Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/C=C(\C)/CCC(OC)=O)=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.N1C=CC=CC=1.[CH3:41][OH:42]>>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:41]=[O:42])=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Reaction time: 0.75 h

Procedure:
A solution of methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (11.0 g) in methanol 125 ml), dichloromethane (125 ml) and pyridine (2 ml) was cooled to -78° C. and a stream of ozonized oxygen was bubbled through. After 45 minutes a blue color developed indicating the presence of unreacted ozone. Dimethyl sulfide (5 ml) was added and the cooling bath was removed. After 16 hours the solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and then water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 2:1 hexane:ethyl acetate, so as to produce 2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) acetaldehyde, mp. 88°-92° C. (ether).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]2[C:7](=[O:9])[CH:8]=1.[C:19]1([P:25]([C:32]2C=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:38](#N)C>>[Cl-:1].[C:13]1([C:10]2[N:6]3[C:7](=[O:9])[CH:8]=[C:3]([C:2]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[P+:25]([CH3:38])([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:4]=[C:5]3[S:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC#N
Reactant: O=c1cc(CCl)nc2scc(-c3ccccc3)n12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cc(=O)n2c(-c3ccccc3)csc2n1
Product: [Cl-]
Reaction time: 24 h

Procedure:
7-chloromethyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 194°-195° C. (7.8 g), prepared according to Example 5, was reacted with triphenylphosphine (8 g) in acetonitrile (250 ml) under stirring at the reflux temperature for 24 hours. After cooling the solution was concentrated in vacuo to a small volume, diluted with isopropyl ether and the precipitate was filtered to give 11 g of [3-phenyl-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]-methyl-triphenylphosphonium chloride, which was suspended in dimethylsulfoxide (50 ml) and treated with potassium tert-butoxide (2.46 g) dissolved in dimethylsulfoxide (50 ml) under stirring at room temperature. The solution of the ylide so obtained was reacted with 3-pyridine-carboxaldehyde (2.36 g) at room temperature for 60 minutes then the reaction mixture was diluted with ice water and neutralized with NaH2PO4.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:28])[NH:14][C:15](=[O:27])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>>[CH3:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:16]2[C:15](=[O:27])[NH:14][C:13](=[O:28])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:31]4[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(Br)ccc34)C(=O)NC2=O)c2ccccc21
Product: Cn1ccnc1-c1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cn(C)c2c1
Yield: 38 %

Procedure:
3-(1-Methyl-1H-indol-3-yl)-4-[1-methyl-6-(1-methyl-1H-imidazol-2-yl)-1H-indol-3-yl]-pyrrole-2,5-dione (46 mg, 38%) was prepared from 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (120 mg, 0.28 mmol) and 1-methyl-2-(tributylstannyl)imidazole (0.8 mL, containing 50% 1-methyl-imidazole) (Molloy, K. C.; Waterfield, P. C.; Mahon, M. F. J. Organonetallic. Chem. 1989, 365, 61.)
Reaction SMILES: [CH2:1]([N:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:24][Br:25]>>[Br-:25].[CH2:7]([N+:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:24])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCN(CCCCC)CCCCc1ccccc1
Reactant: CBr
Product: CCCCCCC[N+](C)(CCCCC)CCCCc1ccccc1
Product: [Br-]

Procedure:
Following the procedure set forth in Example 31, N-n-pentyl-N-n-heptyl-4-phenylbutylamine prepared according to Example 30 was reacted with methyl bromide to provide N-n-heptyl-N-methyl-N-n-pentyl-4-phenylbutylammonium bromide. M.P. 55°-57° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:28]2=[N:29][C:30]3[C:31](=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[N:27]2[CH2:26][CH2:25][CH2:24]1.[CH3:37][C:38](=O)[CH2:39][CH3:40]>CO.C(=O)([O-])O.[Na+]>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:28]2=[N:29][C:30]3[C:31](=[C:32]([NH:36][CH:38]([CH3:37])[CH2:39][CH3:40])[CH:33]=[CH:34][CH:35]=3)[N:27]2[CH2:26][CH2:25][CH2:24]1
Reactant: CCC(C)=O
Reactant: Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(C)Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium triacetoxyborohydride (171 mg, 0.807 mmol) was added to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine (183 mg, 0.549 mmol) and butan-2-one (1.0 mL) in methanol (1.0 ml) at 0° C., and the mixture was stirred at room temperature for 8 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (86.4 mg, 0.222 mmol, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH2:13][C:14]2[C:15]([NH2:21])=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:7]([O:22][CH3:23])[CH:6]=1)=[O:4].[Na].[CH2:25](O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([O:22][CH3:23])[C:8]([CH2:13][C:14]2[C:15]([NH2:21])=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:9]([O:11][CH3:12])[CH:10]=1)=[O:4])[CH3:25]
Reactant: CCO
Reactant: COC(=O)c1cc(OC)c(Cc2cnc(N)nc2N)c(OC)c1
Agent: [Na]
Product: CCOC(=O)c1cc(OC)c(Cc2cnc(N)nc2N)c(OC)c1

Procedure:
2.0 G. of α-(2,4-diamino-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid methyl ester were added to a solution of about 100 mg. of sodium metal in 200 ml. of absolute ethanol. The solution was heated at reflux for 48 hours and filtered. The filtrate was concentrated to 1/4 and cooled. The precipitated α-(2,4-diamino-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid ethyl ester was removed by filtration under vacuum and recrystallized from ethanol, m.p. 201°-202°.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([NH:16]C(=O)OC(C)(C)C)[CH:13]=[CH:14][CH:15]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cn3ncccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cn3ncccc3n2)c1
Yield: 75 %

Procedure:
A solution of tert-butyl 3-(imidazo[1,2-b]pyridazin-2-yl)phenylcarbamate (1 mmol) and TFA (4 mmol) in CH2Cl2 (10 ml) was stirred at 35° C. overnight. Then 1 M NaOH (4 ml) was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give 3-(imidazo[1,2-b]pyridazin-2-yl)aniline with a yield of 75%.
Reaction SMILES: [CH:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([C:20](OC)=[O:21])[CH2:5]1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O>[CH:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([CH2:20][OH:21])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 89.3 %

Procedure:
8 grams of 6-isopropyl-8β-methoxycarbonylergoline was added to a mixture of 8 g of sodium borohydride in 200 ml of methanol. The reaction mixture was heated under reflux for 2 hrs; then a second 2 g batch of sodium borohydride was added. The mixture was cooled after 3 hrs, diluted with water, and the precipitate was filtered to give 6.5 g of 6-isopropyl-8β-hydroxymethylergoline, m.p. 192°-194° C., after crystallization from methanol. A solution of 13 g of 4-toluenesulfonyl chloride in 87 ml of pyridine was added slowly to a cooled solution of 6.5 g of 6-isopropyl-8β-hydroxymethylergoline in 250 ml of pyridine. After 15 hrs the mixture was poured over iced water and the precipitate was filtered to give 7.4 g of 6-isopropyl-8β-toxyloxymethylergoline melting at 180°-184° C. after crystallization from acetone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]([N:15]=[N:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])([O:13][CH3:14])=[O:12].CCCCCC>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:17](=[N:16][NH:15][C:11]([O:13][CH3:14])=[O:12])[CH3:24])[CH3:23]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)/C=C(/C)N=NC(=O)OC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=NNC(=O)OC
Temperature: 70 °C
Yield: 71.1 %

Procedure:
3-Nitroaniline (2.92 g, 21.27 mmol) was added to a solution of ethyl 3-carbomethoxyazocrotonate (4.2 g, 21.13 mmol) (which is known in the literature) in THF (40 mL), and the mixture was stirred at 70° C. for a day and a night. After cooling to room temperature, hexane was added thereto, and the deposited precipitate was filtered out to yield the title compound (5.08 g, 71%).
Reaction SMILES: [OH:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=2)[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16].N1C=CN=C1.[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)Cl)([CH3:26])([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>ClCCl>[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=2)[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(C)C(=O)N(c2ccc(I)cn2)C(=O)C1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(I)cn2)C(=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2.4 g, 3.47 mmol, 50%) (4RS)-4-Hydroxy-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione (Example 14, step 2) was dissolved in dichloromethane (20 ml). Imidazole (520 mg, 7.63 mmol) and tert-butyldiphenylchlorosilane (1.0 g, 3.64 mmol) were added at room temperature and the mixture was stirred for 3 hours at room temperature. Sat. NaHCO3 solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane gradient 0:100 to 30:70). The desired compound was obtained as a white solid (1.5 g, 74% yield), MS: m/e=585.1 (M+H+).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](OCCCC)(=O)[CH:10]=C.C>>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:1]
Reactant: C=CC(=O)OCCCC
Reactant: C=Cc1ccccc1
Agent: C
Product: C=Cc1ccccc1C=C

Procedure:
A monomer composition for core consisting of 78 parts of styrene and 22 parts of n-butyl acrylate (giving a copolymer having a calculated glass transition temperature of 50° C.), 7 parts of carbon black (`Printex 150T` trade name; produced by Degussa AG), 1 part of charge control agent (`Aizen Spilon Black TRH` trade name, produced by HODOGAYA Chemical Co.), 0.3 part of divinylbenzene, 0.8 part of poly-methacrylate macromonomer (`AA6` trade name, glass transition temperature of 94° C., produced by TOA GOUSEI Chemical Industries Co., Ltd.), and 10 parts of penta-erythritol-tetra-stearate were dispersed with a homo mixer(TK Type, produced by TOKUSHUKIKAKOU Co.) of 12,000 rpm to obtain a core monomer mixture.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:15]([N-]C)[CH2:16][CH2:17][CH3:18].[Li+].CCCCCC.C([Li])CCC.[CH2:33]([NH:37]C)CCC>CCCCCC.O1CCCC1>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[Si:2]1([NH:37][CH3:33])[CH2:15][CH2:16][CH2:17][CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CCCC[N-]C
Reactant: CCCCNC
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Si]1(NC)N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
In an argon atmosphere, 5.50 g (23.6 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 10 mL of hexane and after adding a lithium butyl(methyl)amide solution (prepared by mixing 14.2 mL of 1.67 mol/L butyllithium hexane solution, 15 mL of tetrahydrofuran and 2.07 g of N-butyl-N-methylamine and stirring the mixture at room temperature for 1 hour), the mixture was stirred at room temperature for 20 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 109° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-butylmethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NBuMe) as a colorless liquid (yielded amount: 5.67 g, yield: 85%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][S:15][C:11]=2[CH:10]=1.[O:18]=[CH:19][C:20](Cl)(Cl)Cl.Cl.[OH:25][NH2:26]>Cl.C(O)C.O>[S:15]1[C:11]2[CH:10]=[C:9]([NH:8][C:19](=[O:18])[CH:20]=[N:26][OH:25])[CH:17]=[CH:16][C:12]=2[N:13]=[CH:14]1
Reactant: NO
Reactant: Nc1ccc2ncsc2c1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(C=NO)Nc1ccc2ncsc2c1
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate, and 100 mL of water. The mixture was magnetically stirred until all the solids were dissolved. To the resultant aqueous solution was added a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1N aqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred, and chloral (6.0 g, (36 mmol) was added. To the resultant solution was added a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in 30 mL of water. The final mixture was heated with stirring to a gentle boil until all solids dissappeared, and heating was continued for an additional 15 min. The flask was removed from the heat, and the solution was poured onto 500 g of ice. The mixture was stirred as the product precipatated from solution. The precipatate was collected by suction filtration, washed thoroughly with water, filtered, and air dried to provide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: 1H NMR (DMSO-d6): δ 12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI−MS m/z 220 (M−H)−. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 100 ml of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C., and 10.0 g (45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. The solution was heated for ˜1 h, and the reaction mixture was poured into 750 g of ice and water. The residual reaction mixture in the reaction vessel was washed out with an additional 20 mL of cold water. The aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 4.3 g (46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: 1H NMR (DMSO-d6): δ 11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI−MS m/z 203 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[N:36]=[CH:35][CH:34]=[CH:33]N=1)[OH:30].[CH:37](N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[N:36]([CH3:37])[CH:35]=[CH:34][CH:33]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ncccn1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2cccn2C)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyrimidin-2-ylethanol (Preparation 62)(63 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.3.8 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 24 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (86 mg) as a white solid.
Reaction SMILES: Cl.N[C@@H:3]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:4]([NH:6][C@@H:7]([CH2:18][CH2:19][CH2:20][CH3:21])[C:8](=[O:17])[CH2:9][S:10][CH2:11][C:12]1[O:16][CH:15]=[CH:14][CH:13]=1)=[O:5].[O:26]([CH2:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([N:39](CC)CC)C.Cl>C(Cl)Cl>[CH2:11]([S:10][CH2:9][C:8](=[O:17])[C@@H:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:22][C@H:23]([CH3:25])[CH2:24][NH:39][C:34](=[O:35])[CH2:33][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][CH2:20][CH3:21])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)CSCc1ccco1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)CC[C@H](C)CNC(=O)COc1ccccc1)C(=O)CSCc1ccco1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(s)-3-((s)-2-Amino-4-methylvalerylamino)-1-furfurylthio-2-heptanone hydrochloride (4.31 g) obtained in Example 2 was dissolved in methylene chloride (100 ml) and chilled to 0° C. To the solution were added phenoxyacetylchloride (2.07 g) and triethylamine (3.2 ml), and the mixture was stirred at 0° C. for 30 minutes, and at room temperature for 30 minutes. Then, 0.5N aqueous hydrochloric acid (50 ml) was added to the mixture, which was extracted with methylene chloride. The extract was washed with water, saturated sodium hydrogencarbonate and saturated brine sequentially, dried over magnesium sulfate and filtered. The filtrate was concentrated, and chromatographed on a silica gel column, eluting with hexane containing 25% ethyl acetate to give the titled product (3.96 g).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](OCC)=[O:12].[BH4-].[Na+].CC(C)=O>O1CCCC1.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: CCOC(=O)C1CCc2ccccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
A solution of ethyl 2-chromanecarboxylate (1.575 g, 7.68 mmol) in a mixture of tetrahydrofuran (75 ml) and water (2 ml) was added with sodium borohydride (0.686 g, 18.2 mmol) in small portions and the mixture was left under stirring at room temperature for 48 h. Afterwards the mixture was cooled at -10° C. and added with acetone (47 ml) stirring at room temperature for 0.5 h. Subsequently water (100 ml) was added and the mixture was extracted with dichloromethane. The combined organic phases were dried and the solvent was removed by evaporation under reduced pressure, thereby obtaining 1.218 g of the title product (97% yield).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([O:16]CC)=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N:25]1[NH:26][N:27]=[N:28][C:29]=1[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>C(O)C.[Pd].CN(C=O)C>[N:28]1[NH:27][N:26]=[N:25][C:29]=1[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([OH:16])=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:33]
Reactant: CCCCCCC(C(=O)OCC)n1cnc2c([N+](=O)[O-])cccc21
Reactant: O=C(O)c1ccccc1-c1nn[nH]n1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)O)n1cnc2c(NC(=O)c3ccccc3-c3nn[nH]n3)cccc21
Reaction time: 4 h
Yield: 9.6 %

Procedure:
Ethyl 2-(4-nitro-1H-benzimidazol-1-yl)octanoate (4.44 moles, 1.48 g.) was hydrogenated over 0.6 g of 5% Pd/C in 100 ml ethanol. The catalyst was filtered over celite. The solution was concentrated. The residue was dissolved in 25 ml DMF and added to a stirred mixture of 2-(2H-tetrazol-5-yl)benzoic acid (4.21 mmoles, 0.80 g), dicyclohexylcarbodiimide (4.31 mmoles, 0.89 g.), and hydroxybenzotriazole (4.44 mmoles, 0.60 g) in 50 mi DMF. The reaction was stirred for 4 hours. The solid was removed by filtration. The reaction was concentrated. The residue was dissolved in ethyl acetate, and washed with water. The pH was adjusted to 8.0 using 5N NaOH. The aqueous layer was acidified to pH 2.5 using 2N HCL, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried and concentrated. The product was purified over silica gel eluted with 2% EtOH in ethyl acetate with 1% acetic acid to yield 0.18 g of 2-[4-[2-(2H-tetrazol-5-yl)benzamido]-1H-benzimidazol-1-yl]octanoic acid. (MS)