Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[Li+].CCC[CH2-].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](Cl)(C)C>C1COCC1>[CH3:1][Si:2]([N:3]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
In 75 mL of anhydrous THF were added 17.29 mL (75 mmol) of hexamethyldisilazane and 30 mL (75 mmol) of N-butyllithium (2.5M in hexane) at 0° C. under nitrogen. After stirring for one hour, 7.65 mL (75 mmol) of benzaldehyde was added at room temperature, and the mixture was refluxed for 3 hours. Then, 9.52 mL (75 mmol) of freshly distilled trimethylsilyl chloride was added with a syringe. The mixture was refluxed for 2 hours. A white precipitate formed during this process. The reaction mixture was then cooled to room temperature and the liquid layer was transferred with a syringe to a distillation flask under nitrogen. The solvent was evaporated in vacuo, and the oily residue was distilled under reduced pressure (68° C./1 mm Hg) to give pure N-trimethylsilylbenzaldimine as a pale yellow oil (10.6 g, 80%) having the identification data shown below:
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]1([N:22]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27](C(O)=O)=[CH:28]3)=[N:23]2)[CH2:21][CH2:20][CH2:19]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(N(CC)CC)C>[CH:18]1([N:22]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([NH2:15])=[CH:28]3)=[N:23]2)[CH2:21][CH2:20][CH2:19]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2nn(C3CCC3)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1ccc2nn(C3CCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Diphenylphosphoryl azide (4.15 mL) and triethylamine (3.76 mL) were added to a solution of 2-cyclobutyl-2H-indazole-5-carboxylic acid obtained in the above-described Step 1 (3.26 g) in 1,4-dioxane (50 mL), and the reaction solution was stirred at room temperature for 2 hours and 20 minutes. Thereafter, 1 N hydrochloric acid (100 mL) was added to the reaction solution, and then the reaction solution was stirred at 100° C. for 30 minutes. The reaction solution was cooled to room temperature, and potassium carbonate (14 g) was slowly added. The reaction solution was extracted with ethyl acetate, and then the organic layer was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-cyclobutyl-2H-indazol-5-amine as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)CCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C1COCCN1
Solvent: CCCCO
Product: Fc1ccc(-c2nc(Nc3ccc(OC(F)(F)F)cc3)cc(N3CCOCC3)n2)cc1
Temperature: 30 °C
Yield: 55.6 %

Procedure:
A mixture of compound [6-chloro-2-(4-fluoro-phenyl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine (0.25 g, 0.65 mmol) and morpholine (0.113 g, 8.20 mmol) in n-butanol (10 mL) was refluxed for 12 hours under nitrogen. The mixture was then cooled to temperature in the range of 20-40° C. and evaporated under reduced pressure. The crude compound was passed through the silicagel by using 20% ethylacetate—petroleum ether to afford the compound [2-(4-fluoro-phenyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine (0.157 g, 56%) as off white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1.[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[N:35][S@:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH:31]=[CH:32][CH:33]=1)#[N:27]>C1COCC1>[C:26]([C:28]1[CH:29]=[C:30]([CH:34]([NH:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: CC(C)(C)[S@](=O)N=Cc1cccc(C#N)c1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)S(=O)NC(c1cccc(C#N)c1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, diisopropylamine (1.647 mL, 11.75 mmol) was dissolved in anhydrous THF (5 mL) and the solution was cooled to 0° C. nBuLi (2.5 M solution in hexanes, 4.406 mL, 11.02 mmol) was added and the reaction was stirred at 0° C. for 15 min. A solution of 3-(pyridin-3-ylmethyl)pyridine (1.250 g, 7.34 mmol) in anhydrous THF (15 mL) was slowly added and the reaction became dark red. After 15 min, a solution of (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide (1.893 g, 8.08 mmol) in anhydrous THF (10 mL) was added. The reaction was stirred at 0° C. for 2.5 h and was quenched with saturated aqueous NH4Cl (150 mL). The product was extracted with ethyl acetate (4×100 mL). The combined organics were dried over Na2SO4, filtered, concentrated in vacuo and purified by reverse phase HPLC (DeltaPak C18, 47 mm×300 mm, 15 □, 0% CH3OH/100% H2O to 100% CH3OH/0% H2O). The fractions containing each diastereomer were separately combined and concentrated in vacuo to afford N-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-methylpropane-2-sulfinamide as two diastereomers;
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[NH:14][C:15](=[O:24])[N:16]([C:17]4[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=4)[C:7]=3[C:6]=2[CH:5]=1.I[CH3:26]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[N:14]([CH3:26])[C:15](=[O:24])[N:16]([C:17]4[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=4)[C:7]=3[C:6]=2[CH:5]=1
Reactant: CI
Reactant: Cc1nn(C)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaOH (0.568 g, 14.19 mmol) and tetrabutylammonium bromide (0.229 g, 0.710 mmol) were added to a mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 3.10 g, 7.100 mmol) in DCM (108 ml) and H2O (54 ml) and stirred at rt for 5 min. Then iodomethane (1.52 ml, 24.1 mmol) was added and the mixture was stirred for 14 h at rt. Iodomethane (0.4 ml, 6.35 mmol) was added and the RM was stirred at rt for 23.5 h. Then the RM was extracted with DCM (2×), washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH 0%-4.5%) to give the title compound as a brownish solid (HPLC: tR 2.37 min (Method A); M+H=374 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.08 (s, 1H), 7.91-7.99 (m, 1H), 7.64-7.71 (m, 1H), 7.41-7.47 (m, 1H), 3.90 (s, 3H), 3.55 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[CH3:30]>O1CCCC1>[F:22][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: COc1ncnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c12
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(OC)c34)c2F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 58 %

Procedure:
To (3-amino-2,6-difluoro-phenyl)-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (36, 30.0 mg, 0.0986 mmol) 1.0 mL of tetrahydrofuran and pyridine (23.9 μL, 0.296 mmol) are added, followed by 4-ethyl-benzenesulfonyl chloride (59, 40.4 mg, 0.197 mmol). The reaction vial is stirred at room temperature for 5 days, then extracted by adding aqueous saturated sodium chloride and ethyl acetate. The organic layer is washed with water, then sodium bicarbonate, then brine, and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1008, 27 mg). MS (ESI) [M+H+]+=473.0.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH:5]([NH:33][C:34]([NH:36][C:37]1[NH:38][N:39]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH:41]=1)=[O:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[C:9]([F:32])[CH:8]=1)C.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.C(OC(C(N)CC1C=CC(C2N=C(C3C=CC(NC(=O)OC(C)(C)C)=CC=3)ON=2)=C(F)C=1)=O)C.FC1C=CC(C2C=C(N)NN=2)=CC=1>ClCCl.C([O-])(O)=O.[Na+].N1C=CC=CC=1>[C:28]([O:27][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:33][C:34]([NH:36][C:37]4[NH:38][N:39]=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)[CH:41]=4)=[O:35])[C:4]([OH:49])=[O:3])=[CH:8][C:9]=3[F:32])[N:17]=2)=[CH:23][CH:22]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NC(=O)Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: CCOC(=O)C(N)Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1
Agent: Nc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3ccc(CC(NC(=O)Nc4cc(-c5ccc(F)cc5)n[nH]4)C(=O)O)cc3F)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluoro-phenyl}-2-{3-[5-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-ureido}-propionic acid ethyl ester. To a solution of bis(trichloromethyl)carbonate (189 mg, 0.66 mmol) in dichloromethane (12 mL) and saturated aqueous NaHCO3 (0.8 mL) was slowly added a solution of tert-butyl 4-(3-(4-(2-(ethoxycarbonyl)-2-aminoethyl)-2-fluorophenyl)-1,2,4-oxadiazol-5-yl)phenylcarbamate (300 mg, 0.66 mmol) in dichloromethane (12 mL) at 0° C. The reaction mixture was then stirred at room temperature for 1 hr. TLC showed the reaction was completed. Saturated aqueous NaHCO3 (18 mL), pyridine (0.3 mL), and 3-(4-fluorophenyl)-1H-pyrazol-5-amine (177 mg, 1 mmol) were added to the reaction mixture. The resulting mixture was then stirred overnight. TLC showed the reaction was completed. The layers were separated and the aqueous portion was extracted with dichloromethane (2×50 mL). The combined organic layers were washed sequentially with aq. HCl solution (1N, 2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (343 mg, 51% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]([CH3:15])=O.N1CCCCC1>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:13]([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 5-fluoro-1,3-dihydro-indol-2-one (2.84 g, 20 mmol), acetone (2.2 mL, 30 mmol) and piperidine (0.8 mL, 8 mmol) in methanol (100 mL) was heated to reflux for 16 hours. Then the reaction mixture was allowed to cool to room temperature. The solid was collected by filtration, washed with methanol (20 mL) and dried in vacuo to afford 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 68%) as powder.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.CN(C=O)C>C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)[CH:26]=[CH:25][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: O=c1[nH]ccc2c3[nH]c(-c4ccccc4Cl)nc3c3ccc(Br)cc3c12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3c(c2)c2c(=O)[nH]ccc2c2[nH]c(-c4ccccc4Cl)nc32)cn1
Temperature: 130 °C

Procedure:
9-Bromo-2-(2-chlorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one (30 mg, 0.071 mmol), lithium chloride (6 mg, 0.14 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30 mg, 0.14 mmol), and tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.0071 mmol) were placed in a microwave tube. Na2CO3 (2 M, 0.25 mL) and DMF (1 mL) were added and the solution was heated in the microwave at 130° C. for ten minutes. The solution was cooled to ambient temperature diluted with ethyl acetate and Na2CO3 (2 M). The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude residue was purified on silica gel to afford the title compound. 1H NMR (500 MHz, DMSO-d6, δH) 11.56 (bs, 1 H), 10.49 (bs, 1 H), 8.56-8.45 (m, 1 H), 8.18 (s, 1 H), 7.90-7.87 (m, 3 H), 7.69 (d, 1 H, J=7.2 Hz), 7.58-7.54 (m, 3H), 7.34-7.28 (m, 1 H): [M+1]+ 426.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])[N:4]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:34][N:35]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)C(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([N:35]([CH3:34])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:17]=2)[N:4]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc[n+]1[O-]
Reactant: CN(Cc1ccccc1)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N(C)Cc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
20 g (77.1 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate N-oxide, 15 g (116 mmol) of diisopropylethylamine and 46.2 g (308.2 mmol) of sodium iodide were suspended in 200 ml of acetonitrile and stirred at room temperature for 15 minutes. To this mixture, 21.2 g (115.4 mmol) of N-methyl-N-benzylcarbamoyl chloride dissolved in 20 ml of acetonitrile was added at room temperature. The mixture was refluxed. Foaming started at a temperature slightly lower than the boiling point, and such foaming terminated in about 30 minutes. The reaction was continued for further 10 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and then purified by silica gel column chromatography to obtain the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]=1[Cl:20])[CH2:2][CH2:3][CH3:4].[NH2:21][C@@H:22]([CH2:26][OH:27])[CH:23]([CH3:25])[CH3:24].C(O)(=O)C.C([BH3-])#N>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH2:18][NH:21][C@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:26][OH:27])[CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]=1[Cl:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2cccc(C=O)n2)cc1Cl
Reactant: CC(C)[C@@H](N)CO
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CCCCOc1ccc(-c2cccc(CN[C@@H](CO)C(C)C)n2)cc1Cl
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of Example 262A (0.500 g, 1.73 mmol) in MeOH (10 mL) at ambient temperature was added D-valinol (0.20 mL, 1.7 mmol), acetic acid (0.40 ml, 6.9 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.00 g). After 2 hours, the mixture was filtered and concentrated. The residue was partitioned between 1N HCl and ethyl acetate. The organic layer was discarded. The aqueous layer made basic with 1N NaOH and extracted with ethyl acetate. The EtOAc extract was dried (Na2SO4) and concentrated to give 420 mg (65%) of the title compound. MS (DCI+) m/z 377 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=2.3 Hz, 1H), 7.87 (dd, J=8.6, 2.2 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.00 (d, J=4.4 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 4.06-3.92 (m, 2H), 3.69 (dd, J=10.8, 4.0 Hz, 1H), 3.47 (dd, J=10.8, 6.8 Hz, 1H), 2.51 (td, J=6.7, 4.0 Hz, 1H), 1.95-1.78 (m, 4H), 1.63-1.46 (m, 2H), 0.99 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([NH:25]CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1

Procedure:
To a solution of the title compound of Example 48 (the slower moving enantiomer), (−)4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzyl-amino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.07 g, 1.64 mmol) in dichloromethane (6.5 ml) was added trifluoroacetic acid (TFA, 6.5 ml) slowly at 0° C. The reaction mixture was stirred at ambient temperature for 80 minutes after which time it was diluted with DCM (10 ml) and was poured into a chilled aqueous solution of potassium carbonate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (1.5:98.5:0.15) as the eluents to afford the title compound as a white solid (0.588 g, 1.11 mmol, 68% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
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:33][C:34]4[CH:35]=[CH:36][C:37]5[S:41][CH:40]=[N:39][C:38]=5[CH:42]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:35]=[CH:36][C:37]4[S:41][CH:40]=[N:39][C:38]=4[CH:42]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3scnc3c2)n1
Temperature: 120 °C
Yield: 51.7 %

Procedure:
A microwave vial (5 mL) was charged with N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]thiazol-5-amine (45.0 mg, 0.060 mmol) in trifluoroacetic acid (Aldrich, St. Louis, Mo.) (1.50 mL, 20.19 mmol). The mixture was heated in a microwave at 120° C. for 45 min, and then the solvent was removed in vacuo. The residue was purified with reverse phase preperative HPLC using a Phenomenex Gemini columb, 5 micron, C18, 100 Å, 150×30 mm (eluting with 10% to 55% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 45 mL/min) to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]thiazol-5-amine (16.0 mg, 0.031 mmol, 52.3% yield) as a yellow solid after solvent removal and neutralization. 1H NMR (400 MHz, d6-DMSO) δ 12.23 (1H, s); 9.35 (1H, s); 8.90 (1H, d, J=1.8 Hz); 8.76 (1H, d, J=2.0 Hz); 8.34 (1H, d, J=2.0 Hz); 8.06 (1H, d, J=8.8 Hz); 7.91 (1H, br. s.); 7.72-7.86 (2H, m); 3.53 (2H, s); 3.12 (4H, d, J=4.1 Hz); 2.87 (3H, s); 2.48 (7H, br. s.). m/z (ESI, +ve ion) 512 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]=1)=[O:5])[CH3:2].[N+:18]([O-])([O-:20])=[O:19].[K+].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)[CH2:9][CH2:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NCCc2cc(OC)ccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C1=NCCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 35 g of 6-methoxy-3,4-dihydroisoquinoline-1-carboxylic acid ethyl ester in 250 ml of concentrated sulphuric acid was added, at 0° C., 21 g of KNO3 in portions over 5 min. The reaction mixture was stirred for 1 h and then poured with stirring onto 500 g of NaHCO3. The resulting mixture was diluted with 2 l of ice-water and the product was extracted into dichloromethane. The organic layer was washed with water, dried, concentrated and the residue was treated with diethyl ether, to provide 34 g of 6-methoxy-7-nitro-3,4-dihydroisoquinoline-1-carboxylic acid ethyl ester, 5d MS-ESI: [M+1] 279.07. NMR (CDCl3) δ 1.42 (t, 3, OCH2CH3), 2.82 (t, 2, CH2), 3.94 (t, 2, CH2), 4.46 (q, 2, OCH2CH3), 6.92 and 8.44 (2×s, 2, Ar—H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1.[NH3:12]>O1CCCC1>[NH2:12][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1
Reactant: N
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N)c(Cl)c1

Procedure:
1.9 g (10 mmol) of 2,3-dichloro-5-acetylpyridine are heated at 170° C. in a mixture of 80 ml of tetrahydrofuran and 20 ml of concentrated aqueous ammonia in an autoclave for 8 hours. After the tetrahydrofuran has been evaporated off, the residue is diluted with water and the mixture is brought to pH 5 and extracted with ethyl acetate.