Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>O1CCOCC1>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: C=Cc1ccccc1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Solvent: C1COCCO1
Product: O=Cc1ccc(C=Cc2ccccc2)cc1
Yield: 55.8 %

Procedure:
The procedure described in Example 1 is followed, except that 8.43 g (0.05 mol) of 4-formylbenzoyl chloride, 6.5 g (0.0625 mol) of styrene, 17.5 g (0.05 mol) of tri-n-octylamine, 100 ml of dioxane as the solvent and 0.287 g (0.0005 mol) of bis-(dibenzylideneacetone)-palladium(O) are used. After a reaction time of 2 hours at 120° C., 5.8 g (0.0279 mol) of 4-formylstilbene, corresponding to a yield of 56% of theory, are obtained as yellowish crystals; melting point 112°-113° C.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9](=[S:11])[NH2:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.CO[CH:23](OC)[CH2:24]Br.[OH-].[K+].C1C=CC=CC=1>O>[F:20][CH2:19][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]2[S:11][CH:23]=[CH:24][N:10]=2)[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: COC(CBr)OC
Reactant: NC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1nccs1)=CC(CF)(CF)O2

Procedure:
A mixture of 600 mg of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 1.2 ml of bromo-acetoaldehyde dimethylacetal, 11 mg of potassium hydroxide and 3 ml of benzene was refluxed with heating for 1 hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, hexane:ethyl acetate=2:1) to obtain 380 mg of 2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)thiazol represented by the following formula.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:28])([F:27])[C@@:6]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)[CH:19]=1)([NH:8][S@@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH3:7])C.[BH4-].[Li+].C(O)(=O)C.O>O1CCCC1>[Br:26][C:22]1[CH:21]=[C:20]([N:18]2[CH:19]=[C:15]([C@:6]([NH:8][S@@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])([CH3:7])[C:5]([F:28])([F:27])[CH2:4][OH:3])[CH:16]=[N:17]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cnn(-c2cccc(Br)c2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)N[C@](C)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A solution of (R)-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (700 mg, 2.42 mmol) in tetrahydrofuran (5 ml) was treated slowly with lithium borohydride (2M solution in tetrahydrofuran, 0.78 ml, 2.66 mmol) at 0° C., and the mixture was stirred at 25° C. for 2 hours. For the workup, acetic acid (0.26 ml, 4.5 mmol) was added slowly over a period of 15 minutes followed by water (2 ml), and the mixture was stirred for 30 minutes at 25° C. before it was quenched with a solution of sodium hydrogencarbonate (20 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (75 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=85:15 to 80:20 as the eluent to give the (R)-2-methyl-propane-2-sulfinic {(R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-hydroxy-1-methyl-propyl}-amide (460 mg, 67% yield) as a deep brown solid. MS (ISP): m/z=450.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([N+:24]([O-])=O)[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([NH2:24])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C(COC)c1c[nH]c2cccc(COC(C)=O)c12)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(COC(C)=O)c12
Yield: 62.5 %

Procedure:
3-(4-acetoxymethylindol-3-yl)-2-nitro-4-methoxy-butyric acid ethyl ester (226 g) is hydrogenated in ethanol (2.3 l) with Raney nickel as catalyst under hydrogen of normal pressure without addition of heat. 3 mol of hydrogen is taken up in 31/2 hours, whereby the temperature reaches a maximum of 45° C. After filtering of the catalyst and evaporation of the residue, the raw product is chromatographed on silica gel with a mixture of dichloromethane (97.5%) and ethanol (2.5%). 130 g of the title compound as noncrystalline diastereomeric mixture is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:32]1[O:34][C@@H:33]1[CH2:35]O.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[O:11][CH2:35][CH:33]1[CH2:32][O:34]1)[C:6]#[N:7])[CH3:2]
Reactant: OC[C@@H]1CO1
Reactant: CCc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (5.06 g, 31.4 mmol) in THF (80 mL), PPh3 (9.06 g, 34.5 mmol) and (R)-glycidol (2.29 mL, 34.5 mmol) are added. The mixture is cooled to 0° C. before DEAD in toluene (15.8 mL, 34.5 mmol) is added. The mixture is stirred for 18 h while warming up to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-ethyl-5-methyl-4-oxiranylmethoxy-benzonitrile (5.85 g) as a yellow oil; LC-MS: tR=0.96 min; [M+42]+=259.08.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25]>>[Br:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: BrCc1ccccc1Br
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3Br)ccc12
Yield: 4.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (151 mg, 0.71 mmol) and 1-(bromo-methyl)-2-bromobenzene (214 mg, 0.86 mmol) to provide 469 (11 mg, 4% yield) as a white powder. LC-MS (M+H=381, obsd.=381). 1H NMR (400 MHz, DMSO-D6) δ 11.50 (m, 1H), 8.53 (m, 1H), 8.39 (m, 1H), 8.01 (d, J=8.9, 1H), 7.68 (s, 1H), 7.43 (m, 2H), 7.37 (s, 1H), 7.23 (s, 2H), 6.92 (m, 2H), 4.55 (s, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:7].[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH2:13])[CH3:9].C([BH3-])#N.[Na+]>CO>[ClH:7].[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH:13][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: CCOC(=O)CN
Reactant: O=C1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNC1CCCC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Cyclopentanone (10 g) and glycine ethyl ester hydrochloride (21.6 g) are dissolved in 200 ml of methanol, and 7.48 g of sodium cyanoborohydride is added in small portions with stirring at room temperature. The mixture is further stirred at room temperature for 3 hours and the reaction mixture is concentrated under reduced pressure. To the residue is added 500 ml of water and the mixture is adjusted to pH 10 with diluted sodium hydroxide solution and extracted with 300 ml of ethyl acetate. The extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is then distilled off under reduced pressure and the resulting oily product is dissolved in 200 ml of ether, followed by addition of 10 ml of 10% alcoholic hydrochloride, whereupon crystals immediately separates out. The crystals are collected by filtration to give 12.7 g of N-cyclopentylglycine ethyl ester hydrochloride as colorless needles melting at 174°-175° C.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([S:14][CH3:15])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1.[CH2:22](I)C>>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([S:14][CH2:15][CH3:22])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1
Reactant: CCI
Reactant: CSc1nc2c(cnn2CC(O)c2ccccc2)c(=O)[nH]1
Product: CCSc1nc2c(cnn2CC(O)c2ccccc2)c(=O)[nH]1
Yield: 65 %

Procedure:
Compound 8b was prepared according to the synthetic sequence described for compound 8a, by using ethyl iodide as alkylating agent. In this case, the crude was purified by column chromatography (Silica Gel, 100 Mesh) using a mixture of CHCl3:MeOH (9:1) as the eluant, to afford the pure product 8b (2.05 g, 65%) as a light yellow solid: mp 199-200° C. 1H NMR: δ 1.45 (t, J=7.6, 3H, CH3), 3.22 (q, J=7.4, 2H, CH2), 4.44-4.68 (m, 2H, CH2N), 5.21-5.30 (m, 1H, CHO), 7.26-7.47 (m, 5H Ar), 8.10 (s, 1H, H-3). IR cm−1 3470 (NH), 3450-3340 (OH), 1670 (CO). Anal. (C15H16N4O2S) C, H, N, S.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](OCC)=[O:23])[CH:19]=[C:18]([CH2:27][O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.ClCCl.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:27][O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carboxylate (0.49 g, 1.05 mmol) in dry dichloromethane (25 mL) diisobutyl aluminum hydride (2.63 mL, 1M solution in hexane, 2.63 mmol), was added under nitrogen during 10 min at −78° C. The mixture was stirred at −78° C. for 1 h. Diisobutyl aluminum hydride solution (2.8 mL) was added and the mixture was stirred for 10 min. The mixture was quenched with methanol and allowed to warm to ambient temperature. Water (5 mL) was added, the slurry was stirred for 20 min and filtered through a pad of diatomeous earth. The pad was washed with 10% solution of methanol in dichloromethane. The organic phase was separated and the water phase was extracted with 10% solution of methanol in dichloromethane. The combined organic extracts was dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica eluting with 0-5% gradient of methanol in dichloromethane to yield the title compounds, 318 mg (72%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:33][C:29]([CH2:34]O)([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:33][C:29]([CH2:34][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: OCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCC12CCCN(CCC1)C2)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of indole-3-carboxylic acid (1.62 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, and degassed with a stream of nitrogen for 10 minutes giving a suspension. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The 1,1'-carbonyldiimidazole adduct suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little isopropanol and saturated sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 7% methanol/methylene chloride). The filtrated was concentrated in vacuo and the residue was triturated from cold ether and recrystallized from acetonitrile (2 crops) to afford 1.79 g (60%) of colorless crystals; m.p. 207°-209° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:37])=[C:17]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:37])=[C:17]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20]2)[CH:18]=1)=[O:6]
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(F)cc(F)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Yield: 97.1 %

Procedure:
3,5-Difluorobenzoyl chloride (0.91 g) was added to a stirred mixture of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (1.5 g), triethylamine (1.04 g) and methylene chloride (50 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution and the organic phase was evaporated. There was thus obtained the title compound (2.04 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 2.22 (s, 3H), 2.45-2.5 (m, 4H), 3.24-3.3 (m, 4H), 7.41-7.56 (m, 3H), 7.61-7.68 (m, 4H), 7.75-7.79 (m, 2H), 8.06 (s, 1H), 10.5 (s, 1H); Mass Spectrum: M+H+ 490.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[N:20]=[CH:19][N:18]2CC2C=CC=CC=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:30]>CO.C(Cl)Cl.C(OCC)C>[ClH:30].[CH2:15]1[C:16]2([C:21](=[O:22])[NH:20][CH2:19][NH:18]2)[CH2:17][NH:14]1
Reactant: O=C1N=CN(Cc2ccccc2)C12CN(C(c1ccccc1)c1ccccc1)C2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: O=C1NCNC12CNC2
Reaction time: 0.17 h

Procedure:
To a solution of 2-benzhydryl-5-benzyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-3A-50c; 1.83 g, 4.80 mmol) in methanol/methylene chloride was added excess 1 M HCl in diethyl ether (10 ml). After stirring for 10 minutes, the solvent was removed, in vacuo, and the resultant hydrochloride salt was dissolved in methanol (50 ml). After the addition of 20% Pd(OH)2 on carbon (50% water; 1.1 g), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 22 hours. The reaction was filtered through a 0.45 μM disk, and then concentrated, in vacuo, to give a gummy solid. This material was triturated from methanol to afford I-3A-50d (450 mg, 47%) as a tan solid: +APcl MS (M+1) 127.9; 1H NMR (400 MHz, CD3OD) δ 4.51 (s, 2H), 4.41-4.33 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[NH:11][N:10]=[C:9]3[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=4[CH2:14][CH2:15][CH2:16][CH:8]23)=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[NH:11][N:10]=[C:9]3[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=4[CH2:14][CH2:15][CH2:16][C:8]=23)=[CH:5][CH:6]=1
Reactant: c1ccc2c(c1)CCCC1C2=NNC1c1ccncc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: c1ccc2c(c1)CCCc1c-2n[nH]c1-c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a flask eqipped with a magnetic stirring bar is charged 5.0 grams of 3-(4-pyridyl)-2,3,3a,4,5,6-hexahydrobenzo[6,7]cyclohepta[1,2-c] pyrazole, 25 grams of activated manganese dioxide and 150 ml of dry benzene. The mixture is stirred for about 12 hours at room temperature, after which the manganese salts are filtered off and the solvent removed in vacuo. The solid is crystallized from ethanol to give 3-(4-pyridyl)-2,4,5,6-tetrahydrobenzo[ 6,7]cyclohepta[1,2-c]pyrazole (m.p. 217°-219°C).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[S:22][C:23]([CH:26]=O)=[CH:24][N:25]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.O1CCCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:26][C:23]1[S:22][C:21]([NH:20][C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([O:7][CH3:6])[CH:9]=2)=[N:25][CH:24]=1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: COCCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCNCc1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)s1

Procedure:
The title compound was prepared in analogy to example 57 from 14 mg (0.19 mmol) 2-methoxyethylamine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (2 ml), and methylene chloride (1 ml). The reaction was not complete and the same amount of reagent was added like in example 57. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 47 mg (54%) {5-[(2-methoxy-ethylamino)-methyl]-thiazol-2-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow oil. MS ISP (m/e): 374.2 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.64 (s, 1H), 7.26 (s, 1H), 7.18 (d, 1H), 7.12 (s, 1H), 6.95 (d, 1H), 6.87 (s, 1H), 3.93 (s, 2H), 3.85 (s, 3H), 3.51 (t, 2H), 3.36 (s, 3H), 2.83 (t, 2H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH:12]=[O:13].B([O-])=O.[Na+]>>[CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:17])([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13]
Reactant: C=C(C)C1CCC(C)=C1CC(C)(C=O)CCC
Agent: O=B[O-]
Agent: [Na+]
Product: C=C(C)C1CCC(C)=C1CC(C)(CO)CCC
Yield: 55 %

Procedure:
This compound was prepared from the product from Example 2 by reduction with sodium boranate, as described in Example 3. Yield 55%; boiling point 110°-114° C/0.5 mm Hg; nd25 : 1.4910. Odor: mold, green and herbaceous. cl EXAMPLE 9
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=O>O1CCCC1.C(O)(=O)C.C(OC(C)C)(C)C>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([CH3:15])=[C:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C=C(C)Nc1ccccc1N
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: COC(=O)C1=C(C)Nc2ccccc2NC1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 3-[(2-aminophenyl)amino]-2-butenoic acid, methyl ester (4.74 g., 230 mmole) in anhydrous tetrahydrofuran (20 ml.) and acetic acid (0.2 ml.) is treated with 2,6-dichlorobenzaldehyde (4.03 g., 23.0 mmole). The resulting reaction mixture is stirred at room temperature for 4 days. The solvent is stripped off to give a brown oil which is dissolved in isopropyl ether and allowed to stand at 0°-5° (refrigerator) for 24 hours. The solid that precipitates is filtered off and washed with additional isopropyl ether. This product is triturated with isopropyl ether and filtered off to give 2-(2,6-dichlorophenyl)-2,5-dihydro-4-methyl-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester; 119°-120° (with decomposition). TLC (silica gel; ethyl acetate:hexanes, 40:60) Rf =0.38.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1ccc(OC(C)c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(OC(C)c2ccc(C(=O)NCc3c(C)cc(C)nc3O)cc2)cc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of 4-(1-(p-tolyloxy)ethyl)benzoic acid (30 mg, 0.12 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (67 mg, 0.18 mmol), triethylamine (0.1 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (22 mg, 0.14 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (30 mL), dried over sodium, filtered, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(p-tolyloxy)ethyl)benzamide as a white solid (26 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:13][C:14]([CH3:18])=[CH:15][CH:16]=O.C1(B(O)O)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[O:11][C:14]([CH3:18])([CH3:13])[CH:15]=[CH:16]2
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)=CC=O
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2c(c1)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
25 g methyl-4-hydroxyphenylacetate, 14.5 ml 3-methylbut-2-enal and 18.3 g phenylboronic acid were placed together under nitrogen atmosphere in 1 l dry toluene and heated to boiling for 7 hours under reflux cooling. Then 60 ml glacial acetic acid was added to this receiving solution at room temperature (=RT) and the mixture was again heated to boiling for 7 hours under reflux cooling. It was allowed to cool to room temperature, the solvent was largely evaporated at reduced pressure and the remaining residue was poured into 300 ml of a 1:1 (v/v) mixture of ethyl acetate (═EA) and water. The pH value was adjusted to 5 by addition of solid sodium bicarbonate, the organic phase was separated off and largely evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: petroleum ether/EA 10:1 v/v) yielded 16 g methyl-(2,2-dimethyl-2H-chromen-6-yl)acetate as pale yellow oil.