Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[CH:9][C:10]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:13]=[N:12][CH:11]=1)[C:5]([F:8])([F:7])[F:6])C.S(=O)(=O)(O)O>CCOCC.O>[S:15]([N:14]1[C:10]([CH2:9][C:4]([C:5]([F:8])([F:6])[F:7])=[O:3])=[CH:11][N:12]=[CH:13]1)([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)(=[O:16])=[O:17]
Reactant: CCOC(=Cc1cncn1S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cncc2CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 20 mmole of 5-acetoxymethyl-1-tosylimidazole and 22 mmole of triphenylphosphine in 100 ml of benzene is heated at reflux temperature for 4 days. The solid which separates on cooling is filtered, washed with benzene, dried under reduced pressure then added slowly to a solution of 20 mmole of sodium amide in 100 ml of liquid ammonia (prepared by adding 0.46 g of sodium to liquid ammonia in the presence of a catalytic amount of ferric nitrate). After stirring for 10 minutes the ammonia is evaporated under a stream of nitrogen. To the residue is added 100 ml of anhydrous benzene and the heterogeneous mixture is heated at reflux for 10 minutes. The solid residue is filtered, and to the filtrate containing salt-free 1-tosyl-5-imidazolylmethylidene triphenylphosphorane is added 5.10-2M of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature under nitrogen for 12 hours. Concentration of the solvent leaves a residue which is distilled under high vacuum to afford 2-ethoxy-1,1,1-trifluoro-3-(1-tosyl-5-imidazolyl)prop-2-ene. A solution of 3 g of 2-ethoxy-1,1,1-trifluoro-3-(1-tosyl-5-imidazolyl)prop-2-ene in 50 ml of ether is treated with a solution of 1 M of sulfuric acid in 50 ml of water. The reaction mixture is stirred for 1/2 hour at 25° C. The ether phase is separated, washed with brine, dried over magnesium sulfate and concentrated to give trifluoromethyl 1-tosylimidazol-5-ylmethyl ketone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36]([O:38]CC)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36]([OH:38])=[O:37])([CH3:34])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 60 °C
Yield: 91.3 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (700 mg, 1.08 mmol) in methanol (20 mL) was added a solution of NaOH (120 mg, 3 mmol) in water (10 mL). The mixture was heated at 60° C. for 1.5 h, evaporated to remove methanol, cooled to room temperature, and acidified to “pH” 2 with HCl aq. The precipitate was collected, washed with water and dried to give the title compound as a white solid (610 mg).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:9]2[C:8]=1[N:7]=[C:12]([C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[C:11]([CH:1]=[O:4])=[CH:10]2
Reactant: OB(O)c1cccnc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 281.9 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising Intermediate 32 (10 g, 48.7 mmol), Na2CO3 (7.74 g, 73 mmol), 3-pyridylboronic acid (5.98 g, 48.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.81 g, 2.43 mmol) in DME (150 mL) and water (40 mL). The title compound (11.36 g, 94%) was obtained as a brown solid. δH (CDCl3) 10.20 (s, 1H), 9.02 (dd, J 2.3, 0.8 Hz, 1H), 8.86 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1H), 8.10 (ddd, J 7.9, 2.3, 1.7 Hz, 1H), 7.90 (d, J 8.3 Hz, 1H), 7.78-7.75 (m, 1H), 7.58 (dd, J 8.1, 7.2 Hz, 1H), 7.53 (ddd, J 7.9, 4.9, 0.8 Hz, 1H), 2.88 (s, 3H). LCMS (ES+) 249 (M+H)+, RT 1.41 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>C(OCC)(=O)C.CO>[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:29]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 44 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 44%; MS: m/z=446 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[NH:5]C(=O)C)[CH3:2].[OH-].[Na+].NC1C=CC=CC=1>C(O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[NH2:5])[CH3:2]
Reactant: CCc1cc(Cl)ccc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: CCO
Product: CCc1cc(Cl)ccc1N
Temperature: 25 °C

Procedure:
2'-Ethyl-4'-chloroacetanilide (31 grams) was heated to reflux in a mixture containing 80 milliliters of ethanol and 55 milliliters of concentrated HCL for about 2.5 hours. After cooling to room temperature, the mixture was basified to a pH of about 8 by an aqueous NaOH solution (20 percent). An oily aniline layer was observed. The mixture was transferred to a separatory funnel and was extracted with ether (3 times 75 milliliters). The ethereal extracts were combined and dried over MgSO4. After filtration, ether was removed under reduced pressure. 2-Ethyl-4-chloroaniline was purified and isolated by a reduced pressure distillation, yield 14.2 grams (58 percent).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O>CN(C=O)C>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH3:26])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Cc1cnccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: Cc1cnccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3-methylpyridine-4-boronic acid (CAS RN 894808-72-1) and using DMF as solvent for the reaction. Colorless solid (13%). MS (ESI): m/z=440.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:34][C:35]([CH3:42])([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([CH3:42])([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 440 mg (1.12 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 310 mg (1.22 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 70° C. for 6 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 522 mg of a black powder (yield: 74.3%; mp: 205-207° C.)
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:6]2[CH:23]=[CH:24][C:3]([N:2]([CH3:25])[CH3:1])=[CH:4][CH:5]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(C(=O)c2ccc(N)cc2)cc1
Yield: 94.3 %

Procedure:
The compound 4 (51 mg, 0.15 mmol) was stirred in 10% trifluoroacetic acid (TFA) in dichloromethane (10 mL) at room temperature for 1 hour and extracted with ethyl acetate with aqueous NaHCO3. The organic layer was dried over Na2SO4, and the filtrate was concentrated to give intermediate B (34 mg, 95%). 1H-NMR (CDCl3) 7.76 (d, J=8.7, 2H), 7.66 (d, J=8.4, 2H), 6.68 (d, J=8.7, 2H), 6.67 (d, J=8.4, 2H), 4.04 (br. s, 1H), 3.06 (s, 6H) ppm; ESI-MS m/z calcd for C15H16N2O: 240. 3004. found 241.2071 [M+1].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.B([C:19]1[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:21]=[CH:22][CH:23]=1)(O)O>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:19]3[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:21]=[CH:22][CH:23]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
tert-Butyl 2-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert-butyl ester generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 9.96 (s, 1H), 7.32 (m, 1H), 7.23 (m, 1H), 7.15 (d, J=8.24 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.25 (m, 2H), 4.23 (s, 2H), 1.55 (s, 6H), 1.36 (s, 9H); MS (ES) m/z 357 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8](N)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[Cl-].[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21]C2C=CC(I)=C(C)C=2)=[O:20])=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:7][CH:8]=2)=[O:20])=[CH:17][N:16]=1
Reactant: CCn1ccc2cc(N)ccc21
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Agent: [Cl-]
Product: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21

Procedure:
6-Chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide was prepared from 1-ethyl-1H-indol-5-ylamine (prepared as described in J. Med. Chem. 2007, 5509), and 6-chloronicotincyl chloride in a procedure similar to the one described in the synthesis of 6-chloro-N-(4-Iodo-3-methyl-phenyl)-nicotinamide, above. LCMS calcd for C16H14ClN3O (m/e) 299, obsd 300 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH:14]([NH:18]CC2C=CC=CC=2)[C:15]([OH:17])=[O:16])[CH2:11][CH2:10][C@H:9]1[C:26]([OH:28])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:15]([OH:17])(=[O:16])[CH3:14].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH:14]([NH2:18])[C:15]([OH:17])=[O:16])[CH2:11][CH2:10][C@H:9]1[C:26]([OH:28])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1[C@H](CC(NCc2ccccc2)C(=O)O)CC[C@H]1C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H](CC(N)C(=O)O)CC[C@H]1C(=O)O
Reaction time: 0.17 h

Procedure:
1600 mg of (2S,5S)-5-(2-benzylamino-2-carboxyethyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were dissolved in 30 ml of acetic acid. 100 mg of 20% palladium hydroxide on activated carbon were added thereto, and the mixture was hydrogenated under an atmosphere of 1 bar of hydrogen for 1 h. Ar was then passed over the solution for 10 min. The catalyst was filtered off through kieselguhr and the filter cake was washed with 20 ml of acetic acid. The combined organic phases were concentrated in vacuo. The crude product was employed without further purification in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:4]=1[NH2:5].[BH4-].[Na+].[OH-].[Na+].[C:18](O)(=O)[CH2:19][CH3:20]>>[CH2:18]([NH:5][C:4]1[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])[CH2:19][CH3:20]
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1cc(C(=O)OC)ccc1OC
Reaction time: 2 h

Procedure:
15 g of 2-methoxy-5-methoxycarbonylaniline are dissolved in 500 ml of propionic acid under argon and at room temperature and 15.7 g of sodium borohydride are added in small portions. The reaction mixture is stirred for 2 hours and then hydrolyzed and alkalinized with 10 N sodium hydroxide while the temperature is maintained below 20° C. It is extracted with dichloromethane, the organic phase is washed with a saturated NaCl solution, dried and then evaporated under vacuum. The expected product is obtained in the form of an oil with a quantitative yield.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: N#Cc1cc(-c2cccc(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (72 mg, 86%), MS (ISP) m/z=336.4 [(M+H)+], mp 209° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]([O:21][CH2:22][CH3:23])([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:9]([NH2:11])=[O:10])=[C:5]([N+:26]([O-])=O)[CH:4]=1)#[N:2]>C1COCC1.C(O)C.[Pd]>[NH2:26][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:25]=[CH:24][C:6]=1[CH2:7][C:8]([O:21][CH2:22][CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20])[C:9]([NH2:11])=[O:10]
Reactant: CCOC(Cc1ccc(C#N)cc1[N+](=O)[O-])(C(N)=O)c1ccc(OC)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(Cc1ccc(C#N)cc1N)(C(N)=O)c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (RS)-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide in THF (5 ml) and ethanol (15 ml) was added palladium/C (250 mg). After 24 hrs stirring at rt under hydrogen atmosphere the mixture was filtered, and the filtrate was concentrated to leave a light yellow foam. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 1:1) to give (RS)-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (4.45 g) as light yellow foam. MS 358.7 ([M+H]+)
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[CH:13][N+:14]([O-])=O)[CH2:11][CH2:10][CH:9]1[C:17]([O:19]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].CO>[CH2:1]([N:8]1[CH:12]2[CH2:11][CH2:10][CH:9]1[C:17](=[O:19])[NH:14][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Agent: [Pt]
Solvent: CO
Product: O=C1NCC2CCC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Methyl 1-benzyl-5-(nitromethylene)-2-pyrrolidinecarboxylate (9.92 g, 35.9 mmol) and 5% platinum on activated carbon (11.25 g) were combined in methanol (100 mL) and shaken for 56 hours at ambient temperature under a hydrogen atmosphere (60 psi). The misture was filtered and the filtrate concentrated to provide the title compound. MS (DCI/NH3) m/z: 217 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:25]=1[NH2:26]>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:31])=[CH:30][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (800 mg, 2.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was refluxed for 2 hours. After cooling to ambient temperature, the solid was filtered, washed with isopropanol and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (1.0 g, 87%)
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([NH2:38])=[CH:33][CH:32]=[CH:31]2.CCN(CC)CC>C(Cl)Cl>[N:38]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[CH:36]=[CH:37][C:28]([O:27][C:18]1[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=1)=[CH:29]2)=[C:1]=[S:2]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc4c(N=C=S)cccc4c3)c2cc1OC
Reaction time: 0.25 h

Procedure:
Thiocarbonyl diimidazole (108 mg, 0.606 mmol) was added to a solution of 6-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-1-amine (210, 0.606 mmol) and NEt3 (84.5 μL, 0.606) in DCM (1.52 mL) in one portion at RT. After 15 minutes of stirring, LCMS and TLC indicated that the reaction was complete. The crude mixture was purified by silica gel chromatography (Hex:EtOAc). MS (ESI, pos. ion) m/z: 389.0 (M+1). Mass Calc'd for C18H15NO3: 388.45.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])[CH3:9])=[CH:4][CH:3]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:27]2=[O:29])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(O)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CC1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 7-((1S)-1-(4-bromophenyl)ethylamino)-2-methyl-4-phenylhept-1-en-4-ol (2.2 g, 5.5 mmol) in CH2Cl2 (50 mL) was added triphosgene (3.2 g, 11 mmol) and Et3N (1.7 g, 16.5 mmol) at 0° C. The mixture was stirred at room temperature overnight, and put at room temperature for 3 days, the volatile was evaporated. The resulting mixture was washed with 1 N aq HCl and extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated to give the crude final product, which was purified by chromatography to afford two isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][CH:20]2[NH:24][CH2:23][CH2:22][S:21]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([N:24]1[CH2:23][CH2:22][S:21][CH:20]1[CH2:19][C:9]1[CH:10]=[N:11][N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(-c2c(CC3NCCS3)cnn2-c2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCSC1Cc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
A mixture of 3.56 g of 5-p-chlorophenyl-1-phenyl-4-(thiazolidin-2-yl-methyl)-pyrazole and 55 ml of acetic anhydride is boiled for 3 hours. 55 ml of pyridine is then added and the mixture is heated for a further 5 hours at 50° and subjected to the customary working up. 4-(3-Acetylthiazolidin-2-yl-methyl)-5-p-chlorophenyl-1-phenylpyrazole is obtained; m.p. 121°-122°.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][OH:3].[C:5]([Si:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>CN(C)C=O>[Si:9]([O:4][CH2:1][CH:2]=[O:3])([C:5]([CH3:8])([CH3:7])[CH3:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC=O)(c1ccccc1)c1ccccc1

Procedure:
In the manner described in Example 14c, 5.15 g of glycolaldehyde and 26.78 ml of tert-butyldiphenylchlorosilane were reacted in the presence of 7.61 g of imidazole and 26 ml of absolute dimethylformamide whereby after column chromatography with ether/petroleum ether (1:2) 21.26 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:31])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3c(-c4ccccc4)n[nH]c3c(=O)n2-c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cc1ccc(-c2nc3c(-c4ccccc4)nn(C)c3c(=O)n2-c2ccc(Br)cc2)cc1

Procedure:
To a solution of 6-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (11.0 mg, 0.024 mmol) in acetonitrile (0.3 mL) are added K2CO3 (6.6 mg, 0.048 mmol) and MeI (5.99 μL, 0.096 mmol). The reaction mixture is stirred at room temperature for overnight before the removal of K2CO3 by filtration. The filtrate is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, 2H), 7.47 (t, 2H), 7.44 (d, 2H), 7.35 (t, 1H), 7.22 (d, 2H), 7.04 (m, 4H), 4.37 (s, 3H), 2.31 (s, 3H); HPLC-MS calculated for C25H19BrN4O (M+H+) 471.1. found: 471.1.