Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][CH2:11][CH2:12][CH2:13][OH:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:10][CH2:11][CH2:12][CH:13]([Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[OH:14]
Reactant: OCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)C(O)CCBr
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diisopropylethylamine (25.488 g, 34.35 mL, 0.197 mol) was added dropwise to the solution of 3-bromopropanol (25 g, 0.18 mol), t-butyldimethylsilyl chloride (29.81 g, 0.197 mol), and DMAP (0.880 g, 7.2 mmol) in methylene chloride (250 mL) placed in a dry 500 mL three-necked, round-bottomed flask kept at ice bath and equipped with a Teflon-coated magnetic stirring bar, a 50 mL pressure-equalizing dropping funnel, a stopper, and a reflux condenser connected to an argon flow line. The reaction mixture was stirred at room temperature for 24 hours, washed successively with water (2×150 mL), dilute ammonium chloride solution (1×100 mL), and brine (2×150 mL). The organic solution was dried (sodium sulfate), the solvent was removed in vacuo, and the residual oil was distilled: bp 62°-64° C. (2 mm Hg); ; 1H-NMR (CDCl3, 200 MHz) δ3.71 (t, J=6.1 Hz, 2H), 3.46 (t, J= 7.0, 2H), 2.00 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H); CIMS m/e 253.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.[CH2:34](Br)[CH:35]=[CH2:36]>CN(C)C=O>[CH2:30]([N:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH2:36][CH:35]=[CH2:34])[CH:28]=[CH2:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: C=CCBr
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 82.4 %

Procedure:
1.5 g (4.4 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 20 ml of N,N-dimethylformamide, 210 ml (12 mmol) of N-ethyldiisopropylamine and 1.16 g (9.6 mmol) of allyl bromide were stirred at room temperature for 4 hours. The reaction solution was evaporated and the residue was chromatographed on 250 g of silica gel while eluting with ethyl acetate. The uniform fractions were evaporated. There were obtained 1.54 g (82%) of 3-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 126°-130°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>CN(C)C=O>[OH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([O:9][C:12]2[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)=[C:6]([CH3:10])[CH:5]=1
Reactant: Cc1cc(O)c(C)cc1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Yield: 44.3 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,5-dimethylhydroquinone (1.38 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (1.72 g).
Reaction SMILES: C1(C)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:22][S:23]([CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH:30]=[CH:29]1)([F:27])([F:26])([F:25])[F:24]>CCCCC>[F:22][S:23]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)([F:27])([F:26])([F:25])[F:24]
Reactant: FS(F)(F)(F)(F)C1C=CCc2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: FS(F)(F)(F)(F)c1cccc2ccccc12
Temperature: 65 °C

Procedure:
Toluene and dichlorodicyanobenzoquinone (2 equivalents) were added to the product of step 2 and heated to 65° C. The reaction was monitored by GC. When the reaction was complete pentane was added. Resulting solids were removed by filtration. Color was removed by filtering through silica. The crude product was isolated by removing the solvent using rotary evaporation.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9]O[C:11]=2[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20]>>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:18]([CH:17]=[CH:9][N:8]=2)[C:19]([OH:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CCCCc1ocnc1-c1ccccc1
Product: CCCCc1c(C(=O)O)ccnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-phenyl-5-butyloxazole (12, 5 g, 25 mmol) and maleic acid (3.5 g, 30 mmol) is heated at 100° C. for 30 min. After cooling, the semisolid mass is triturated with ether and the solid collected by filtration. 1H NMR (δ, CDCl3, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7.44 (m, 2H), 6.25 (s, 1H), 2.86 (d, J=7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 2H), 0.68 (t, J=7.6 Hz, 3H). MS (M+1): 256, (M−1) 254.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c([N+](=O)[O-])c2)cc1-c1c(Br)cnn1C
Yield: 69.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 4-fluoro-3-nitrophenyl isocyanate (0.025 g, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), similar manner as described in Example 1.2 to afford Compound 16 (0.042 g, 0.09 mmol, 69%) as a yellow solid. LCMS m/z (%)=464 (M+H79Br, 100), 466 (M+H81Br, 96). 1H NMR (400 MHz, acetone-d6) δ: 8.55 (s, 1H), 8.44-8.50 (m, 1H), 8.29 (s, 1H), 7.77-7.83 (s, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.37-7.46 (m, 2H), 7.16 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][C@H:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Reaction time: 8 h
Yield: 116.6 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.5 g, 3.0 mmol) in NMP (10 mL) was added 1-Boc-piperazine (1.2 g, 2.17 mmol). The mixture was stirred at 110° C. overnight. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to afford (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.806 g, 86%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 3.68 (m, 2H), 3.60-3.40 (m, 7H), 2.84 (m, 2H), 2.30 (m, 1H), 1.67 (m, 1H), 1.49 (m, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H] +319.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16].[ClH:21]>C1(C)C(C)=CC=CC=1>[Cl:21][C:9]1([Cl:16])[CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cl
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)NC(=O)C(Cl)(Cl)CC2
Reaction time: 0.5 h

Procedure:
A solution of 8-methoxy-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one (7.0 g, described in Example 14) and phosphorus pentachloride (30.0 g) in xylene (200 ml) was heated with stirring under an atmosphere of nitrogen to 90° (oil bath temperature) during 30 minutes with pauses at 30° and at 50°. There was a copious evolution of hydrogen chloride gas. The temperature was maintained at 90° for 30 minutes. The reaction mixture was filtered while hot to remove a small amount of suspended solid, and the filtrate was evaporated under reduced pressure until all the solvent was removed. The residue was added with stirring to saturated aqueous sodium carbonate (20 ml). The product was filtered after the solidification process was complete, slurried in ethanol (30 ml), washed with ethanol (10 ml) and ether (10 ml) and dried to give 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 148°-150°.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=1[OH:13])([CH3:10])([CH3:9])[CH3:8].Cl.O>O1CCCC1.C(N(CC)CC)C>[C:1]([O:18][C:16]1[CH:17]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]([OH:13])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl methacrylate was prepared by adding drop wise a solution of 5.8 grams of methacryloyl chloride in 25 milliliters of tetrahydrofuran to a solution of 11.1 gram of 2,6-di tert.butyl hydroquinone in 80 milliliters of tetrahydrofuran and 20.2 grams of triethylamine. The addition was completed in 15 minutes and the reaction mixture was stirred at room temperature for 5-1/2 hours. The reaction mixture was then poured into a mixture of 20 milliliters of concentrated hydrochloric acid and 400 milliliters of water, and the solid which precipitated was filtered off, dried, and recrystallized from hexane. There was obtained 10 grams of product which melted at 135° C. to 138° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[K].Cl[CH2:17][CH2:18][N:19]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][N:21]=[C:20]1[CH3:27].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:27][C:20]1[N:19]([CH2:18][CH2:17][N:9]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:8])[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][N:21]=1
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Agent: [K]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
3-Nitrophthalimide is converted to the potassium salt by the procedure described in Example 13 and then reacted with 1-(2-chloroethyl)-2-methyl-5-nitroimidazole according to the procedure described in Example 1. The crude reaction mixture is digested with toluene and then filtered to remove some insoluble material. Evaporation of the solvent leaves a syrup which is diluted with chloroform and then filtered to remove some insoluble material. The filtrate is further diluted with toluene and again filtered to remove some precipitate. The solvent is then evaporated from the filtrate and the resulting residue is recrystallized first from ethanol and then from acetone to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3-nitrophthalimide melting at about 175°-176° C.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([O:15]C)=[O:14])=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: COC(=O)c1ccnc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: O=C(O)c1ccnc(NC(=O)C(CS)Cc2ccccc2)c1

Procedure:
Following the procedure of Example 3, but substituting an equivalent amount of methyl 2-(2-acetylthiomethyl-3-phenyl-propionamido)-isonicotinate, obtained as disclosed in Example 27, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate and purifying by chromatography on silica gel column, eluting with methylene chloride/methanol 95:5; 2-(2-mercaptomethyl-3-phenyl-propionamido)-isonicotinic acid is obtained; m.p. 234°-236° C., from absolute ethanol.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O-])=O.[ClH:13].[OH:14][C:15]([CH3:20])([CH3:19])[C:16](=[NH:18])[NH2:17]>>[Cl:13][C:10]1[C:3]2[CH2:4][C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:2]=2[N:17]=[C:16]([C:15]([OH:14])([CH3:20])[CH3:19])[N:18]=1
Reactant: CC(C)(O)C(=N)N
Reactant: CC1(C)CCC(O)=C(C(=O)[O-])C1
Reactant: Cl
Product: CC1(C)CCc2nc(C(C)(C)O)nc(Cl)c2C1

Procedure:
Synthesized according to the method of reagent preparation 8 using 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate and 2-hydroxy-2-methylpropanimidamide hydrochloride in step 2. MS (ES) for C13H19ClN2: 255 (MH+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:20][CH2:21]CCC)CCC.[NH:25](CCO)CCO.C(NC(C)C)(C)C.C(NCC1C=CC=CC=1)C.CNCC1C=CC=CC=1>>[NH2:25][C:16]1[N:8]2[C:1]3[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:9]2[CH2:21][N:20]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: OCCNCCO
Reactant: CCCCNCCCC
Agent: CCNCc1ccccc1
Agent: CNCc1ccccc1
Solvent: CC(C)NC(C)C
Product: NC1=NCC2c3ccccc3Cc3ccccc3N12

Procedure:
adding a base selected from the group consisting of N,N-dibenzylamine, N,N-dibutylamine, diethanolamine, diisopropylamine, N-ethylbenzylamine, sarcosin-Na salt and N-methylbenzylamine to the reaction mixture, to produce 3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:10][C:11](=[O:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:10][CH:11]([OH:13])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(CC(C)=O)NC(=O)OC(C)(C)C)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(C)O)NC(=O)OC(C)(C)C)ccc1OC
Temperature: -15 °C
Reaction time: 4 h

Procedure:
A mixture of (tert-butoxy)-N-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]carboxamide (2.0 g, 5.92 mmol) and sodium borohydride (0.4 g, 12.0 mmol) in methanol (40 mL) and tetrahydrofuran (10 mL) was stirred at −10 to −20° C. for 4 hours. The mixture was quenched with water (10 mL) and then concentrated in vacuo to afford an oil. The oil was dissolved in ethyl acetate and washed with water, brine, dried, and concentrated in vacuo to afford an oil. The oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to give the two diasteromers of (tert-butoxy)-N-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl)carboxamide:
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]3[CH2:10][N:11]([CH2:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[C:12](=[O:13])[C:3]=23)=[CH:29][CH:28]=1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Reactant: OB(O)c1ccc(F)cc1
Product: Cn1cc2c(c(-c3ccc(F)cc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 4-fluorophenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH3:22])[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CN(C)c1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 20.3 %

Procedure:
0.50 g (0.00153 mol) of 4-amino-N-(2-dimethylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide were dissolved in 20 ml (0.176 mol) of 8M methylamine in ethanol and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent and the residue was chromatographed on silica gel with methanol/dichloromethane 1:1 9. There was obtained 0.10 g (21 %) of 4-amino-N-(2-dimethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p: 253-254° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH3:23])[N:21]=1)[C:16](Cl)=[O:17].Cl.CCCCCC.C(OC(=O)C)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:13]([Cl:12])[CH:14]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(Cl)n1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: COc1cc(C(=O)NS(=O)(=O)c2ccc(F)cc2)cc(Cl)n1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
1.75 g (0.01 mol) of 4-fluorobenzenesulfonamide were dissolved in 30 ml of pyridine, and added dropwise by 2.06 g (0.01 mol) of 2-chloro-6-methoxyisonicotinoyl chloride at 0° C. to 5° C., followed by agitation for 2 hrs. at room temperature. After acidified by adding aqueous hydrochloric acid, the precipitate was extracted by ethyl acetate. The organic layer obtained was dried and them concentrated to precipitate crude crystals, which were recrystallized by n-hexane/ethylacetate to 2.1 g (yield: 61.0%) of N-(4-fluorophenylsulfonyl)-2-chloro-6-methoxy isonicotinamide as white crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([NH:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Yield: 46.9 %

Procedure:
A stirred solution of 6-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (354 mg, 47%).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C#N
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 18) (200 mg, 0.534 mmol), DIPEA (0.327 ml, 1.869 mmol) and ethyl 4-bromobutanoate (0.153 ml, 1.068 mmol) were stirred at room temperature in DMF (10 ml) for 5 hours, the reaction mixture then heated to 60° C. for 5 h, the reaction mixture was allowed to stand overnight at room temperature, further ethyl 4-bromobutanoate (0.076 ml, 0.534 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between ethylacetate (˜30 ml) and water (˜30 ml) and the aq. layer extracted once more with ethylacetate (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (218 mg, 0.402 mmol) as an orange oil. MS (ES): C28H32N4O4 requires 488; found 489 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O1CCCC1>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNCCO
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Product: CN(CCO)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
A solution of 2-chlorobenzoxazole (15.4 g) in dry tetrahydrofuran (50 ml) was added dropwise to an ice cooled solution of 2-methylaminoethanol (15.0 g) in dry tetrahydrofuran (100 ml) with stirring and protection from atmospheric moisture. The mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the product was dissolved in ethyl acetate (200 ml) and washed with brine (2×150 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated. Chromatography of the residue on silica-gel in dichloromethane gave the title compound (mp 62-3° C.) which was used in Preparation 3 without further purification.