Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([N:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]2=[O:24])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([N:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:42][CH2:43][CH:44]3[CH2:46][CH2:45]3)=[CH:19][C:18]2=[O:24])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a stirred solution of N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide (0.20 g, 0.59 mmol) in N,N-dimethylformamide (4 mL) at ambient temperature was added potassium carbonate (0.082 g, 0.59 mmol), followed by the addition of 2-cyclopropylethyl 4-methylbenzenesulfonate (0.13 g, 0.59 mmol). The reaction mixture was stirred at 70° C. for 2 hours, and then allowed to cool to ambient temperature and partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.14 g, 58%): mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=7.8 Hz, 1H), 7.36-7.27 (m, 5H), 6.83 (s, 1H), 6.18 (t, J=5.6 Hz, 1H), 6.06 (dd, J=7.8, 2.6 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.02 (t, J=6.6 Hz, 2H), 2.53 (s, 3H), 1.72-1.64 (m, 2H), 0.89-0.73 (m, 1H), 0.55-0.45 (m, 2H), 0.15-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.2, 162.9, 162.3, 139.7, 139.6, 138.0, 134.3, 128.7, 127.8, 127.5, 126.9, 121.9, 103.4, 97.4, 68.8, 43.9, 33.6, 15.9, 7.6, 4.2; MS (ES+) m/z 409.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C(Cl)Cl.[OH-].[Na+]>[C:15]([O:14][C:12]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-fluorobenzylamine (10 g, 41 mmol) and TEA (14 mL, 104 mmol) in CH2Cl2 was added BOC2O (9.1 g, 41 mmol). The resulting solution was stirred for 16 h at RT, then diluted with aq. 1 N NaOH and CH2Cl2. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated to give (tert-butoxy)-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide.
Reaction SMILES: N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26](F)[CH:25]=2)=CC3)CC1.[I-].[K+].P(=O)(O)(O)O.[K]>C(#N)C>[C:28]([OH:30])(=[O:29])[C:27]1[CH:32]=[CH:33][CH:24]=[CH:25][CH:26]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1ccccc1
Temperature: 120 °C
Reaction time: 66 h

Procedure:
To a sealable flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate (50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) and phosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture was diluted with acetonitrile (1 mL) and a solution of the crude mixture from the reaction above (1.718 mL, 0.445 mmol) was added. The mixture was flushed with N2 and the vial was sealed and heated to 120° C. After stirring the mixture for 66 h it was cooled to rt. The mixture was adsorbed to silica gel and was purified by flash chromatography using a 12 g Thomson silica gel column and a 0-5% MeOH in DCM gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give benzoic acid, 4-[(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[3-(1,1-dioxido-4-thiomorpholinyl)propyl]amino]-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-5a,5b,8,8,11a-pentamethyl-1-(1-methylethenyl)-1H-cyclopenta[a]chrysen-9-yl]-2-fluoro-, methyl ester (43 mg, 0.058 mmol, 65.6% yield) as a yellow film. LCMS: m/e 737.5 (M+H)+, 1.88 min (method 2).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:29]3[C:33](=[O:34])[CH2:32][CH2:31][C:30]3=[O:35])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:29]3[C:33](=[O:34])[CH2:32][CH2:31][C:30]3=[O:35])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CCC(=O)N1Cc1csc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (1.79 g, 3.53 mmol) (obtained as described in Reference Example 69(1)) in anhydrous tetrahydrofuran (141 ml) was added a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (4.24 ml, 4.24 mmol) in an ice bath and the mixture was stirred in an ice bath for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (20:1) as the eluant to afford 3-hydroxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (456 mg, yield 49%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Br[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:11][CH2:12][CH3:13])[CH:7]=1
Reactant: CCCBr
Reactant: Oc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
A mixture 5-Bromo-2-fluoro-phenol (prepared by the method of Elliott, M. et al. GB2187731) (500 mg, 2.62 mmol, 1 eq.), 1-bromopropane (322 mg, 2.62 mmol, 1 eq.), and K2CO3 (434 mg, 3.14 mmol, 1.2 eq.) in acetone (20 mL) is heated at 65° C. for 24 h. After cooling to room temperature, the reaction is concentrated, diluted with EtOAc and sequentially washed with 1 N aqueous NaOH and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (3:1 hexanes/EtOAc) to give 4-Bromo-1-fluoro-2-propoxy-benzene as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[N:14]=[C:13](Cl)[CH:12]=[C:11]([N:16]4[CH2:21][CH2:20][C:19]5([O:25][CH2:24][CH2:23][O:22]5)[CH2:18][CH2:17]4)[N:10]=3)[CH2:5][CH2:4]2)[O:2]1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[N:10]=[C:11]([N:16]4[CH2:21][CH2:20][C:19]5([O:25][CH2:24][CH2:23][O:22]5)[CH2:18][CH2:17]4)[CH:12]=[C:13]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:14]=3)[CH2:5][CH2:4]2)[O:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCC3(CC2)OCCO3)n1
Product: c1c(N2CCNCC2)nc(N2CCC3(CC2)OCCO3)nc1N1CCC2(CC1)OCCO2
Yield: 55.7 %

Procedure:
2,6-bis(4,4-Ethylenedioxy-1-piperidinyl)-4-chloropyrimidine is reacted with piperazine in the way described in Example 5 to obtain the title compound in a yield of 55.7%, m.p.:130°-140° C.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[NH2:2].[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10]N[C:8]1=[O:13])=[O:6].C(Cl)(Cl)=O>>[Cl:4][C:1]([N:2]1[CH2:10][CH2:11][CH2:12][N:7]([CH:8]=[O:13])[C:5]1=[O:6])=[O:3]
Reactant: NC(=O)Cl
Reactant: O=CN1CCCNC1=O
Agent: O=C(Cl)Cl
Product: O=CN1CCCN(C(=O)Cl)C1=O

Procedure:
This carbamic acid chloride was produced as described in Example 27 B from 5 parts by weight of 1-formyl-2-oxo-1,3-diaza-cyclohexane and 6 parts by weight of phosgene. The substance, an oil, was used without further purification for the production of the penicillin of Example 35 A. IR-bands at 1790, 1685, 1300 and 1165 cm-1.
Reaction SMILES: [Li].[OH-].O.[O:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([CH2:20][C:21](OC)=[O:22])=[CH:19][C:6]1=2>O1CCCC1>[OH:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][OH:22])=[CH:19][C:6]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Li]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
In this process, 20 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate is dissolved in 500 ml of tetrahydrofuran. To the solution is added 6.0 g of lithium alminium hydroxide and the mixture is stirred at room temperature for one hour. After decomposing an excess of the reagent by the addition of water to the solution, the mixture is filtered to remove an inorganic salts and the filtrate is concentrated to dryness under reduced pressure to obtain 17.7 g of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:20]([CH:26]4[CH2:28][CH2:27]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:29][CH:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH:23]1([C:22]2[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[CH:4]=[CH:3][C:2]([N:34]5[CH:30]([CH3:29])[CH2:31][CH2:32][C:33]5=[O:35])=[N:7][C:6]=4[CH3:8])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=[C:20]([CH:26]3[CH2:28][CH2:27]3)[CH:21]=2)[CH2:25][CH2:24]1
Reactant: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC1CCC(=O)N1
Product: Cc1nc(N2C(=O)CCC2C)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 58.6 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 251 and 5-methylpyrrolidin-2-one (34 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (61 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH:11]CC2C=CC(OC)=CC=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:11][C:5]1[N:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COc1ccc(CNc2ncc(F)cc2C(N)=O)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(F)cnc1N
Yield: 81.2 %

Procedure:
5-Fluoro-2-(4-methoxy-benzylamino)-nicotinamide (220 mg, 0.80 mmol) in CH2Cl2 (2 ml) and anisole (1 ml) was treated with TFA (2.57 ml, 34.6 mmol) at 60° C. for 3 hours. The reaction mixture was brought to dryness and the residue purified by column chromatography (silica gel, EtOAc/heptane, 1/4) to yield 2-amino-5-fluoro-nicotinamide (100 mg, 0.65 mmol; 81%) as yellow solid. MS (m/e): 156.1 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=4)[NH:8][N:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.O>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]1[C:14]2[N:15]([C:11]([C:9]3[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=3)=[CH:12][N:13]=2)[C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:29]([F:31])([F:30])[F:32])=[CH:18][CH:17]=2
Reactant: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Reaction time: 24 h

Procedure:
A solution of 5-[4-(3-Hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (0.12 mmol; 54 mg), LiOH (0.13 mmol; 3 mg), in THF/H2O (0.2+0.1 mL), was stirred at 40° C. overnight. Further LiOH (0.26 mmol; 6 mg) was added, and the reaction was continued at 50° C. another 24 hr. Concentration, and washing with water affords the title compound, as a white solid, lithium salt (51 mg; 0.12 mmol; 100%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:21]([OH:22])[C@@H:20]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][C@@H:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:10]1[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>N1C=CC=CC=1>[C:43]([O:22][C@@H:21]1[C@@H:20]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:19][C@@H:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[C@H:10]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[C@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)CCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1N1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OCc2ccccc2)[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](OCC[Si](C)(C)C)O[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(trimethyl silyl)ethyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (compound 14, 8.0 g, 13.6 m mol) in pyridine (40 ml), was added acetic anhydride (10 ml) at 0° C., and the mixture was stirred for 5 hrs at room temperature, and concentrated. Column chromatography (1:2 ethyl acetate-hoxane) of the residue on silica gel (200 g) gave compound 15 (8.6 g, quantitative yield) as crystals:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[CH:18][N:17]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.CCOC(C)=O>C1COCC1>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:19]=[CH:18][N:17]=[C:16]([NH:15][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:8]=3[NH:7][C:6]([CH2:4][OH:3])=[CH:14]4)[CH:21]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cc2cccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2cccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indole-2-carboxylic acid ethyl ester (285 mg, 0.67 mmol) in THF (2 mL) at 0° C. was added 1 M solution of LiAlH4 in THF (1.0 mL, Aldrich). The mixture was stirred at room temperature and the progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, to the mixture was added Na2SO4.10H2O (2 g), followed by the addition of MeOH (1 mL) and EtOAc (20 mL) with stirring at 0° C. The stirring was continued for 5 min and the mixture was filtered through a pad of Celite®. The filtrate was concentrated under vacuo and the residue was purified by silica gel column chromatography with gradient from 2% to 10% solution of (2 M NH3 in MeOH) in CH2Cl2 to afford the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 385 (M+1). MP: 221-223° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=[C:17]([C:16]#[N:20])[C:18]#[N:19]
Reactant: Cc1c(C=O)cc(C(C)(C)C)c(O)c1Br
Reactant: N#CCC#N
Product: Cc1c(C=C(C#N)C#N)cc(C(C)(C)C)c(O)c1Br

Procedure:
In a similar manner as described in Example 2 reaction of 3-bromo-5-tert-butyl-4-hydroxy-2-methyl-benzaldehyde and malononitrile gave 3-bromo-5-tert-butyl-4-hydroxy-2-methylbenzylidenemalononitrile m.p. 144°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][CH2:11][C@@H:12]([N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1)[CH3:13]>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C@@H:12]([CH3:13])[CH2:11][NH:10][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Product: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1

Procedure:
The title compound was prepared using the method of Example 247 starting from 2-methyl-1H-imidazole-4-carboxylic acid and (S)-4-[1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile. The crude product was purified by triturating in DCM at RT. 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, d), 2.27 (3H, s), 3.57 (1H, m), 3.67 (1H, m), 4.68 (1H, m), 6.96 (1H, d), 7.44 (1H, s), 7.89 (1H, d), 7.95-7.99 (3H, m), 8.12 (1H, s), 12.1 (1H, broad s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3]1.[O:25]1[C:34]2[CH:33]=[C:32]([CH:35]=O)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:25]1[C:34]2[CH:33]=[C:32]([CH2:35][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=5)[CH:12]=[C:11]4[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:7]3)[N:31]=[CH:30][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(N)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2ccc(OC)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of methyl 1-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-1H-indole-2-carboxylate (Intermediate 12, 200 mg, 0.60 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (100 mg, 0.60 mmol) in dry chloroform/methanol (10 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., sodium triacetoxy borohydride (384 mg, 1.8 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (150 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), the aqueous phase back extracted once with dichloromethane (70 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (5:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound, 239 mg (82% yield), as a colorless solid, mp 130° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>O1CCOCC1>[OH:1][C:2]1[C:3]([C:8]([NH2:10])=[S:20])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: NC(=S)c1ncccc1O
Yield: 71.6 %

Procedure:
A suspension of 3-hydroxypicolinamide (1 g) and Lawesson's reagent (2 g) in dry dioxane (75 ml) was allowed to react under Argon atmosphere at 95° C. for 4 hours. Then, insoluble solids in the reaction mixture was filtered off with suction and the filtrate was concentrated. The residue was dissolved in methylene chloride and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1). The second yellow fraction was concentrated. the residual solids were recrystallized from CHCl3 -n-hexane to give yellow crystals of 3-hydroxythiopicolinamide (546 mg, 46%), m.p. 150°-151° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1B(O)O>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:16]2[CH:15]=[CH:14][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CCCNC(=O)c1cccc(-c2ccc3ccccc3c2)c1
Yield: 57 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A was reacted with 2-naphthylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum ether 80:20 to CH2Cl2/AcOH 80:20 to give a white solid (57%). NMR 1H (ppm, CDCl3): 8.12 (t, J4=1.65 Hz, 1H), 8.06 (s, 1H), 7.91 (t, J3=8.37 Hz, 2H), 7.83 (d, J3=7.81 Hz, 2H), 7.73 (td, J3=8.51 Hz, J4=1.79 Hz, 2H), 7.55-7.46 (m, 3H), 6.18 (br. s., 1H), 3.49-3.43 (m, 2H), 1.67 (sext., J3=7.31 Hz, 2H), 1.00 (t, J3=7.37 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH3:16]>>[C:5]([CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: CCCCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CCCCCC(C(C)=O)C(=O)OC

Procedure:
Analogously to Example 14A, 30 g (217 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate (Example 13A) and 1.24 g (7.5 mmol) of potassium iodide are reacted with 32.8 g (217 mmol) of n-pentyl bromide to give methyl 2-acetylheptanoate.
Reaction SMILES: ClCCl.[Br:4][C:5]1[C:6]([O:29]C)=[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([C:20]#[N:21])=[C:9]([CH3:19])[C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrB(Br)Br.O>[Cl-].[Na+].O>[Br:4][C:5]1[C:6]([OH:29])=[C:7]([NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:8]([C:20]#[N:21])=[C:9]([CH3:19])[C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1c(Br)c(C=Cc2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1C=Cc1ccccc1
Temperature: -78 °C
Reaction time: 1.17 h
Yield: 97.3 %

Procedure:
A dichloromethane (1.0 ml) solution of N-(3-bromo-6-cyano-2-methoxy-5-methyl-4-styrylphenyl)-2,2-dimethylpropionamide (I-11) (34 mg, 79.6 μmol) was cooled at −78° C., a dichloromethane solution of 1 N tribromoborane (239 μl, 239 μmol) was dropwise added, followed by stirring at −78° C. for 70 minutes. Afterwards, this was heated up to −12° C. and stirred for 1 hour. The reaction liquid was put into cold water (50 ml), saturated brine (50 ml) was added, the intended product was extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain the entitled compound (32 mg, 96%) as a yellow white semi-solid.