Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([C:20]#[N:21])[C:18]#[N:19].N1CCCCC1>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCC#N
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
14.22 g (67 mmol) of 4-benzyloxybenzaldehyde and 5.31 g (80.4 mmol) of malonodinitrile were suspended in 80 ml of isopropanol in the presence of 0.2 ml of piperidine. In so doing the mixture increased in temperature from 19 to 31° C. A solution resulted, from which a solid was finally obtained. This was filtered off after stirring for 30 min. There were obtained 10.3 g (59%) of 2-(4-benzyloxy-benzylidene)-malononitrile with m.p. 146-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:27]1([CH3:33])[CH:32]=CC=[CH:29][CH:28]=1.BrCC=C(C)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:29][CH:28]=[C:27]([CH3:33])[CH3:32])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CCNCc1ccc(F)cc1
Agent: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=C(C)C)CNCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A solution of 3-(4-fluoro-benzylamino)-propionic acid ethyl ester (158 mg, 0.701 mmol) in anhydrous tetrahydrofuran (8 mL) was stirred under an environment of nitrogen at −78° C. and treated via syringe with 0.5 M in toluene potassium bis(trimethylsilyl)-amide (1.4 mL, 0.701 mmol). After 15 min, 4-bromo-2-methyl-2-butene (104 mg, 0.701 mmol) was added and the reaction mixture was stirred at −78° C. for 6 h. The reaction was allowed to warm to 25° C. and was diluted with a saturated aqueous sodium bicarbonate solution (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 5 to 60% ethyl acetate in hexanes) to give 2-[(4-fluoro-benzylamino)-methyl]-5-methyl-hex-4-enoic acid ethyl ester (181 mg, 37%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.25 (t, 3H, J=7.0 Hz), 1.60 (s, 3H), 1.68 (s, 3H), 2.18-2.25 (m, 1H), 2.28-2.37 (m, 1H), 2.55-2.62 (m, 1H), 2.69 (dd, 1H, J1=11.7 Hz, J2=4.7 Hz), 2.86 (dd, 1H, J1=11.7 Hz, J2=8.6 Hz), 3.67-3.81 (m, 2H), 4.10-4.18 (m, 2H), 5.04-5.08 (m, 1H), 6.98 (t, 2H, J=8.5 Hz), 7.23-7.27 (m, 2H). LC-MS (ESI) calculated for C17H24FNO2: 293.4, found 294.5 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[C:16]([NH:17]C(=O)C(F)(F)F)[C:11]2=[CH:10][C:9]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:10]=2)[O:14][C:15]=1[C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25]
Reactant: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a magnetically stirred solution of 0.273 g (0.50 mmol) of the product of Example 182 in 5 mL MeOH was added 0.343 g (0.248 mmol) of potassium carbonate and 0.5 mL water. The reaction mixture was stirred at 60° C. for 3 h then cooled to room temperature and partitioned between EtOAc and 10% aq. NaHSO4. The organic extracts were separated, washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the titled compound. HPLC/MS: 453.9 (M+1), 455.8 (M+3); Rt=4.15 min.
Reaction SMILES: [F:1][C:2]1([F:65])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5([CH3:52])[CH2:49][O:48]C(C)(C)[O:46][CH2:45]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:65][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:43][C:44]([CH2:49][OH:48])([CH3:52])[CH2:45][OH:46])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:61])([F:63])[F:62])=[CH:56][CH:55]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6(C)COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(C)(CO)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of 375 mg (0.411 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 18, in 5 ml of 1,4-dioxane, 1 ml of 6 N hydrochloric acid was added, and the reaction mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=50/50-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Heptane was added to the obtained residue, and the precipitate was obtained by filtration to provide 221 mg of the title compound as a white solid (yield: 72%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][NH2:13]>O>[CH3:12][NH:13][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: CN
Solvent: O
Product: CNCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
2-(Chloromethyl)benzoxazole (3.99 g, 23.8 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a nitrogen atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with water and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (5% MeOH/CH2Cl2) to afford 3.18 g (82%) of pure product as a yellow oil.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH:25]1([CH2:24][O:23][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:13]=2[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:17]([O:19][CH3:20])=[O:18])[CH2:26][CH2:27]1
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c(OCC2CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of methyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (for reference procedure see Example 18, WO 2010/089107, which is incorporated herein by reference) (3.00 g, 7.51 mmol) in dry DCM (40 ml), HCl 4M in Dioxane (9.39 ml, 37.6 mmol) was added, and the mixture was stirred at RT for 3 days. The solvent was evaporated, the residue was triturated with iPr2O (50 ml) and filtered to give methyl 3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoate as an off-white powder (2.15 g, 7.18 mmol, 96% yield, MS/ESI+ 299.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(O)cc2C1=O
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Yield: 93.5 %

Procedure:
A mixture of 4-(4-chlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (14.7 g), sodium hydride (80% oil dispersion, 1.65 g) and 2-dimethylaminoethyl chloride (5.8 g) was heated under reflux in toluene (150 ml) for 6 hr. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated, basified, extracted with ether and the extract dried (MgSO4). Evaporation gave 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone as a yellow oil (17 g, 91%) which was contaminated with ether. A portion was converted to the hydrochloride salt (64%), which crystallised as white prisms from ethanol-ether, m.p. 209°-211°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][CH:31]=[CH:30]3)[N:25]=[C:24]([CH:37]([CH3:39])[CH3:38])[CH:23]=1)=[O:20].[NH4+].[Cl-]>CO.[Zn]>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:18][C:19]([NH:21][C:22]3[N:26]([C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[CH:32][CH:31]=[CH:30]5)[N:25]=[C:24]([CH:37]([CH3:38])[CH3:39])[CH:23]=3)=[O:20])[CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC(C)c1cc(NC(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccc2F)n(-c2ccc3ncccc3c2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)c1cc(NC(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.6 %

Procedure:
1-(2-fluoro-5-(6-nitropyridin-3-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.129 g, 0.245 mmol) was dissolved in MeOH (2.0 mL), to which NH4Cl (0.131 g, 2.45 mmol) and zinc power (0.160 g, 2.45 mmol) were added and the reaction mixture was stirred at RT for 4 h. The reaction mixture was filtered through Celite and washed with methanol (30 mL) and EtOAc (50 mL). The filtrate was concentrated in vacuum, partitioned between EtOAc (30 mL) and water (20 mL). The separated organic phase was washed with brine (10 mL), dried (MgSO4) and concentrated to afford 1-(5-(6-aminopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0495 g, 41% yield) as a white foam. MS (ESI) m/z: 498.2 (M+H+).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14]C(=O)C)[CH2:9][CH2:8]2)(=[O:4])(=[O:3])[NH2:2].[ClH:18]>>[ClH:18].[NH2:14][CH:10]1[C:11]2[C:7](=[CH:6][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: CC(=O)NC1CCc2cc(S(N)(=O)=O)ccc21
Agent: Cl
Product: NC1CCc2cc(S(N)(=O)=O)ccc21

Procedure:
To a round bottom flask containing N-(5-sulfamoyl-2,3-dihydro-1H-inden-1-yl)acetamide (1 g, 3.9 mmol) was added 12N hydrochloric acid (100 mL) and the reaction was heated to a reflux for 2 days. The reaction was cooled and concentrated to afford MIP-1153 (785 mg, 96%) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.20 (m, 3H), 3.78 (br, 6H), 3.21-1.97 (m, 4H); (M+H)+ (212).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCN(C)CC1

Procedure:
12 G. of 2,10-dichloro-10,11-dihydro-7-methyl-dibenzo[b,f]-thiepin and 12.4 g. of N-methylpiperazine are dissolved in 310 ml. of chloroform and the solution heated at reflux for 16 hours. The cooled solution is washed with 2N sodium hydroxide and water. The organic phase is decanted and extracted with a dilute methanesulfonic acid solution. The acid solution is made alkaline earth sodium hydroxide and the oil that separates is taken up in ether. The organic phase is washed with water, dried over magnesium sulfate and concentrated under vacuum, and there is obtained 1-(2-chloro-10,11-dihydro-7-methyl-dibenzo-[b,f]thiepin-10-yl)-4-methylpiperazine which melts at 136°-137.5°C. This base is converted into the dimethanesulfonate by reaction with methanesulfonic acid.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=O)[C:28]4[C:23](=[C:24]([F:32])[CH:25]=[CH:26][C:27]=4[F:31])[CH:22]3[OH:33])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[C:24]([F:32])[CH:25]=[CH:26][C:27]=4[F:31])[C:22]3=[O:33])=[CH:18][CH:19]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2O)cc1)C1CCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2Cc3c(F)ccc(F)c3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
90.0 mg (0.20 mmol) of tert-butyl cyclopentyl{4-[(4,7-difluoro-1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate were initially charged in 1 ml of dichloromethane, and 300 μA of trifluoroacetic acid and 62 μl (0.39 mmol) of triethylsilane were added. The mixture was stirred at RT for 2 h. The reaction mixture was then concentrated on a rotary evaporator, the residue was taken up in ethyl acetate and the solution was washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. This gave 77.0 mg of the target compound.
Reaction SMILES: F[C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][C:24]=1[O:35][CH3:36]>>[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[NH:30][CH2:31][CH2:32][N:33]([C:20]3[CH:2]=[CH:3][C:4]4[C:5]([CH:19]=3)=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=4)[CH2:34]2)=[CH:25][C:24]=1[O:35][CH3:36]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: COc1cc(C2CNCCN2)ccc1N
Product: COc1cc(C2CN(c3ccc4cc5c(=O)c(C(=O)O)cn(C)c5nc4c3)CCN2)ccc1N
Yield: 76.2 %

Procedure:
Working under the conditions of Example 16, but starting with 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.16 g) and (RS)-2-(4-amino-3-methoxyphenyl)piperazine (1.82 g), (RS)-8-[3-(4-amino-3-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.40 g) is obtained in the form of a yellow solid, decomposing at 259° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.ClCC(O)[C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])(C)C)[CH3:30]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:30][C@H:29]1[C@H:34]([CH2:37][N:12]2[CH:11]=[C:10]([C:8]3[CH:7]=[C:6]([NH:15][C:16]4[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=4)[CH:5]=[C:4]([CH3:3])[CH:9]=3)[CH:14]=[N:13]2)[O:33][C:32](=[O:38])[NH:31]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C[C@@H]3OC(=O)N[C@H]3C)c2)c1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.71 mmol) was added to a mixture of N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.47 mmol) in DMF (3 mL), and the mixture was stirred for 5 minutes. A mixture of tert-butyl ((2S)-4-chloro-3-hydroxybutan-2-yl)carbamate (110 mg, 0.49 mmol) in DMF (2 mL) was added and the mixture was heated to 40° C. for 4 hours. The mixture was then allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel. The purified diasteromeric mixture was separated by chiral SFC (Chiralpak ID, 21×250 (mm), 25% CO2 with methanol as the diluent) to afford (4S,5S)-4-methyl-5-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (Isomer 1, early eluting): MS ESI calc'd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=4.3 Hz, 1H), 8.06 (s, 1H), 7.85-7.76 (m, 2H), 7.73 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=4.6 Hz, 1H), 7.06 (s, 1H), 4.47-4.35 (m, 3H), 3.75-3.59 (m, 1H), 2.29 (s, 3H), 1.10 (d, J=5.8 Hz, 3H).
Reaction SMILES: [Cl:1]Cl.BrBr.[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][N:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:18]1[S:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[N:11][CH:12]=2)=[CH:20][CH:19]=1
Reactant: CCCCCc1ccc(-c2cccs2)cn1
Reactant: ClCl
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCc1ccc(-c2ccc(Cl)s2)cn1
Reaction time: 1 h

Procedure:
7.3 g of chlorine are passed in, or 17 g of bromine are added dropwise, with stirring, to a solution of 23.1 g of 2-(2-pentyl-5-pyridyl)-thiophene in 40 ml of CCl4 at 20°. After the mixture has been left to stand for 1 hour, it is warned at 50° for 2 hours, washed with dilute sodium hydroxide solution and worked up in the customary manner to give 5-chloro-2-(2-pentyl-5-pyridyl)-thiophene, m.p. 32°, c.p. 18° (or 5-bromo-2-(2-pentyl-5-pyridyl)-thiophene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold mixture of 2-(3-bromophenoxy)ethanol (15) (16.06 g, 74.0 mmol) and triethylamine (9.12 g, 90.13 ml) in anhydrous CH2Cl2 (120 ml) under argon was slowly added neat methanesulfonyl chloride (6 ml, 77.2 mmol) and the reaction mixture stirred at 0° C. for 15 min. A precipitate formed after the addition was complete. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed twice with water, once with brine, dried over MgSO4 and concentrated under reduced pressure. 2-(3-Bromophenoxy)ethyl methanesulfonate (16) was isolated as a brown oil and used in the next synthetic step without further purification. Yield (21.32 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=7.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.07 (m, 1H), 6.39 (ddd, J=7.6, 2.5, 1.8 Hz, 1H), 4.56 (m, 2H), 4.22 (m, 2H), 3.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[CH:23][CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[C:31]([N:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[CH:23][CH:22]=2)=[CH:3][C:2]=1[NH:1][CH:41]1[CH2:42][CH2:43][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39][CH2:40]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)ccc2C(C)(C)C)CC1

Procedure:
The title compound was prepared from N-(3-amino-4-tert-butyl-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide and Boc-piperidin-4-one by a method analogous to that described in Example 42. MS (ES+): 584 (M+H), Calc'd for C33H41N7O3−583.7.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[CH3:29])[C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].Cl.[CH3:31][C:32]1[N:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34](O)=[O:35]>>[C:17]([C:16]1[CH:20]=[CH:21][C:13]([N:12]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[CH3:29])[CH:9]2[CH2:10][CH2:11][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]3[C:37]([CH3:41])=[CH:38][CH:39]=[N:40][C:32]=3[CH3:31])[CH2:7][CH2:8]2)=[CH:14][CH:15]=1)(=[O:18])[NH2:19]
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: Cc1ccncc1CN(c1ccc(C(N)=O)cc1)C1CCN(C(C)CCN)CC1
Agent: Cl
Product: Cc1ccncc1CN(c1ccc(C(N)=O)cc1)C1CCN(C(C)CCNC(=O)c2c(C)ccnc2C)CC1
Yield: 84.6 %

Procedure:
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-amino]-benzamide (see EXAMPLE 355) (21.8 mg, 0.055 mmol) and 2,4-dimethylnicotinic acid hydrochloride (15 mg, 0.080 mmol) gave COMPOUND 366 as an off-white solid (24.6 mg, 84%). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.09-1.38 (m, 2H), 1.53-1.63 (m, 1H), 1.72-1.90 (m, 3H), 2.24 (t, 1H, J=11.0 Hz), 2.29 (s, 3H), 2.39 (s, 3H), 2.53 (s, 3H), 2.59 (t, 1H, J=11.0 Hz), 2.74-2.93 (m, 3H), 3.31-3.42 (m, 1H), 3.71-3.84 (m, 2H), 4.12 (s, 2H), 5.64 (br s, 2H), 6.53 (d, 2H, J=8.9 Hz), 6.84 (d, 1H, J=5.0 Hz), 7.12 (d, 1H, J=4.9 Hz), 7.61 (d, 2H, J=8.9 Hz), 7.65 (br s, 1H), 8.18 (s, 1H), 8.18 (d, 1H, J=5.0 Hz), 8.37 (d, 1H, J=4.9 Hz). 13C NMR (CDCl3) δ 13.44, 18.65, 18.72, 22.26, 29.28, 30.17, 31.72, 39.11, 44.05, 44.86, 51.61, 56.13, 59.29, 112.07, 121.24, 122.44, 125.08, 129.13, 131.84, 133.50, 143.83, 144.19, 147.41, 148.19, 148.63, 150.95, 154.03, 168.20, 169.02. ESI-MS m/z 529 (MH)+. Anal. Calcd. for C31H40N6O2.0.6CH2Cl2: C, 65.48; H, 7.16; N, 14.50. Found: C, 65.26; H, 7.46; N, 14.25.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1CO
Reaction time: 1 h

Procedure:
A suspension of 2-amino-5-nitrobenzaldehyde (6.0 g.) in ethanol (250 ml.) was stirred at ambient temperature while sodium borohydride (1.6 g.) was added in small portions, and the reaction mixture was stirred for 1 hour. The reaction mixture was made acid with 2 N hydrochloric acid to destroy the excess of sodium borohydride, and then basified to pH 8 to 9 with solid sodium carbonate and extracted with diethyl ether (3×200 ml.). The extracts were combined and dried, the solvent was evaporated and the residue was crystallised from water (about 200 ml.) to give the required 2-amino-5-nitrobenzyl alcohol, m.p. 141°-142° C.;