Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][OH:15])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(CO)OC2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC12CCC(Cc3ccc(Cl)cc3)C1(COS(C)(=O)=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 6 ml of toluene, 300 mg of Compound 8a-1 synthesized in Production Example 19 was dissolved. To the solution thus obtained, 235 μl of triethylamine and 122 μl of methanesulfonyl chloride were added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was carried out. The organic layer thus extracted was washed with an aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 378.3 mg of Compound 9a-1-1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](S(C)(=O)=O)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4].[NH3:27].CO>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:27])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4]
Reactant: N
Reactant: CCOc1c(Cl)ccc(-c2nc(C(=O)OC)c(Cl)c(S(C)(=O)=O)n2)c1F
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1c(Cl)ccc(-c2nc(N)c(Cl)c(C(=O)OC)n2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
5-Chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-6-methane-sulfonylpyrimidine-4-carboxylic acid methyl ester (350 mg, 0.83 mmol) was dissolved in 10 mL p-dioxane and 7N ammonia in methanol (0.43 mL, 3 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was partitioned between ethyl acetate and water and the organic phase was dried and concentrated. The product was purified by column chromatography to yield 6-amino-5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-pyrimidine-4-carboxylic acid methyl ester (160 mg, 54% yield): 1H NMR (CDCl3): δ 7.65 (dd, 1H), 7.24 (dd, 1H), 5.67 (br s, 2H), 4.22 (q, 2H), 4.03 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[N:20]1([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][N:23]2[CH2:22][CH2:21][N:20]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that 4,4-bis(4-fluorophenyl)butyl bromide was used instead of 3,3-diphenylpropyl bromide and the compound prepared in step (a) of Example 80 was used instead of ethyl 3-piperazin-1-yl-benzoate. Thus, ethyl 4-[4-[4,4-bis(4-fluorophenyl)-1-butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1O.CS(Cl)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: COc1cccc2c1CC(C)(C)C2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(C)(C)C2N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (10 ml) is added to a stirred solution of the 1-hydroxy indane of Step 2. above (8.4 g) in methylene chloride (190 ml) at RT under nitrogen; the mixture is cooled to 0° C. and methanesulfonyl chloride (4 ml) is added. The mixture is stirred for three hours at RT, cooled to 0° C., piperidine (128 ml) added and stirred at RT overnight. Sat'd aq. sodium bicarbonate is added to the mixture and the organic phase separated, washed with aq. sodium bicarbonate, sat'd NaCl, dried, filtered and the filtrate evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH:53]1([C:58](Cl)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:58]([CH:53]5[CH2:57][CH2:56][CH2:55][CH2:54]5)=[O:59])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: O=C(Cl)C1CCCC1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(C1CCCC1)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Cyclopentane carbonyl chloride (80 μl, 0.6 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E43); MS (ES+) m/e 397 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9](F)[CH:10]=2)[N:5]=1)[CH3:2].Cl.[OH:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([N:29]3[CH:30]=[C:26]([CH2:25][OH:24])[N:27]=[CH:28]3)[CH:10]=2)[N:5]=1)[CH3:2]
Reactant: OCc1c[nH]cn1
Reactant: CCOC(=O)c1cc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Temperature: 120 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of ethyl 2-ethoxy-6-fluoro-7-nitroquinoline-3-carboxylate (1.00 g, 3.24 mmol) in acetonitrile (10 ml) were added 4-(hydroxymethyl)imidazole hydrochloride (2.18 g, 16.2 mmol) and successively triethylamine (3 ml), and the mixture was stirred for 16 hours at 120° C. in a sealed tube under shading. After cooling, solvent was distilled off and the residue was submitted to silica gel column chromatography [dichloromethane-methanol(50:1→20:1)] under shading to obtain 583 mg of title compound as light brown powder. Yield 47%. 1H-NMR(DMSO-d6, δ): 1.35(3H,t,J=7.3 Hz), 1.42(3H,t,J=7.3 Hz), 4.38 (2H,q,J=7.3 Hz), 4.42(2H,d,J=6.8 Hz), 4.58(2H,d,J=7.3 Hz), 5.05(1H, t,J=5.4 Hz), 7.27(1H,s), 7.88(1H,s), 8.39(1H,s), 8.50(1H,s), 8.87 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: CSc1ccc(CC(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC)c(Cl)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid (7.00 g, 32.30 mmol) in methanol (150 mL) was treated slowly with concentrated sulfuric acid (2.8 mL, 52.65 mmol). The resulting reaction mixture was heated under reflux for 1.5 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (500 mL). The organic phase was successively washed with a saturated aqueous sodium bicarbonate solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.41 g, 99.4%) as a light yellow oil: EI-HRMS m/e calcd for C10H11ClO2S (M+) 230.0168, found 230.0166.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:15]=1)=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]=2[CH3:10].[H-].[Na+].[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29]Br.C(OC(C)C)(C)C>CN(C)C=O>[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][N:15]1[C:5]2=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: BrCc1ccc2ccccc2c1Br
Reactant: COC(=O)c1cc(C)c2[nH]c(C)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc4ccccc4c3Br)c2n1
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To a suspension of methyl 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (625 mg) in N,N-dimethylformamide (6 ml) was added sodium hydride (70% in mineral oil, 125 mg) under ice-cooling, and the mixture was stirred for 30 min. 1-Bromonaphthalen-2-ylmethyl bromide (1.05 g) was added to the reaction mixture, and the mixture was stirred under ice-cooling for 3 hr. Diisopropyl ether (12 ml) was added to the reaction mixture and the precipitate was collected by filtration to give the objective compound (1.35 g) as a white powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1C(=O)C[S:8][CH:7]1[CH3:12].[CH3:13]I.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[CH2:26]1[CH2:30][O:29]C[CH2:27]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:30](=[O:29])[C:26]([CH3:27])([CH3:13])[S:8][CH:7]1[CH3:12]
Reactant: CC1SCC(=O)N1CCCCBr
Reactant: C1CCOC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: CC1SC(C)(C)C(=O)N1CCCCBr
Temperature: -40 °C

Procedure:
To a −73° C. solution of 3-(4-bromobutyl)-2-methyl-4-thiazolidinone (6.00 g), methyliodide (10.99 g) and THF (50 ml) under nitrogen was added lithium bis(trimethylsilyl)amide (0.0500 mol) in THF (50 ml) at a rate to maintain the internal temperature below −55° C. The resulting solution was stirred at <−55° C. for 10 mintues, allowed to warm to −40° C., and at which temperature 1 N HCl (250 ml) was added. The aqueous mixture was extracted with 25% benzene/ether (3×125 ml). The combined extracts were washed with brine (200 ml), dried (Na2SO4), and concentrated to a liquid which was chromatographed on silica gel yielding 5.07 g of a liquid. The liquid was distilled to give 3.80 g of a clear liquid, b.p. 109-114° C. at 0.20 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O.ClCCl>ClCCl>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of the product from step 4 (0.8 g, 2.63 mmol) in dichloromethane (7.6 mL) was added triethylamine (0.78 mL, 5.60 mmol) and t-butyl bromoacetate (0.45 mL, 3.05 mmol). The resulting solution was stirred at 30° C. overnight. The reaction mixture was poured into water/dichloromethane (50 mL/50 mL). The crude residue was extracted into dichloromethane. The organic portion was washed with water (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.83 g, 75%);
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)([CH3:22])[CH3:21])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)([CH3:22])[CH3:21])=[CH:24][CH:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(OS(=O)(=O)c2ccccc2)cc1

Procedure:
A solution of benzenesulphonyl chloride (0.51 g) in dichloromethane (5 ml) was added in portions over 5 minutes to a solution of 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenol (0.75 g) and triethylamine (0.29 g) in dichloromethane (5 ml) at 0° C. with stirring. The mixture was stirred at ambient temperature for 3 hours then diluted with dichloromethane and washed with water. The organic layer was separated, dried and evaporated. The residue was purified by flash column chromatography on silica using methanol as the mobile phase to give 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl benzenesulphonate as an oil.
Reaction SMILES: [OH-:1].[CH2:2]([N+](C)(C)C)[C:3]1[CH:8]=CC=C[CH:4]=1.[OH:13][CH2:14][CH2:15][C:16]1[CH:44]=[CH:43][C:19]([CH2:20][CH2:21][N:22]2[CH2:42][CH2:41][C:25]3([O:30][CH2:29][CH2:28][N:27]([C:31]([C:33]4[N:34]=[C:35]([CH:38]([CH3:40])[CH3:39])[S:36][CH:37]=4)=[O:32])[CH2:26]3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH:38]([C:35]1[S:36][CH:37]=[C:33]([C:31]([N:27]2[CH2:26][C:25]3([CH2:41][CH2:42][N:22]([CH2:21][CH2:20][C:19]4[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][O:13][CH2:16][CH2:15][C:14]([O:13][C:3]([CH3:2])([CH3:4])[CH3:8])=[O:1])=[CH:44][CH:43]=4)[CH2:23][CH2:24]3)[O:30][CH2:29][CH2:28]2)=[O:32])[N:34]=1)([CH3:40])[CH3:39]
Reactant: [OH-]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Reactant: C[N+](C)(C)Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Benzyltrimethylammonium hydroxide (40% in methanol, 0.031 mL) was added to a solution of (9-(4-(2-hydroxyethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 1, step c] (0.62 g) in toluene (20 mL). The solvent was removed under reduced pressure and the residue azeotroped with toluene. The resultant liquid, which was just mobile with traces of toluene, was treated dropwise with tert-butyl acrylate (0.225 g). The reaction mixture was stirred at 20° C. for 18 hours. The mixture was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.550 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[N:11][C:5]2=[N:4][C:3]=1Cl.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[N:11][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nc2cccnc2nc1Cl
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1nc2cccnc2nc1-c1ccccc1
Temperature: 25 °C

Procedure:
2,3-Dichloropyrido[2,3-b]pyrazine (step 2) (500 mg, 2.5 mmol) in dry dioxane (10 ml), under nitrogen was treated with phenylboronic acid (305 mg, 2.5 mmol), potassium carbonate (691 mg, 5 mmol) in water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (144 mg, 0.125 mmol). The resulting mixture was heated using microwave radiation at 100° C. for 1 hour. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (×3). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with 0-30% EtOAc in iso-hexane to afford the titled compound as a solid;
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-:30].[K+].O>C(O)(C)(C)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:21]=[CH:20][C:19]([C:22]([NH2:23])=[O:30])=[CH:18][C:17]=4[CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C#N)cc1C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(C(N)=O)cc1C
Temperature: 800 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 6-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-5-methylpyridine-3-carbonitrile (100 mg, 0.245 mmol) and potassium hydroxide (41 mg, 0.735 mmol) in tert-butanol (2 mL) was stirred at 800° C. for 2 hr. After cooling, water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from ethyl acetate/isopropyl ether to afford the title compound (70 mg, 67%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:15]2([CH2:19][CH2:18][C:17](=[S:20])[NH:16]2)[CH:13]2[CH2:14][CH:10]1[CH2:11][CH2:12]2.[CH3:21][I:22]>CC(C)=O>[IH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:15]2([CH2:19][CH2:18][C:17]([S:20][CH3:21])=[N:16]2)[CH:13]2[CH2:14][CH:10]1[CH2:11][CH2:12]2
Reactant: CI
Reactant: COc1ccccc1C1C2CCC(C2)C12CCC(=S)N2
Solvent: CC(C)=O
Product: COc1ccccc1C1C2CCC(C2)C12CCC(SC)=N2
Product: I

Procedure:
56 mmoles of 3-(2-methoxyphenyl)-spiro[bicyclo[2.2.1]-heptane-2,2'-pyrrolidine]-5'-thione and 7 ml of methyl iodide in 220 ml of acetone are refluxed for 10 minutes. After cooling the mixture, the residue is filtered off. Pale yellow compound of melting point 228° C. (decomposition)
Reaction SMILES: [CH3:1][C@@H:2]([CH2:45][CH3:46])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:18]=2)[C:12]1=[O:44])[C:4]([O:6]C(C)(C)C)=[O:5].ClCCl>FC(F)(F)C(O)=O>[CH3:1][C@@H:2]([CH2:45][CH3:46])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:18]=2)[C:12]1=[O:44])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O

Procedure:
A solution of the product of Example 286B (0.35 g) in trifluoroacetic acid:dichloromethane (3 mL, 2:1) was stirred at 25° C. for 2 hrs. The solvents were evaporated and the residue was directly used for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]([O-:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[H][H]>[Ni].C(OC(=O)C)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH:13][CH:12]([CH3:14])[CH2:11][C:10]([O-:16])=[O:15]
Reactant: [H][H]
Reactant: CC(=O)CC(=O)[O-]
Agent: [Ni]
Solvent: CC1(C)OCC(CO)O1
Solvent: CCOC(C)=O
Product: CC(O)CC(=O)[O-]
Temperature: 60 °C
Reaction time: 7 h
Yield: 91.8 %

Procedure:
A Zipperclave Autoclave (Autoclave Engineers) was charged with ethylacetate (2.4 L), solketal acetoacetate from Example 1 (609.5 g, 2.82 mole) and Raney Nickel (25 g, W-2 grade, PM-77, water wet) under an inert atmosphere of nitrogen. The nitrogen was displaced with hydrogen to a pressure of approximately 1100 psi. The reaction mixture was then heated with vigorous stirring (1500 rpm) at 60° C. for approximately seven hours. A small (ca. 5 ml) sample of the reaction mixture was removed from the reactor, filtered through celite and concentrated in vacuo. Proton NMR analysis revealed that roughly 2 mole % of unreduced acetoacetate remained. The crude reaction mixture was then heated at 60° C. and 1000 psi hydrogen with vigorous stirring for an additional 5 hours. The autoclave was cooled to room temperature and the hydrogen atmosphere was displaced with nitrogen. The crude reaction mixture was filtered through celite. The resulting solution was extracted in a separatory funnel with saturated aqueous sodium chloride. The organic phase was isolated, filtered through magnesium sulfate and sodium sulfate. The resulting filtrate was concentrated in vacuo to provide an oil (565.11 g, 2.59 mole, approximately 92%). This oil was not purified further but was shown by NMR to be of high purity. Small amounts, <15 total mole %, of ethyl acetate and acetone were also detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:16]([S-])=[S:17])C.[K+].C(O)C>O>[S:17]=[C:16]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CC(C#N)c1ccc(O)c(N)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C#N)c1ccc2oc(=S)[nH]c2c1

Procedure:
A mixture of 2-(3-amino-4-hydroxyphenyl)propionitrile (4.86 g.), potassium ethylxanthate (5.3 g.), ethanol (30 ml.) and water (5.0 ml.) was heated under reflux for four hours. The mixture was filtered, diluted with water (15 ml.), acidified with acetic acid and then diluted with more water. The resulting brown precipitate was filtered off and recrystallised from aqueous ethanol to give 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl) propionitrile, m.p. 173°-6° C. Dry chlorine was passed into a suspension of the thione (8.0 g.) in freshly dried and distilled chloroform (200 ml.). After 20 hours, most of the solid had dissolved and the mixture was filtered. The filtrate was washed with water (100 ml.), 1N sodium hydroxide (50 ml.) and water (3 × 100 ml.) The dried (Na2SO4) organic solution was evaporated to yield 2-[2-chloro-5-benzoxazolyl]propionitrile as a brown oil which was shown to be a single compound by thin layer chromatography. The oil distilled at 128°-134° C/0.3 mm.Hg.