Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[OH:41][C@@H:39]([CH3:40])[CH2:38][NH:37][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 86.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: Cl.NO.N1C=CC(C=[O:11])=CC=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[N:19][OH:20])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[OH:11][C:13]1[CH:14]=[C:15]([CH:18]=[N:19][OH:20])[CH:16]=[CH:17][N:12]=1
Reactant: O=Cc1ccncc1
Reactant: ON=Cc1ccncc1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: O
Product: ON=Cc1ccnc(O)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
1.3 g of hydroxylamine hydrochloride was solved to 5 g of ion-exchange water, and the solution was heated to 65° C. Then 2 g of 4-pyridinecarbaldehyde was added dropwise. The reaction was carried out at 65° C., for 30 minutes, and a solution containing 2.2 g of 4-pyridinaldoxime was obtained. The resulting 4-pyridinaldoxime was identified by HPLC analysis. Thereafter, the reaction solution was cooled to 30° C., and was neutralized by saturated sodium hydrogen carbonate solution to be adjusted to pH 6. Six hundred mL of 0.1M potassium phosphate buffer (adjusted to pH 7.0) was added to the neutralized solution. Further, as in Example 1, the Delftia species YGK-A649 (FERM BP-10389) was cultured, and thus, the bacterial cells in 1000 mL of the culture was collected by centrifugation to obtain the resting bacterial cells and then form a suspension thereof. The suspension was charged to a reaction vessel (2000 mL volume) capable of shaking, aerating, controlling temperature, and controlling pH, and a reaction was carried out at 20° C., and pH 7-8, while shaking and aerating. After the reaction for 108 hours, 2-hydroxy-4-pyridinaldoxime was obtained at yield rate of 87% in the reaction. The analysis values of the resulting 2-hydroxy-4-pyridinaldoxime by IR analysis, proton NMR analysis and MS analysis were the same as the values described in Example 3, and thus, the structure of the resulting 2-hydroxy-4-pyridinaldoxime was identified.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1>CCOC(C)=O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
1-[2-(3,5-Dimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3,5-dimethoxyphenyl)boronic acid following general procedures as described in these Examples. Silica gel chromatography using 10-50% EtOAc in hexanes as eluant provided 90 mg (52%) of a yellow solid. MP 206.9-207.7° C., M+H=340.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=3)[C:5]=2[N:6]=1.[Br-].[C:23]1([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=4)[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COc1ccc2c(c1)CCc1sc(S)nc1-2
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Br-]
Product: O=C(O)COc1ccc2c(c1)CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 50 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-7-yl)oxy]acetate and diphenylmethane bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 50%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:17])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.C([Li])(CC)C.[CH3:23][CH:24]([CH3:27])[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:25]([CH:24]([CH3:27])[CH3:23])[CH2:17][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CC(O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (1.42 g) in tetrahydrofuran (30 mL) was slowly added dropwise sec-butyllithium (1.06 mol/L hexane-cyclohexane solution, 12.5 mL) at −40° C., and the mixture was stirred for 15 minutes. Then, a solution of 2-methylpropionaldehyde (476 mg) in tetrahydrofuran (3 mL) was added dropwise thereto, and the mixture was stirred at −40° C. for 15 minutes, and then stirred at room temperature for additional 40 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (929 mg). 1H-NMR (CDCl3) δ ppm: 0.96-1.06 (6H, m), 1.52 (9H, s), 1.70-1.83 (1H, m), 1.90 (1H, d, J=3.8 Hz), 2.57-2.75 (2H, m), 3.48-3.59 (1H, m), 3.80 (3H, s), 6.59 (1H, dd, J=2.8, 8.5 Hz), 7.00 (1H, d, J=8.5 Hz), 7.43 (1H, br s), 7.91 (1H, br s).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[CH3:13][CH3:14]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: CC
Reactant: N#CCc1ccc(Br)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CC1(c2ccc(Br)cc2)CC1
Temperature: 0 °C

Procedure:
Sodium hydroxide (50% aqueous solution, 29.3 g, 0.505 mol) was added to a mixture of 4-bromo-benzeneacetonitrile (9.80 g, 0.0500 mol), benzyltriethylammonium chloride (0.90 g, 0.0040 mol), ethane, and 1-bromo-2-chloro-(14.5 g, 0.101 mol) at 50° C. overnight. The mixture was poured into ice-water (80 mL) and was extracted with ethyl ether (4×50 mL). The combined organic phase was washed with HCl aqueous solution (1N, 20 mL) and brine (2×30 mL) successively, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was the desired product, which was directly used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1CCNC(=O)c2cc3cc(F)cc(Br)c3n21
Product: CC1CCNC(=O)c2cc3cc(F)cc(-c4ccc(F)cc4)c3n21

Procedure:
The title compound, grey solid (79 mg, 97%), MS (ISP) m/z=327.2 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 1 from (RS)-7-bromo-9-fluoro-5-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 3) (77.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:12][CH:13]1[CH2:14][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:16][CH2:17][O:18]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1CNCCO1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC1CN(c2ccc([N+](=O)[O-])c(N)c2)CCO1
Temperature: 100 °C
Yield: 70 %

Procedure:
5-Chloro-2-nitroaniline (200 mg, 1.159 mmol) was added to a solution of 2-methylmorpholine (176 mg, 1.738 mmol) in NMP (5 mL) in the presence of triethylamine (0.404 mL, 2.90 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h. and upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound as a solid in a 70% yield. 1H NMR: (400 MHz, DMSO-d6): δ 7.79 (d, 1H, J=9.6 Hz), 7.25 (bs, 2H), 6.39 (dd, 1H, J=2.8 and 9.6 Hz), 6.20 (d, 1H, J=2.8 Hz), 3.88 (dd, 1H, J=2.8 and 12.0 Hz), 3.69 (d, 1H, J=12.8 Hz), 3.56 (m, 2H), 2.82 (m, 1H), 2.15 (t, 1H, J=7.6 Hz), 1.88 (m, 1H), 1.12 (d, 3H, J=6.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(C)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(C)nc1
Reaction time: 4 h
Yield: 96.1 %

Procedure:
A suspension of ethyl β-(6-methylpyridin-3-yl)acrylate (3.86 g, 20.2 mmol) in 200 ml of ethyl acetate and 1.4 g of 5.3% Pd/C was hydrogenated under hydrogen (50 psi) for 4 h. The mixture was filtered through SUPERCEL™, the filtrate was concentrated in vacuo to afford 3.75 g (96%) of ethyl 3-(6-methylpyridin-3-yl)propionate, as a pale orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+].O>CN1CCCC1=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)c2ccc(Cl)nc2)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(=O)c2ccc(OCc3ccccc3)nc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The above 6-chloro-3-pyridyl 4-ethylphenyl ketone (1.68 g) was dissolved in N-methyl-2-pyrrolidinone (20 ml), and thereto were added benzylalcohol (815 ml) and 60% sodium hydride (275 mg). The mixture was stirred at room temperature for 6 hours, and then at 90° C. for one hour. The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and subsequently with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-95:5) to give 6-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.68 g) as colorless oil. APCI-Mass m/Z 318 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][Si](C(C)(C)C)(C)C.[Li]C(C)(C)C.[CH3:22][N:23]([CH2:25][CH:26]1[C:32](=[O:33])[CH2:31][CH:30]2[CH2:34][CH:27]1[CH2:28][CH2:29]2)[CH3:24]>C1COCC1.CCCCCC>[CH3:24][N:23]([CH2:25][CH:26]1[C:32]([C:2]2[CH:3]=[C:4]([OH:5])[CH:13]=[CH:14][C:15]=2[F:16])([OH:33])[CH2:31][CH:30]2[CH2:34][CH:27]1[CH2:28][CH2:29]2)[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(Br)c1
Reactant: CN(C)CC1C(=O)CC2CCC1C2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1C2CCC(C2)CC1(O)c1cc(O)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (5.81 g, 19.03 mmol) in THF (100 mL) to −78° C. under N2. Then add dropwise a solution of t-BuLi (14.6 mL, 19.03 mmol) in hexane via syringe to the reaction solution. After being stirred at −78° C. for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (2.87 g, 15.86 mmol) in THF (1.5 mL) to the reaction mixture and stir the mixture at −78° C. for additional 1 hour. Quench the reaction with 60 mL of diluted HCl (2N), and stir at ambient temperature for 2 hours. Basify the resultant mixture with K2CO3 to pH=9, and extract with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH=10:1) to afford 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (2.38 g, yield: 51.2%). MS (m/z): 294 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:46])([CH3:45])[O:38]C3CCCCO3)=[CH:29][CH:28]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>S(=O)(=O)(O)O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:46])([OH:38])[CH3:45])=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC(C)(CCCCc1ccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cc1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCc1ccc(C=Cc2ccc(CO)c(CO)c2)cc1

Procedure:
In a manner similar to Example 25(d), by reacting 10 drops of concentrated sulphuric acid with 265 mg (0.4 mmol) of 2-[5-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylpentyloxy]tetrahydropyran in 5 ml of THF and 5 ml of water, white crystals (m=73 mg; Y=51%) are obtained. m.p.=102-4° C.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[N:24]([CH3:27])[CH:25]=O)=[O:15])(=O)C1C=CC=CC=1>ClCCl>[F:22][C:20]1[CH:21]=[C:16]2[C:17](=[CH:18][C:19]=1[F:23])[N:24]([CH3:25])[CH:27]=[C:13]([OH:12])[C:14]2=[O:15]
Reactant: CN(C=O)c1cc(F)c(F)cc1C(=O)COC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(O)c(=O)c2cc(F)c(F)cc21
Reaction time: 1.5 h

Procedure:
Sodium methoxide (4.37 g) was added to a solution of 2-[4,5-difluoro-2-(N-methylformamido)phenyl]-2oxoethyl benzoate (11.2 g) in dichloromethane (840 ml) at 0° under nitrogen and the mixture stirred for 90 minutes. The mixture was extracted with water (11) and then aqueous sodium hydroxide (5M, 2×100 ml). The combined extracts were acidified with hydrochloric acid (5M, 250 ml). The precipitate was collected by filtration and washed with water (100 ml) to give the novel compound 6,7-difluoro-3-hydroxy-l-methyl-4quinolone, m.p. 264°-265°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)N1CCOCC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)N2CCOCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(morpholine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using morpholin-4-carbonyl chloride instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 496.2 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:19][CH:18]=[C:17]([O:20]C)[CH2:16][CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1=CCC([C@H](C)NC(=O)OCc2ccccc2)=CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C1=CCC(=O)CC1

Procedure:
To a vigorously stirred solution of the above diene (32) (44.2 g) in ethyl acetate (250 mL) was added aqueous 1N HCl (250 mL). After stirring for 1 h the ethyl acetate phase was removed, washed with saturated NaCl, dried over MgSO4 and evaporated. The product (33) was obtained by flash chromatography on silica gel eluted with 35% ethyl acetate in n-hexane (39.69 g, 91%). TLC Rf 0.51 (30% ethyl acetate, n-hexane); 1H NMR (CDCl3)δ1.25(3H, d, J=7 Hz), 2.44(4H, br s), 2.88(2H, br s), 4.35(1H, q), 4.95(1H, br d), 5.13(2H, s), 5.72(1H, t), 7.38(5H, s).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(O)(=O)C.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:3]=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccncc1
Reactant: CN(N)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(N=Cc1ccncc1)c1ccccc1
Temperature: 0 °C

Procedure:
One equivalent of methyl phenylhydrazine (58.76 g; 0.4809 mol, compound 2) was diluted in 50 ml of ethanol and 1.5 ml of acetic acid in a three-necked flask on which was mounted a condenser. The reaction medium was then stirred at 0° C. Using a dropping funnel, 1 equivalent of 4-pyridinecarboxaldehyde (51.5 g; 0.4808 mol, compound 1) was added. After addition of the aldehyde, the reaction medium was heated at 65° C. (oilbath temperature) for 13 hours.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[C:12]([C:20](=[O:34])[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([O:32]C)=[O:31])[CH:25]=3)[OH:23])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Li+]>CO>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[C:12]2[C:20](=[O:34])[CH:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=1)[OH:23]
Reactant: COC(=O)c1cccc(C(O)=CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C(O)=CC(=O)c2c[nH]c3ccc(Cl)cc23)c1

Procedure:
The carboxylic acid in Example 100 was esterified to 1-(1-benzenesulfonyl-5-chloroindol-3-yl)-3-(3-methoxycarbonylphenyl)-3-hydroxy-propen-1-one. The compound was hydrolyzed with lithium hydroxide in methanol to give the tiled compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]2=[N:17][CH:18]=1)=[O:11].[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]2=[N:17][CH:18]=1)=[O:11])(=[O:35])=[O:34]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCN3)cnc21
Agent: Cl
Product: CC(C)CS(=O)(=O)N1CCCC1CNC(=O)Nc1cnc2c(ccn2COCC[Si](C)(C)C)n1

Procedure:
Racemic 1-[1-(2-methyl-propane-1-sulfonyl)-pyrrolidin-2-ylmethyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-pyrrolidin-2-ylmethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2-methyl-propane-1-sulfonyl chloride.
Reaction SMILES: [F:1][CH:2]([F:35])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:13])[F:12])=[CH:7][C:6]=1[C:14]1[C:15]2[N:16]([N:20]=[C:21]([NH:23][C:24]3[CH:34]=[CH:33][C:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][C:26]=4[CH:25]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1.Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>>[F:35][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:13])[F:12])=[CH:7][C:6]=1[C:14]1[C:15]2[N:16]([N:20]=[C:21]([NH:23][C:24]3[CH:34]=[CH:33][C:27]4[CH2:28][CH2:29][N:30]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:31][CH2:32][C:26]=4[CH:25]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)COc1ccc(C(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(C(F)F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.065 g, 0.130 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.045 mL, 0.200 mmol) in a manner analogous to Example 313 to give product (0.045 g, 59%). MP=200-201° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.49 (s, 1H), 8.78 (d, 1H), 7.90 (s, 1H), 7.65 (m, 2H), 7.42 (m, 3H), 7.05 (m, 2H), 7.02 (br m, 1H), 6.30 (br m, 1H), 4.42 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.80 (m, 7H), 2.60 (m, 4H). MS=571 (MH)+.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([C:12]1[NH:13][C:14]([CH2:33][CH3:34])=[C:15]([C:29]([O:31][CH3:32])=[O:30])[CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:17]=1[C:18]([O:20]C)=[O:19])[CH3:11].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:33]([C:14]1[NH:13][C:12]2[CH:10]([CH3:11])[O:20][C:18](=[O:19])[C:17]=2[CH:16]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:15]=1[C:29]([O:31][CH3:32])=[O:30])[CH3:34]
Reactant: CCC1=C(C(=O)OC)C(c2ccc(Cl)cc2)C(C(=O)OC)=C(CC)N1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC1=C(C(=O)OC)C(c2ccc(Cl)cc2)C2=C(N1)C(C)OC2=O
Reaction time: 0.5 h

Procedure:
In a similar manner 2.02 grams (2.52 grams of 80 percent; 6.31 millimoles) of pyridinium bromide perbromide is added in a single portion to a cooled to 0° C. solution of 1.91 grams (5.26 millimoles) of dimethyl 2,6-diethyl-4-(4-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.79 gram (10.1 millimoles) of pyridine in 40 milliliters of chloroform. The resulting mixture is stirred at this temperature for 30 minutes, then at reflux temperature for 90 minutes. The mixture is then allowed to cool, diluted with chloroform, the diluted solution washed with 2N hydrochloric acid and brine, and dried; the solvent then is evaporated to obtain the methyl 2-ethyl-4-(4-chlorphenyl)-5-oxo-7-methyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine 3-carboxylate product as residue. The residue is purified by chromatographing on silica gel using ethyl acetate-hexane as eluant.