Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].O>CO.C(O)=O>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(N=Cc2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(NCc2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1

Procedure:
To a solution of 1.75 g (4.10 mmol) of N-[(6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridin-2-yl)methylene]-2,4,6-trimethylaniline in 20 ml of methanol, 0.42 g (6.70 mmol) of NaBH3CN was added in one portion followed by addition of three drops of 88% formic acid. The reaction mixture was refluxed under inert atmosphere for 1 hour and then poured into 50 ml of water. The crude product was extracted with 3×20 ml of ether. The organic extract was washed with water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 1.60 g (90%) of orange oil. Anal. calc. for C30H35N3: C, 82.34; H, 8.06; N, 9.60. Found: C, 82.56; H, 8.21; N, 9.59. 1H NMR (CDCl3): 7.89 (d, J=8.5 Hz, 1H, 4-H in naphthyl), 7.86 (m, 1H, 8-H in naphthyl), 7.77 (m, 1H, 4-H in Py), 7.65 (d, J=8.5 Hz, 3-H in naphthyl), 7.43 (m, 1H, 7-H in naphthyl)), 7.87 (m, 1H, 3-H in Py), 7.30-7.35 (m, 3H, 5-H in Py and 5,6-H in naphthyl), 6.80 (s, 2H, 3,5-H in mesityl), 4.35 (m, 2H, CH2NHtBu), 3.55 (m, 2H, CH2NMes), 2.94 (br. s, 2H, NH), 2.24 (s, 6H, 2,6-Me in mesityl), 2.22 (s, 3H, 4-Me in mesityl), 0.96 (s, 9H, tBu).
Reaction SMILES: [C-:1]#[N:2].C[Mg+].[Br-].[CH2:6]1[CH2:10]O[CH2:8][CH2:7]1>CCOCC>[N:2]1([N:2]2[CH2:1][CH2:10][CH2:6][CH2:7][CH2:8]2)[CH2:1][CH2:10][CH2:6][CH2:7][CH2:8]1
Reactant: [C-]#N
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: C1CCN(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
The cyanide (4.87 g, 15 mmol) was taken up in THF (75 ml). CH3MgBr (25 ml of a 3.0 M solution in Et2O) was added to the reaction mixture at 0° C. The solution was allowed to warm to 25° C. and was stirred at that temperature for 18 h. The solution was partitioned between 25 wt % aqueous solution of sodium citrate and EtOAc. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration and concentration gave a yellow oil. Purification via flash chromatography (95/5 to 90/10 EtOAc/MeOH. SiO2) gave 3.7 g (79%) of the piperidino-piperidine 12 as a yellow gum. Step 2:
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14](OC)[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.C(#N)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: COC(c1c(C)nn(-c2ccccc2)c1Cl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(methoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (P-0079, 0.030 g, 0.085 mmol) was added acetonitrile (10 mL, 0.2 mol). Trifluoroacetic acid (500 uL, 0.006 mol) and triethylsilane (500 uL, 0.003 mol) were added and the reaction allowed to stir at room temperature for 16 hours. The reaction was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane followed 5% methanol in dichloromethane to give the compound as a yellowish foam (P-0080, 29 mg, 98%). MS (ESI) [M+H+]+=323.2.
Reaction SMILES: [S:1](Cl)(Cl)=O.C(OC([NH:10][N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:13])=O)C>>[C:15]1([CH3:20])[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[N:11]=[N:10][S:1][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)NN=C(C)c1ccccc1C
Product: Cc1ccccc1-c1csnn1
Temperature: 60 °C

Procedure:
To thionyl chloride (1 ml), cooled to 0° C. was added N′-(1-o-tolyl-ethylidene)-hydrazinecarboxylic acid ethyl ester. The reaction mixture was heated to 60° C. for 1 h. Solvent evaporation gave 4-o-tolyl-[1,2,3]thiadiazole; 1 H NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 7.65 (d, 1H, J=7.3 Hz), 7.36 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3ccc(F)cc3F)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 2,4-difluorophenylboronic acid. LC-MS Method 3, tR=1.238 min, m/z=785. 1H NMR (CDCl3) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.58-3.67 (m, 1H), 4.35-4.45 (m, 1H), 6.93-7.08 (m, 2H), 7.30-7.48 (m, 5H), 7.62-7.65 (m, 1H), 8.15-8.23 (m, 1H), 8.78-8.81 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[O:21])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:29]=1)=[O:21]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2F)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.10 g, 7.0 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.83 g, 7.0 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-Amino-2'-fluoro benzophenone (1.00 g, 4.6 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered to yield a brown solid. Purification by flash column chromatography (5% v/v ethyl acetate/methylene chloride) yielded the title propanamide as a white solid (1.23 g, 75%); mp 141°-142° C. 1H-NMR (300 MHz, d6-DMSO): 1.60 (s, 3H, CH3) 7.35-7.42 (m, 2H, aromatic) 7.53-7.59 (m, 2H, aromatic+OH) 7.65-7.68 (m, 1H, aromatic) 7.75 (d, 2H, J=8.5 Hz, aromatic) 7,96 (dd, 2H, J=8.6, 1.7 Hz, aromatic) 10.37 (s, 1H, NH). MS (CI, CH4): 356 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1)[CH:11]=[CH:10]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCc1cccc(F)c1
Reactant: NCc1ccccc1
Product: Fc1cccc(CNc2ccc3cc(NCc4ccccc4)ccc3n2)c1

Procedure:
The title compound, MS: m/e=358.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-fluorobenzylamine and benzylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[O:26][CH2:25]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2[C:13]1=[O:22])=[O:5])[CH3:2].[OH2:44].NN>C(O)C>[C:36]([O:44][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[O:26][CH2:25]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:22])([CH3:39])([CH3:38])[CH3:37]
Reactant: O
Reactant: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 175 %

Procedure:
A mixture of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g), hydrazine hydrate (0.27 g) and ethanol (10 ml) is allowed to stand overnight at room temperature. The mixture is concentrated in vacuo, diluted with water (50 ml) and extracted with ethyl acetate (50 ml×4). To a mixture of the organic extract, water (50 ml) and sodium bicarbonate (0.65 g) are added dropwise di-tert-butyl dicarbonate (0.36 g) with stirring at room temperature. After stirring for 30 minutes, the ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is subjected to silica gel column chromatography using hexane:ethyl acetate (2:1-1:1) as an eluent to yield tert-butyl 3(S)-[6-tert-butoxycarbonylamino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.54 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=[C:14]([C:27]([O:29]CC)=[O:28])[CH:13]=2)=[CH:8][CH:7]=1.C1COCC1.[Na].Cl>C(O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[N:15]=[C:14]([C:27]([OH:29])=[O:28])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)cc1

Procedure:
To a stirred solution of Ethyl 5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate (prepared according to the procedure of Example 63, step 1) (0.1 g) in ethanol (5 mL)-THF (3 mL) was added 2N-Sodium hydroxied solution in water (1 mL) and the mixture was heated at reflux temperature for 1.5 hours. After cooling, 2N—HCl solution (2 mL) and water (20 mL) were added to the mixture. The whole was extracted with CH2Cl2 (50 mL×2), the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized with isopropanol-water to give the title compound (0.08 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:22][Cl:23])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:25]1C2C(=CC=CC=2)N=C(CCl)N=1.ClC1C=C(N)C=CC=1OC.Cl.ClCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1>Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:22][Cl:23])[N:13]=2)[CH3:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(Nc2nc(CCl)nc3ccccc23)cc1Cl
Agent: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: COc1ccc(N)cc1Cl
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1Cl

Procedure:
(3-Chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-amine hydrochloride: The title compound was prepared from 4-chloro-2-chloromethyl-quinazoline (500 mg, 2.3 mmol), 3-chloro-4-methoxy-phenylamine (444 mg, 2.8 mmol) and HCl (12 M, 7 drops) in i-PrOH (8 mL) by a procedure similar to the preparation of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride in Example 203c. 1H NMR (CDCl3) δ 8.6 (d, 1H), 8.1 (t, 1H), 7.85 (m, 3H), 7.62 (d, 1H), 7.20 (d, 1H), 4.8 (s, 2H), 3.92 (s, 3H); LC-MS (ESI+; 334 ([M+H]+)).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>ClCCl.CN(C)C1C=CC=CC=1>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C@H:5]2[S:4]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Nc3ccccc3)[C@H]2S1
Yield: 90.4 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) was suspended in dichloromethane (30 ml), and then dissolved by adding triethylamine (0.9 g) and dimethylaniline (0.1 g). To the solution was added phenylisocyanate (1.2 g) under stirring and ice-cooling, and the mixture was stirred for 5 hours. 10% Hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 10 minute. The reaction mixture was filtered, and the dichloromethane layer was separated from the filtrate, washed in turn with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give 2,2,2-trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate (4.2 g), mp 172° to 174° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH3:28])[CH3:7]>C1COCC1.CO>[Cl:27][C:22]1[CH:21]=[C:20]([S:17]([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([CH:6]([CH3:7])[C:5]([OH:29])=[O:4])=[C:9]2[CH3:28])(=[O:18])=[O:19])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)C(C)c1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(C)C(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (0.25 mL) is added to a stirring solution of 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid methyl ester (17 mg, 0.04 mmol) in 1:1 THF/MeOH (1 mL). After 4 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and resulting solid is collected by filtration. The crude product is purified by flash chromatography (10:1 EtOAc/MeOH), followed by trituration with iso-hexane, to afford 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid; MH+=413.
Reaction SMILES: [OH:1][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:3].C1COCC1.C(N(CC)CC)C.Cl[C:29]1([CH2:34][CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[CH2:34]([C:29]1([O:3][C:2]([C:4]([F:14])([F:15])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:1])[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:35]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Reactant: CCC1(Cl)CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC1(CC)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A 2 L reactor was charged under nitrogen with 5.6 g (purity 78%, 20.0 mmol) of methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester and 240 mL of THF (dehydrated), followed by cooling down to 0° C., adding 5.2 mL (37.6 mmol/1.9 equivalents) of triethylamine, and stirring at 0° C. for 10 minutes. Then, furthermore 14.24 g (3.2 mmol/1.6 equivalents) of 1-chloro-1-ethylcyclopentane was added, followed by stirring at 0° C. for 20 minutes. To the reaction liquid 800 mL of water was added, followed by extraction two times with diisopropyl ether, removing water by magnesium sulfate, conducting a filtration, and distilling diisopropyl ether out, thereby obtaining 5.52 g of the target methacrylic acid 1-(1-ethylcyclopentyloxycarbonyl)-1,1-difluoro-2-butyl ester. Upon this, purity was 96%, and yield was 83%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].[H-].[Na+].[H][H].[CH3:18]I>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:18])[N:6]=1)=[O:4]
Reactant: [H][H]
Reactant: CI
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C)c2ccccc12
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of indazole-3-carboxylic acid methyl ester (2.76 g, 0.0159 mole) in dry dimethylformamide (20 ml) was added dropwise to a stirred suspension of 60% sodium hydride (oil dispersion) (0.67 g, 0.0176 mole) in dimethylformamide (50 ml). After the addition was completed and the evolution of the hydrogen ceased, the mixture was heated to 80° C. and then cooled to ambient temperature. A solution of methyl iodide (4.23 g, 0.030 mole) in dimethylformamide (10 ml) was added dropwise to the stirred reaction mixture. After stirring for 15 minutes, the mixture was warmed to 50° C. for 30 minutes, and then cooled to ambient temperature. The reaction mixture was diluted to a volume of 300 ml with ice/water and extracted with two 100 ml portions of methylene chloride. The extract was dried (magnesium sulfate), and concentrated to an oil. Dimethylformamide was distilled from the mixture and the residual oil was triturated with petroleum ether to obtain a solid. The solid (1.66 g, 55%) was collected by filtration and recrystallized from isooctane to give 1.20 g; mp 78°-79° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[C:8]2[C:33]([NH:35][C@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([F:40])([F:39])[F:38])=[O:34])(=[O:4])=[O:3].C(O)(=O)C.[CH3:51][C@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:51][C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:11][C:12]3[C:7]([C:8]=2[C:33]([NH:35][C@H:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][CH:13]=3)[CH2:31][CH2:30]1
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Reactant: C[C@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1C1CCN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(C)(=O)=O)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.1 %

Procedure:
6-(Methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.093 g, 0.140 mmol) was dissolved in dichloromethane (1.4 mL) and acetic acid (0.012 mL, 0.210 mmol). (S)-2-Methylpyrrolidine (0.036 g, 0.420 mmol) was added followed by sodium triacetoxyborohydride (59.4 mg, 0.280 mmol). The mixture was stirred at room temperature for 2 d. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA) to afford 3-({4-[(2R)-2-methyl-1-pyrrolidinyl]-1-piperidinyl}methyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.035 g, 32% yield). MS (m/z) 733.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:51][CH2:50][C:45]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:44][CH2:43]1)=O>>[O:49]1[C:45]2([CH2:50][CH2:51][N:42]([CH2:40][CH2:39][O:37][C:36]3[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]4[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=4[CH:17]4[CH2:26][CH2:25][C:24]5[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=5[CH2:18]4)=[CH:3][C:2]=3[F:1])[CH2:43][CH2:44]2)[O:46][CH2:47][CH2:48]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC4(CC3)OCCO4)c(F)c2)c1
Yield: 36.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.4 mg) was obtained.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.Cl>C(Cl)(Cl)Cl.CO.O1CCOCC1>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1nccc1-c1ccc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)n1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cn1nccc1-c1ccc(C(=O)NC(CN)Cc2ccccc2)n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1-dimethylethyl[2-({[1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (20 mg, 0.05 mmol) [prepared in Example 48] in CHCl3 (4 mL) and MeOH (1 mL) was treated with 4 M HCl in dioxane (2 mL). After stirring for 18 h at RT, the reaction solution was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:20](=[O:40])[C:19]=3[C:18]=2[O:41][CH3:42])=[O:16])[CH:10]([CH3:43])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:42][O:41][C:18]1[C:19]2[C:20](=[O:40])[N:21]([CH2:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]=2[N:29]([CH3:30])[C:17]=1[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:43])=[O:16]
Reactant: COc1c(C(=O)NC2CCN(Cc3ccccc3)CC2C)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(=O)NC2CCNCC2C)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution of the compound of Example 677 (373 mg, 0.65 mmol) in THF (40 mL) was added 1-chloroethyl chloroformate (0.67 mL, 6.5 mol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. 1-Chloroethyl chloroformate (0.67 mL, 6.5 mol) and diisopropylethylamine (0.30 mL, 3.2 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether. The residue was dissolved in methanol (50 mL), and the mixture was stirred at room temperature for 7 hr and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; methanol/ethyl acetate=0/100-10/90) and recrystallized from ethyl acetate-hexane to give the title compound (90 mg, 29%) as a pale-brown solid.