Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[OH:22])[C:5]2=[O:23].[CH3:24][C:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])[C:5]2=[O:23]
Reactant: O=c1c2cc(Br)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Br)c3ccccc32)c1=O

Procedure:
To a solution of 6-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (1.00 g, 2.67 mmol) in CH2Cl2 (40 mL) was added DMAP (1.68 g, 13.3 mmol) and then tert-butyl dimethylsilyl trifluoromethane sulfonate (1.84 mL, 8.00 mmol) and the reaction was stirred overnight. The reaction was diluted with saturated, aqueous NaHCO3 and extracted 1× with CH2Cl2. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried. The oily residue was purified via silica gel chromatography, eluting with 5-55% ethyl acetate in hexanes to provide 1,5-anhydro-3-(6-bromo-4-oxobenzo quinazolin-3(4H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol that gave a mass ion (ES+) of 490.8 for [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=3)[C:6](=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:5]=2[CH:4]=1.[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][C:34](O)=O)[CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>C(Cl)Cl>[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][N:21]2[CH2:20][CH2:19][C:18](=[C:6]3[C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:16]=[CH:15][C:14]=4[S:13][C:12]4[C:7]3=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=4)[CH2:23][CH2:22]2)[CH2:29][CH2:28]1
Reactant: Fc1ccc2c(c1)Sc1ccc(C(F)(F)F)cc1C2=C1CCNCC1
Reactant: O=C(O)C[C@H]1CC[C@@H](O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: O[C@H]1CC[C@@H](CCN2CCC(=C3c4ccc(F)cc4Sc4ccc(C(F)(F)F)cc43)CC2)CC1
Reaction time: 8 h

Procedure:
7.3 Grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine were dissolved in 50 milliliters of dry methylene chloride. Then 3.8 grams of cis-4-hydroxycyclohexane acetic acid (J.Am.Ch.Soc. 70, pg. 1898-99 (1948)) and 5 grams of dicyclohexylcarbodiimide were added. The mixture was heated at temperatures from 22 to 30 degrees Centigrade during which the dicyclohexylurea formed separated out and was then left standing overnight. The precipitate was filtered from the solution which was then evaporated, and the residue was dissolved in ether. The solution was washed with dilute hydrochloric acid, dried over anhydrous potassium carbonate, filtered and evaporated. The residue, which was an oil, was dried by evaporation in vacuum with toluene and consisted of somewhat impure 1-(cis-4-hydroxycyclohexylmethylcarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine which was used without further purification in the next step. The oil was dissolved in dry ether, and 2 grams of lithium aluminium hydride were added in small portions. The mixture was heated under reflux for one hour. Then water was added dropwise until the precipitate formed clotted. The ether phase was decanted, the precipitate washed thoroughly with ether, the combined ether phases were dried over anhydrous potassium carbonate and treated with active carbon and filtered. The ether was evaporated, and 1-(cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine was obtained as a yellow oil.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2.CN([CH:22]=[O:23])C.C(O)CC>C1COCC1>[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[CH:22]=[O:23])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2
Reactant: CN(C)C=O
Reactant: COc1ccc2ncc(F)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCO
Product: COc1ccc2ncc(F)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of DIPA (15.5 mL) in THF (300 mL), cooled to −78° C., was added n-BuLi (2.35N in hexanes, 44 mL). The reaction mixture was stirred 5 min at this temperature before warming to 0° C. The reaction mixture was stirred 15 min before cooling to −78° C. 3-fluoro-6-methoxy-quinoline (prepared as described in FR 2004/01105, 15 g) in THF (50 mL+10 mL rinse) was added and the mixture was stirred 3 h at −78° C. DMF (3 mL) was added quickly. After 45 min., 1-propanol (8 mL) was added and the mixture was warmed to rt. The mixture was partitioned between water (100 mL) and EA (200 mL). The aq. layer was extracted with EA (200 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue triturated in Hept to give an orange solid (9.0 g, 51% yield).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(CN2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 5.3 parts of chloroacetonitrile, 14.4 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl) -3H-imidazo[4,5-b]pyridine, 7.4 parts of sodium carbonate and 288 parts of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was stirred into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13 parts (79.2%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineacetonitrile; mp. 80.7° C. (compound 75).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7][N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N+:2]=[N-:3].O.NN>CO>[NH2:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C@@H:5]1[CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N2C(=O)c3ccccc3C2=O)[C@H]1CN=[N+]=[N-]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of the compound 6 (493 mg) in methanol (13 mL), hydrazine monohydrate (339 mg) was added. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was concentrated and then added dichloromethane. The appeared solid was collected by filtration and then the residue was concentrated and obtained the title compound (245 mg) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CO.O1C[CH2:21][CH2:20][CH2:19]1>>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1Br
Solvent: CO
Product: CCCCCCCCC=Cc1ccccc1Br
Yield: 90 %

Procedure:
2-Bromobenzaldehyde (0.09 mol) was then added in tetrahydrofuran (25 mL) and after the mixture had been stirred for a further 30 min at 0 C hexane and aqueous methanol (40:60) was added. The hexane extract was concentrated and the residue was distilled to yield 2-(1-decenyl)-1-bromobenzene (90%).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[OH-].[Na+].[CH:14]([CH:16]=[CH2:17])=[O:15].O=CC1C=CC=C(OC)C=1O.O.Cl>O>[CH3:8][O:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:3]2[C:4]=1[O:5][CH2:17][C:16]([CH:14]=[O:15])=[CH:2]2
Reactant: C=CC=O
Reactant: COc1cccc(C=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1OCC(C=O)=C2

Procedure:
One mole of o-vanillin was stirred with 3 liter H2O and 0.05 mole NaOH. A stream of nitrogen was bubbled through 1.5 moles acrolein and then into the o-vanillin-water mixture. When all the acrolein had been driven into the solution (16 hours) the mixture was acidified with 0.06 mole of HCl and the intermediate product (a light yellow crystalline solid) was filtered off and washed with H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCCC1.CO>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a 20 mL vial was added a solution of 4-{4-(4-chlorobenzyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-2-methylpyridine (0.1654 g, 0.365 mmol) in anhydrous tetrahydrofuran (2.000 mL) and methanol (2.000 mL). 4.0 M hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and the reaction mixture was allowed to stir at 50° C. for 18 hours. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL) then was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC to afford the product (0.0351 g, 39.9%) as a white solid. LC/MS (AA) ES+ 368, 370. 1H NMR (400 MHz, d6-DMSO) δ: 8.73 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J=5.2, 1.6 Hz, 1H), 7.37-7.32 (m, 4H), 4.65 (s, 2H) 2.55 (s, 3H).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[C:12]([NH:15][NH2:16])(=[O:14])[CH3:13].CN1CCOCC1.CN(C)CCCN=C=NCC.[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[C:51](O)=[O:52])(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl>[C:12]([NH:15][NH:16][C:51]([C@@H:46]1[CH2:47][CH2:48][CH2:49][CH2:50][N:45]1[S:42]([C:39]1[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=1)(=[O:44])=[O:43])=[O:52])(=[O:14])[CH3:13]
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
1-Hydroxybenzotriazole hydrate (162 mg), acethydrazide (81 mg), N-methylmorpholine (275 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (230 mg) were added to a stirred solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38] (287 mg) in dichloromethane (3 ml). The reaction mixture was stirred for 3 hours after which time the mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford N′2-acetyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbohydrazide (340 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]([O:15][C@@H:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>CCOC(C)=O>[Br-:30].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([O:15][C@@H:16]2[CH:21]3[CH2:20][CH2:19][N+:18]([CH2:31][C:32](=[O:33])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([CH2:23][CH2:22]3)[CH2:17]2)=[O:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(4-chlorophenylsulfonamido)-2-phenylacetate (C70) (62 mg, 0.14 mmol) in EtOAc (2.5 ml), was added 2-bromo-1-phenylethanone (31.2 mg, 0.16 mmol), and the reaction was stirred at RT for 3 hours. Then the solvent was evaporated, and the crude was triturated with Et2O to obtain (3R)-3-(2-(4-chlorophenylsulfonamido)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (38 mg; 42% yield).
Reaction SMILES: C(N)CN.O1CCOCC1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@:18]2([CH3:33])[C@H:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[NH:21]S(=O)(=O)[NH:19]2)=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:22]([NH2:21])[C@:18]([C:15]2[CH:14]=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=2)([NH2:19])[CH3:33])=[CH:24][C:25]=1[F:30]
Reactant: C[C@]1(c2ccc(Cl)nc2)NS(=O)(=O)N[C@H]1c1ccc(Cl)c(F)c1
Solvent: NCCN
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C[C@](N)(c1ccc(Cl)nc1)[C@H](N)c1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 96.9 %

Procedure:
Ethylenediamine (7.40 ml, 111 mmol) was added to a dioxane (80 ml) solution of the compound (4.15 g, 11.0 mmol) obtained in Step 8 above and the resulting mixture was stirred under heating at 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with chloroform, washed with 1 N aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=93:7 (v/v)] to give the title compound (3.35 g, 97%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[F:10][C:11]1[CH:16]=[C:15](F)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[N:21]1[C:29](=[O:30])[C:24]2=[CH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22]1=[O:31].Cl>C(OCC)(=O)C.O1CCOCC1>[CH2:8]([O:7][C:3]([CH2:4][O:5][C:15]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]([N:21]2[C:29](=[O:30])[C:24]3=[CH:25][CH2:26][CH2:27][CH2:28][N:23]3[C:22]2=[O:31])=[C:11]([F:10])[CH:16]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CO
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)COc1cc(F)c(N2C(=O)C3=CCCCN3C2=O)cc1[N+](=O)[O-]
Yield: 48.9 %

Procedure:
Sodium hydride (0.06 g, 2.4 mmol) was put in to a flask, to which 1,4-dioxane (5 mL) and ethyl glycolate (0.12 mL, 1.32 mmol) was added with stirring under cooling in an ice-water bath after replacing the inside of flask throughly with argon gas, and the mixture was stirred for 15 minutes at the ambient temperature. Then, 2-(2,4-difluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.37 g, 1. mmol) was added to the mixture at the same temperature. The reaction mixture was wormed up to room temperature and stirred for 3 hours, and further stirred for 13 hours at 80° C. 1N Hydrochloric acid (10 mL) and ethyl acetate (10 mL) were added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (10 mL ×2 times). The organic layer combined was washed with a saturated sodium bicarbonate (20 mL) and a saturated sodium chloride solution (20 mL), and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(4-ethoxycarbonylmethoxy-2-fluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.23 g, yield:48.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[NH:14][C:13](=O)[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:17][NH2:18]>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[CH2:10][O:11][CH2:12][C:13]([CH2:17][NH2:18])=[N:14]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(C2(C)COCC(=O)N2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C2(C)COCC(CN)=N2)cc1
Temperature: 0 °C

Procedure:
A solution of 69.5 mmol of 5-(4-methoxyphenyl)-5-methylmorpholin-3-one in 200 ml of tetrahydrofuran and 25 ml of benzene is cooled to 0° C. and saturated with methylamine. A solution of 19 g of titanium tetrachloride in 25 ml of benzene is added dropwise over the course of 15 minutes. After addition is complete, the reaction mixture is heated to reflux for 3 hours. The reaction mixture is then cooled to 0° C. and cautiously quenched with 60 ml of water. It is filtered through Hyflo, and the filter cake is washed several times with tetrahydrofuran. The phases of the filtrate are separated, and the organic phase is dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1]C[O-].[Na+].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1C=O.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:18]([O:17][C:15]([C:14](=[CH:1][C:8]1[CH:7]=[CH:6][O:5][CH:9]=1)[CH2:13][C:12]([OH:21])=[O:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CC[O-]
Reactant: O=Cc1ccco1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccoc1)CC(=O)O
Yield: 48.1 %

Procedure:
Sodium ethylate (6.5 g, 95 mmol) was added under vigorous stirring to a solution of 2-furaldehyde (10 g, 79 mmol) and diethyl succinate (27.6 g, 158 mmol) in ethanol (300 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 200 mL of 10% HCl and 300 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 200 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 400 mL of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions containing the target product were collected and evaporated in vacuum to give the product 9.3 g (38 mmol, 49%) as a light-brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22]Cl)[CH3:19].[H-].[Na+]>>[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][N:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[CH3:19]
Reactant: c1ccc2c(c1)ccn2Nc1ccncc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN(c1ccncc1)n1ccc2ccccc21

Procedure:
The title compound was prepared from N-(4-pyridinyl)-1H-indol-1-amine and dimethylaminopropyl chloride with the aid of NaH in substantially the same manner as in Example 4. The product was obtained as an oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)CCC2
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of indane (50 mmol, 6.11 mL) in dichloromethane (50 ml) at 0° C. is added dropwise chlorosulfonic acid (200 mmol, 13.3 ml). The resulting solution is allowed to return to room temperature and is stirred for 2 hr. The solution is then poured slowly onto a mixture of ice (200 g) and dichloromethane (50 ml). The organic layer is separated, washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated to produce indan-5-sulfonic acid chloride.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:39])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:39]
Reactant: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1O

Procedure:
0.4 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 10 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 202°-204° C. is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:37])=[CH:31][CH:30]=1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CN(C(=O)Cc1ccc(Cl)cc1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound 2-(4-chloro-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-chlorophenylacetyl chloride instead of 4-fluorobenzoyl chloride and was obtained as an off-white semi-solid. MS m/e: 562.2 [M]+.