Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1.CN([CH:22]=[O:23])C.O>C1COCC1>[Br:9][C:10]1[C:11]([CH:22]=[O:23])=[C:12]([F:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of LDA (62 mmol) in THF (100 mL) was added 4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowly at −78° C. The reaction mixture was left to stir at −78° C. for 2 h, treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at −78° C. for 1 h, and allowed to warm to room temperature as the bath did. The reaction mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04 (t, 1H); 3.92 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[N:28]([C:36]1[CH:41]=[C:40]([N:42]([CH3:66])[C:43]([N:45]([C:54]2[C:59]([Cl:60])=[C:58]([O:61][CH3:62])[CH:57]=[C:56]([O:63][CH3:64])[C:55]=2[Cl:65])COCC[Si](C)(C)C)=[O:44])[N:39]=[CH:38][N:37]=1)C(=O)OC(C)(C)C)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[CH:8][C:7]([NH:28][C:36]3[CH:41]=[C:40]([N:42]([CH3:66])[C:43]([NH:45][C:54]4[C:59]([Cl:60])=[C:58]([O:61][CH3:62])[CH:57]=[C:56]([O:63][CH3:64])[C:55]=4[Cl:65])=[O:44])[N:39]=[CH:38][N:37]=3)=[C:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:11]=2)[CH2:13][CH2:14]1
Reactant: C=CC(=O)Nc1cc(N2CCN(CCNC(=O)OC(C)(C)C)CC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(N2CCN(CCN)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.9 %

Procedure:
tert-butyl (2-acrylamido-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)phenyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)carbamate (17 g, 0.017 mmol) was stirred in DCM (1.0 ml), TFA (200 μl, 2.6 mmol) was added and the mixture was stirred at room temperature for 2 hours. Solvent was evaporated and remaining material was triturated with ether. The resulting solid was collected washed with ether and dried under stream of nitrogen to afford the title compound (15 mg, yield: 96%). 1H-NMR (400 MHz, MeOH-d4) δ 2.90 (br. s., 6H) 3.15-3.22 (m, 2H) 3.33-3.41 (m, 4H) 3.94 (s, 6H) 5.74-5.79 (m, 1H) 6.17 (s, 1H) 6.32-6.44 (m, 2H) 6.81 (s, 1H) 6.92-6.98 (m, 1H) 7.35 (d, 2H) 8.32 (d, 1H); ESI-MS: 644 [M+H]+.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[NH2:14][C:15]1[C:24]([S:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1>[CH3:26][S:25][C:24]1[C:15]([NH:14][C:3](=[O:5])[C@H:2]([Br:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2
Reactant: CCCCCCCC[C@@H](Br)C(=O)O
Reactant: CSc1ccc2ncccc2c1N
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Product: CCCCCCCC[C@@H](Br)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
(R)-2-Bromodecanoic acid (210 mg, 0.83 mmol), 5-amino-6-methylthioquinoline (160 mg, 0.84 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 223 mg, 0.90 mmol) were stirred in 6 ml of toluene at 0° C. The reaction was allowed to warm to rt and stirred under N2 for 18 hours. The reaction was quenched with 100 ml of 10% citric acid and extracted with ethyl acetate (3×50 ml). The organic phase was washed with 0.5N NaHCO3, brined and dried over Na2SO4. Purification by silica gel column chromatography (eluent: 100% CHCl3) yielded 120 mg (34% yield) of the desired product: 1H NMR (CDCl3) δ8.85 (1H, d, J=3 Hz), 8.09 (1H, d, J=9 Hz), 8.08 (1H, d, J=9 Hz), 7.98 (1H, bs), 7.65 (1H, d, J=9 Hz), 7.42 (1H, dd, J=9, 9 Hz), 4.61 (1H, dd, J=8, 8 Hz), 2.58 (3H, s), 2.33 (1H, m), 2.21 (1H, m), 1.76-121 (12H, m), 0.88 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[N:14]#[C:15]Br.C(#N)C>CCOCC.C(OCC)(=O)C>[CH2:7]1[C:8]2=[C:13]3[C:12](=[CH:11][CH:10]=[CH:9]2)[C:2]([NH:1][C:15]#[N:14])=[CH:3][CH:4]=[C:5]3[CH2:6]1
Reactant: N#CBr
Reactant: Nc1ccc2c3c(cccc13)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCOCC
Product: N#CNc1ccc2c3c(cccc13)CC2
Reaction time: 8 h

Procedure:
5-aminoacenaphthene (7.0 g, 41.4 mmol) was dissolved in a mixture of ether (100 mL) and ethyl acetate (25 mL). To this solution was added 5.2 mL of a 5 M solution of cyanogen bromide in acetonitrile (25.6 mmol of cyanogen bromide). The solution was stirred overnight, with the gradual appearance of gray precipitate. The solid was removed by filtration (the hydrobromide of 5-aminoacenaphthene) and the resulting filtrate concentrated in vacuo to afford a semi-solid residue. Ether (60 mL) was added to the residue and the mixture was stirred overnight. The solid was removed (more hydrobromide of 5-aminoacenaphthene) and the filtrate concentrate to approximately 20 mL and then diluted with warm cyclohexane (15 mL). Upon standing at room temperature, off-white crystals were deposited. They were collected, washed with cyclohexane-ether (1:1) and dried in vacuo to give 1.5 g of pure product, mp: 163-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Br.Br.Br[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:25][C:26]2[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)[CH2:11][CH2:10]1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: COc1ccccc1N1CCNCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(Cc2cnc(N)nc2N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A solution of 3.2 g (0.017 mol) of 1-(2-methoxy-phenyl)-piperazine in 100 ml of tetrahydrofuran was treated with 11.6 ml (0.084 mol) of triethylamine and 6.1 g (0.017 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 2.0 g (38%) of 5-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as white crystals; m.p. 195°-196°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31][C:32]3C=CC=C4C(=O)NCC[C:38]=2[C:37]=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.N1CCCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([CH2:15][N:31]5[CH2:32][CH2:37][CH2:38][CH2:30]5)=[CH:17][CH:18]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Solvent: C1CCNC1
Product: O=C1NCCc2c(-c3ccc(CN4CCCC4)cc3)[nH]c3cc(F)cc1c23

Procedure:
In a manner similar to that described for Compound PPP, 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl) benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with pyrrolidine (115 mg, 1.62 mmol) to yield 8-fluoro-2-(4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3 -cd]indol-6-one, 16 mg (14%) as a yellow solid: m.p. 264-265° C. (dec), 1H NMR (300 MHz, d6-DMSO) 1.72 (m, 4H), 2.49 (m, 4H), 3.04 (m, 2H), 3.39 (m, 2H), 3.64 (br s, 2H), 7.31 (dd, J=9.3, 2.4 Hz, 1H), 7.43 (m, 3H), 7.58 (d, J=8.1 Hz, 2H), 8.2 (br t, 1H), 11.66 (br s, 1H). HRMS (MALDI MH+) Calcd for C22H22N3OF: 362.1825. Found: 364.1810. Anal. (C22H22N3OF.0.5 H2O) C, H, N.
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)C.C([Li])CCC.[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22]>C(OCC)C.CCCCCC>[CH3:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22])[CH:4]=[O:13]
Reactant: O=Cc1cccnc1
Reactant: CCOC(OCC)c1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(C=O)ccc1C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 76.7 %

Procedure:
To a solution of 1.88 g of 4-bromo-3-methylbenzaldehyde diethylacetal in 20 ml of diethyl ether was added dropwise 5.0 ml of a 1.4 M solution of butyllithium in hexane at -70° to 0° C., and the mixture was stirred at 0° to -50° C. for 50 minutes. To it was added dropwise 0.89 g of 3-formylpyridine at -30° to -20° C., and the reaction mixture allowed to warm to room temperature with stirring. After concentration under reduced pressure the residue was stirred with 10 ml of tetrahydrofuran and 10 ml of 2 N hydrochloric acid at room temperature for 45 minutes. The reaction mixture was basified with sodium bicarbonate, extracted with diethyl ether, and the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:2) as eluent to give 1.20 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Mg].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20](Br)[CH:19]=[CH:18]2.[Br-].[Mg]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:10]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:20]1[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH:21]=1)=[O:8])[CH:19]=[CH:18]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(OC)cc2-c2ccc3cc(OC)ccc3c2)c(-c2ccc3cc(OC)ccc3c2)c1

Procedure:
36 g of p-methoxybenzoyl chloride are reacted with 1 Eq of 6-methoxy-2-bromonaphthalene magnesium in a solution in THF (solution prepared by reacting the bromide with 1.5 Eq of magnesium, followed by filtration) at 0° C. for 2 h. The medium is then poured into a mixture of 300 g of ice and 50 mL of concentrated HCl. The precipitate formed is recovered and washed with water (3×500 mL). After drying, 61 g of 2-(6-methoxynaphth-2-yl)-(4-methoxyphenyl) ketone are obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[S:5][CH:6]=1.C(O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[C:4]([N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3=[O:13])[S:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCCCN1c1nc(Br)cs1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCCCN1c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
To a solution of 1-(4-bromothiazol-2-yl)piperidin-2-one (Step-1 of compound 10, 1.0 g, 3.83 mmol) in a mixture of toluene:ethanol (10 ml: 30 ml) were added (4-chlorophenyl) boronic acid (0.72 g, 4.60 mmol) and potassium carbonate (1.06 g, 7.66 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.44 g, 0.38 mmol) under nitrogen the tube was sealed. The reaction mixture was heated at 100° C. for 10 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethyl acetate (2×30 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.80 g, 71.4%). MS: m/z 293 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[NH:21]1[C:22]2[C:18](=[C:17]([NH:14][C:15]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=3)=[O:16])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cccc2[nH]ccc12
Yield: 65.8 %

Procedure:
4-(Trifluoromethoxy)benzylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound (0.23 g). mp 177° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.36 (d, 2H), 6.52 (m, 1H), 6.95 (m, 3H), 7.24 (t, 1H), 7.36 (d, 2H), 7.48 (d, 2H), 7.63 (dd, 1H), 8.32 (1H), 11.06 (s, 1H); MS (DCI+) m/z 349.9 (M+H)+; Anal. Calcd. For C17H14N3F3O2: C, 58.63, H, 4.34, N, 12.07. Found: C, 58.51, H, 3.98, N, 12.03.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)C.[C:23](#[N:25])[CH3:24].C([Li])CCC>C1COCC1.C1CCCCC1>[N:16]1([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:22])[CH2:24][C:23]#[N:25])=[CH:11][CH:10]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC#N
Reactant: CCOC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The [4-(3-morpholin-4-yl-propoxy)-phenyl]-acetic acid ethyl ester is then condensed with the lithium anion of acetonitrile by the following method: A solution of dry acetonitrile (0.254 mL) in 5 mL of THF, that had been cooled in a dry ice-acetone bath for 2 h under Ar(g), is treated dropwise with 2.43 mL of a 2M solution of n-butyl lithium in cyclohexane. This mixture is allowed to stir at −78° C. for an additional 1.5 h, and is subsequently treated with 1.15 gms. of [4-(3-morpholin-4-yl-propoxy)-phenyl]-acetic acid ethyl ester in dropwise fashion. The resulting solution is allowed to stir at −78° C. for an additional 30 minutes, and is then allowed to warm to room temperature overnight. The reaction mixture, subsequently, is vacuum filtered affording the desired nitrile, 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile, as a white solid (11% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.[Cl:12]C1C=CC(OC[CH2:19][CH2:20][CH:21]2[CH2:29][CH2:28][C:24]3[NH:25][CH:26]=[N:27][C:23]=3[CH2:22]2)=CC=1.O>CN(C=O)C>[ClH:12].[CH2:1]([O:8][CH2:19][CH2:20][CH:21]1[CH2:29][CH2:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(OCCCC2CCc3[nH]cnc3C2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCCC2CCc3[nH]cnc3C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 31.3 %

Procedure:
A mixture of dry DMF (5 ml), benzylalcohol (216 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) placed under an atmosphere of nitrogen was heated at 50° C. for 30 minutes. The mixture was allowed to cool to ambient temperature and methanesulfonic acid 2-(1(3)-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)ethyl ester (0.5 g, 1.2 mmol, prepared as described in Example 34) dissolved in dry DMF (5 ml) was added and the reaction mixture was stirred for 2 days. The mixture was poured into H2O (100 ml) and extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with H2O (3×50 ml) and the solvent was evaporated. The residue was dissolved in 90% acetic acid (20 ml) and the mixture was heated at reflux for 1-2 hours. The volatiles were evaporated and the residue was stirred with a mixture of H2O (25 ml) and diethyl ether (20 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×20 ml). The aqueous phase was adjusted to pH 10-11 with 4 N sodium hydroxide and the oily precipitate was extracted with ethyl acetate (2×20 ml). The combined organic extracts were evaporated and the residue was dissolved in 1 N hydrochloric acid and re-evaporated. The residue was re-evaporated with acetone several times and then stirred with acetonitrile (5 ml). The mixture was filtered and the solid was discarded. The filtrate was evaporated to give 110 mg (31%) of the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH:13]=[O:14].Cl>CN(C)C=O>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:13]=[O:14]
Reactant: OCC(F)(F)F
Reactant: O=Cc1ccc(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.844 g) in N,N-dimethylfounamide (30.0 mL), 2,2,2-trifluoroethanol (2.11 g) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 3,4-difluorobenzaldehyde (2.00 g) in N,N-dimethylformamide (10.0 mL) was added and thereafter the mixture was stirred at room temperature for 30 minutes. After adding 1 mol/L hydrochloric acid at 0° C., three extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-30:70) to give the titled compound as a colorless oil (2.50 g).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (51.2 mg, 0.134 mmol), 3-methoxytetrahydro-4H-pyran-4-one (70 mg, 0.40 mmol) and triethylamine (0.0374 mL, 0.269 mmol) in dry methylene chloride (5.0 mL, 0.078 mol) was treated with sodium triacetoxyborohydride (85.4 mg, 0.403 mmol) at room temperature under N2 overnight. The reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (90 mg) was passed through a short silica gel pad (30:70 MeOH/EtOAc). The filtrate was concentrated and separated by chiral HPLC to give two isomers: first isomer 26.3 mg; second isomer: 17.3 mg. LC-MS calculated for C26H36F3N3O3: (M+H) 496; found 496.2 for both isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:37]1[S:36][CH:40]=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A mixture of methyl 6-(benzyloxy)-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.26 g, 20 mmol), 2-thiopheneboronic acid (3.07 g, 24 mmol), sodium carbonate (5.30 g, 50 mmol), toluene (50 ml), methanol (10 ml) and water (10 ml) was stirred at room temperature for 30 min under an argon atmosphere. To the resulting mixture was added tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol), the mixture was refluxed under heating for 10 h under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylate (2.11 g, 23.6%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[NH:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:23]=[C:22]([CH3:21])[NH:26][N:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cc(C(=O)O)n[nH]1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n[nH]1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-1H-pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 409.2 (M−H).