Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][O:11]C(C)(C)C)[C:6]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][OH:11])[C:6]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(COC(C)(C)C)noc1C1CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(CO)noc1C1CCC1
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-{[(1,1-dimethylethyl)oxy]methyl}-4-isoxazole carboxylate (1.40 g, 5.48 mmol) in dichloromethane (250 mL) was added trifluoroacetic acid (250 mL, 3.25 mol). The solution was stirred for approximately 30 minutes and then concentrated. The residue was taken up with ethyl acetate and poured into water. The mixture was stirred as solid sodium carbonate was added until the pH was basic. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford ethyl 5-cyclobutyl-3-(hydroxymethyl)-4-isoxazolecarboxylate (848 mg, 69%). 1H-NMR (400 MHz, DMSO-d6) δ 5.27 (t, J=6 Hz, 1H), 4.63 (d, J=6 Hz, 2H), 4.21 (q, J=7 Hz, 2H), 4.18-4.08 (m, 1H), 2.33-2.27 (m, 4H), 2.10-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.26 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Yield: 78.4 %

Procedure:
A mixture of 2.6 g (0.010 mol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and 1.1 g (0.012 mol) of 1,2,4-triazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.3 g of colorless solid, m.p. 79°-86°. Recrystallization from a mixture of 25 ml of hexanes and 2 ml of ethyl acetate gave 1.1 g (38%) of the title compound: m.p. 92°-93°; ir (Nujol®) 1255, 1130, 1000, 825, 760, 695 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 3.9 (2H, s), 7.2-7.7 (9H, m), 7.8 (1H, s), 7.9 (1H, s); analysis for C17H19N3Si (mw 293.43):
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.CN(C)[CH:12]=[O:13]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:13][C:12]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: BrCc1ccccc1Br
Reactant: CN(C)C=O
Product: Brc1ccccc1COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture is stirred at room temperature and 37.2 g of 2-bromobenzyl bromide in solution in 15 ml of dimethylformamide are introduced at 5° C. After 2 hours at 20° C., the reaction medium is poured over ice-cold water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 36 g of oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].[CH3:20]O>>[Cl:8][C:7]1[C:2]([CH3:20])=[C:3]([CH:9]([NH2:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: NC(Cc1ccccc1)c1cccc(Cl)c1Cl
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(Cl)cccc1C(N)Cc1ccccc1
Yield: 75 %

Procedure:
To 2,3-dichlorobenzaldehyde (2.58 g, 19.2 mmol) in THF (5 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1M in THF, 23 mL). The ice-water bath was removed and the reaction mixture was stirred from 0° C. to room temperature for 2 h. The reaction mixture was then cooled back to 0° C. and benzylmagnesium chloride (1M in THF, 23 mL) was added. The reaction mixture was stirred from 0° C. to room temperature for 1 h then quenched with NH4Cl (Sat.), extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. HCl (1.25M in methanol) was added to the above residue until a pH of 2 to form the amine salt solution. Methanol was removed to give yellow solid. To the solid was added dichloromethane. The suspension was filtered and washed with dichloromethane to yield white solid as pure amine salt. The amine salt was converted to free amine by dissolving the white solid in methanol, basified with NaOH (1N) and extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated to produce 1-(3-chloro-2-methylphenyl)-2-phenylethanamine (3.26 g, 75%) as light yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.57-2.65 (m, 1H), 3.11-3.17 (m, 1H), 4.68-4.72 (m, 1H), 7.20-7.35 (m, 6H), 7.36-7.40 (m, 1H), 7.51-7.54 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]#[N:22])=[CH:16][C:15]=2[C:14]2[CH2:23][C@H:24]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][C:13]1=2)=[O:5])C.[Li+].[OH-].Cl>CCO.C1COCC1>[C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:12]([CH2:11][C:10]3[S:9][CH:8]=[N:7][C:6]=3[C:4]([OH:5])=[O:3])[C:13]3[CH2:25][C@@H:24]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][C:14]=3[C:15]=2[CH:16]=1)#[N:22]
Reactant: CCOC(=O)c1ncsc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3scnc3C(=O)O)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.8 %

Procedure:
Treat a mixture of 5-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-thiazole-4-carboxylic acid ethyl ester (3.745 g, 8.28 mmol) in EtOH (100 mL) and THF (40 mL) with 5 M LiOH (8.3 mL, 41.4 mmol) and stir at room temperature for 18 h. Add 5 N HCl (9 mL) bringing pH to 2. Concentrate the reaction mixture by rotavap, extract into EtOAc (3×330 mL), dry organics (MgSO4), filter, and concentrate to give 3.86 g (>100%) of 5-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-thiazole-4-carboxylic acid as a pale yellow solid. LC-ES/MS m/z 425 (M+1), 423 (M−H), TR=2.3 min.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Reactant: C=CCCNN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 230 mg (2.7 mmol) of 3-butenylhydrazine in 10.5 mL of THF was cooled to 0° C. and treated sequentially with 800 mg (2.4 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 370 μl (2.6 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 25 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 99.5:0.5) to give the title compound 85. 1H-NMR (DMSO-d6) δ 3.17 (d, J=5.2 Hz, 2H), 3.31 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.04 (d, J=10.3 Hz, 1H), 5.13 (d, J=17.1 Hz, 1H), 5.77-5.88 (m, 1H), 7.35 (t, J=8.3 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 8.15 (s, 1H), 10.19 (s, 1H). Mass Spectrum (ESI) m/e=385.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[O:16][CH2:17][CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH:4][CH:3]=1.Cl.[OH-:29].[Na+]>C(O)C.O>[CH3:21][C:20]([NH:19][CH2:18][CH2:17][O:16][C:15]1[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=1[CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:29])[NH:4]2)([CH3:23])[CH3:22]
Reactant: [OH-]
Reactant: CC(C)(C)NCCOc1ccccc1CCCc1cccc2[nH]cc(Cl)c12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCOc1ccccc1CCCc1cccc2c1CC(=O)N2
Reaction time: 19 h

Procedure:
A mixture of 3.76 g of the product of Step A in 94 ml of 94% ethanol and 94 ml of aqueous N hydrochloric acid was stirred under an inert atmosphere for 19 hours and was diluted with water and iced. The mixture was made alkaline by addition of 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.18 g of 1,3-dihydro-4-[3-(2-{2-[1,1-dimethylethylamino]-ethoxy}-phenyl)-propyl]-2H-indol-2-one.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 hours. The solvent was removed by rotary evaporation to afford the title compound (31 mg, 72% yield). 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.36 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H23F3N3O: 378.18; Observed: 378.5 (M++1) [corresponding to the free base].
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:30][O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 20 h

Procedure:
35 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid was dissolved in 0.4 ml of N,N-dimethylformamide and mixed with 29 mg of cesium carbonate and 50 μl of methyl iodide. It was stirred for 20 hours, then concentrated by evaporation in a vacuum and chromatographed on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.CS(O[CH:26]1[CH2:29][N:28]([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:28]2[CH2:29][CH:26]([N:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]4[N:13]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:12]=[CH:11][CH:10]=4)=[N:6]3)[CH2:27]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(C2CN(C(c3ccccc3)c3ccccc3)C2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 9.6 %

Procedure:
A suspension of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (200 mg), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (354 mg) and cesium carbonate (729 mg) in DMF (5 mL) was stirred at 100° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:21])[CH2:11]2)[CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[F:40])#[N:30].C([O-])(O)=O.[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.O1CCOCC1>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:21])[CH2:11]3)[CH:3]=2)=[CH:33][C:32]=1[F:40])#[N:30]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: [Na+]
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To cis-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (204 mg, 0.486 mmol) and (4-cyano-3-fluorophenyl)boronic acid (104 mg, 0.632 mmol) were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube for 5 minutes. Pd(Ph3P)4 (28 mg, 0.024 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured onto water. The precipitate formed was filtered. EtOAc was added to the solid in the filter, and the mixture was stirred gently with a spatula until the solid dissolved. The resulting solution was filtered, and the filtrate was dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc/Hexanes) afforded the title compound (152 mg) as a yellow foam. LC-MS (ES) m/z=505 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][C:35]#[CH:36])[C:28]=2[CH:37]=1.C(O)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][C:35]#[C:36][C:16]3[S:17][C:13]4[N:12]5[C:19]([CH3:22])=[N:20][N:21]=[C:11]5[CH2:10][N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:14]=4[CH:15]=3)[C:28]=2[CH:37]=1
Reactant: C#CCN1C(=O)COc2ccc(Cl)cc21
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)COc4ccc(Cl)cc43)cc1C(c1ccccc1Cl)=NC2
Reaction time: 72 h

Procedure:
The titIe compound was prepared by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 6-chloro4-(2-propynyl)-2H-1,4-benzoxazin 3(4H)-one [ref. p. Rao et al. Indian J. Chem. 24 B, 1120 (1985)]as described in Example 37 but the reaction time was extended to 72 hours. The product was isolated by chromatography over the 100 -fold amount of silica gel (Merck 230-400 mesh) using 10% (v/v) of ethanol in methylene chloride. Crystallization of the residue obtained after evaporation of the combined clean fractions from ethyl acetate gave colorless crystals of 6-chloro-4-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 a][1,4]diazepin-2-yl]-2-propynyl}-2H-1,4-benzoxazin-3(4H)-one with m.p. 202°-205°.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([O:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg), N,N-Diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (80 mg, 0.26 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (55 mg, 10% over two steps) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.57-7.60 (m, 2H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.94 (m, 1H), 1.62-1.82 (m, 8H), 1.24-1.35 (m, 2H), 1.24 (s, 9H); LC-MS (ESI) m/z 545 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]=[C:18]=[O:19])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:18](=[O:19])[NH:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2
Reactant: O=C=Nc1cccnc1
Reactant: Brc1ccc2c(c1)CCN2
Product: O=C(Nc1cccnc1)N1CCc2cc(Br)ccc21
Yield: 72 %

Procedure:
5-Bromoindoline (D50) (0.5 g, 2.5 mmol) was treated with 3-pyridylisocyanate as in the method of Example 1. The product was filtered-off and recrystallised from methanol/water to afford the title compound (0.58 g, 72%) as a white crystalline solid m.p. 220° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=4)[NH:8][N:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.O>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]1[C:14]2[N:15]([C:11]([C:9]3[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=3)=[CH:12][N:13]=2)[C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:29]([F:31])([F:30])[F:32])=[CH:18][CH:17]=2
Reactant: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Reaction time: 24 h

Procedure:
A solution of 5-[4-(3-Hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (0.12 mmol; 54 mg), LiOH (0.13 mmol; 3 mg), in THF/H2O (0.2+0.1 mL), was stirred at 40° C. overnight. Further LiOH (0.26 mmol; 6 mg) was added, and the reaction was continued at 50° C. another 24 hr. Concentration, and washing with water affords the title compound, as a white solid, lithium salt (51 mg; 0.12 mmol; 100%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].[C:26](Cl)(=[O:28])[CH3:27].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:26]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
29.9 g (0.09 mol) of III-15 was dissolved in a mixed solution of 150 ml of toluene and 50 ml of pyridine, followed by addition of 9.42 g (0.12 mol) of acetyl chloride at 15°-20° C. over a period of 2 hours. The mixture was maintained at the same temperature for 2 hours and then at 40°-45° C. for another 2 hours. The reaction mixture was cooled below 10° C. and added with 300 ml of 3N hydrochloric acid. After separating the liquid phase, the organic layer was washed with water, 5% sodium hydrogencarbonate and water successively in that order and concentrated under reduced pressure. The residue was purified by column chromatography to give 33.0 g (98% yield) of benzyl 4'-(1-acetoxyethyl)-4-biphenylcarboxylate (IV-15).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(Br)c1
Temperature: 60 °C
Yield: 81 %

Procedure:
To a solution of 7.0 g of 3-bromophenol and 7.8 g of ethyl 4-bromobutyrate in 50 ml of DMF is added 11.2 g of K2CO3. The mixture is heated at 60° C. for 1 day and then poured into an ice-water mixture. This mixture is extracted with ether, and the ether extract is washed with water and dried over MgSO4. After filtration and concentration, a solution of 9.3 g of the ethyl 4-(3-bromophenoxy)butyrate obtained in 100 ml of THF is cooled to 0° C.; and 130 ml of a 1.5M solution of DIBAL-H in toluene is added dropwise. The reaction is stirred for 1 hour at 0° C. and 2 hours at room temperature, following which the reaction mixture is poured into a mixture of ice/3N HCl and extracted with ether. The ether extract is washed with water and dried over MgSO4. Filtration and concentration yields 4-(3 -Bromophenoxy)butan-1-ol.