Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.5 %

Procedure:
To a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (47 mg, 0.15 mmol), prepared as described in Example 113A, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (89 mg, 0.3 mmol). The reaction mixture was stirred at rt for 24 h. Concentration under reduced pressure gave a residue which was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (14.9 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.66 (s, 6H), 3.99 (s, 6H), 6.92 (d, J=8.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.30-7.40 (m, 4H), 7.57-7.66 (m, 4H), 8.56 (s, 1H), 8.90 (d, J=7.5 Hz, 2H); LC-MS (ESI) m/z 484 (M+H)1
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][O:8][C:9]1[C:14]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20][CH:19]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH3:38])[CH:29]=2)=O)=[CH:13][CH:12]=[C:11]([O:39][CH3:40])[N:10]=1.C(N(CC)CC)C.O>ClCCl>[CH3:7][O:8][C:9]1[C:14]([C:15]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:37][CH3:38])=[C:31]([O:34][CH3:35])[CH:32]=3)[CH:19]3[CH:18]([CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20]3)[N:17]=2)=[CH:13][CH:12]=[C:11]([O:39][CH3:40])[N:10]=1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=NC1CCC(OC(C)=O)CC21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
1.67 g of phosphorus pentachioride are suspended in 5 ml of dichloromethane. 1.227 g of crude acetic acid (1RS,3RS,4RS)-4-{[1-(2,6-dimethoxy-pyridin-3-yl)methanoyl]amino}-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound A1) dissolved in 15 ml of dichloromethane are added and the reaction mixture stirred at room temperature over night. The reaction mixture is cooled with an ice bath and 20 ml of triethylamine are added, than cautiously 10 ml of water with vigorous stirring. The organic layer is separated, concentrated and the crude product purified by flash chromatography to give 715 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Cl:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Cl)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-chlorosuccinimide (257 mg) and acetonitrile (10 mL) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0→40% ethyl acetate/hexane) to give the title compound (437 mg, 79%) as a yellow oil.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[OH:21]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
Into a 500-mL 4-necked round-bottom flask, was placed a solution of sodium hydride (4.05 g, 168.75 mmol, 1.70 equiv) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14 g, 99.22 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0° C. over 20 min. The resulting solution was stirred for 2 hr at room temperature. Cu2Cl2 (9.83 g, 100.31 mmol, 1.01 equiv) was added and a solution of 2,6-difluorophenol (15.5 g, 119.15 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath, diluted with 500 mL of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was placed on a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 20 g (80%) of 1,3-difluoro-2-(4-nitrophenoxy)benzene as brown oil.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)C.[OH-].[Na+:18]>CO>[C:1]12([C:11]([O-:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Na+:18]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=C([O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 0.25 h

Procedure:
Approximately 10 g (0.06 mole) of adamantane carboxylic acid was added to 150 ml of ethanol. An equivalent number of moles (2.2 g) of sodium hydroxide also was added to the methanol and the solution was stirred for approximately 15 minutes. This resulted in the formation of sodium adamantane carboxylate. To this reaction mixture was added 7.72 g (0.05 mole) of o-nitrobenzyl chloride. The resulting solution was heated to reflux temperature and stirred at this temperature for 3 hours. The ester thus formed was precipitated by adding 250 ml, in 1 aliquot, of water. The mixture was cooled to ambient temperature and the precipitate was separated by vacuum filtration. The precipitate was recrystallized from 500 ml of a one-to-one by volume solution of ethanol and water to yield approximately 6.4 g of o-nitrobenzyl adamantane carboxylate.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1.[C:22]([NH:30][C:31]1[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:42]1([CH2:48][CH2:49][CH2:50]O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:22]([NH:30][C:31]1[CH:40]=[C:39]([O:41][CH2:50][CH2:49][CH2:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCCc2ccccc2)cc1NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
0.28 mL of 40% diisopropyl azodicarboxylate /toluene was added dropwise to 1 mL of tetrahydrofuran solution containing 0.10 g of methyl 2-(benzamido)-4-hydroxybenzoate, 0.060 mL of 3-phenyl-1-propanol and 0.15 g of triphenylphosphine at room temperature, and stirred at the same temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified wish silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to obtain 45 mg of methyl 2-(benzamido)-4-(3-phenylpropoxy)benzoate as white solid.
Reaction SMILES: [ClH:1].Cl.[Cl:3]C1C=C([CH:10]([C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)C=CC=1.[Cl:34][C:35]1[CH:36]=[C:37](C(C2(O)CCCCC2)CN2CCNCC2)[CH:38]=[CH:39][CH:40]=1.C1(C(C)C=O)C=CC=CC=1.Cl>>[ClH:3].[ClH:34].[Cl:1][C:35]1[CH:40]=[C:39]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:27]2([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:14][CH2:13]2)[OH:33])[CH:38]=[CH:37][CH:36]=1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Reactant: CC(CN1CCN(CC(c2cccc(Cl)c2)C2(O)CCCCC2)CC1)c1ccccc1
Agent: CC(C=O)c1ccccc1
Agent: Cl
Product: CC(CN1CCN(CCC2(O)CCCCC2c2cccc(Cl)c2)CC1)c1ccccc1

Procedure:
In an analogous manner to Example 117, 1-{1-(3-chlorophenyl)-2-[4-(2-phenylpropyl)piperazin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) and 2-phenylpropionaldehyde. MS (ESI) m/z 441/443 ([M+H]+); HRMS: calcd for C27H37ClN2O.2.00 HCl, 512.2128; found (ESI), 441.2662.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:10]=2[N:11]=1>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:10]=2[N:11]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Brc1ccc2c(n1)NCCO2
Temperature: 70 °C

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.35 g, 5.89 mmol) was dissolved in THF (40 mL). Boranedimethylsulphide complex (2.0 M in THF, 5.89 mL, 11.79 mmol) was added and the resulting mixture heated to 70° C. under nitrogen for 15 minutes. Next, the reaction mixture was cooled to room temperature, quenched with methanol (˜5 mL), and then dried under vacuum to obtain a white solid. The crude material was dissolved in dichloromethane and washed with H2O. The aqueous phase was discarded and the organic phase was dried under vacuum to give 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. Yield: 1.1 g (87%). LCMS (ESI): calc. C7H7BrN2O=214, 216; obs. M+H=215, 217.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].O>C(COC)OC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (500 mg, 0.001 mol) and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (594 mg, 0.0015 mol) were reacted under palladium catalyzed Suzuki coupling conditions with Pd(dppf)C12 and Cs2CO3 water and dimethoxyethane to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate together with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[CH2:13]([NH2:17])[C:14](=[CH2:16])[CH3:15].C(O)(=O)C(O)=O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29]C1CNC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:14](=[CH2:15])[CH2:13][NH:17][C:1]([N:8]1[CH2:9][CH:11]([O:29][C:28]2[CH:34]=[CH:35][CH:36]=[C:26]([C:25]([F:24])([F:37])[F:38])[CH:27]=2)[CH2:12]1)=[O:2]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: C=C(C)CN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 1 h
Yield: 106.6 %

Procedure:
A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 75 ml of methylene chloride was stirred under nitrogen while 1.6 g (0.022 mole) of methallylamine was added with a syring and needle through a septum installed in one neck of the reaction flask. The reaction was slightly exothermic. The reaction mixture was stirred for 1 hr, then treated with 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate followed in 0.5 hr with 5 ml of triethylamine and stirring continued for 16 hr. The reaction mixture was washed with 2×30 ml of water, dried over magnesium sulfate, and concentrated on a rotary evaporator to yield 6.7 g of oily residue which solidified. The residue was recrystallized from isopropyl ether to yield 5.4 g (85.9%) of fine white crystals, m.p. 90°-91° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[CH:8]2[CH2:17][CH2:18][OH:19].[CH3:20][S:21]SC.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[C:8]2([S:21][CH3:20])[CH2:17][CH2:18][OH:19]
Reactant: CSSC
Reactant: COc1cc2c(cc1OC)C(CCO)C(=O)N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(CCO)(SC)C(=O)N2
Yield: 57.6 %

Procedure:
To 50 ml of dimethylformamide was added 360 mg of sodium hydride, and 1.76 g of 5,6-dimethoxy-3-hydroxyethyl-1,3-dihydro-2(2H)-indolone and 706 mg of dimethyl disulfide were added thereto. To the reaction mixture was added a sodium hydrogencarbonate aqueous solution, and the solvent was evaporated. The residue was extracted three times with methylene chloride, and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate) to yield 1.21 g of the title compound.
Reaction SMILES: [I:1]I.[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].Cl>O>[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:1])[N:5]=1
Reactant: Oc1cccnc1Br
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add I2 (21.0 g, 82.7 mmol) in solid form, a little at a time, in the space of 5 min, to a solution of 2-bromo-3-pyridinol (14.0 g, 80.8 mmol) and of K2CO3 (22.3 g, 161 mmol) in H2O (180 mL). Stir the reaction medium at room temperature for 2 h, then cool it (ice/H2O) to 0-5° C. and neutralize it to pH 6 by adding 2N HCl. A precipitate forms, which is filtered, washed with H2O and dried under vacuum at 70° C. to give 2 (19.48, 80.7%) in solid form, of an ivory color: 1H NMR (CDCl3) δ 7.54 (d, 1H, J=8.1 Hz), 6.98 (d, 1H, J=8.1 Hz), 5.55 (s broad, 1H); m/z obs.=299.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[N:5]([CH3:7])[CH3:6].[CH3:11][CH:12]([OH:16])[CH2:13][CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][N:5]([CH3:7])[C:4]1[CH:3]=[C:2](/[CH:15]=[CH:14]/[CH2:13][CH:12]([OH:16])[CH3:11])[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)c1cccc(Br)c1
Reactant: C=CCC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(O)C/C=C/c1cccc(N(C)C)c1
Yield: 63.7 %

Procedure:
A mixture of 3-bromo-N,N-dimethylaniline (1.00 g, 5.00 mmol), 4-penten-2-ol (450 mg, 5.23 mmol), palladium(II) acetate (11 mg, 0.050 mmol) and tri-o-tolylphosphine (61 mg, 0.20 mmol) was diluted with triethylamine (1.5 mL) and acetonitrile (3 mL) and refluxed under nitrogen for 16 h. The mixture was cooled, poured into water (15 mL) and extracted with chloroform (2×15 mL). The chloroform extracts were dried (Na2SO4) and evaporated. The residue was column chromatographed on 35 g of Merck silica gel 60 (70-230 mesh) with 10-20% (v/v) ethyl acetate, 20% (v/v) chloroform in hexane to give 657 mg (63.7% yield) of light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:6][CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.O>CN(C=O)C>[CH3:19][O:20][CH2:21][N:12]([C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1)[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Nc1cccc2c1CCCC2=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(c1cccc2c1CCCC2=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 15A (4.0 g, 17 mmol) in anhydrous DMF (40 mL) under a nitrogen atmosphere was treated with a 60% dispersion of sodium hydride (0.74 g, 18 mmol) in portions over 5 minutes, stirred for 45 minutes, cooled to 0° C., treated dropwise with chloromethyl methyl ether (1.3 mL, 18 mmol), stirred at ambient temperature for 2 hours, treated with cold water (250 mL) and extracted with diethyl ether (3×). The combined diethyl ether extracts were washed with water, washed with brine, dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel with 1:1 hexanes:ethyl acetate provided the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>C(COC)OC>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:25]([F:31])[CH:26]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc(N)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1.6 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 200 mg of tetrakistriphenylphosphine palladium, 5 ml of aqueous saturated sodium carbonate solution and 5 ml of water were added in order to a dimethoxyethane (10 ml) solution of 1 g of 4-bromo-3-fluoro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 70° C. for 3 hours. After cooled, the reaction liquid was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to obtain the entitled compound as a pale brown solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:44])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][C:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])[C:21](=[O:43])[CH:20]=3)=[CH:15][CH:14]=2)[CH2:5][CH2:4]1>O1CCOCC1.O>[ClH:1].[F:44][C:3]1([F:2])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][C:27]([CH3:42])([S:38]([CH3:41])(=[O:39])=[O:40])[C:28]([NH:30][OH:31])=[O:29])[C:21](=[O:43])[CH:20]=3)=[CH:17][CH:18]=2)[CH2:5][CH2:4]1
Reactant: CC(CCn1ccc(-c2ccc(OCCCN3CCC(F)(F)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(CCn1ccc(-c2ccc(OCCCN3CCC(F)(F)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
HCl (4.0 M in 1,4-dioxane, 1.0 mL) was added to a solution of 4-[4-{4-[3-(4,4-difluoropiperidin-1-yl)propoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (209 mg, 0.334 mmol) in 1,4-dioxane/water (1:1, 5 mL). After 10 minutes the reaction was concentrated to give a white solid, the solid was triturated with 2-propanol at 50° C. for 1 h. The title compound was isolated by filtration as a white solid (146 mg, the hydrochloride salt, 75%). LCMS m/z 542.8 (M+1)1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.22 (br. s., 3H) 2.38 (br. s., 5H) 3.11 (s, 3H) 3.13-3.26 (m, 2H) 3.31 (br. s., 2H) 3.74 (br. s., 3H) 4.14 (t, J=5.76 Hz, 3H) 6.59-6.72 (m, 2H) 7.05 (d, J=8.78 Hz, 2H) 7.63-7.79 (m, 3H) 11.03 (br. s., 1H) 11.18 (br. s., 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][N:10]([CH:14]([CH3:16])[CH3:15])[C@@H:9]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][C@@H:12]([CH3:26])[S:11][N:10]([CH:14]([CH3:16])[CH3:15])[C@@H:9]2[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N1SCC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)N1S[C@H](C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a degassed solution of 239.9 mg (0.602 mmol) of (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazinan (Example 117, Step D) in THF (2.0 mL) was added iodomethane (60.0 μl, 0.960 mmol), followed by dropwise addition of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (640.0 μl, 0.640 mmol). After stirring at room temperature for 17 hours, the reaction was quenched with MeOH (3 mL), then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 70% DCM in hexanes gradient) provided the title compound as a white solid. The 1H NMR showed 6% of the 6S epimer was also isolated.
Reaction SMILES: [N+]([O-])(O)=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[CH:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:22]([CH3:31])=[C:21]1[C:32]([O:34][CH3:35])=[O:33].N([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:30][C:24]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:20]([C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])[C:21]([C:32]([O:34][CH3:35])=[O:33])=[C:22]([CH3:31])[N:23]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCBr
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1cc([N+](=O)[O-])ccc1OCCCCBr
Yield: 52.2 %

Procedure:
To 140 ml of 50% dioxane-water solution was added 12.8 ml conc. nitric acid (d=1.40), and suspended therein 20 g of dimethyl 4[(4-bromobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate while maintaining the system at 5° to 10° C. under ice cooling. After adding 5.6 g of sodium nitrite, the reaction mixture was vigorously stirred and then filtered. The filtrate obtained was adjusted to pH8 with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. After washing with water, the organic layer was dried over anhydrous magnesium sulfate and the solvent distilled off. The resultant residue was recrystallized from ethyl acetate--ether to yield 10.4 g of dimethyl 2,6-dimethyl-4-[(4-bromobutoxy)-5-nitrophenyl]pyridine-3,5-dicarboxylate.