Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[OH:29])[C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34].Cl>O.CN(C=O)C.C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH2:34][CH:33]=[CH2:32])[C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(OC(=O)c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a solution of 1.17 g (3 mmoles) of 4-[3-(1-adamantyl)-4-hydroxybenzoyloxy] benzoic acid in 100 ml of a 50:50 mixture of THF and DMF, there are added, by small portions, 180 mg (6 mmoles) of sodium hydride (80% in oil). The mixture is stirred at ambient temperature until the cessation of gaseous emission. There are then added 260 μl (3 mmoles) of allyl bromide and the mixture is stirred at ambient temperature for 3 hours. The reaction medium is poured into water, acidified to pH 4 with 1N HCl and extracted with ethyl ether. The organic phase, is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on silica eluted with ethyl ether. After evaporation of the solvent, 880 mg (68% yield) of 4-[3-(1-adamantyl)-4-allyloxybenzoyloxy] benzoic acid having a melting point of 260°-261° C. are recovered.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1>Cl.CC(C)=O>[CH:2]([C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)=[O:1]
Reactant: O=C(O)c1cnc(C2OCCO2)s1
Agent: Cl
Solvent: CC(C)=O
Product: O=Cc1ncc(C(=O)O)s1
Yield: 229.1 %

Procedure:
A solution of 2-(1,3-dioxolan-2-yl)thiazole-5-carboxylic acid (20 g, 0.1 mol) in hydrochloric acid (1000 mL, 3 N) and acetone (1000 mL) was heated to reflux for 6 h. The solution was then extracted with ether (5×500 mL). The combined organic phases were dried (Na2SO4) and concentrated. Flash column chromatography (petroleum ether: EtOAc, 100:1 to 5:1) afforded 2-formylthiazole-5-carboxylic acid (36 g, 76%). %). 1H NMR (DMSO-d6, 300 MHz) δ 13.90 (br, 1H), 9.92 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)CC=C.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:37]C)C=C4)N(CC2)C1.[O-]S([O-])=O.[Na+].[Na+].[CH:80]([OH:83])([CH3:82])[CH3:81]>O>[C:10]1([C:7]2[CH:6]=[C:5]([CH2:1][CH2:81][C@@H:80]([OH:83])[CH2:82][OH:37])[NH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)O
Reactant: C=CCCc1cc(-c2ccccc2)n[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H](O)CCc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(but-3-enyl)-3-phenyl-1H-pyrazole (3.0 g, 15.13 mmol) in iso-propanol (20 mL) and H2O (20 mL), was added AD-mix-α (20.0 g) at room temperature. The reaction was stirred for 48 h at room temperature. The reaction was poured into saturated Na2SO3 (20 mL) and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound (2.45 g) as an oil, which was used without further purification. LCMS m/z=232.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH2:17][CH2:18]O)[C:11]=1[OH:20])([CH3:9])[CH3:8])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([OH:25])([C:21]([F:23])([F:22])[F:24])[CH2:6][C:7]([C:10]1[C:11]2[O:20][CH2:18][CH2:17][C:12]=2[CH:13]=[C:14]([F:16])[CH:15]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)cc(CCO)c1O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)cc2c1OCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.1 %

Procedure:
4-(5-Fluoro-2-hydroxy-3-(2-hydroxyethyl)phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (3.90 g, 10.2 mmol) is dissolved with triphenylphosphine (3.14 g, 12 mmol) and triethylamine (2.1 ml, 15 mmol) in acetonitrile (150 ml), mixed with carbon tetrachloride (2 ml) and stirred for 3 days in a nitrogen atmosphere at room temperature. The solvent is distilled off in a rotary evaporator, and the residue is taken up in ethyl acetate (150 ml) and water (75 ml). The ethyl acetate phase is separated, washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 3.31 g of the product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:21][CH2:20][CH2:19][O:18][CH3:17])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: COCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCCOc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. ES-MS m/e (%): 271 (M+H+, 100).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[CH:2]=1.O1CCOCC1>[OH-].[Na+].O>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: CCOC(=O)c1cccc(Oc2cccc(C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Oc2cccc(C(=O)O)c2)c1

Procedure:
A mixture of ethyl 3-(m-tolyloxy)benzoate (0.084 g, 0.326 mmol) in NaOH 1M in water (2 mL) and dioxane (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue washed with dichloromethane, acidified to pH 2 with a 6N solution of hydrochloric acid in water, and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to yield quantitatively the title compound which was used without further purifications.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:12]=[C:13]([C:35](O)=[O:36])[C:14]2[CH2:15][C:16]([CH3:34])([CH3:33])[CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)[NH:18][C:19]=2[CH:20]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:12]=[C:13]([C:35]([NH:9][S:6]([CH:3]2[CH2:5][CH2:4]2)(=[O:8])=[O:7])=[O:36])[C:14]2[CH2:15][C:16]([CH3:33])([CH3:34])[CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)[NH:18][C:19]=2[CH:20]=1
Reactant: CC1(C)Cc2c(cc(F)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cc(F)cc2C(=O)NS(=O)(=O)C2CC2)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (630 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.52 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (100 mg, 40%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.60, observed: 488.1.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([O:15]C)=[CH:6][CH:5]=2.B(Br)(Br)[Br:25].C(Cl)Cl.Cl>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[C:8]([Br:25])[C:7]([OH:15])=[CH:6][CH:5]=2.[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([OH:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(Br)n2Cc1ccccc1
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)c(Br)c12
Product: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)cc12

Procedure:
A solution of 600 mg (1.6 mmol) of 2-bromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (lot was contaminated with 2,4-dibromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide) and 10 mL of 1M BBr3 /CH2Cl2 in 100 mL of CH2Cl2 was stirred for 2.5 hours, 100 mL of 1N HCl added, stirred well, and the CH2 Cl2 layer separated. After washing and drying (Na2SO4), the solvent was removed at reduced pressure. The residue was chromatographed on silica and eluted with a gradient (1% MeOH/CH2 Cl2 →4% MeOH/CH2Cl2) to give in the early fractions 2,4-dibromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (115 mg) and in the later fractions 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (115 mg). The material from the later fractions (100 mg, 0.28 mmol) was dissolved in 20 mL of DMSO, 20 mg of 60% NaH/mineral was added, and after 10 minutes, 0.1 mL of ethyl 4-bromobutyrate was added. After heating for 1.25 hours at 85° C., the mixture was diluted with water, extracted with EtOAc, and the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with 1% MeOH/CH2Cl2 →3% MeOH/CH2Cl2) to give 80 mg of 4-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester as an oil. This material was dissolved in 20 mL of EtOH, 1 mL of 2N NaOH added, and the mixture stirred for 19 hours. After acidifying with 1N HCl, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was crystallized from EtOH/ether to give 80 mg of 4-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]-butanoic acid.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16](=[O:18])[CH3:17])=[C:11]([CH3:19])[CH:10]=1.[ClH:20]>C(#N)C.[Cu](Cl)Cl>[Cl:20][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16](=[O:18])[CH3:17])=[C:11]([CH3:19])[CH:10]=1
Reactant: CC(=O)c1c(C)cc(N)cc1C
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC(=O)c1c(C)cc(Cl)cc1C
Temperature: 0 °C
Yield: 76 %

Procedure:
Anhydrous copper(II) chloride (98.9 g, 0.74 mol) was mixed with tert-butyl nitrite (94.8 g, 0.83 mol) in acetonitrile (1.02 L). The solution was cooled to 0° C. and slowly added with 1-(4-amino-2,6-dimethylphenyl)ethanone (100 g, 0.61 mol) in a period of 5.0 min. After the addition was completed, the reaction mixture was warmed to room temperature, and was poured into an aqueous hydrochloric acid solution (20%, 1.0 L). The solution was extracted with EtOAc (800 mL), and the organic layer was separated, washed with H2O (1.0 L), dried over MgSO4 (s), and concentrated under reduced pressure. The liquid was distilled to give 1-(4-chloro-2,6-dimethylphenyl)ethanone (85.0 g) as yellow oil in 76% yield: 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 2H), 2.45 (s, 3H), 2.22 (s, 6H).
Reaction SMILES: [OH:1]S(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>O>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:1])[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCC#Cc1ccccc1Br
Solvent: O
Product: O=C(O)CCCC(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into 20 cc of concentrated H2SO4 was dissolved 0.1 g (0.4 mmol) of the product of Example 1 to give a brown solution. The solution was allowed to stand at room temperature for 10 minutes. Thereafter, the solution was cooled to 0° C. in an ice bath and ice was then added to it. The solution was then diluted with water and extracted twice with ethyl acetate. The combined extracts were sequentially washed once each with water and brine and then dried (MgSO4). Removal of the solvent under reduced pressure produced a yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH:13]CC)[CH3:12].[CH:16]1C=CC=C[CH:17]=1>>[CH2:1]([N:8]([CH2:16][CH3:17])[C:9]([NH:13][CH2:11][CH3:12])=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: c1ccccc1
Reactant: CCNCC
Reactant: CCCCCCCN=C=S
Product: CCCCCCCN(CC)C(=S)NCC

Procedure:
To a solution of 3.14 grams (0.02 mole) of heptyl isothiocyanate dissolved in 15 milliliters of benzene was added 1.46 grams (0.02 mole) of diethylamine. The temperature rose to about 50° C. The mixture was refluxed on a steam bath for 20 minutes until a neutral pH was obtained. The mixture was then evaporated under vacuum to give 4.8 grams of n-heptyl-diethyl-thiourea. To this product, 4.1 grams (0.02 mole) of bromoethylamine hydrobromide and 25 milliliters of ethanol 2B was added. The mixture was refluxed on a steam bath for four hours and then permitted to stand overnight at ambient temperature. The mixture was then refluxed an additional three hours. The mixture was evaporated under vacuum to yield 8.83 grams of a yellow gel-like liquid, ND30 =1.5410. The structure of the product was confirmed by NMR.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH2:23][NH:22][C:21]=2[CH:26]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10].[Cl:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[ClH:27].[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH2:23][N:22]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:26]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]
Reactant: ClCc1cccc2ccccc12
Reactant: CCCN(CCC)CCc1ccc2c(c1)NCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1ccc2c(c1)N(Cc1cccc3ccccc13)CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (316 mg, 2.29 mmol) was added to a solution of 3,4-dihydro-6-[2-(N,N-dipropylamino)ethyl]-2H-1,4-benzoxazine hydrochloride (200 mg, 0.76 mmol) obtained in Example 134 and 1-chloromethyl naphthalene (400 mg, 2.29 mmol) in DMF (15 ml). After the reaction solution was stirred at room temperature for 2 hours, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1), treated with 4 N hydrochloric acid in ethyl acetate and crystallized from acetone-pentane, whereby the title compound (80 mg) was obtained as crystals with a mp of 177 to 178° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12]Br.Cl>CO.[OH-].[Na+]>[Br:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: BrBr
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Temperature: 40 °C
Yield: 92 %

Procedure:
1H-Indazole-5-carbonitrile (5.3 g, 36.8 mmol) was dissolved in methanol (60 mL) and aqueous sodium hydroxide (30 mL). Bromine (7.07 g, 44.4 mmol) in solution in 2.0 N aqueous sodium hydroxide (30 mL) was added with a disposable pipet. The reaction mixture was then heated to 40° C. for 1.5 hours. The reaction was cooled to room temperature and acidified with 6.0 N aqueous hydrochloric acid. The resulting solid was collected by filtration and washed 3 times with 20-mL portions of water. The solid was dried under vacuum for 1 day. The solid was used without further purification. (7.54 g, 92% yield): 1H NMR (CDCl3) δ 13.3 (br s, 1H), 8.0 (s, 1H), 7.5 (s, 2H); ES-MS (m/z) 224 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:41]/[C:42](/[CH3:49])=[CH:43]\[C:44]([O:46][CH2:47][CH3:48])=[O:45]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:42]([CH3:49])[NH:41][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)[CH2:22][CH2:21]1)=[O:16]
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccc(C)cc2)c2ccc(C)cc2)CC1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)C1c1cccc(Cl)c1Cl
Yield: 27.3 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde, 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl ethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 85°-88° C. (sintering). Yield 27.3%. IR(Nujol)cm-1 : 3330, 1690. NMR(CDCl3) δ: 1.14(3H,t,J=7,--CH2CH3), 2.25(12H,s, ##STR37## 4.05(2H,q,J=7,--CH2CH3), 4.08(1H,s,>N--CH<), 4.08(2H,t, J=6,--COOCH2CH2 --), 5.41(1H,s,C(4) --H), 5.68(1H,broad s, NH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.1 g, 4.95 mmol) and tetrahydro-2H-pyran-4-amine (500 mg, 4.95 mmol) in DMF (6 mL) was added K2CO3 (1.37 g, 9.9 mmol) and the mixture stirred in sealed tube at 85° C. for 16 h. After cooling, water (100 mL) was added to the mixture and extracted with DCM (3×50 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4 then filtered and concentrated to yield the title compound which was directly used for next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:28]3)[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1
Reactant: NC1=Nc2ccc(F)cc2Nc2sccc21
Reactant: COCCC[C@H]1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 48 h
Yield: 21.4 %

Procedure:
Combine 6-fluoro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (742.0 mg, 2.75 mmol), (S)-2-(3-methoxy-propyl)-piperazine (870.7 mg, 5.50 mmol), DMSO (2.0 ml), and toluene (8.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 220.1 mg (21%) of the title compound: mass spectrum (ion spray): m/z 375.1 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([F:11])=[C:9]([Br:12])[C:8]([CH3:13])=[C:7]([C:14]#[N:15])[C:6]=1[NH2:16])(=O)[CH3:2].O.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C1(C)C=CC=CC=1>[Br:12][C:9]1[C:10]([F:11])=[C:5]2[O:4][C:1]([CH:2]3[CH2:19][CH2:18]3)=[N:16][C:6]2=[C:7]([C:14]#[N:15])[C:8]=1[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)Oc1c(N)c(C#N)c(C)c(Br)c1F
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N

Procedure:
2-Amino-5-bromo-3-cyano-6-fluoro-4-methylphenyl acetate (I-76) (7.95 g, 25.38 mmol) was dissolved in toluene (80 ml), p-toluenesulfonic acid monohydrate (1.60 g, 20 wt. %) was added, followed by stirring under reflux for 19 hours.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+].[C:12]([O:16][C:17](=[O:36])[N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[C:21]([Cl:27])[N:20]=1)([CH3:15])([CH3:14])[CH3:13].O>CO>[C:12]([O:16][C:17](=[O:36])[N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[C:21]([Cl:27])[N:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncccc23)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 465 mg, 3.93 mmol) in methanol (50 mL) were added sodium hydroxide (0.630 g, 0.0157 mol) and (4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (541, 1.5 g, 0.0039 mol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (542, 1.0 g, 51%). MS (ESI) [M+H+]+=499.1.