed by removing deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 6.5 g of 1-ethoxy-2,3-difluoro-4-[4-(2-methoxyvinyl)cyclohexylmethoxy]benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26](=[N:40][NH2:41])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](N1C=CN=C1)(N1C=CN=C1)=[O:43]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:42]([OH:43])=[N:41][N:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1cc(C(=NN)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-[4-(morpholin-4-yl)-phenyl]-benzene-carbohydrazonamide (F370-IM4: crude product) was suspended in tetrahydrofuran (10 mL), mixed with 1,1′-carbonyldiimidazole (1.12 g, 6.9 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and 5% aqueous sodium hydrogencarbonate (50 mL), and the organic layer was separated. The organic layer obtained was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate 100%). The obtained product was purified by suspending in ethyl acetate to obtain the title compound (F370-IM5: white crystals, 1.2 g, 45% in 3 steps).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:12]O)=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1)[CH3:2].[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][CH:27]2[C:32]([NH:34][C:35]1[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=1)=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][CH:27]2[C:32]([N:34]([CH2:12][C:5]1[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[C:8]([F:9])([F:10])[F:11])[C:35]1[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=1)=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1nc(C(F)(F)F)c(CO)s1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CCc1nc(C(F)(F)F)c(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)s1
Yield: 22.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 2-ethyl-5-hydroxymethyl-4-trifluoromethylthiazole (0.63 g) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.2 g) as starting materials, 5-benzyloxy-N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.4 g) was obtained.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:10](O)=[O:11])=O)(C)(C)C>O1CCCC1>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(F)(F)F)c1)C(=O)O
Solvent: C1CCOC1
Product: N[C@H](CO)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-(trifluoromethyl)phenyl]-propanoic acid (Aldrich) (10.00 g, 30.00 mmol) in tetrahydrofuran (25 mL) with stirring, 1.0 M borane-THF complex in THF (100.0 mL, 100.0 mmol) (newly opened) was added dropwise to keep the internal temperature at 0° C. (release gas, about 15 min). After addition the reaction was stirred at room temperature (rt) for 6 hrs, cooled down with ice-bath, quenched with AcOH:MeOH (1:5, 50 mL), and partitioned between saturated aqueous NaHCO3 and DCM, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an oil residue, which was purified by combi-flash chromatography to give the desired intermediate. LC-MS found: 320.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:15]([C:17]1[O:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:16].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:20]1[O:21][C:17]([CH2:15][CH3:16])=[N:18][N:19]=1)=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CCc1nnc(N)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(NC(=O)c2ccc(C(F)(F)F)nc2Cl)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 mg (0.887 mmol) of 2-chloro-6-(trifluoromethyl)nicotinic acid and 100 mg (0.887 mmol) of 5-ethyl-1,3,4-oxadiazol-2-amine are dissolved at RT in 8 ml of CH2Cl2. Then 846 mg (1.33 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.618 ml (4.43 mmol) of triethylamine, 22 mg (0.177 mmol) of 4-dimethylaminopyridine are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 4 ml each time of water, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 80 mg (28%).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:40][NH:41][CH3:42]>ClCCl.CN(C=O)C>[CH3:40][N:41]([CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1)[CH3:42]
Reactant: CNC
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (200 mg, 0.42 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as an off-white solid (80 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:3]=1[NH:14][C:15]([C:17]1[N:21]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24](OC)=[O:25])[N:20]=[C:19]([C:32]([F:35])([F:34])[F:33])[CH:18]=1)=[O:16].[BH4-].[Li+]>O1CCCC1>[OH:25][CH2:24][C:23]1[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=1[N:21]1[C:17]([C:15]([NH:14][C:3]2[C:4]([C:8]([NH:10][CH:11]([CH3:12])[CH3:13])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:16])=[CH:18][C:19]([C:32]([F:34])([F:35])[F:33])=[N:20]1
Reactant: COC(=O)c1ccccc1-n1nc(C(F)(F)F)cc1C(=O)Nc1c(C)cccc1C(=O)NC(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of the ester from Step B (240 mg) in tetrahydrofuran (3 mL) was added a solution of lithium borohydride (2 mL, 2 M in tetrahydrofuran). After being stirred at room temperature overnight, the reaction was quenched with water. The reaction mixture was diluted with 1 N aqueous HCl, extracted with ethyl acetate, washed with brine, dried and concentrated to give a white solid. The solid was washed with ethyl ether (3×2 mL) to give the title compound (96 mg), a product of the present invention.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH:42]([CH3:44])[CH3:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:28][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:40]=[CH:39][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:36]=1)[CH:42]([CH3:44])[CH3:43])=[O:33])[CH3:30]
Reactant: CC(C)N(C(=O)CN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C(=O)CN(C)C)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-isopropyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H32N4O4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[N:29]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:32]4[CH2:33][CH2:34][CH2:35][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30][CH2:31]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100.0 mg, 0.2040 mmol, prepared according to Example 7, step B), tert-butyl 1,4-diazepane-1-carboxylate (204.3 mg, 1.020 mmol), copper(I)iodide (15.54 mg, 0.08159 mmol), (S)-pyrrolidine-2-carboxylic acid (18.79 mg, 0.1632 mmol), K2CO3 (140.9 mg, 1.020 mmol) and DMSO (10 mL). The reaction mixture was stirred at 100° C. overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (110.4 mg, 96.2%). LRMS (APCI pos): m/e 563 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH3:18]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([NH2:18])=[O:13]
Reactant: O=C(O)CC1Cc2ccccc2C1
Reactant: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)CC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
35.3 g (0.20 mol) of (indan-2-yl)acetic acid was dissolved in 350 ml methylene chloride, to which was added 26.5 g (0.22 mol) of thionyl chloride and stirred for 4 hours at room temperature, followed by refluxing for further 1.5 hours. After cooled and condensed under reduced pressure, the obtained oily residue was dissolved in 100 ml ethyl acetate and added dropwise to 200 ml conc. aqueous ammonia while stirred vigorously under ice-cooling. After stirring for 20 minutes, the precipitates were collected by filtration and recrystallized from a solvent mixture of ethyl acetate and ethanol. 32.1 g of colorless crystal was obtained. Yield: 95%
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CCOC(=O)c1c(Nc2ccc(OC)cc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: COc1ccc2c(c1)N=C(N1CCN(C)CC1)c1c(sc3ccccc13)N2

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-methoxy-anilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 9-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][C:37]1[CH:41]=[CH:40][NH:39][N:38]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][C:37]3[CH:41]=[CH:40][NH:39][N:38]=3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: Nc1cc[nH]n1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNc2cc[nH]n2)no1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and 3-aminopyrazole (249 mg, 2.97 mmol) as starting materials.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]4([CH2:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:27]([C:29]1([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:26][CH2:25][C:20]1([CH2:19][O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:27][C:29]5([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: OCC1(COc2cccc3onc(OCC4CCNCC4)c23)CCCC1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5(CO)CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using [1-({[3-(Piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}methyl)cyclopentyl]methanol (EXAMPLE 51, Step 4) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutane-carboxylate.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21](OCC)=[O:22]>>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][CH:21]=[O:22])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC=O
Reactant: NCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Product: O=CNCc1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
2-(α, α, β, β-Tetrafluorophenethyl)benzylamine, 1.4 g. (0.005 mole), in 100 ml. of ethyl formate, is stirred and heated to refluxing for about 20 hours. Evaporation of the solution to dryness and trituration of the residual solid with petroleum ether gives N-[2-(α, α, β, β-tetrafluorophenethyl)benzyl]formamide, m.p. 61°-75° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([OH:21])=O)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[CH2:28]([NH:35][OH:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([OH:36])[C:19]([C:15]1[N:16]=[CH:17][C:18]2[N:6]([CH2:5][C:4]3[C:22]([F:25])=[CH:23][CH:24]=[C:2]([Cl:1])[C:3]=3[F:26])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Reactant: ONCc1ccccc1
Agent: Cl
Product: O=C(c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1)N(O)Cc1ccccc1

Procedure:
The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and N-benzyl hydroxylamine hydrochloride under conditions similar to those provided in step (b) of example 7.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([NH:9][CH:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)[CH3:7]>C(O)(=O)C>[CH3:7][C:6]1[NH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([CH3:17])[N:5]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)nc1C
Yield: 66.9 %

Procedure:
Ammonium acetate (185 mg, 2.4 mmol) was added to a solution of ethyl 2-(acetylamino)-3-oxobutanoate (90 mg, 0.48 mmol) in acetic acid (1.0 mL). The mixture was heated to reflux overnight. After cooling, the solvent was evaporated under reduced pressure and the residue was taken up in saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (0-4% 2M NH3 solution of MeOH in DCM) to give the title compound (54 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCl3-d) δ ppm 4.30 (q, J=7.20 Hz, 2H) 2.44 (s, 3H) 2.38 (s, 3H) 1.34 (t, J=7.14 Hz, 3H). LCMS: m/z 169 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][C:13](OCC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CCOC(=O)CCc1cc2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CCCO)cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To an ice-cooled solution of ethyl 3-(1-methylindol-2-yl)propionate (2.0 g, 8.65 mmol) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (328 mg, 8.65 mmol) by small portions under nitrogen atmosphere. After the mixture was stirred for 1 hour, water and aqueous 15% sodium hydroxide solution were added successively to the mixture. The resulting precipitates were filtrated off through Celite and washed with tetrahydrofuran. The filtrate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel (36 g) chromatography eluting with dichloromethane-methanol (100:1 to 50:1) to give 3-(1-methylindol-2-yl)propan-1-ol (1.05 g, 64.1%) as a yellow syrup.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[C:19](=S)(OCC)[S-:20].[K+]>[C].[Pd].C(OCC)(=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:19]([SH:20])[O:1][C:2]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1C(=O)OC
Reactant: CCOC(=S)[S-]
Agent: [Pd]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(S)oc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A 10% palladium carbon catalyst (2.5 g) was added to a solution of the nitro compound mixture (4.3 g, 16.8 mmol) in ethyl acetate (60 ml) and stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered off through celite and the filtrate was concentrated. The residue was dissolved in methanol (50 ml), potassium O-ethyl dithiocarbonate (1.76 g, 11.0 mmol) was added thereto and the mixture was heated to reflux for 16 hours. After cooling, the solvent was evaporated in vacuo. The residue was diluted and acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was crystallized from ether to provide 1.61 g (yield 60%) of 6,7-bis(methoxycarbonyl)-2-mercaptobenzooxazole as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1>O1CCOCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[C:21]([F:22])[C:16]([F:15])=[N:17][CH:18]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC1(C)OB(c2cnc(F)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(-c2ccc(Cl)cn2)cnc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a pressure vessel was added 2-bromo-5-chloropyridine (3.0 g, 16 mmol), cesium carbonate (15 g, 47 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (2.5 g, 3.1 mmol), and 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.5 g, 19 mmol) in 1,4-dioxane (120 mL) and water (22 mL). The mixture was flushed with argon, sealed and stirred at 90° C. for three hours. The mixture was concentrated, diluted with dichloromethane and washed with water. Organic extracts were concentrated and purified by MPLC (eluted with 0-10% methanol in dichloromethane) to yield 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine as a yellow solid (2.4 g, 68%). MS m/z=227.2 [M+1]+. Calc'd for C10H5ClF2N2: 226.6.