Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCNc1cccc(Cl)c1
Yield: 51.2 %

Procedure:
3-Chloroaniline (3.8 g, 0.03 moles) was dissolved in ethanol (5 ml) and ethyl acrylate (3.3 g, 0.033 moles) was added in ethanol (5 ml). Concentrated hydrochloric acid (1 ml) was added and the reaction mixture was heated at reflux for 48 hours. Evaporated to a low bulk and dissolved the residue in dichloromethane and water. Basified to pH 9 with aqueous ammonia and separated. Evaporated off the dichloromethane under reduced pressure to give the crude product as a yellow oil (5.4 g) Purified using a silica column eluted with isohexane:ethyl acetate 9:1 to give the required product (3.5 g, 51%) as a colourless oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16]>CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:20])=[O:4])=[C:7]([O:13][C:14]([F:18])([F:19])[CH:15]([F:17])[F:16])[CH:8]=1
Reactant: COC(=O)c1ccc(F)cc1OC(F)(F)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(F)cc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.9 %

Procedure:
A 5N aqueous solution of NaOH (1.96 mL, 9.82 mmol) was added into a solution of 4-fluoro-2-(1,1,2,2-tetrafluoro-ethoxy)-benzoic acid methyl ester (884 mg, 3.27 mmol) in MeOH (10 mL). The resulting mixture was stirred at RT for 15 hours, then concentrated under vacuum. The residue was taken up with water (20 mL) and acidified until pH=1 with a 1N aqueous solution of HCl. The precipitate was filtered off, washed with water (3×) and dried under vacuum to give the title compound as a white powder (661 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.02-7.93 (m, 1H), 7.43-7.32 (m, 2H), 6.73 (tt, J=51.7, 3.5 Hz, 1H). HPLC (max plot) 96.8%; Rt 3.72 min. UPLC/MS: (MS−) 255.2 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+]([O-])=O)=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([CH3:20])[N:3]=1.CO.C(Cl)(Cl)[Cl:24]>Cl[Cu]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:24])=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl
Reactant: ClC(Cl)Cl
Agent: Cl[Cu]
Solvent: CO
Product: Cc1nc(N)nc(N)c1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 47 by reduction to the amine (PtO2, H2, AcOH), formation of the diazonium salt (NaNO2, H2SO4), and reaction of this with CuCl (as for Example 57). Sublimes at 275° C. Homogenous on TLC (methanol/chloroform, 1:9) Rf=0.36.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][CH:7]1[C:12]2[C:13](=[O:21])[N:14](Cl)[CH:15]=[C:16]([S:18][CH3:19])[O:17][C:11]=2[NH:10][CH2:9][NH:8]1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][CH:7]1[C:12]2[C:13](=[O:21])[N:14]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH3:31])[CH:15]=[C:16]([S:18][CH3:19])[O:17][C:11]=2[NH:10][CH2:9][NH:8]1
Reactant: CSC1=CN(Cl)C(=O)C2=C(NCNC2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Reactant: Cc1ccccc1B(O)O
Product: CSC1=CN(c2ccccc2C)C(=O)C2=C(NCNC2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Yield: 80.8 %

Procedure:
In a similar manner to Reference Example 11, 4-[3,5-bis(trifluoromethyl)benzyl]-6-chloro-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine (Compound of Reference Example 10; 2.36 g) was reacted with 2-methylphenylboronic acid (816 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine (2.13 g, 81%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[C:9]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[NH2:25].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[C:22]([CH3:21])[CH:23]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[C:9]1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH3:15]
Reactant: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 140 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (76 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140° C. for 2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diisopropyl ether-hexane was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (78 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis using HATU. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.65 (m, 6 H) 1.65-1.86 (m, 6 H) 1.93 (d, J=3.3 Hz, 1 H) 2.07 (s, 1 H) 2.04 (d, J=13.1 Hz, 1 H) 2.81 (d, J=5.1 Hz, 1 H) 2.78 (d, J=4.6 Hz, 3 H) 2.99-3.17 (m, 2 H) 3.27 (s, 4 H) 3.48 (d, J=11.6 Hz, 2 H) 4.83 (t, J=7.8 Hz, 1 H) 7.53 (dd, J=8.3, 1.8 Hz, 1 H) 7.55 (s, 1 H) 8.08 (d, J=8.3 Hz, 1 H) 8.17 (s, 1 H) 8.43 (d, J=7.3 Hz, 1 H) 8.98 (br. s., 1 H) 9.54 (br. s., 1 H). [M+H] calc'd for C28H38FN7O3, 540; found 540.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C1C=CC=CC=1.C(OCC)C>[C:4]([O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])([CH3:9])([CH3:5])[CH3:3]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1

Procedure:
0.50 g (3.10 mmol) indole-5-carboxylic acid is suspended in 20 ml absolute benzene and heated under reflux. A solution of 2.80 g (12.39 mmol) 90% N,N-dimethylformamidedi-tert-butylacetal in 20 ml absolute benzene is added drop-wise within 30 min. Following another heating under reflux for 30 minutes and subsequent cooling, the reaction mixture is diluted with diethyl ether, washed with 5% sodium carbonate solution and with saturated NaCl solution. Drying on sodium sulfate, filtration and concentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[F:23])=[O:4].O1CCCC1>C(O)C.[C].[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[C:10]2[CH:9]=[CH:8][C:7]([F:23])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:24])[CH:11]=2)=[N:14][CH:15]=1
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 128.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N-{2-fluoro-5-[methyl(5-nitropyridin-2-yl)amino]phenyl}acetamide (18.0 g, 50.2 mmol) in ethanol (100 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (1.8 g), and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 14 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate/hexane to give the title compound (21.2 g, 68%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Reactant: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cnc2s1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of N-((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)methanesulfonamide (236 mg, 0.732 mmol), 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (300 mg, 0.0.732 mmol) and tris(2-furyl)phosphine (34 mg, 0.146 mmol) and Tris(dibenzylideneacetone) dipalladium(0) (68 mg, 0.0732 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 5 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product. Obtained product purified by HPLC to give the title compound (90 mg): 1H NMR (DMSO-d6): 3.07 (s, 3H), 4.27-4.39 (m, 1.5H), 4.40-4.48 (m, 0.5H), 4.52-4.60 (m, 0.5H), 4.64-4.71 (m, 2.5H) 4.88-4.94 (m, 1H), 6.22 (t, 1H), 7.50 (d, 2H), 7.83 (d, 2H), 8.22-8.33 (m, 1H), 8.62 (bs, 1H), 8.85 (d, 1H), 8.94 (s, 1H). m/z (CI) M+H 489.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][C:43]3[N:44]=[CH:45][S:46][C:42]=3[CH:41]=2)O1.C(OCC)(=O)C>COCCOC.O.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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:40]2[CH:48]=[CH:47][C:43]3[N:44]=[CH:45][S:46][C:42]=3[CH:41]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: CC1(C)OB(c2ccc3ncsc3c2)OC1(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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc2ncsc2c1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.109 g; 0.786 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g; 0.026 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.137 g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-80%) in heptane furnished 0.024 g (18%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC=C1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of the product of above-mentioned (10-b) (88 mg, 0.27 mmol) in ethanol (10 ml) was added 18 mg of 10% palladium on carbon, and stirred vigorously under a hydrogen atmosphere at 25° C. for 2 hrs. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 20 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1coc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A −78° C. solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (1.50 g, 6.81 mmol) in dichloromethane (20 mL) is treated with boron tribromide (20 mL) dropwise. The mixture is stirred at 0° C. for 60 minutes. The reaction is quenched by adding MeOH (10 mL) dropwise over 10 minutes. The mixture is concentrated. The residue is purified via flash chromatography eluting with 25% EtOAc/hexanes to provide the title compound (0.95 g, 68%). ES/MS m/e 207.0 (M+1), 205.0 (M−1).
Reaction SMILES: [C:1](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(NCC4C=CC=CC=4)=CN=C3CC2)=O)=CC=1)=N)(C)([CH3:3])[CH3:2].[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH2:60])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH:60][CH:1]([CH3:3])[CH3:2])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)NC(C)C
Yield: 28.1 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, 26a (30 mg, 0.045 mmol), acetone (5.3 mg, 0.090 mmol) and NaBH(OAc)3 (26.8 mg, 0.127 mmol) yielded 8.9 mg (28.1%) of 27a. MS (ESI) 706.2 (M+H+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][N:26]([CH2:39][CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(C)(=O)=O)C2CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(CC)S(C)(=O)=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide (Example 289, Step A, 86 mg, 0.161 mmol) in DMF (1.5 ml) was added sodium hydride (16.06 mg, 0.401 mmol) at rt and the reaction was stirred at rt for 30 minutes. To this reaction was added iodoethane (0.058 mL, 0.723 mmol) and the reaction was stirred at rt for 2 hours. The reaction was diluted with EtOAc, washed with water and sat. NaCl, dried with Na2SO4 and then concentrated. The crude was used on next reaction.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[C:28]([CH3:33])[CH:27]=[CH:26]5)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]=[C:28]([CH3:33])[CH:27]=[CH:26]4)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4nc(C)ccc4c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2cc(Nc3ncccc3-c3nc(C)nc(N)n3)ccc2n1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-2-methylquinolin-6-amine (0.116 g, 0.199 mmol) in TFA (5.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature, and the mixture was concentrated to about 50% of the original volume. The remaining mixture was pipetted carefully into a saturated solution of NaHCO3, which had been cooled in an ice bath. The resulting precipitate was collected by filtration and washed with water. The solid was then suspended in IPA and the precipitate collected by filtration to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-2-methylquinolin-6-amine (0.0581 g, 0.169 mmol, 85% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 12.30 (s, 1H); 8.83 (d, J=7.0 Hz, 1H); 8.62 (s, 1H); 8.45 (d, J=2.7 Hz, 1H); 8.15 (d, J=8.4 Hz, 1H); 8.03 (d, J=8.0 Hz, 1H); 7.82-7.93 (m, 2H); 7.80 (br. s., 1H); 7.36 (d, J=8.6 Hz, 1H); 6.99 (dd, J=7.3, 4.8 Hz, 1H); 2.63 (s, 3H); 2.48 (br. s., 3H). m/z (ESI, +ve ion) 344.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14]C(=O)OC(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:14][C@@H:3]1[CH2:4][C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[C:2]1([CH3:22])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCCC2)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCCC1
Yield: 100 %

Procedure:
A solution of tert-butyl (1R,3S)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutylcarbamate (step 1, 0.500 g, 1.612 mmol) in TFA:DCM (1:2) (3 ml) stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.34 ml, 9.677 mmol) then the resulting solution as such used for the next reaction. Wt: 0.338 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][O:21][CH:22]1[C:27]([O:30][CH3:31])([O:28][CH3:29])[CH2:26][CH2:25][NH:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][C:27]([O:30][CH3:31])([O:28][CH3:29])[CH:22]([O:21][CH3:20])[CH2:23]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: COC1CNCCC1(OC)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCC1(OC)OC

Procedure:
A mixture of 56.2 parts of 1,1'-(4-chlorobutylidene) bis[4-fluorobenzene], 31.5 parts of 3,4,4-trimethoxypiperidine, 42.5 parts of sodium carbonate, 1 part of potassium iodide and 960 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours. The reaction mixture was cooled, filtered and the filtrate was evaporated, yielding 82.5 parts of 1-[4,4-bis(4-fluoro-phenyl)butyl]-3,4,4-trimethoxypiperidine as a residue (intermediate 66).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][CH2:19][C@@H:20]([N:30]2[CH:34]=[C:33]([C:35]([NH2:37])=[O:36])[N:32]=[CH:31]2)[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>C1CCCCC=1.C(O)C.[OH-].[OH-].[Pd+2]>[Si:23]([O:22][CH2:21][C@H:20]([N:30]1[CH:34]=[C:33]([C:35]([NH2:37])=[O:36])[N:32]=[CH:31]1)[CH2:19][CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[CH:14]1)([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(OCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(O)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 1-[(R)-4-(6-Benzyloxyindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (975 mg, 1.88 mmol) in cyclohexene (10 ml) and ethanol (20 ml) was added 20% palladium hydroxide on carbon (488 mg). The resulting mixture was stirred at reflux for 1 hour. After cooling to room temperature, the mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (20 g) chromatography eluted with chloroform/methanol (100:1 to 50:1) to give 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-hydroxyindol-1-yl)-2-butyl]imidazole-4-carboxamide (772 mg, 95.8%) as a colorless solid.