Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:19](=[O:22])[CH:20]=[CH2:21])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCCCC(=O)OCC
Reaction time: 3 h

Procedure:
A mixture of ethyl-6-hydroxyhexanoate (49.44 grams, 0.31 moles), methylene chloride (200 mL), and triethylamine (36.26 grams, 0.36 moles) was cooled in an ice bath. Acryloyl chloride (29.87 grams, 0.33 moles) was added dropwise over 60 minutes. The mixture was stirred for 3 hours and filtered. The solution was concentrated under vacuum and diluted with ethyl acetate (300 mL). The mixture was washed with saturated aqueous sodium bicarbonate and water, and then dried over magnesium sulfate. The solvent was removed under vacuum to give a crude oil that was purified by vacuum distillation. A slightly yellow oil (ethyl-6-acryloxy-hexanoate) was collected at 90-92° C. at 0.70 mm Hg (51.27 grams). A portion of this oil (40 grams) was further purified by column chromatography over silica gel using 10 volume percent ethyl acetate in hexane to give the product as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-(trifluoromethoxy)benzene boronic acid according to the general procedure B. Obtained as an orange solid (569 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]([C:25]([NH2:27])=[O:26])=[N:12][C:13]([CH:22]([CH3:24])[CH3:23])=[C:14]([O:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[N:15]=2)[CH:6]=[N:5]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C(Cl)(Cl)Cl>[C:37]([N:19]1[CH2:20][CH2:21][C@@H:17]([O:16][C:14]2[N:15]=[C:10]([NH:9][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][OH:1])[CH:8]=3)[C:11]([C:25]([NH2:27])=[O:26])=[N:12][C:13]=2[CH:22]([CH3:23])[CH3:24])[CH2:18]1)(=[O:40])[CH:38]=[CH2:39]
Reactant: CC(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1O[C@@H]1CCNC1
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CC[C@@H](Oc2nc(Nc3cnn(CCO)c3)c(C(N)=O)nc2C(C)C)C1
Reaction time: 1 h

Procedure:
To a mixture of 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-isopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyrazine-2-carboxamide (476 mg), chloroform (5 mL), and diisopropylethylamine (867 μL) was added acryloyl chloride (226 μL) at 0° C., followed by stirring at the same temperature for 1 hour. The solvent of the reactant was evaporated, and then to the obtained residue were added tetrahydrofuran (5 mL) and a 1 M aqueous sodium hydroxide solution (5 mL), followed by stirring at 50° C. for 4 hours. After leaving to be cooled, the mixture was extracted by the addition of chloroform, and the organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=980:18:2-90:9:1), and then washed with diisopropyl ether to obtain 5-{[(3R)-1-acryloylpyrrolidin-3-yl]oxy}-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-isopropylpyrazine-2-carboxamide (343 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[N:6][CH:7]=1.[CH:13](O)=O>C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(C2CCCN2)c1
Reactant: O=CO
Agent: C=O
Product: CN1CCCC1c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Enantiomerically enriched 5-bromo-3-(2-pyrrolidinyl)pyridine (1.82 g, 8 mmol) was dissolved in a mixture of 98% formic acid (16 mL) and 37% aqueous formaldehyde (8 mL). The solution was heated with stirring for 3 h at 80° C. After cooling to 25° C. the mixture was concentrated in vacuo and water (30 mL) added. The mixture was basified with solid NaOH to pH 12 and extracted with methylene chloride (3×40 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel with ethyl acetate:hexane (1:3) as eluant to afford 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 1.63 g,84%. LRMS (EI) m/e 242 (C10H13N281Br), 241 (C10 H13N279Br--+H), 240 (C10H13 N279Br), 239 (C10H13N279Br--+H); 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (d, J=2.1 Hz, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.88 (t, J=1.9 Hz, 1H), 3.24 (b-dt, J=8.1 Hz, 1H), 3.10 (t, J=8.0 Hz, 1H), 2.36 (m, 1H), 2.18 (s, 3H), 1.95 (m, 1H), 1.85 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[C:3]=1[CH3:21].B(F)(F)F.[CH3:26]COCC.CC[CH2:33][CH2:34][CH3:35]>C(O)(C)(C)C>[CH3:26][C:34]([C:19]1[C:2]([OH:1])=[C:3]([CH3:21])[C:4]2[CH2:5][CH2:6][C@@H:7]3[C@@H:16]([C:17]=2[CH:18]=1)[CH2:15][CH2:14][C@@:12]1([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]1=[O:20])([CH3:33])[CH3:35]
Reactant: CCCCC
Reactant: Cc1c(O)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(C)(C)O
Product: Cc1c(O)c(C(C)(C)C)cc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a suspension of the known 3-hydroxy-4-methylestra-1,3,5(10)-trien-17-one (ref. Kaneko et al., 1964; Chemical Abstracts Registry Number [68969-90-4], 30 mg, 0.11 mmol) in 1 mL of anhydrous pentane and 0.5 mL of t-butanol, was added 0.03 mL of boron trifluoride diethyl etherate while cooling with an ice bath and stirring. After 20 min., the reaction was stirred at room temperature for 2.5 h. Ice was added and the solid that formed was filtered, washed with water and dried overnight in a vacuum desiccator. The crude product was purified by chromatography (silica gel eluted with 10% ethyl acetate in hexanes) and then recrystallized from methylene chloride-hexanes to give 20 mg of pure product (56% yield): m.p.190-192° C.; 1H NMR(CDCl3) δ 0.90 (s, 3H, CH3), 1.42 (s, 9H, C(CH3)3) 2.13 (s, 3H, CH3) 2.79-2.81 (m, 2H, CH2), 7.16 (s, 1H, Ar—H); 13C NMR (CDCl3) δ 11.06, 13.70, 21.44, 26.16, 26.60, 26.68, 27.54, 29.82 (3×C), 31.55, 34.43, 35.84, 37.63, 44.52, 47.89, 50.34, 121.42, 131.28, 133.00, 133.55, 150.56, 221.45. (Anal. calc'd. for C23H32O2: C, 81.13; H, 81.09. Found: C, 81.09; H, 9.59.)
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)[O:21][C:19](=O)[CH2:18][C:16](=O)O1>CCO>[C:1]1([C:7]2[NH:8][N:9]=[C:10]3[C:11]=2[CH:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][C:19](=[O:21])[NH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CCO
Product: O=C1CC(c2ccccc2)c2c(n[nH]c2-c2ccccc2)N1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 142.6 %

Procedure:
To 3-phenyl-1H-pyrazol-5-amine (0.20 g, 1.26 mmol) in EtOH (8 mL) was benzaldehdye (0.14 mL, 1.39 mmol) followed by Meldrum's Acid (0.318 g, 1.39 mmol) and then the reaction was heated to 75° C. After 1.5 hr, the reaction mixture was cooled to room temperature and placed in an ice bath. The product was filtered off and dried under reduced pressure to give the title compound (0.26 g, 71% yield) as a white solid. LRMS m/z (APCI+) 290 (M+1).
Reaction SMILES: BrCCBr.[Li+].[Br-].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.C(O)C.[Zn]>[C:31]([O:30][C:28]([C:25]1[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]\[C:17]2[CH:16]=[CH:15][C:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[CH:19][CH:18]=2)=[CH:23][CH:24]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(/C=C\c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
52.6 g of Zn and 70 ml of ethanol are heated together with 13 g of 1,2-dibromoethane until evolution of gas ceases. A solution of 13 g of CuBr and 15.8 g of anhydrous LiBr in 70 ml of THF is added at 40° to 50° C. and the reaction mixture is stirred for 10 minutes. A hot solution of 50 g of 4,4'-tolan-dicarboxylic acid di-tert.-butyl ester in 70 ml of ethanol and 130 ml of THF is added and the mixture is heated under reflux for 72 hours. After filtration, the filtrate is concentrated by evaporation, taken up with CH2Cl2, washed twice with dilute HCl and H2O, dried and concentrated by evaporation. 46.3 g of Z-4,4'-stilbene dicarboxylic acid di-tert.-butyl ester are obtained.
Reaction SMILES: [S:1](=[O:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][C:6]=1[CH:12]([CH3:14])[CH3:13].N([O-])=O.[Na+].[ClH:19]>C(O)(=O)C.O.[Cu]Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:1]([Cl:19])(=[O:3])=[O:2])=[CH:7][C:6]=1[CH:12]([CH3:14])[CH3:13]
Reactant: O=S=O
Reactant: Cl
Reactant: CC(C)c1cc(N)ccc1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
Amounts used: 25 mL of acetic acid was saturated with sulfur dioxide, 671 mg of copper(I) chloride, 4.60 g (27.1 mmol) of 4-chloro-3-isopropyl-phenylamine dissolved in a mixture of 4 mL of acetic acid and 9 mL of concentrated hydrochloric acid, 2.3 g of sodium nitrite in 10 mL of water. Flash chromatography on silica using 3-20% ethyl acetate in hexanes afforded 2.18 g of the product as a white solid. LC-MSD spectrum not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:20][CH:22]2[O:24][CH2:23]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: ClCC1CO1
Reactant: O=C1CCc2c(O)ccc(Cl)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1CCc2c(OCC3CO3)ccc(Cl)c2N1
Reaction time: 6 h

Procedure:
20.0 Grams of 8-chloro-5-hydroxy-3,4-dihydrocarbostyril and 18 g of potassium carbonate are suspended in 160 ml of isopropyl alcohol, then 40 ml of epichlorohydrin are added and the reaction is carried out at 70°-80° C. for 6 hours. The reaction mixture is concentrated under reduced pressure and the thus-obtained residue is stirred with 100 ml of 2N-sodium hydroxide under cooling conditions. The insoluble matter is separated by filtration, washed with water and dried. The crude crystals are recrystallized from isopropanol to obtain 18.5 g of 8-chloro-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 161°-165° C.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+:10](C)C3C=CC=CC=3)[S:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].N[N:27]1[C:31](=[O:32])[CH2:30][S:29][C:28]1=[S:33].CN(C)C=O>O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:10][N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[S:33])[S:9][C:5]=2[CH:4]=1
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Reactant: NN1C(=O)CSC1=S
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC(=S)N1N=c1sc2ccc(Cl)cc2s1
Temperature: 50 °C
Yield: 79 %

Procedure:
A mixture of the methiodide of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (1.9 g), sodium carbonate (121 mg), N-aminorhodanine (338 mg) and dimethylformamide (20 ml) is heated at 50° C for 3 hours. The mixture is poured into water and the precipitate which forms is filtered and washed with water. The product is recrystallized from dimethylformamide to yield 600 mg of the title compound, melting point 312°-314° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][N:5]=1)C.B(Br)(Br)Br.[C:25]([O-])(O)=[O:26].[Na+]>ClCCl>[CH3:25][O:26][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:3][CH3:1])=[N:5][CH:6]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: O=C([O-])O
Reactant: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To N-ethyl-5-(6-methoxy-1,3-benzothiazol-2-yl)pyridin-2-amine (52.8 mg, 0.185 mmol) in dichloromethane (2 mL) was added BBr3 in dichloromethane (1 M, 925 μL) at 0° C. under an argon atmosphere. The reaction was then stirred at 0° C. for 3 h before it was neutralized with NaHCO3 (sat aq). The precipitated product was filtered off, washed with water and DCM and dried. Recrystallization from (MeOH/toluene) gave the title compound (11 mg) as a white solid. 1H NMR δ ppm 9.75 (br s, 1H) 8.58 (d, 1H) 7.93 (dd, 1H) 7.73 (d, 1H) 7.34 (d, 1H) 7.19 (t, 1H) 6.92 (dd, 1H) 6.56 (d, 1H) 3.32-3.38 (m, 2H) 1.16 (t, 3H); MS m/z (M+H) 272.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH3:15][C:16]1([CH3:22])[CH2:20][O:19][NH:18][C:17]1=[O:21].C(=O)(O)[O-:24].[Na+]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:18][O:19][CH2:20][C:16]([CH3:22])([CH3:15])[C:17]([OH:24])=[O:21]
Reactant: O=C([O-])O
Reactant: O=Cc1ccccc1Cl
Reactant: CC1(C)CONC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CON=Cc1ccccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (4 mL) was added to a stirred mixture of 2-chlorobenzaldehyde (24.5 grams; 0.174 mole) and 4,4-dimethyl-3-isoxazolidinone (20.1 grams; 0.174 mole) in toluene (150 mL) cooled in an ice bath and under a nitrogen atmosphere. Upon completion of addition, the reaction mixture was stirred at ambient temperature overnight under a nitrogen atmosphere. The reaction mixture was then neutralized by the careful addition of solid sodium bicarbonate and then extracted with aqueous sodium bicarbonate (3×500 mL). The combined aqueous extracts were acidified to pH 3 with concentrated hydrochloric acid and then extracted with methylene chloride (3×150 mL). The dried (sodium sulfate) organic layer was concentrated under reduced pressure to afford 16 grams of 2-(2-chlorobenzylideneaminooxymethyl)-2-methylpropanoic acid as a solid, m.p. 78°-80° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:44])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(F)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
2-{[4-(2-{(4′Fluorobiphenyl-4-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (675 mg) synthesized in Example 256-2 and thiophenol (169 mg) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (425 mg) was added, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (454 mg) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](C=O)=[CH:15]2.[BH3-]C#[N:25].[Na+]>CO>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([NH:25][NH:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9])=[CH:15]2
Reactant: [BH3-]C#N
Reactant: NC(=O)c1[nH]cnc1N
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1[nH]cnc1NNc1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
A reaction mixture of 4-amino-5-imidazolecarboxamide hydrochloride (0.48 g, 2.94 mmol), 5-fluoro-1H-indole-2-carbaldehyde (0.40 g, 2.45 mmol), and NaCNBH3 (0.15 g, 2.45 mmol) in methanol (3 mL) was stirred at r.t. for 1 h. Additional 5-fluoro-1H-indole-2-carbaldehyde (0.42 equiv.) was added and after stirring at r.t. for 1 h the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.75 g (70%) of the title compound. MS (ESI) m/z 272 (M−1).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[OH:10][CH2:9][C:7]1[N:8]=[C:3](/[CH:2]=[CH:18]/[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH:4]=[CH:5][CH:6]=1.[OH:10][CH2:9][C:7]1[N:8]=[C:3](/[CH:2]=[CH:18]\[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CO)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cccc(CO)n1
Product: CC(C)(C)OC(=O)/C=C\c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Hydroxymethylpyridine-2-carbaldehyde (15.3 g) was dissolved in 250 mL of dry DMF, and 50 g of (t-butoxycarbonylmethylene)triphenylphosphorane was added to the above solution, and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was thrown into ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 300 mL of a mixture of hexane-ethyl acetate (2:1), the insoluble portion was filtrated off. The filtrate was concentrated under reduced pressure, the residue was purified by chromatography on silica gel (hexane-ethyl acetate=2:1) to give 16.86 g of t-butyl 3-(6-hydroxymethylpyridin-2-yl)-trans-acrylate and 5.69 g of t-butyl 3-(6-hydroxymethylpyridin-2-yl)-cis-acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.[CH:27](O)=O.C=O>CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCNCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: O=CO
Agent: C=O
Solvent: CO
Product: COc1ccc(N2CCN(C)CC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 34 %

Procedure:
To a solution of 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide (100 mg, 0.26 mmol) in methanol (8 ml) were added formic acid (100 μl, 2.6 mmol) and formaldehyde (23 μl, 0.31 mmol) and the mixture refluxed for 18 h. Workup and purification as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide afforded the product as light yellow powder (34%), MS: m/e=403(M+H+).
Reaction SMILES: [CH3:1][SH:2].[OH-].[Na+].Cl.[NH2:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18]Cl)[CH:12]=1)[C:8]([OH:10])=[O:9]>O>[NH2:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][S:2][CH3:1])[CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reactant: CS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCc1cc(C(N)C(=O)O)ccc1O
Reaction time: 8 h

Procedure:
To a solution of methanethiol (3 g, 0.04 mmole) in 250 ml of water is added sodium hydroxide (0.04 mole) followed by (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid hydrochloride (5 g, 0.02 mole). The solution obtained is stirred overnight. Removal of the solvent by flash evaporation gives a quantitative yield of the title compound combined with 2 equivalents of sodium chloride.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:41]1([C:47]2[CH:48]=[CH:49][C:50]([C:53](O)=[O:54])=[N:51][CH:52]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[CH3:12][C:11]([CH3:14])([CH3:13])[C@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:8]([N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH2:6][N:5]2[C:53]([C:50]1[CH:49]=[CH:48][C:47]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:52][N:51]=1)=[O:54])=[O:9]
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a 10 ml vial was added N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (100 mg, 0.268 mmol), EDC (128 mg, 0.670 mmol), HOBt (41.0 mg, 0.268 mmol), 5-phenyl-2-pyridinecarboxylic acid (64.1 mg, 0.322 mmol), CH2Cl2 (2.8 ml) and DIEA (0.187 ml, 1.072 mmol). The mixture was stirred at room temperature for 4 h, then diluted with sat. Na2CO3. The organic layer was passed over a phase separator and concentrated and purified by reverse phase HPLC: 30×75 mm sunfire column 50 ml/min, 0.1% TFA, 20-60% ACN/Water over 14 min. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the resulting aqueous layer was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were combined, dried and concentrated to afford the desired product (123 mg, 0.227 mmol) as an off white solid. LCMS (m/z): 536.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 1H), 1.05 (s, 2H), 1.07 (s, 2H), 1.10 (s, 4H), 1.73-2.09 (m, 2H), 3.37-4.07 (m, 4H), 4.45-5.27 (m, 3H), 6.90-7.25 (m, 2H), 7.26-7.96 (m, 9H), 8.03-8.38 (m, 2H), 8.42-9.10 (m, 1H), 11.55-11.83 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:7][CH2:8]C(O)=O)=[CH:5][CH:6]=1.C([Li])CCC.[N+:17]([O-])([O:19]CCC(C)C)=[O:18]>CCCCCC>[CH3:1][C:2]1[S:3][C:4]([S:7][CH2:8][N+:17]([O-:19])=[O:18])=[CH:5][CH:6]=1
Reactant: Cc1ccc(SCC(=O)O)s1
Reactant: CC(C)CCO[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1ccc(SC[N+](=O)[O-])s1
Yield: 9 %

Procedure:
The starting material was obtained using a similar procedure to that described for that in Example 9, but starting with 2-(2-methylthien-5-ylthio)acetic acid (described in Zh. Obsch. Khim. 1959, 29, 3631; 8.87 g), adding the butyllithium in hexane at -30° C. and the isoamyl nitrate at 0° C. The product 2-methyl-5-(nitromethylthio)thiophene, was obtained as an oil in 9% yield after column chromatography eluting with 10% ethyl acetate/hexane; NMR: 2.48 (s,3H), 5.38 (s,2H), 6.7 (m,1H), 7.1 (d,1H).