Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[CH:19][CH:18]=1)([O-])=O>[Pd].CO.ClCCl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])c1ccc(-c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
The nitro compound 171 (20 mg, 0.05 mmol) was hydrogenated (1 atm) in the presence of 10% palladium on charcoal (catalytic amount) in methanol (1 mL) at room temperature for 2-3 hrs. The reaction mixture was filtered through a pad of Celite®, the filtrate was evaporated to give the crude product which was suspended in dichloromethane and stirred overnight at room temperature, then filtered to provide the title compound 172 (6.3 mg, 27% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.71 (s, 1H), 8.07 (d, J=8.2 Hz, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.34 (d, J=5.1 Hz, 1H), 7.28 (dd, J=8.2, 2.0 Hz, 1H), 7.24 (d, J=3.5 Hz, 1H), 7.03 (t, J=3.7 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.17 (s, 2H). MS: 362.09 (calc), 363.1 (obs).
Reaction SMILES: [CH:1]([C:4]1[C:9]([N:10]=[C:11]=[S:12])=[C:8]([CH:13]([CH3:15])[CH3:14])[CH:7]=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([NH:28][C:11]([NH:10][C:9]1[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][C:6]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:7][C:8]=1[CH:13]([CH3:15])[CH3:14])=[S:12])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=S
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1NC(=S)NC(C)(C)C
Reaction time: 2 h

Procedure:
8.15 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl isothiocyanate are diluted with 30 ml of toluene, and 2.0 g of tert.-butylamine are added dropwise. The reaction mixture is then further stirred for 2 hours at approximately +60° C. The reaction mixture is concentrated and hexane is added to the residue. The resulting solid is filtered off and subsequently washed with hexane. 1-tert.-Butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-thiourea is obtained in the form of colourless crystals, m.p. 165°-167° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:16]([CH3:29])[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22]3)=[O:18])[CH2:12][CH2:11]1.[BH4-].[Na+].Cl>CO>[OH:18][CH:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH2:11][CH2:12]1)[CH3:29]
Reactant: COc1ccccc1N1CCN(C(C)C(=O)c2ccc3c(c2)CC(=O)N3)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1N1CCN(C(C)C(O)c2ccc3c(c2)CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
The 5-(2-(4-(2-methoxyphenyl)piperazin-1-yl)propanoyl)indolin-2-one hydrochloride (1.66 g, 4 mmol) was dissolved in 50 ml of methanol solution, and sodium borohydride (0.15 g, 8.4 mmol) was added in proportions, mixed and stirred at room temperature for 3 hours. Working up according to general procedure B gave 0.55 g of (1RS,2SR)-5-(1-hydroxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)indolin-2-one (IV-1) hydrochloride having a melting point of 213 to 215° C., with a yield of 32.9%; and 0.51 g of (1RS,2RS)-5-(1-hydroxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)indolin-2-one (IV-2) hydrochloride having a melting point of 237 to 239° C., with a yield of 30.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10.0 g of 1-(2,4-dimethoxy-benzyl)-2,3-dioxopiperazine, 1.66 g of sodium hydride (60%, oil) and 100 ml of N,N-dimethylformamide was stirred at 50° C. for 30 minutes and then cooled to room temperature. To the reaction mixture was added 3.6 ml of methyl bromoacetate, after which the resulting mixture was stirred at the same temperature for 30 minutes and added to a mixed solvent of 200 ml of ethyl acetate and 200 ml of ice water, and the pH was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with five 50-ml portions of ethyl acetate. The combined organic layer was washed with 50 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=10:1) to obtain 10.7 g of methyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]acetate as a colorless oil.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[OH:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH3:17].O>O1CCCC1.C(O)=O>[CH3:1][N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][OH:5])[C:12]([CH3:17])=[CH:13][CH2:14]1
Reactant: [BH3-]C#N
Reactant: Cc1ccnc2c(CO)cccc12
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: C1CCOC1
Product: CC1=CCN(C)c2c(CO)cccc21
Yield: 23.5 %

Procedure:
Sodium cyanoborohydride (7.9 g) was dissolved in tetrahydrofuran (50 ml). After adding and dissolving 8-hydroxymethyl-4-methylquinoline (3.5 g) in the solution, formic acid (50 ml) was added dropwise thereto with stirring under ice-cooling in nitrogen stream. The mixture was stirred for 5 hours at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was adjusted to alkalinic with a sodium hydroxide aqueous solution and extracted with chloroform. After drying the extract over anhydrous magnesium sulfate, chloroform was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: dichloromethane-methanol(200:1)], then 1,4-dimethyl-8-hydroxymethyl-1,2-dihydroquinoline (0.9 g) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].C[NH+](C)C.C([O:17][C:18]1[C:19]([C:25](=[O:27])[CH3:26])=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[N:20]=[C:19]([C:25](=[O:27])[CH3:26])[C:18]([OH:17])=[CH:23][CH:22]=1
Reactant: CC(=O)c1nc(Cl)ccc1OCc1ccccc1
Agent: C[NH+](C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)c1nc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a suspension (80 mL) of aluminum chloride (14.3 g) in toluene was added trimethylammonium chloride (4.75 g), and the mixture was stirred under argon atmosphere at room temperature for 1 hr. To the mixture was added a solution (80 mL) of 1-[3-(benzyloxy)-6-chloropyridin-2-yl]ethanone (8.66 g) synthesized above in toluene, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous Rochelle salt solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% ethyl acetate/hexane) to give the title object compound (4.89 g, 86%) as a pale-yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:23][C:22]2[S:21][C:20]3[N:19]=[C:18]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31]([C:34]5[CH:43]=[CH:42][C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:35]=5)[CH2:30][CH2:29]4)[NH:17][O:16][C:15]=3[C:14]=2[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C.C(=O)([O-])O.[Na+]>>[N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:42]=[CH:43][C:34]=1[N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:18]2[NH:17][O:16][C:15]3[C:14]4[CH2:13][CH2:12][NH:11][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=2)[CH2:29][CH2:30]1
Reactant: O=C(OCc1ccccc1)N1CCc2c(sc3c2ONC(CCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2nc(N3CCN(CCCCC4=Nc5sc6c(c5ON4)CCNC6)CC3)ccc2c1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To 100 mg of 7-benzyloxycarbonyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene as synthesized in Example 3-14, 5 ml of hydrogen bromide-acetic acid solution was added and stirred at room temperature. After neutralizing the system with saturated aqueous sodium hydrogencarbonate solution, the reaction product was extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated to provide 78 mg (100%) of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene.
Reaction SMILES: [OH:1][C@H:2]1[C@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:27])[CH2:20][C@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:5]([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:4][CH2:3]1.P([O-])([O-])([O-])=O.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O>[OH:1][C@H:2]1[C@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:27])[CH2:20][C@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:5]([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH2:3]1
Reactant: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=CC[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)O)=CC[C@H]1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.9 %

Procedure:
To methyl (11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (37.2 mg, 0.093 mmol) in acetone (1 mL) was added pH 8 phosphate buffer (10 mL). To this was further added esterase containing solution (derived from pig's liver, made by Sigma Co., 100 μl). This was agitated at room temperature for 15 hours. Dilute hydrochloric acid was added to the reaction solution to make the solution pH 4. Further, The solution was made saturated by ammonium sulfate, then the target produce was extracted with ethyl acetate. The extract was washed with brine, then was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then subjected to thin layer chromatography for separation (development solution: ethyl acetate) to obtain (11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoic acid (4.6 mg, 12%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>N#[Ti]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: N#[Ti]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered titanium nitride from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 21.6%, wherein 0.03 g of phenyl chloroformate and 34.3 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 99%.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:37]=[CH:36][C:17]([C:18]([NH:20][C:21]2[C:26]3[O:27][CH:28]([C:31]4[NH:35][N:34]=[N:33][N:32]=4)[CH2:29][O:30][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1)(=O)C>CO>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[C:26]3[O:27][CH:28]([C:31]4[NH:35][N:34]=[N:33][N:32]=4)[CH2:29][O:30][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:36][CH:37]=1
Reactant: CC(=O)OCCCCCCOc1ccc(C(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cccc2c1OC(c1nnn[nH]1)CO2)c1ccc(OCCCCCCO)cc1
Reaction time: 0.17 h
Yield: 104.1 %

Procedure:
A 1N aqueous solution of sodium hydroxide (0.5 ml) was added to a solution of 8-[p-(6-acetyloxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane (100 mg; synthesized in example 1 (96)) in methanol (0.5 ml) at room temperature. The reaction solution was stirred for 10 min at the same temperature, and then concentrated under reduced pressure. To the residue, dil. hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=100:1) to give the title compound (95 mg) having the following physical data:
Reaction SMILES: [N:1]([CH:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH2:5]1)=[N+]=[N-].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:26]1([P:19](=[N:1][CH:4]2[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH2:5]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC1OC(=O)CC1N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC1OC(=O)CC1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 102.1 %

Procedure:
A solution of 4-azido-5-ethoxy-dihydrofuran-2-one (0.05 g, 0.29 mmol) and triphenylphosphine (0.078 g, 0.29 mmol) in toluene (5 mL) was stirred at room temperature under nitrogen for 5 h. The solvent was evaporated to afford 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-dihydrofuran -2-one (0.12 g, 100% yield) as an off-white, waxy solid. 1H-NMR (500 MHz, CDCl3) δ 7.50 (m, 6H), 7.40 (m, 3H), 7.33 (m, 6H), 5.08 (d, J=3.1 Hz, 1H), 3.63 (m, 1H), 3.23 (m, 1H), 2.50 (dd, J=17.1, 5.9 Hz, 1H), 2.27 (dd, J=17.1, 5.9 Hz, 1H), 0.91 (t, J=7.0 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58](=[O:61])[O:59][CH3:60])=[C:51]([OH:62])[CH:50]=1>>[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58]([O:59][CH3:60])=[O:61])=[C:51]([CH:50]=1)[O:62][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: COC(=O)NCCc1ccc(F)cc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.40 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of methyl N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]carbamate are reacted. The title compound is obtained as a yellow oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=5.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]1[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([N+:19]([O-])=O)[CH:11]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[In].II>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]2[N:5]([C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=3)[N:19]=[C:12]3[C:13]=2[CH:16]=[C:17]([F:18])[C:10]([F:9])=[CH:11]3)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [In]
Product: Fc1cc2nn(-c3cccc(Cl)c3)c(Nc3cccc(Cl)c3)c2cc1F

Procedure:
In analogy to the procedure described in example 35.1, 3-chloroaniline was reacted with 4,5-difluoro-2-nitro-benzaldehyde (Daubie, Christophe; Legrand, Jean Jacques; Pemberton, Clive. Eur. Pat. Appl. (1993), EP 538 100 A1) in the presence of Na2SO4, indium and iodine to give the title compound as brown solid. MS: m/e=388.0 [M−H−].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH:35]=[CH:34][N:33]=[CH:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.[Cl-].[NH4+].Cl>CN(C=O)C.C(Cl)Cl.CO>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH:35]=[CH:34][N:33]=[CH:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(C#N)cc43)ncnc2cc1OCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
A solution of 5-cyanooxindole (2.96 g, 18.7 mmol), (Tet. Lett., 1987, 28, 4027), in DMF (35 ml) was added dropwise under nitrogen to sodium hydride (749 mg, 18.7 mmol, prewashed with hexane) in DMF (15 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (1.98 g, 18.7 mmol), (prepared as described for the starting material in Example 22), was added as a solid. The mixture was heated at 55° C. for 45 minutes, allowed to cool and poured into a mixture of methylene chloride (400 ml) and saturated aqueous ammonium chloride solution (400 ml). The resulting precipitate was collected by filtration, resuspended in water and stirred for 15 minutes at ambient temperature. The solid was collected by filtration, washed with water and then ether, and dried under vacuum to give a white solid. This solid was suspended in methylene chloride (50 ml) and methanol (50 ml) and 2.2M ethereal hydrogen chloride (6 ml) was added. The mixture was stirred for 15 minutes at ambient temperature, the solid product was collected by filtration, washed with ether and dried under vacuum at 60° C. to give 4-(5-cyanooxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (2 g, 61%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11].[CH2:18]([OH:22])[CH2:19][C:20]#[CH:21]>[Pd](Cl)Cl.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([C:21]#[C:20][CH2:19][CH2:18][OH:22])=[CH:15][CH:16]=1)=[O:11]
Reactant: C#CCCO
Reactant: COC(=O)c1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCCO)s1
Reaction time: 0.17 h

Procedure:
To a 20-mL vial for microwave reaction, were added a mixture of palladium chloride (57 mg, 0.32 mmol), triphenylphosphine (104 mg, 0.32 mmol), copper iodide (243 mg, 1.28 mmol), triethylamine (8.08 g, 80 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (1.77 g, 8 mmol) and anhydrous acetonitrile (10 mL). To the stirred mixture, were added copper iodide (243 mg, 1.28 mmol) and but-3-yn-1-ol, 1 (588 mg, 8.4 mmol), and the vial was sealed and put into the microwave reactor at 100° C. for 10 min. After evaporation of solvent under reduced pressure, MeOH (20 mL) was added followed by silica gel (5 g). The resulting plug was loaded on to a silica gel column (3.5×12 cm) and eluted with hexane followed by 20% EtOAc in hexane. Fractions with an Rf=0.42 (hexane/EtOAc 4:1) were pooled and evaporated to afford 1.17 g of 2 as yellow oil. 1H NMR (DMSO-d6): δ 2.59-2.63 (t, J=6.4 Hz, 2H), 3.56-3.59 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 4.95-4.98 (t, J=5.6 Hz, 1H), 7.27-7.28 (d, J=4.0 Hz, 1H), 7.69-7.70 (d, J=4.0 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.ClN1[C:29](=[O:30])[CH2:28][CH2:27]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]1[CH:16]2[N:21]([CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:22][CH2:23][CH:14]1[CH2:13][O:12][C:10]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:1]2[CH2:27][CH2:28][CH2:29][O:30][C:2]=12)=[O:11]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCC1CCN2CCCCC2C1)c1c2n(c3ccccc13)CCCO2
Yield: 51 %

Procedure:
eq-Quinolizidin-2-ylmethyl 1H-indole-3-carboxylate was treated initially with N-chlorosuccinimide (1.5 equivalents) for 2 h, then with 3-bromo-1-propanol (2 equivalents) for 16 h, followed by anhydrous potassium carbonate in acetone, using the method described in Example 1b. The crude product was purified using the same chromatography conditions as in Example 1b to afford the title compound as a colourless oil (51%). This was converted to its hydrochloride salt and crystallised from acetone mp 164-167° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C@H:8]2[CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:14]([O:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:9]1)([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Yield: 56.1 %

Procedure:
A mixture of (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (0.04 g, 0.128 mMol), triethylamine (71 uL, 0.512 mMol) and 4-chloro-6-(trifluoromethyl)quinazoline (0.035 g, 0.192 mMol) were taken in EtOH and microwaved at 100° C. for 45 min. The reaction mixture was concentrated and chromatographed to yield (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonyl methyl)cyclohexyl)-3-(6-(trifluoro methyl)quinazolin-4-ylamino)pyrrolidin-2-one as a white solid (0.04 g). MS found: (M+H)+=557.2.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][Si:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromobenzyl alcohol (4.86 g, 26 mmol) in CH2Cl2 (80 mL) cooled to 0° C. was added Me3SiCl (3.12 g, 28.6 mmol), triethylamine (4.34 g, 31.2 mmol) and 4-N,N-dimethylaminopyridine (0.32 g, 2.6 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature and stirred whereupon reaction was determined by thin layer chromatography to be completed after 2 h. The solution was washed with 1N aqueous HCl (30 mL) H2O (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was dried (MgSO4) and concentrated under vacuum to provide a brown oil, 6.67 g. Purification by column chromatography (80 g SiO2 eluted with 10% diethyl ether/hexane) afforded the product of Step A as a clear, yellow oil, 5.94 g, (88%); IR (neat): 2956, 2897, 1441, 1251 cm-1 ; 1H NMR (CDCl3); δ7.5 (dd, 2h), 7.3 (t,1H), 7.1 (t,1H), 4.7 (s,2H), 0.2 (s,9H).