Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:38])[C:19]([C:35](=[O:37])[CH3:36])=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:17][C:18](=[O:38])[CH:19]([C:35](=[O:37])[CH3:36])[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Reactant: Br[Mg]Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(C)=O)C(Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Cuprous iodide (1.15 g, 6.05 mmol) in dry THF (10 ml) was treated at 0° C. with benzylmagnesium bromide (2M in THF, 6.05 ml, 12.1 mmol) over a 3 minute period. The cuprate was stirred at 0° C. for 30 minutes and then cooled to −78° C. and then TMSCl (3.28 g, 30.2 mmol) in THF (5 ml) was added dropwise keeping the reaction temperature below −60° C. The mixture was stirred at below −60° C. for a further 10 minutes and then ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-prop-2-enoate (1 g, 3.01 mmol) in THF (5 ml) was added dropwise over 3 minutes. The mixture was stirred at below −60° C. for 45 minutes and then saturated NH4Cl (30 ml) and water (20 ml) were added. The mixture was allowed to warm to room temperature, the resultant precipitate was removed by filtration and the filtrate evaporated, the residue was dissolved in methylene chloride (200 ml), washed with water (30-ml), 1n HCl (50 ml) and water (30 ml), dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2; EtOAc:hexane (1:9)) afforded ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-4-phenyl-butanoate (1.19 g), 92%) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:10]2=3)=[CH:5][CH:4]=1.[H-].[Na+].S(Cl)([Cl:34])=O.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:10]2=3)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(CO)cc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(CCl)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the compound of Example 88 (130 mg, 0.32 mmol) in THF (2 mL) was added NaH (14 mg of 60% dispersion in oil, 0.35 mmol). DMF (0.5 mL) was added to aid solubility and the reaction was stirred for 1 h. Thionyl chloride (25 μL, 0.35 mmol) was added to the reaction mixture cooled in an ice-bath. The mixture was stirred in the ice-bath for 30 mins before quenching the reaction with water (20 mL) and basifying with NaHCO3(aq). The product was extracted into DCM (2×15 mL) and the combined DCM layers dried over MgSO4, filtered and concentrated in vacuo to give ethyl 7-(4-chloromethylphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate LCMS (ES+) RT 3.97 minutes, 424 (M+H)+. To a solution of this compound in DMF (1 mL) was added 2-methylimidazole (13 mg, 0.16 mmol) and caesium carbonate (52 mg, 0.16 mmol) and the mixture heated at 80° for 3 h. DMF was removed in vacuo and the residue purified by column chromatography (silica, 40–100% EtOAc in isohexane followed by 5% MeOH in DCM) and also mass directed hpic to give the title compound as a solid (3 mg). δH (MeOH-d4) 7.47–7.27 (10 H, m), 7.06 (1H, d, J 1.4 Hz), 6.82 (1H, d, J 1.4 Hz), 6.50 (1H, d, J 9.6 Hz), 5.26 (2H, s), 4.00 (2H, q, J 7.1 Hz), 2.28 (3H, s), 0.99 (3H, t, J 7.1 Hz). LCMS (ES+) RT 2.53 minutes, 470 (M+H)+.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14](I)=[C:13]3[CH2:19][C@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][C@@H:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C[SiH](C)C.[CH:33]#[CH:34].C[Sn](C)C>C1(C)C=CC=CC=1>[C:33]([C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@H:11]3[CH2:21][C@@H:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:19][C:13]=1[C:12]=23)#[CH:34]
Reactant: CCCN(CCC)[C@H]1Cc2c(I)ccc3c2[C@H](C1)CN3C(=O)c1ccccc1
Reactant: C#C
Agent: C[SiH](C)C
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c3c1C[C@H](N(CCC)CCC)C[C@@H]3CN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 136.4 %

Procedure:
1-benzoyl-(2aS,4R)-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (100 mg, 0.205 mmol) and trimethyltin acetylene trimethylsilane (272 mg, 1.0 mmol, 3 eq) was dissolved in anhydrous toluene (5 mL), to which was then added tetrakis-triphenylphosphine palladium (20 mg, 0.017 mmol, 0.05 eq). The resulting light yellow solution was brought to reflux under N2 atmosphere. After 4 hr, the reaction mixture was cooled to room temperature, filtered and concentrated to dryness. The residue was chromatographed over silica gel with hexanes:ethyl acetate (1:1) to afford the desired product (79 mg, 84%). This material was dissolved in a 1N solution (5 mL) of tetrabutylammonium fluoride in THF, and stirred at room temperature overnight (12 h). The solution was diluted with EtOAc (10 mL) and rinsed successively with H2O (3×10 mL), brine (10 mL) and dried over Na2SO4. The residue was chromatographed over silica gel with hexanes:ethyl acetate (1:1) to afford a mixture of the 1-benzoyl (61%) and the N-deprotected indoline (33%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[O:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:13]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[C:16]([CH3:27])[O:15][N:14]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc(N)c([N+](=O)[O-])c1
Temperature: 95 °C
Yield: 93.1 %

Procedure:
To a mixture of 4-bromo-2-nitro-phenylamine (150 g, 0.691 mol, 1.0 eq) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (169 g, 0.725 mol, 1.05 eq) in 1,2-dimethoxyethane (1.5 L) and water (700 mL) were added PdCl2(dppf) (56 g, 69 mmol, 0.1 eq) and K2CO3 (190 g, 1.38 mol, 2.0 eq). The reaction mixture was heated at 95° C. overnight. The reaction mixture was diluted with EtOAc (3 L), washed with brine (2×500 mL). The organic solvent was evaporated and the residue was purified with flash chromatography on silica (PE/EA=10:1-1:1) to give 150 g 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(F)cc3)nsc2c1
Product: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole, MS: 379 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](Cl)=[O:14])[CH:8]=2)[N:3]=1.[BH4-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][OH:14])[CH:8]=2)[N:3]=1
Reactant: O=C(Cl)c1ccc2nc(Cl)c(Cl)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc2nc(Cl)c(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 25.3 g portion of 2,3-dichloroquinoxaline-6-carbonyl chloride synthesized in accordance with the procedure disclosed in JP-A 57-98274 in 400 ml of anhydrous 1,4-dioxane, was added 14.0 g of sodium borohydride, and the mixture was stirred at room temperature for 10 minutes in an atmosphere of nitrogen. With cooling on an ice bath, to this was added dropwise 100 ml of water. Thereafter, 1,4-dioxane was evaporated under a reduced pressure, and the resulting residue was purified by chromatography on a silica gel column (eluent, hexane/ethyl acetate) to obtain 8.75 g of 2,3-dichloro-6-hydroxymethylquinoxaline.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][NH:25][C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[N:29]=[C:28](Cl)[C:27]=2[N+:35]([O-:37])=[O:36])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]C1C=CC=CC=1>COCCOCCOC>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][NH:25][C:26]2[C:27]([N+:35]([O-:37])=[O:36])=[C:28]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:29]=[C:30]([CH3:33])[C:31]=2[CH3:32])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCC2CCN(Cc3ccccc3)CC2)c1C
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCC2CCN(Cc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
Sodium hydride (1.196 g of 60%, 29.9 mmol) was added to a solution of phenol (2.81 g, 29.9 mol) in diglyme (40 mL). The mixture was stirred for 15 minutes after the cessation of gas evolution. A solution of N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine (10.9 g, 27.2 mmol) in hot diglyme was added to the phenoxide mixture. The reaction mixture was heated at reflux for 1.5 hours, cooled to ambient temperature, and then concentrated to remove the diglyme (60° C. bath, 21 Pa). The residue was purified by column chromatography eluting first with 1% methanol in dichloromethane to remove residual diglyme and then with 5% methanol in dichloromethane to elute product. The fractions were concentrated to provide 5.91 g of N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine as an orange-brown oil which solidified on standing.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide (Stage 222.2) and (R)-pyrrolidin-3-ol to afford an amorphous off-white solid. HPLC (Condition 4) tR=4.83 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=478.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:10](=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:10](=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CO)CBr
Reactant: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(OC[C@@H](C)CO)cc2c1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A suspension of 2-[3-(3-chlorophenyl)-7-hydroxy-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (INTERMEDIATE III.7) (347 mg, 0.936 mmol), K2CO3 (674 mg, 4.68 mmol) and (S)-(+)-3-bromo-2-methyl-1-propanol (0.48 mL, 4.7 mmol) in dry acetonitrile (5 mL) was stirred for 18 h at 80° C. The resultant mixture was poured into H2O (20 mL), cooled to 0° C. and filtered. The precipitate was washed with cold H2O and dried in vacuo to furnish 2-[3-(3-chlorophenyl)-7-((S)-3-hydroxy-2-methylpropoxy)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (382 mg, 0.862 mmol, 92%) as white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[O:12][N:11]=1>O1CCCC1>[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][O:6][C:10]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[O:12][N:11]=1
Reactant: Clc1ccc2onc(Cl)c2c1
Reactant: CC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(N)COc1noc2ccc(Cl)cc12
Yield: 73.6 %

Procedure:
To a suspension of 0.43 g of 60% (w/w) sodium hydride in 15 ml of tetrahydrofuran is added a solution of 0.80 g of 2-amino-2-methyl-1-propanol in 20 ml of tetrahydrofuran at 20°-25° C., and they are refluxed for two hours. To the reaction mixture is added a solution of 2.36 g of 3,5-dichloro-1,2-benzoisoxazole in 20 ml of tetrahydrofuran under reflux, and they are refluxed for a further one hour. After cooling, the solvent is removed by distillation under reduced pressure, and ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then purified by a column chromatography [eluant:chloroform:methanol=20:1], to obtain 1.59 g of oily 3-(2-amino-2-methylpropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]#[N:9].B.C1COCC1>>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][NH2:9]
Reactant: N#CCc1ccsc1Br
Agent: B
Solvent: C1CCOC1
Product: NCCc1ccsc1Br
Yield: 91.2 %

Procedure:
2-(2-Bromothiophen-3-yl)acetonitrile (1.44 g, 7.13 mmol) was added slowly to a stirred solution of borane in THF (1.0 M, 15.7 mL, 15.7 mmol). The mixture was then heated to reflux for 14 h. The reaction mixture was allowed to cool to ambient temperature before residual borane was destroyed by careful dropwise addition of MeOH (10 mL). After the quench was complete, HCl gas was bubbled through the solution for 20 min and then the solvent was removed in vacuo. The residue was dissolved again in MeOH (20 mL) and concentrated twice more. The resulting white solid was dissolved in a biphasic mixture of dichloromethane and 1 N aqueous NaOH. The organic layer was separated, washed with brine, dried and concentrated to a colorless oil (1.34 g, 6.50 mmol, 92% yield). MS (M+H)+ 206/208.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([OH:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CCOCC>ClCCl>[CH:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC=O
Reaction time: 4 h
Yield: 90.1 %

Procedure:
An 18 g portion of pyridinium chlorochromate was slurried in 200 ml of dichloromethane. A solution of 15 g of oleyl alcohol in 200 ml of dichloromethane was added. This mixture was stirred for 4 hours, then poured into ether and filtered through hydrous magnesium silicate. The filtrate was evaporated, giving 13.42 g of the desired compound as a colorless liquid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=O)=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C[CH2:23][N:24]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CN>CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:24][CH3:23])=[O:21])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylic acid (116 mg, 0.404 mmol) in DMF (3 mL) was added EDCl (93 mg, 0.484 mmol), HOBt (60 mg, 0.444 mmol), NMM (0.111 mL, 1.01 mmol) followed by the methylamine solution (2 M in THF, 0.303 mL, 0.606 mmol) and the mixture stirred at ambient temperature for 16 hours. The solvents were removed in vacuo and the residue azeotroped with MeOH (10 mL). The resulting yellow gum was purified directly by Biotage 25M; loaded in 2% MeOH/CH2Cl2, and eluted with 2-7% MeOH/CH2Cl2 over 520 mL. Product not fully eluted so continued over another 300 mL to 10% MeOH/CH2Cl2 to give a solid that was then triturated with EtOAc, filtered and dried in vacuo to yield the title compound as a yellow solid, 78 mg, 65%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.11 (1H, s) 8.68 (1H, d, J=3.54 Hz) 7.90 (1H, s) 7.81 (1H, d, J=8.34 Hz) 7.57 (1H, d, J=8.34 Hz) 7.39 (1H, d, J=6.57 Hz) 4.56 (1H, d, J=4.29 Hz) 3.79 (1H, s) 3.36-3.50 (1H, m) 2.79 (3H, d, J=4.55 Hz) 1.80-2.03 (4H, m) 1.17-1.43 (4H, m); MS (API+) for C16H20N4O2 m/z 301.2 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:40]([N:48]1[CH:52]=[C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:50]=[N:49]1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 87.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66K) (150 mg, 0.227 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 59) (101 mg, 0.34 mmol) using sodium carbonate (73 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.011 mmol) in toluene/ethanol/water (3/5/1 ml) to afford 140 mg (88.0% yield) of the pure product after column purification using 5% methanol in dichloromethane as eluent. MS: m/z=704.3 (M+1).
Reaction SMILES: [N+](C1C=CC([N:10]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH2:26][C@@H:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@H:24]([N:34]([C:36](=[O:53])[N:37]([C:39]4[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=4)[CH3:38])[CH3:35])[CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[C:11](=O)[O-:12])=CC=1)([O-])=O.[CH3:54][NH:55][CH2:56][CH3:57]>C(#N)C.C(OCC)(=O)C>[F:48][C:45]([F:46])([F:47])[C:43]1[CH:44]=[C:39]([N:37]([CH3:38])[C:36]([N:34]([C@H:24]2[C@H:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:26][N:22]([C:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([NH:10][C:11](=[O:12])[N:55]([CH2:56][CH3:57])[CH3:54])[CH2:19][CH2:18]3)=[O:21])[CH2:23]2)[CH3:35])=[O:53])[CH:40]=[C:41]([C:49]([F:50])([F:51])[F:52])[CH:42]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N(C(=O)[O-])c3ccc([N+](=O)[O-])cc3)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCNC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(C)C(=O)N[C@H]1CC[C@H](C(=O)N2C[C@@H](N(C)C(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(F)cc3)C2)CC1

Procedure:
A solution of the compound (0.20 g) obtained in Example 261 and N-methylethanamine (0.11 mL) in acetonitrile (2.7 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 80→100% ethyl acetate/hexane) to give the title compound (0.15 g, 83%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3([CH3:20])OCC[O:16]3)[C:12]([CH3:21])=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:35])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH3:21])=[C:13]([C:15](=[O:16])[CH3:20])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(OC(C)C)c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1C1(C)OCCO1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C

Procedure:
A solution of 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (84 mg, 0.15 mmol) in 5 mL 1,4-dioxane is treated with 1 mL of aqueous 1N HCl at 22° C. for 2 hrs. The reaction is worked up and affords 1-(5-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-4-isopropoxy-2-methyl-phenyl)-ethanone (36). MS (ES+): 517.2 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(OCc2ccsc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccsc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
A mixture of 4-(thiophen-3-ylmethoxy)-benzaldehyde (3.61 g, 16.5 mmol) described in Manufacturing Example 77-1-1, nitromethane (4.44 mL, 82.5 mmol), ammonium acetate (2.54 g, 33 mmol) and acetic acid (36 mL) was stirred for 5 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.1 g).