Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[N:9]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.11) (0.197 g, 0.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.21 g, 0.6 mmol) according to the general procedure III. Obtained as an off-white solid (0.1 g), which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[CH3:17][C:18]1[N:19]([C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[CH:20]=[CH:21][N:22]=1
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1cncc(N[C@H](C)c2ccccc2)n1
Yield: 96.2 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (150 mg, 0.64 mmol) and 2-methylimidazole (58 mg, 0.71 mmol) furnished the product (172 mg, 40%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(Cl)=[O:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:27](=[O:28])[O:20][C:18](=[O:19])[C:17]3=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Reactant: O=C(Cl)Cl
Product: COc1ccc2c(c1)c(=O)oc(=O)n2-c1ccc(OCc2ccccc2)cc1
Yield: 79 %

Procedure:
N-(4-Benzyloxyphenyl)-5-methoxyisatoic anhydride [VIII; R=5--CH3O, R"=H, OR°=4--OCH2C6H5 ] was prepared from 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid and phosgene according to the procedure of Example 1, part (b), and was obtained in 79% yield as a colorless solid used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:34]([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl.CN(C)C=O>[C:34]([O:38][C:39]([CH:40]1[CH2:44][CH2:43][CH2:42][N:41]1[C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:45])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 991.6 %

Procedure:
To a solution of 2 (6.01 g, 2.0 mmol) in CH2Cl2 (30 ml) and anhydrous DMF (dimethylformamide)(10 ml) at 0° C. was added HOBT (3.16 g, 2.0 mmol), EDC (1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride) (7.19 g, 4.0 mmol) and L-proline-tert-butyl ester (4.22 g, 2.0 mmol). The solution was stirred at 0° C. for 10 minutes, then at room temperature for 5 hours. The solvents were evaporated in-vacuo and the resulting oil dissolved in EtOAc which was washed with H2O (3×200 ml) and brine (200 ml). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. Flash chromatography on silica gel using hexanes/EtOAc (95/5 to 80/20%) afforded the title compound as a colorless oil (8.30 g, 87.5% yield): 1H-NMR (500 MHz, CDCl3) δ1.04 (s, 9H), 1.45 (s, 9H), 1.89–1.96 (m, 2H), 2.02–2.05 (m, 1H), 2.18–2.22 (m, 1H), 3.65–3.69 (m, 1H), 3.79–3.82 (m, 1H), 4.34–4.37 (m, 2H), 5.03–5.19 (m, 2H), 5.53 (d, 1H), 7.26–7.38 (5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](=[NH:25])[NH:23][OH:24])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](OC(=O)C)(=O)[CH3:33]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]3[N:25]=[C:32]([CH3:33])[O:24][N:23]=3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C(=N)NO)cn2)cc1Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cnc(NC(=O)C(CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)no1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 21.1 %

Procedure:
A mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxycarbamimidoyl)-pyrazin-2-yl]-propionamide (197.0 mg, 0.423 mmol) and acetic anhydride (970 μL, 10.281 mmol) was placed into a one-dram glass vial. The vial was tightly sealed, and the reaction was stirred at 120° C. for 3.5 h. The reaction was diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were back-extracted with ethyl acetate (50 mL). The resulting combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/1 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yl]-propionamide (43.8 mg, 21%) as a white foam; mp 101.9–104.8° C. (foam to gel); (ES)+-HRMS m/e calcd for C22H24ClN5O4S (M+H)+ 490.1311, found 490.1315.
Reaction SMILES: C(O)(=O)CCC(O)=O.[C:9]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:34](=[O:37])([O-])[O-:35].[K+].[K+].ClC(O[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=O>ClCCl.O>[C:44]1([NH:28][C:34](=[O:37])[OH:35])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[C:9]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C(O)CCC(=O)O
Agent: [K+]
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(O)Nc1ccccc1
Temperature: 20 °C

Procedure:
To a cooled suspension of compound 11 in dichloromethane (6 mL/g 11) was added a solution of potassium carbonate (3.2 eq) in water (4 mL/g potassium carbonate). To this two-phase mixture was slowly added a solution of phenyl chloroformate (1.03 eq) in dichloromethane (2 g/g phenyl chloroformate). The reaction mixture was warmed to 20° C. Upon reaction completion (1-2 hr), the layers were separated. The organic layer was washed with water, and dried over anhydrous potassium carbonate. The product 35 was isolated by crystallization from acetonitrile. Yield=80%
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:20][C@@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>>[Cl:19][C:18]1[C:13]([N:25]2[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: C[Si](C)(C)c1cccc(N)c1
Product: CC1CN(c2ncccc2Cl)CCN1
Yield: 86.8 %

Procedure:
More specifically, compound 1 is 2,3-dichloro pyridine (2 g); compound 2 is (R)-2-methyl-piperazine; the synthesized compound 3 is 1-(3-chloro-2-pyridyl)-3-methyl-piperazine (8 g, yield 86.8%). From p-dimethyl(vinyl)silyl phenyl isocynate (compound 7c, 200 mg), it gave about 250 mg of compound A-15 (yield about 61.2%).
Reaction SMILES: IC.[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH3:13])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Iodomethane (12.2 mL, 195 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (15.0 g, 97.7 mmol) and cesium carbonate (47.7 g, 146.5 mmol) in DMF (200 mL). The reaction mixture was stirred at room temperature 1 h, quenched with H2O (500 mL), and extracted with EtOAc (3×200 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 2:8→3:7 EtOAc:hexanes) provided the title compound as an off-white solid (15.4 g, 94%). MS: 168.5 (MH+); HPLC Rf: 3.45 min. (HPLC method 4); HPLC purity: 96%.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]4=[CH:25][S:26][CH:27]=[C:21]4[NH:20][C:19]3=[O:28])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33].CN(C=O)C>CCOCC.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]4=[CH:25][S:26][CH:27]=[C:21]4[N:20]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[C:19]3=[O:28])[CH2:10][CH2:9]2)=[O:7])=[CH:29][CH:30]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cscc3c2=O)CC1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)CCn1c(=O)n(CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 64.6 %

Procedure:
The title compound was prepared by starting with 3-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (2.91 g, 6.8 mmol) was reacted with methyl acrylate as described in Example 1 using DMF as the solvent to produce 2.26 g (64.6%) of methyl 3-[3-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as a creamed-colored solid after trituration with ether/hexane, mp 102.5°-103.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1>O1CCCC1.ClCCl>[Cl:20][C:21]1[C:26]([C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH3:12])=[CH:4][CH:3]=2)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1
Reactant: CNS(=O)(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC(=O)c2c(Cl)ncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
4-Hydroxy-N-methylbenzenesulfonamide (650 mg, 3.47 mmol) was dissolved in tetrahydrofuran (18 ml) and triethylamine (1.06 ml, 7.61 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (808 mg, 3.82 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dropwise added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to give 1.4 g (91% yield) of the title compound, that was used in the next step without further purification. Purity 82%.
Reaction SMILES: [C:1]([CH:4]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([OH:3])=O.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH2:27]>>[O:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH:4]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:1](=[O:3])[NH:27][C:23]2[S:22][CH:26]=[CH:25][N:24]=2)[CH2:7][CH2:8]1
Reactant: Nc1nccs1
Reactant: COC(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Product: COC(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1

Procedure:
Methyl 4-tert-butoxycarbonylmethylbenzoate (1.71 g, 6.84 mmol) was alkylated with 4-iodomethyltetrahydropyran (1.86 g, 8.21 mmol), employing the method described in Preparation 41, to afford methyl 4-[1-tert-butoxycarbonyl-2-(tetrahydropyran-4-yl)ethyl]benzoate: RTA=3.86 min. A solution of this compound (1.37 g, 3.94 mmol) in CH2Cl2 (5 mL) was treated with TFA-CH2Cl2 (2:1, 15 mL) at 0° C. over 10 min. The mixture was stirred at 20° C. for 3 h, before being concentrated in vacuo. The residue was treated with PhMe and the solvents were evaporated off under reduced pressure. This process was repeated twice to provide crude methyl 4-[1-carboxy-2-(tetrahydropyran-4-yl)ethyl]benzoate. This carboxylic acid was condensed with thiazol-2-ylamine, utilizing the protocol outlined in EXAMPLE 65, to furnish methyl 4-[2-(tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzoate: m/z (ES+)=375.2 [M+H]+. This ester (1.20 g, 3.21 mmol) was saponified with LiOH.H2O, using the procedure described in Preparation 22, to furnish the title compound: m/z (ES−)=359.2 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:22][C:23](=[CH2:25])[CH3:24].[ClH:26].CCOCC>C(Cl)Cl.COCCOC>[ClH:26].[NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([O:6][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: COCCOC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
In a Fischer-Porter tube, a mixture of 2-1b (10.2 g, 42 mmol) and DME (150 mL) was sequentially treated with H2SO4 (6.4 mL, 0.12 mol), cooled to -78° C., and then condensed isobutylene (75 mL). The tube was sealed and the cooling bath was removed. After 24 h, ice/water (250 mL) was added followed by washing with ether (2×). The aqueous phase was basified with aq 6N NaOH, then saturated with NaCl, followed by extraction with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a white solid. This was dissolved in CH2Cl2 and treated with 1N HCl/ether (22 mL), and then concentrated to give 2-1 as a glassy yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2.[CH:12](N(C(C)C)CC)(C)C.[CH2:21]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([N:11]([CH3:12])[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([O:25][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:27][CH:28]=1)[CH2:5]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)N(C)[C@@H]2Cc3ccc(Br)cc3C2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of (R)-5-bromoindan-2-ylamine (hydrochloride; 3.50 g), diisopropylethylamine (5.0 ml) and dichloromethane (20 ml) was admixed at 0° C. with 4-butoxybenzoyl chloride (3.00 g). After 30 minutes, the reaction mixture was partitioned between water and dichloromethane. The organic phase was concentrated and the residue was stirred with diethyl ether. The resulting amide was methylated on the amide nitrogen according to method D. This afforded the product with the molecular weight of 402.33 (C21H24BrNO2); MS (ESI): 402 (M+H+).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][N:8]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[CH2:6]1)(OC)=[O:2].C(Cl)(Cl)Cl.C(O)C>C(O)C.[Ni]>[OH:2][CH2:1][CH:5]1[CH2:9][N:8]([CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[CH2:6]1
Reactant: COC(=O)C1CC(=O)N(C(C)C)C1
Agent: [Ni]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)N1CC(CO)CC1=O
Reaction time: 24 h

Procedure:
92.5 g (0.5 mol) of 4-carbomethoxy-1-isopropyl-pyrrolidone in 1.2 l of ethanol were hydrogenated in the presence of about 50 g of Raney-Nickel for 48 hours at 160° - 180° C under a hydrogen pressure of 200 atmospheres. Then it was determined with the aid of thin layer chromatography (CHCl3 /C2H5OH= 95:5) if the reduction was finished. Otherwise 20 g of Raney-Nickel were added again and hydrogenated for another 24 hours. In most of the tests hydrogenation had finished after this time.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:23])=[CH:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cn2ccnc2)cc1
Yield: 27.4 %

Procedure:
4-((1H-Imidazol-1-yl)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), imidazole (0.062 g; 0.907 mmol) and sodium iodide (0.152 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.021 g (41%) of the title compound as a white solid.
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].CO>C1(C)C=CC=CC=1>[CH3:9][C:6]([CH3:7])([CH3:8])[C:5](=[O:10])[CH2:4][C:3]([NH:16][C:15]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:11]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C(C)(C)C
Reaction time: 4 h

Procedure:
Methyl-4,4-dimethyl-3-oxovalerate (15.8 g, 0.1 mol) and 2-methoxy-5-nitroaniline (16.8 g, 0.01 mol) were taken up in toluene (150 mL) in a round bottomed flask fitted with a Dean-Stark trap. The mixture was heated to a vigorous reflux while the MeOH side-product was distilled off and removed. After 4 hours, the mixture was cooled and the toluene removed in vacuo. The residue was recrystallized from acetonitrile to yield 27 g of the desired condensation product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1[NH:21]C=CN=1)=O.C(Cl)Cl.CO>CN(C=O)C>[NH2:8][C:9]1[C:14]([C:15]([NH2:21])=[O:17])=[CH:13][N:12]=[CH:11][CH:10]=1.[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][C:14]=1[C:15](=[O:17])[NH2:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccncc1C(N)=O
Product: NC(=O)c1cnccc1N
Temperature: 60 °C

Procedure:
4-tert-Butoxycarbonylamino-nicotinic acid (1.0 g, 4.20 mmol) was suspended in dry DMF (50 mL) followed by carbonyl-diimidazole (CDI, 1.36 g, 8.40 mmol). The mixture was heated to 60° C. for 1 h, then cooled. Dry ammonia gas was slowly bubbled through this solution for 1 h, followed by evaporation of the mixture. The residue was dissolved in water (20 mL)/chloroform (50 mL) and shaken then the layers separated. The aqueous layer was extracted further with chloroform (3×50 mL) and the combined organic extracts dried (MgSO4) and evaporated to give a yellow oily solid. Silica gel chromatography (CH2Cl2, 0–15% MeOH gradient) gave the desired product, (3-Carbamoyl-pyridin-4-yl)-carbamic acid tert-butyl ester, as a yellow solid. This material was directly treated with trifluoroacetic acid (TFA, 20 mL) stirred at r.t. for 45 min., then evaporated to give the desired amine, 4-Amino nicotinamide, as its TFA salt (892 mg, 85% yield over 2 steps).
Reaction SMILES: C12CC3CC(CC(C3)[CH:2]1[NH:11][C:12]([C:14]13[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])([CH2:18][CH2:19]1)[CH2:16][CH2:15]3)=[O:13])C2.C12CC3CC(CC(C3)C1N)C2.CN(C=O)C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:27]([S:24]([CH2:23][CH2:22][C:17]12[CH2:18][CH2:19][C:14]([C:12]([NH:11][CH3:2])=[O:13])([CH2:21][CH2:20]1)[CH2:15][CH2:16]2)(=[O:26])=[O:25])[CH3:28]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)NC3C4CC5CC(C4)CC3C5)(CC1)CC2
Agent: NC1C2CC3CC(C2)CC1C3
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Reaction time: 8 h

Procedure:
Amide 1-6 was made from acid chloride 1-5 (810 mg, 2.96 mmol) as one member of a 96 compound library, employing the technique of parallel synthesis using the Myriad Core System/nMiniblock. According to the general procedure, 0.10 mmol of each amine (2-adamantylamine for this product) was weighed into the miniblock reaction tubes, and 0.350 ml of dry DMF and 0.55 ml of dry diisopropylethylamine was added to each tube. A 0.25 M solution of the acid chloride in dry acetonitrile was prepared, and 0.400 ml of this solution was dispensed to each tube and the reactions were incubated and stirred overnight under an inert nitrogen atmosphere. The products were purified using a Fraction Lynx HPLC (with detection according to mass spectrum) equipped with a Waters Xterra MS C18 5 um 19×50 nm reverse phase column running a gradient of water/acetonitrile (0.1% TFA). The fractions containing product were concentrated to remove some of the acetonitrile and the lyophilized to provide pure product 4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 1-6 as a white fluffy amorphous solid.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]/[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.Cl>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]/[CH2:15][NH2:16]
Reactant: COc1ccc(F)c(/C=C/CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(F)c(/C=C/CN)c1
Temperature: 0 °C

Procedure:
Hydrazine hydrate (88%)(358 mg, 6.3 mmol) was slowly added to a stirring solution of trans - 2-[3-(2-fluoro-5-methoxyphenyl)prop-2-en-1-yl]-isoindole-1,3-dione (650 mg, 2.1 mmol) in EtOH (40 mL) and the solution was heated to reflux for 5h. The resulting mixture was made acidic (pH<2.0) (10N HCl) followed by heating on a steam bath for 60 min. Cooling of the suspension to 0° C. precipitated the hydrazide which was filtered off, the filtrate was then diluted with H2O (20 mL) and extracted with EtOAc(2×). The aqueous layer was made basic (50% NaOH), and extracted with Et2O (3×). The ethereal layers were combined, washed with brine, dried over MgSO4, and concentrated to give a crude white wax. Purification by Kugelrohr distillation afforded the titled compound as a clear oil, 380 mg, quantitative: 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 2H, br), 3.43 (m, 2H), 3.71 (s, 3H), 5.75 (m, 1H), 6.28 (d, J=11.4 Hz, 1H), 6.65 (m, 2H), 6.90 (m, 1H).