Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]=[N+:12]=[N-:13])[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1C=CC=CC=1>CCO>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]=[N+:12]=[N-:13])=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[CH3:2]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN=[N+]=[N-]
Temperature: 60 °C
Yield: 42.5 %

Procedure:
A mixture of 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester (3 g, 13.94 mmol), 2-chlorobenzaldehyde (3 g, 21.34 mmol) and pyridine (1.5 mL, 1.47 g, 18.55 mmol) in EtOH (14 mL) was heated to 60° C. and maintained at this temperature for 3 h. The mixture was concentrated in vacuo. The concentrate was taken up in EtOAc (100 mL), washed successively with 1N HCl (25 mL) and brine (25 mL), dried (Na2SO4), filtered, concentrated in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 gram Redisep silica gel column, 0 to 60% EtOAc in hexanes for 30 min at 40 mL/min) to afford 2.00 g of 2-[2-(2-azido-ethoxy)-acetyl]-3-(2-chloro-phenyl)-acrylic acid ethyl ester (mixture of E/Z isomers) and 1.01 g of recovered starting material.
Reaction SMILES: C([O-])(=O)C.[Co+2:5].C([O-])(=O)C.[C:10]1([NH:16][C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]([OH:21])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[Co:5].[C:10]1([NH:16][C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C(O)c1ccccc1Nc1ccccc1
Solvent: CN(C)C=O
Product: [Co]
Temperature: 50 °C

Procedure:
24.9 g (0.1 mol) of cobalt acetate was added to 500 ml of dimethylformamide and completely dissolved. The solution was heated to 50° C., and 42.6 g (0.2 mol) of N-phenylanthranilic acid was gradually added thereto. The mixture was allowed to react for 3 hours at about 145° C. under refluxing, and the heating was terminated. The mixture, when cooled down to 100° C., was dispersed in 2 liters of water and, after 1 hour, subjected to filtration. The precipitate was washed with water until neutrality and then dried at 90° C., whereby about 40 g of pale reddish grey powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C.CCCCCC>[C:4]([C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([CH:2]([CH3:11])[CH3:1])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])#[N:5]
Reactant: CC(C)C(C#N)c1cccs1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(C#N)(c1cccs1)C(C)C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
3-Methyl-2-(2-thienyl)butane nitrile 5.56 g 33.6 mmol and ethyl acrylate 4.00 ml 37.0 mmol were dissolved in tetrahydrofuran 100 ml. Potassium t-butoxide, 566 mg 5.04 mmol, was added little by little thereto at room temperature. Generation of heat continued during this step. After stirring for 1 hour, brine 100 ml and aqueous saturated ammonium chloride 150 ml were added thereto successively, and the mixture was extracted with ether 1 L. The organic layer was washed with brine 500 ml and water 500 ml successively, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound (5.57 g 21.0 mmol, 62.5%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:21]=[C:20]([CH3:22])[S:19][C:10]=3[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH:3]1[CH2:23][N:24]1C(=O)C2C(=CC=CC=2)C1=O>CN>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:21]=[C:20]([CH3:22])[S:19][C:10]=3[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH:3]1[CH2:23][NH2:24]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)C(CN2C(=O)c3ccccc3C2=O)C1
Agent: CN
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)C(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-((1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-2-yl)methyl)isoindoline-1,3-dione, prepared as described in the previous step, (1.0 g) in ethanolic methylamine (20 mL) was stirred at ambient temperature overnight. The solvent was removed under vacuum and the residue purified by HPLC to give the hydrochloride salt of (1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-2-yl)methanamine as a red solid. 1H NMR (400 MHz, MeOD) δ 7.46-7.44 (m, 1H), 7.31-7.48 (m, 1H), 7.19-7.15 (m, 1H), 6.97-6.95 (m, 1H), 6.74 (s, 1H), 4.80-4.71 (br, 1H), 4.28-4.20 (br, 2H), 4.07-4.04 (br, 2H), 3.82-3.70 (br, 3H), 3.53-3.48 (m, 1H), 3.18 (s, 3H), 2.42 (m, 3H); ESI-MS (M+1): 342 calc. for C18H23N5S Exact Mass: 341.17.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:37].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[O:37])[C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
4-[4-(2-Methyl-benzoylamino)-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester (1.12 g, 2.24 mmol) was dissolved in acetone (25 mL) and a 15% aqueous solution of magnesium sulfate(2.5 mL). The solution was cooled in an ice bath and potassium permanganate (1.9 g, 12.3 mmol) was added and the solution was stirred for 15 min at which time the solution was allowed to warm to room temperature and stirred for 3 hr. The solution was concentrated and diluted with 150 mL water. The product was exhaustively extracted from the aqueous layer with methylene chloride. The organic was then washed with brine, dried over anhydrous magnesium sulfate, concentrated and purified on silica (Isco flash column, 0 to 40% ethyl acetate in hexane). The title compound was isolated in 17% yield (200 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:23][CH2:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Fc1c(F)c(F)c(-c2c(F)c(F)c(CBr)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixed solution of a mixture comprising the 4-methylperfluorobiphenyl mentioned above, an N-bromo succinic imide (NBS) (26.7 g, 150 mmol), AIBN (0.99 g, 6 mmol) andacarbon tetrachloride (100 mL) was subjected to heating under reflux for 1 week. During this process, the progress of the reaction was confirmed by TLC, and NBS and AIBN were added on a timely basis. Ultimately, 285 mmol NBS and 15 mmol AIBN were added to the solution. After the reaction was completed, the solution was cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=100:1), and the 4-(bromomethyl)perfluorobiphenyl (7.36 g, 18 mmol, total yield from methyl lithium 60%) was isolated.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:30]2[N:29]=[C:26]([NH:27][CH3:28])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].[C:31]1([N:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:30]2[N:29]=[C:26]([NH:27][CH3:28])[N:25]=[C:23]([O:24][C:38](=[O:39])[N:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CNc1nc2c(ncn2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2′,3′,5′-tri-O-acetyl-2-N-methylguanosine 3 (3.0 g, 7.1 mmol, 1.0 eq) in dry pyridine (50 mL) were added diphenylcarbamoyl chloride (3.45 g, 15 mmol, 2.1 eq) and diisopropylethylamine (1.9 mL, 11.4 mmol, 1.6 eq). The dark brown reaction mixture was then stirred at room temperature for 1 h to obtain 2′,3′,5′-tri-O-acetyl-6-O-(diphenylcarbamoyl)-2-N-methylguanosine 4. TLC showed complete conversion at this stage of the reaction. The reaction mixture was then diluted with pyridine (15 mL) and EtOH (30 mL). To this solution cooled at 0° C. was added 2 M NaOH (25 mL), which was precooled at 0° C. The reaction mixture was stirred for 10 min at 0° C. Acetic acid (c.a. 5 mL) was then added to neutralize the solution. Extraction with CH2Cl2 followed by chromatography on silica gel afforded 5 in 55% yield (1.92 g). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.5; 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.81 (d, 3H), 3.51-3.56 (m, 1H), 3.61-3.66 (m, 1H), 3.90 (m, 1H), 4.02 (q, 1H), 4.15 (br.d, 1H), 4.62 (br.s, 1H), 4.99 (br.s, 1H), 5.21 (d, J=4.8 Hz, 1H), 5.48 (d, J=5.6 Hz, 1H), 5.82 (d, J=5.6 Hz, 1H), 7.28-7.32 (m, 4H), 7.4-7.44 (m, 6H), 8.19 (s, 1H); 13C NMR (DMSO-d6, 400 MHz) δ (ppm): 28.3, 61.5, 70.5, 73.1, 85.5, 116.4, 127.1, 129.4, 140.9, 141.8, 150.4, 155.6, 155.9, 159.6; ESI-MS (ES+) calculated for C24H24N6O6 492.1757, found 493.2 (M+H+), 515.2 (2M+Na+), 1007.4 (2M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[C:28](F)=[CH:27][C:26]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=O)=[C:25]([N+:39]([O-])=O)[CH:24]=1)(=[O:17])[CH3:16].O.O.[Sn](Cl)Cl>C(=O)(O)[O-].[Na+].CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:28]2[C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:15](=[O:17])[CH3:16])=[CH:24][C:25]3[NH:39][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:30][C:26]=3[CH:27]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Reactant: Fc1ccc(S)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Sc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
20 mg of 4-fluoro-benzenethiol and 30 mg of potassium carbonate were added in order to an N,N-dimethylformamide (1 ml) solution of 50 mg of pyridine-2-carboxylic acid-(4-(1-acetyl-pyrrolidin-2-yl)-5-fluoro-2-nitro-phenyl)-amide, and the reaction liquid was stirred at 100° C. for 2 hours. 30 mg of tin(II) chloride dihydrate was added to the reaction liquid, and the reaction liquid was stirred at 100° C. for 3 hours. After cooled, the reaction liquid was diluted with aqueous saturated sodium bicarbonate and extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CC1C=CC(S(O[CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:62])[C@H:42]([O:44][Si:45]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH3:43])[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:33][CH2:34][CH:35]3[CH2:36][CH2:37][N:38]([C:41](=[O:62])[C@H:42]([O:44][Si:45]([C:58]([CH3:59])([CH3:61])[CH3:60])([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH3:43])[CH2:39][CH2:40]3)[C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)[C@@H](C)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)cc1
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)CC1

Procedure:
The alkylation reaction was carried out according to the procedure described for example 1 and 2 using 8-(6-Bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9H-purin-6-ylamine (0.172 g, 0.47 mmol) and 2-[1-((2R)-2-{[tert-butyl-(diphenyl)-silyl]-oxy}-propanoyl)-piperidin-4-yl]-ethyl 4-methylbenzenesulfonate (0.280 g, 0.47 mmol) obtained from step 3 to afford 8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9-{2-[1-((2R)-2-{[tert butyl(diphenyl)silyl]oxy}propanoyl)piperidin-4-yl]ethyl}-9H-purin-6-amine; LC-MS [M+1]+ 787.1 and 8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-3-{2-[1-((2R)-2-{[tert-butyl(diphenyl)silyl]oxy}propanoyl)piperidin-4-yl]ethyl}-3H-purin-6-amine; LC-MS [M+H]+ 787.1
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][N:6]=1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:6]=1
Reactant: CCOC(=O)c1c[nH]nc1OC
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ncccn2)nc1OC
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
Sodium hydride (60% in mineral oil, 528 mg, 13.2 mmol) is added portion wise to a solution of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (1.5 g, 8.81 mmol) in 40 mL of THF at RT. Evolution of H2 (g) is observed. After about 5-10 min, 2-chloropyrimidine (1.0 g, 8.81 mmol) is added, and the resulting reaction mixture is stirred at reflux for 15 h. After cooling to RT, the reaction is quenched with 10 mL of sat. NH4Cl and 10 mL of water and extracted with CH2Cl2 (2×40 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to EtOAc) affords the title compound as a fluffy white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[N:3][CH:2]=1.[ClH:19].P(Cl)(Cl)([Cl:22])=O>C(#N)C.O1CCOCC1>[ClH:22].[Cl:19][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[N:9][N:10]=1
Reactant: O=c1[nH]nc(Cc2ccncn2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Clc1nnc(Cc2ccncn2)c2ccccc12
Temperature: 50 °C
Reaction time: 36 h

Procedure:
850 mg (3.57 mmol) 4-(4-pyrimidinylmethyl)-1 (2H)-phthalazinone in 15 ml acetonitrile is mixed with 1.78 ml (7.14 mmol) 4N HCl solution in dioxane and finally with 1.14 ml (12.5 mmol) phosphoryl chloride. After stirring for 36 h at 50° C., the red suspension is filtered and washed with acetonitrile: FAB MS (M−H)+=255. Further product is obtainable from the evaporated filtrate by distribution between dichioromethane and sat. NaHCO3 solution.
Reaction SMILES: C[N:2]1CCOCC1.[CH:8](=[C:12]1[C:21]2[CH:20]=[C:19]([C:22]([OH:24])=O)[S:18][C:17]=2[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][CH3:11].ClC(OCC(C)C)=O.N>CCOC(C)=O.O.C1COCC1>[CH:8](=[C:12]1[C:21]2[CH:20]=[C:19]([C:22]([NH2:2])=[O:24])[S:18][C:17]=2[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CN1CCOCC1
Reactant: CCCC=C1CCCCc2sc(C(=O)O)cc21
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC=C1CCCCc2sc(C(N)=O)cc21
Reaction time: 0.03 h

Procedure:
N-Methylmorpholine (0.69 ml) was added to a mixture of 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxylic acid (1.05 g) and THF (10 ml) at -15~-20° C. under nitrogen atmosphere, and isobutyl chloroformate (0.82 ml) was added thereto over 2 minutes. The mixture was stirred under the same condition for 30 minutes, and conc. ammonia (c.NH3) was added thereto. The mixture was stirred at r.t. for 2 hours. The reaction mixture was poured into a mixture of water and AcOEt to precipitate. The precipitate was collected by filtration, washed with water and Et2O, and dried in vacuo to give 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide (0.59 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8](=[O:20])(=[O:19])[CH2:7][C:6]=2[C:21]=1[N+:22]([O-])=O.Cl[Sn]Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[C:21]([NH2:22])=[C:6]2[CH2:7][S:8](=[O:20])(=[O:19])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2c3ccc(F)c([N+](=O)[O-])c3CS2(=O)=O)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2c3ccc(F)c(N)c3CS2(=O)=O)cc1
Reaction time: 12 h
Yield: 95.8 %

Procedure:
A mixture of 5-fluoro-1,3-dihydro-1-[(4-methoxyphenyl)methyl]-4-nitro-2,1-benzisothiazole 2,2-dioxide (1.54 g, 4.37 mmol) and SnCl2.H2O (4.93 g, 21.9 mmol) in ethyl acetate (200 mL) was heated at reflux for 3 h. Then the reaction mixture was cooled, diluted with ethyl acetate (200 mL) and solid Na2CO3 (15 g) was added. The resulting mixture was vigorously stirred for 12 h and filtered through a pad of diatomaceous earth (Celite®). The filtrate was concentrated and the residue was subjected to flash chromatography to give 1.35 g of the title compound of Step C as brown solid melting at 154°-157° C. 1H NMR (CDCl3, 400 MHz): δ7.33 (d,2H), 6.87 (d,2H), 6.82 (dd,1H, J=11.3 and 8.75 Hz), 5.91 (dd,1H, J=8.5 and 3.5 Hz), 4.65 (s,2H), 4.22 (s,2H), 3.79 (s,3H), 3.75 (br s,2H).
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].[CH3:8][O:9][C:10]1[C:19]([O:20][CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:22]Br)[N:11]=1>CO>[CH3:8][O:9][C:10]1[C:19]([O:20][CH3:21])=[N:18][C:17]2[C:16]([CH:22]=[O:2])=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COc1nc2cccc(CBr)c2nc1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: COc1nc2cccc(C=O)c2nc1OC
Reaction time: 0.08 h

Procedure:
17 ml (188 mmol) of 2-nitropropane are added to a solution of 3.7 g (163 mmol) of sodium in 700 ml of methanol. After 5 minutes' stirring, 35.5 g (125.4 mmol) of solid 2,3-dimethoxy-5-bromomethyl-quinoxaline are added. The mixture is heated at reflux for 1 hour, a homogeneous solution being formed. After cooling, the solution is concentrated under reduced pressure. The residue is taken up in ethyl acetate and 1 N HCl, the phases are separated and the organic phase is washed with water and brine, dried over sodium sulfate and concentrated. The title compound is isolated in the form of white crystals by crystallization from ethyl acetate.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([C@@H:17]2[CH2:19][C@H:18]2[NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC#N>[C:11]1([C@@H:17]2[CH2:19][C@H:18]2[NH:20][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
N,N-Diisopropylethylamine (3 mL, 17.16 mmol) was added to a solution of (trans)-2-phenylcyclopropanamine hydrochloride (1.5 g, 8.58 mmol) in 70 mL of CH3CN. After complete dissolution of the amine the methyl 2-bromoacetate (930 μL, 9.44 mmol) was added and then stirred overnight at room temperature. After solvent removal the crude was purified by flash chromatography eluting with CH2Cl2/MeOH (99:1 to 90:10) to get methyl 2-((trans)-2-phenylcyclopropylamino)acetate as colourless oil (1.76 g, Yield=100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([N:19]([CH3:26])[CH:20]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21]2)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)[CH:47]=1)[NH2:44].CO>O>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:44][C:43]3[CH:45]=[C:46]([N:48]4[C:52]([CH3:53])=[N:51][N:50]=[N:49]4)[CH:47]=[C:41]([O:40][CH3:39])[CH:42]=3)[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[C:17]([N:19]([CH3:26])[CH:20]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21]3)=[O:18])[C:5]2=[N:10][CH:9]=1)#[N:12]
Reactant: COc1ccc(CN(c2cccc(C(=O)N(C)C3CCN(C)C3)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: COc1cc(N)cc(-n2nnnc2C)c1
Solvent: O
Solvent: CO
Product: COc1cc(Nc2cc(Nc3cccc(C(=O)N(C)C4CCN(C)C4)c3)c3ncc(C#N)n3n2)cc(-n2nnnc2C)c1

Procedure:
Example 254 was prepared from 254A and 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline by utilizing the procedure as described in Example 6. HPLC: Rt=1.53 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min. with 1 min. hold time, flow rate=5 mL/min., detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). MS (ES): m/z=579.13 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>COC(O)C>[N:1]1([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Brc1nccs1
Agent: COC(C)O
Product: c1csc(N2CCNCC2)n1
Yield: 72.3 %

Procedure:
A mixture of piperazine (6.88 g) and 2-bromothiazole (2.28 g) in methoxyethanol (30 ml) was refluxed for 2.5 hr and evaporated. Water was added and the mixture was extracted with dichhloromethane. The extract was washed with water, dried over sodium sulfate and evaporated to give an oil (1.7 g) of 2-(1-piperazinyl)-thiazole.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH2:2][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH2:8]
Reactant: C=C(CBr)C(=O)OC
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CN1CCOCC1)C(=O)OC
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(bromomethyl)acrylate (119 μl, 1 mmol) and K2CO3 (138 mg, 1 eq) in acetonitrile (2 ml) was added morpholine (96 μl, 1.1 mmols). The mixture was stirred overnight, filtered and concentrated. The residue was partitioned between ether and water, and organic layer was isolated, washed with brine and dried (MgSO4). Solvent was removed and residue was purified by column chromatography. Ethyl acetate eluted out the title compound as clear oil (110 mg, 59%).