Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][N:29]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Product: CC(=O)Nc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Yield: 31.9 %

Procedure:
Following the above procedure, 2-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyrimidin-5-ylamine (60 mg, 0.15 mmol) and acetic anhydride (22.2 μL, 0.235 mmol) afford the title compound (21 mg, 31%).
Reaction SMILES: CO[C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4].[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>CO.C(OCC)(=O)C>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: NCCCO
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCCC(=S)N1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](C(=O)NCCCO)CSC2
Temperature: 50 °C

Procedure:
A solution of 43 mg of the product of Example 23 in a mixture of 0.5 ml of methanol and 0.5 ml of 3-amino-propanol was heated to 50° C. 20 min. The mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated in vacuo and the solid residue was recrystallized from ethyl acetate/hexane to afford 12 mg (R)-16-hydroxy-14-methoxy-13-methyl-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid 3-hydroxy-propylamide as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[C:21](O)(=[O:25])[C:22](O)=[O:23]>Cl>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[NH:18][C:22](=[O:23])[C:21]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc([N+](=O)[O-])ccc1NCc1ccccc1
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A mixture of 0,5 g (2.1 mmol) N-benzyl-2-amino-4-nitroaniline and 0,55 g (4,4 mmol) oxalic acid dihydrate in 30 ml 4N hydrochloric acid was refluxed for 5 h. After cooling to 25° C. the product was filtered off and washed with water. The crude product was recrystallized (dimethylformamidewater), washed with 10 ml water, 5 ml ethanol and 5 ml ether to give 0.3 g (49%) 1-benzyl-6-nitroquinoxaline-2,3(1H,4H)-dione. M.p. (DSC): 292.2 ° C. 1H-NMR (DMSO-d6): 12.4 (H, broad s), 8.2-7.0 (8H, m), 5.4 (2H, s).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[Cl:16].[H-].[Na+].CC1C=CC(S(O[CH2:30][C:31]2([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:30][C:31]2([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:5]=[CH:4][C:3]=1[Cl:16]
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(CN(C(=O)OC(C)(C)C)c2ccc(Cl)c(Br)n2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6-bromo-5-chloropyridin-2-ylcarbamate (140 mg, 0.455 mmol) in DMF (2 ml) under nitrogen was added NaH (60%, 30 mg, 0.774 mmol). The resulting mixture was stirred at ambient temperature for one hour. A solution of (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (intermediate O, 164 mg, 0.546 mmol) in DMF (1.5 ml) was then added to the preceding mixture. The resulting mixture was then stirred overnight at about 85° C. The stirred mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml×3) and dried. After concentration the resulting residue was purified by silica gel chromatography using a 12 g column, eluting with 5-20% ethyl acetate in hexane to yield the desired compound “P” as a viscous oil (92 mg), which solidified upon standing overnight. LCMS (m/z): 437.0 [M+H]+; Retention time=1.158 min.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1cccs1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-thiophenecarbonyl)hydrazine (1 g) was dissolved in 10 ml toluene and treated with 50% aqueous sodium hydroxide (1.0 g) and water (2 ml) followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-thiophenecarbonyl)-N'-benzoylhydrazine, was removed by filtration and washed with water. m.p. >190° C.
Reaction SMILES: C(O[CH2:5][C:6]1[C:7]2[N:8]([C:12]([CH3:15])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=O)C.[SH:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>Br.C(O)(=O)C>[CH3:15][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][S:16][C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)[C:7]2=[N:14][CH:13]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CC(=O)OCc1cccn2c(C)cnc12
Agent: Br
Solvent: CC(=O)O
Product: Cc1cnc2c(CSc3nc4ccccc4[nH]3)cccn12
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 5.0 g (30 mmole) of 3-(acetoxymethyl)-2-pyridinamine and 4.8 g (35 mmole) of 2-bromopropanal spontaneously heated upon mixing. After cooling, the mixture was partitioned between aqueous potassium carbonate and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (using ethanol-dichloromethane as eluent) yielded 2.3 g of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C11H12N2O2 : C, 64.69; H, 5.92; N, 13.72. Found: C, 63.70; H, 5.85; N, 14.24). A mixture of 2.3 g (11 mmole) of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine and 1.65 g (11 mmole) of 2-mercaptobenzimidazole in 40 ml of 15% hydrogen bromide in acetic acid was heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. Chromatography yielded 2.1 g of the title compound. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:7].O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:7]
Reactant: COc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(4-methoxybenzyl)-4-benzylpiperazine (4.90 g) in ethanol (50 ml) were added water (5 ml), ammonium formate (1.44 g), and 10% palladium on activated carbon [50% wet] (0.49 g) under nitrogen atmosphere. The reaction mixture was heated at 60° C. with stirring for 2 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (40 ml) and water (40 ml) were added to the residue, and the organic layer was separated, washed with brine, and dried over magnesium sulfate. After removal of the solvent by evaporation, the resulting residue was purified by column chromatography on silica gel (70 g) using a mixed solvent of ethyl acetate and methanol (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)piperazine (3.18 g) as syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([OH:23])[C:10]=1[C:24](=[O:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)[C:10]=1[C:24](=[O:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 73 %

Procedure:
A stirred suspension of 1-[2,4-bis(benzyloxy)-6-hydroxyphenyl]ethanone (Bulletin of the Chemical Society of Japan (1985), 58(1), 136-41) (5.2 g, 15 mmol), potassium carbonate (3.1 g, 22 mmol) and 1-fluoro-4-nitrobenzene (2.1 g, 15 mmol) in DMF (10 mL) was heated at 110° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and thoroughly washed with brine (4×50 mL). The organic phase was dried over Na2SO4 and then evaporated to dryness. The crude was chromatographed on a small pad of silica gel eluting with hexane/ethyl acetate 5/1, to provide the title compound (5 g, 73% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([CH3:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:26][C:24]1[CH:23]=[C:22]([CH3:29])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-nitro-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (11.4 grams, 27.4 mmol) in a mixture of ethanol (200 mL and ethyl acetate (200 mL) was added catalyst (10% palladium on carbon, 2.3 grams). The mixture was hydrogenated under 45 psi at room temperature for 4 hours. The mixture was filtered through Celite and concentrated to give the title compound of Step D (10.5 grams) as a tan solid. The product was used in the next step without further purification. 1H NMR (400 MHz, CD3OD) δ7.98-7.92 (m, 2H), 7.29-7.22 (m, 2H), 7.21 (d, 1H), 6.92 (dd, 1H), 6.78 (d, 1H), 1.98 (s, 6H). MS (APCI−) Calc.:387.1, Found: 386.2 (M−1).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:8]
Reactant: Clc1ccc(Cl)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A mixture of o-toluoyl chloride (22 g, 0.17 mol) and 1,4-dichlorobenzene (120 g, 0.82 mol) was heated to 100° C. in a flask. Aluminum chloride (60 g, 0.45 mol) was added in one portion. The mixture was heated to 170° C. in 30 min and stirred at this temperature for 3 hours. The resulting brownish solution was cooled to about 80° C. and poured onto ice. Ether (50 ml) was added. The organic layer was separated and distilled under vacuum after the removal of ether. The residue from distillation was recrystallized twice from hexane to give 16 g of white crystals (36%).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)cc1
Yield: 66.1 %

Procedure:
By working in accordance with Use Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride and 0.28 g of (4-methoxyphenyl)-acetic acid, 0.61 g of (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-methoxyphenyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC(N[N:27]1[CH2:32][CH:31]2[CH2:33][CH:28]1[CH2:29][NH:30]2)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:27]3[CH2:32][CH:31]4[CH2:33][CH:28]3[CH2:29][NH:30]4)=[N:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NN1CC2CC1CN2
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: Clc1ccc2c(c1)N=C(N1CC3CC1CN3)c1ccccc1N2
Yield: 42 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and N-(tert-butoxycarbonylamino)-2,5-diazabicyclo[2.2.1]heptane (34 mg, 0.2 mmol) were reacted according to GP8 to give 15 mg of the title compound (166JO39-2). MS (ESI) 324 (MH+). Purity for MH+ (UV/MS) 93/100.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[N:6][CH:7]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1.C([O-])(=O)C.[K+]>>[NH2:8][C:3]1[C:2]([B:9]([OH:13])[OH:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Nc1ncncc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Product: Nc1ncncc1B(O)O
Temperature: 105 °C
Reaction time: 18 h

Procedure:
To a vial was added 5-bromopyrimidin-4-amine (0.200 g, 1.149 mmol), bis(pinacolato)diboron (0.438 g, 1.724 mmol), and potassium acetate (0.338 g, 3.45 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2. Dioxane (volume: 0.120 ml) was added via syringe through the septum. The reaction mixture was sparged with N2, then 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) dichloromethane complex (0.042 g, 0.057 mmol) was added. The septum was then replaced with a Teflon screw valve and the vial sealed. The reaction mixture was heated at 105° C. in a metal pie block. After 18 h, the reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was concentrated to afford a brown solid. The crude material was used without further purification. MS (ESI): m/z=140.0 [M+H]+. HPLC Peak tr=0.24 minutes. HPLC conditions: Column:Luna C18 4.6×30 mm 3u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 290. Product isolated as a white foam as a mixture of diastereomers (429 mg, 69%). LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 7.93 (s, 1H), 7.42-7.24 (m, 2H), 7.13-7.04 (m, 1H), 6.94-6.85 (m, 1H), 5.46-5.35 (m, 2H), 4.31-4.20 (m, 1H), 3.98-3.76 (m, 2H), 3.60-3.30 (m, 3H), 3.30-3.10 (m, 3H), 2.80 (s, 3H), 2.28-2.18 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.70 (m, 4H), 1.43-1.30 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[S:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O.[CH3:27]O>C(Cl)(Cl)Cl>[CH3:27][O:15][C:13](=[S:14])[CH2:12][CH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:2]([NH2:1])[N:10]=1
Reactant: Nc1nc(CCC(O)=S)nc2c1ncn2Cc1ccccc1
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=S)CCc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 68 %

Procedure:
To 3-(6-amino-9-benzyl-2-purinyl) thiopropionic acid (100 mg, 0.30 mmol) suspended in 10 ml of chloroform was added thionylchloride (0.14 ml, 2 mmol). After refluxing under heating for 1 hour methanol was dropped to the mixture under ice cooling. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (70 mg, yield 68%).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.Cl[CH2:27][C:28]1[O:32][N:31]=[C:30]([CH2:33][O:34][CH3:35])[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:27][C:28]3[O:32][N:31]=[C:30]([CH2:33][O:34][CH3:35])[N:29]=3)[C:4]=2[CH:3]=1
Reactant: COCc1noc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1

Procedure:
According to the procedure describe for compound B99 of tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (10.00 g; compound B53) is reacted with 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole (3.78 g, D14) in the presence of potassium carbonate (3.21 g) in DMF (93 ml) to afford the title compound as a solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[C:10]2[C:11](=[O:23])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][O:14][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1>C1COCC1>[CH3:25][O:24][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[C:10]2[C:11](=[O:23])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][O:14][C:9]=2[CH:8]=1
Reactant: C[S-]
Reactant: COc1ccc(-c2coc3cc(OC)cc(F)c3c2=O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2coc3cc(OC)cc(SC)c3c2=O)cc1
Yield: 87.2 %

Procedure:
Sodium thiomethoxide (600 mg) was added to a solution of 5-fluoro-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (325 mg) in THF (10 mL). The mixture was refluxed for 1 h and cooled. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over MgSO4. Purification by chromatography on silica gel (eluant: ethyl acetate-chloroform, gradient from 0:100 to 5:95) gave the title compound (310 mg) as a pale yellow solid. 1H NMR (CDCl3): 7.81 (s, 1H), 7.50 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=8.7 Hz), 6.67 (d, 1H, J=2.1 Hz), 6.59 (d, 1H, J=2.1 Hz), 3.91 (s, 3H), 3.83 (s, 3H); MS: 329 (MH+); HPLC tR: 2.68 min.
Reaction SMILES: [OH:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[C:14](O)(=O)C.[BH4-].[Na+].Cl>O1CCCC1>[CH3:14][O:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C1C=CC=CC1(O)C(=O)O
Reactant: CC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(=O)O)C=CC=CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous 2-methoxyphthalic acid (640 mg), which was prepared with using anhydrous 2-hydroxyphthalic acid by the same procedure as reference example 12, was suspended in tetrahydrofuran (20 ml). Acetic acid (430 mg) and sodium borohydride (135 mg) were added to the suspension. The mixture was stirred for 30 min. at room temperature and for 2 hr. at 50° C. The reaction solution was cooled. 1N hydrochloric acid (7 ml) was added to the cooled solution. The solution was stirred for 15 min. The reaction solution was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (314 mg) having the following physical data.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].CO.[CH3:22]OC(OC)OC>C1(C)C=CC=CC=1>[CH3:22][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: COC(OC)OC
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCBr
Temperature: 55 °C
Yield: 100 %

Procedure:
A mixture of 16-bromohexadecanoic acid (15.5 g, 46.2 mmol), MeOH (100 ml), PhMe (30 ml), trimethylorthoformate (30 ml), and polystyrene-bound benzenesulfonic acid (3.6 g) was stirred at 55° C. After 69 h the mixture was filtered through celite and the filtrate was concentrated to yield 16.85 g of an oil (100% yield).