Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([N:34]=[C:35]=[O:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:36])[CH:28]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)c1ccc(C)c(N=C=O)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-isocyanato-4-methyl-benzoic acid methyl ester in 1,2-dichloroethane in the presence of Et3N (2.2 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=517.2 [M+H+].
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1(OC)C=CC=CC=1.N(CC1C=CC(OC)=CC=1)=[N+]=[N-].[F:25][C:26]1[C:27](=[O:47])[NH:28][C:29](=[O:46])[N:30]([C@H:32]2[CH2:35][C@@H:34]([CH2:36][CH2:37][O:38]CC3C=CC=CC=3)[CH2:33]2)[CH:31]=1>CO>[F:25][C:26]1[C:27](=[O:47])[NH:28][C:29](=[O:46])[N:30]([C@H:32]2[CH2:35][C@@H:34]([CH2:36][CH2:37][OH:38])[CH2:33]2)[CH:31]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@@H](CCOCc3ccccc3)C2)cc1F
Agent: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@@H](CCO)C2)cc1F
Temperature: 0 °C

Procedure:
In a 10 mL flask with AlCl3 (0.81 g, 6.2 mmol) inside, dry anisole 3 mL was added under argon to give a light yellow solution. In another flask with N3-PMB -5-fluoro-1-[cis-3-(benzyloxyethyl)cyclobutyl]uracil (0.27 g, 0.62 mmol) inside, dry anisole 2 mL was added, after which time AlCl3 solution was added to it slowly at room temperature by syringe pump. After addition finishes, the mixture was cooled to 0° C. and dry MeOH was added slowly to give a colorless solution at the end. Then the solvents were removed and the product was purified by silica gel flash chromatography (CH2Cl2:MeOH=20:1) to give a white solid (73.7 mg, 53.4%) combined with some three-membered ring by-products. 1H NMR (CD3OD, 300 MHz): δ 1.68-1.74 (m, 2H), 1.86-1.95 (m, 2H), 2.11-2.20 (m, 1H), 2.48-2.55 (m, 2H), 3.52-3.59 (m, 2H), 4.57-4.69 (m, 1H), 7.90-7.93 (d, J=6.9, 1H). 13C NMR (CDCl3, 100 MHz): δ 10.02, 10.93, 15.94, 18.55, 26.78, 36.15, 37.49, 40.11, 47.47, 53.57, 61.10, 62.87, 127.81, 128.14, 131.01, 131.35, 140.70, 143.01, 151.84, 152.19, 160.41. MS (FAB): expected for C10H13FN2O3 (M+H)+ 229.22. Found 229.09835. IR (neat) νmax 3411, 3187, 3063, 2934, 1697, 1473, 1357, 1272, 1243, 1043, 899, 807, 751, 704.
Reaction SMILES: [OH:1][CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=S)[S:12][C:4]=2[C:3]1=[O:14].[OH2:15]>CC(C)=O.C(O)(=O)C.[Hg](OC(C)=O)OC(C)=O>[OH:1][CH:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[S:10][C:11](=[O:15])[S:12][C:4]=2[C:3]1=[O:14]
Reactant: CC1(C)OC(O)C(=O)c2sc(=S)sc21
Reactant: O
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC1(C)OC(O)C(=O)c2sc(=O)sc21
Reaction time: 0.17 h

Procedure:
13 mg (0.05 mmol) of 6-hydroxy-4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-7(6H)-one 6 was dissolved in acetone (5 mL) and added to a solution of Hg(OAc)2 (50 mg, 0.15 mmol) in 1 ml of acetic acid. The color of the reaction mixture changed very fast from yellow to white. The solution was stirred for 10 minutes and then 20 mL of water was added. The resulting mixture was extracted with CH2Cl2 (3×5 mL). The organic layer was separated and then was washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated again and the aqueous layer was re-extracted again with CH2Cl2 (2×5 mL). The organic layers were combined and evaporated to get 6-hydroxy-4,4-dimethyl-4H[1,3]dithiolo[4,5-c]pyran-2,7(6H)-dione 8 as a pale beige oil. Yield: 7 mg (0.03 mmol, 57%). 1H NMR in CDCl3 (δ, ppm): 5.51 (1H, s, hemiacetal), 1.74 (3H, s, CH3), 1.68 (3H, s, CH3). 13C NMR in CDCl3 (δ, ppm): 187.09, 181.81, 159.93, 124.38, 91.15, 76.16, 31.47, 28.27. IR (neat, cm−1): 3419, 2978, 2929, 2864, 1670, 1625, 1548.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].[Cl:20][C:21]([CH2:23]Cl)=[CH2:22]>CN(C)C=O>[Cl:20][C:21](=[CH2:22])[CH2:23][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:3][C:2]([F:16])([F:1])[F:17])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Reactant: C=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC(C#N)(C#N)Cc1ccc(SC(F)(F)F)cc1
Yield: 46.5 %

Procedure:
Using 0.50 g of (4-(trifluoromethylthio)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 90 mg of sodium hydride (60% in oil), and 0.26 g of 2,3-dichloropropene, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(2-chloro-2-propenyl)-2-(4-(trifluoromethylthio)benzyl)malononitrile (the present compound (2)).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.O.[NH2:21][NH2:22]>C(O)C>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[O:7][C:8]=2[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)c1cc2ccc(N(CC)CC)cc2o1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccc2cc(C(=O)NN)oc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
Equimolar amounts of 6-diethylaminobenzofuran-2-carboxylic acid ethyl ester (Example 3) and hydrazine hydrate are boiled under reflux for three hours in solution in ethanol and after cooling to ambient temperature stirred for another twelve hours. The reaction mixture is poured into ice-water and the precipitate is suction filtered and washed with water. After recrystallization from alcohol the hydrazide is obtained in colorless crystals having a melting point of 127° to 129°C in a yield of 97%. (N: calculated 16.99, found 17.1). It dissolves in alcohol to give a colorless solution with a strong blue fluorescence.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4=[CH:26][S:27][CH:28]=[C:22]4[NH:21][C:20]3=[O:29])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CN([CH:35]=[O:36])C>>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4=[CH:26][S:27][CH:28]=[C:22]4[N:21]([CH2:22][CH2:23][C:24]([O:36][CH3:35])=[O:25])[C:20]3=[O:29])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cscc2c(=O)n1CCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: COC(=O)CCn1c(=O)n(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)c2cscc21
Yield: 80.5 %

Procedure:
The title compound was produced following the procedure of Example 1 using 4.28 g (9.5 mmol) of 3-[4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl]thieno[3,4-d]pyrimidine-2,4-dione in DMF at 45° C. for 16 hours to produce methyl 3-[3-[4-[4(3-trifluoromethylpheny)piperazin-1-yl]butyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate in 80.5% yield (4.1 g).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH2:8]=[O:9].[OH-].[Na+]>>[OH:9][CH2:8][C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7]
Reactant: C=O
Reactant: O=C1C=CC(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=C(CO)C(=O)N1

Procedure:
24 Parts of maleimide (manufactured by Aldrich Corporation), 21 parts of 35% HCOH (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.7 parts of a 5% aqueous NaOH solution are placed in a reactor and reacted at 40° C. for 2 hours. As a result, a white crystal of hydroxymethylmaleimide precipitates. This white crystal is filtered under reduced pressure and then dried at normal temperature under vacuum. The crude crystal of hydroxymethylmaleimide obtained in this manner is recrystallized from ethyl acetate to obtain 22 parts of hydroxymethylmaleimide.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][C:17]=2[NH:16][C:15]1=[O:31]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:28]2[CH2:29][CH2:30][CH:25]([O:24][C:22]3[CH:21]=[CH:20][C:18]4[O:19][CH:14]([CH3:13])[C:15](=[O:31])[NH:16][C:17]=4[CH:23]=3)[CH2:26][CH2:27]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Reactant: CCNC(=O)c1ccc(F)cc1
Product: CCNC(=O)c1ccc(N2CCC(Oc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Yield: 6 %

Procedure:
Using N-ethyl-4-fluorobenzamide 281 as the alkylating agent, the reaction with 394E was carried out as described for 395 providing the title compound as a tan solid (0.0051 g, 6.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 1.40 (d, J=6.57 Hz, 3H) 1.59-1.74 (m, 2H) 1.92-2.07 (m, 1H) 3.08-3.34 (m, 3H) 3.54-3.69 (m, 2H) 4.36-4.50 (m, 1H) 4.58 (q, J=6.65 Hz, 1H) 6.50 (d, J=2.78 Hz, 1H) 6.52-6.63 (m, 1H) 6.88 (d, J=8.59 Hz, 1H) 6.92-7.04 (m, 2H) 7.72 (d, J=8.84 Hz, 2H) 8.18 (s, 1 H) 10.56 (s, 1H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:10]([CH2:11][NH:12][C:13](=O)[C:4]=2[CH:3]=1)=[C:9]([C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)[N:8]=[CH:7]3.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:37])=O>ClC1C=CC=CC=1>[Cl:37][C:13]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=2[N:6]2[C:10]([CH2:11][N:12]=1)=[C:9]([C:15]1[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=1)[N:8]=[CH:7]2
Reactant: O=C1NCc2c(-c3noc(C4CC4)n3)ncn2-c2ccc(Cl)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: ClC1=NCc2c(-c3noc(C4CC4)n3)ncn2-c2ccc(Cl)cc21
Yield: 62.2 %

Procedure:
8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (0.84 g, 2.5 mmol) was suspended in chlorobenzene (8 mL), N,N-dimethyl-p-toluidine (1.1 mL, 7.4 mmol) and phosphorus oxychloride (0.34 mL, 3.7 mmol) were added and the mixture was refluxed overnight. The resulting solution was evaporated and the residue was purified by chromatography on silica gel in CH2Cl2/acetone 10:1. One obtained a white solid (0.56 g, 63%). mp 200° C. m/z 359(M).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([OH:15])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][O:24][C:20]=2[N:21]=[CH:22][N:23]=1>C1COCC1>[C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:18]2[C:19]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2occ(-c3ccccc3)c12
Reactant: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Oc2ncnc3occ(-c4ccccc4)c23)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolve 500 mg (2.17 mmol) of (+/−)-cis-{[3-hydroxycyclohexyl]oxy}acetic acid tert-butyl ester in 2.0 ml of dry THF, cool to 0° C. and add 1.24 ml (approx. 2.5 mmol) of a 2N solution of phosphazene base P2-t-Bu in THF. After removing the cooling, stir the mixture at RT for a further 30 min, before adding 500.7 mg (2.17 mmol) of 4-chloro-5-phenylfuro[2,3-d]pyrimidine at RT. Stir the mixture at RT overnight and then concentrate under reduced pressure. Purify the residue by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→8:1). The target product is obtained after further purification by means of RP-HPLC (eluent: acetonitrile/water). 380 mg (41.2% of theory) are isolated.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].S=[C:9]1[CH2:13][S:12][C:11](=[O:14])[NH:10]1>C(O)C>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1
Reactant: CC(C)(CN)CO
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CC(C)(CO)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 3-amino-2,2-dimethylpropan-1-ol (4.05 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.07 g). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([OH:11])=[O:10].ClC1C=C(O)C([N+]([O-])=O)=CC=1Cl>>[Cl:1][C:2]1[C:3]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Product: O=[N+]([O-])c1cccc(Cl)c1O

Procedure:
6-chloro-2-nitrophenol (12A) was prepared by treating 2-chlorophenol with nitric acid according to the procedure described for preparing 9A, in Example 9.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCO.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.N#N>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:17]([CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Agent: N#N
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Yield: 66.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester was prepared by the addition of tryptamine-HCl (1.33 g, 6.76 mmol), EtOH (12 mL), and a 50% toluene solution of ethyl glyoxylate (1.66 g, 8.11 mmol) to a 50 mL flask purged with N2. The reaction solution was allowed to reflux 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude material was chromatographed (SiO2, 100% DCM to 4% MeOH) to provide 1.10 g (68% yield) of 2,3,4,9-tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester; 1H NMR (CDCl3) δ 8.59 (1H, br s), 7.46 (1H, d), 7.39 (1H, d), 7.23 (1H, t), 7.14 (1H, t), 5.40 (1H, s), 4.24 (2H, q), 3.51 (1H, m), 3.07 (1H, m), 2.86 (1H, d), 1.30 (3H, t); 13C NMR (CDCl3) 6166, 137, 126, 123, 122, 120, 119, 112, 108, 64, 60, 53, 41, 14; MS(ESI): 245 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:19]1[C:20]([CH3:21])=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=32)=[CH:18]1
Reactant: COC(=O)CBr
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc2c(c1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 30 ml of dry dimethylformamide. After stirring at 0° C. for 15 minutes, 0.65 ml (7.7 mmol) of methyl bromoacetate was added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to an oily residue. Purification of the residue by column chromatography (silica gel, 40 g; eluent, 5% ether in methylene chloride) gave after crystallization from a mixture of ether and petroleum ether 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester as off-white prisms, mp 174°-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(O)nc1
Reactant: Clc1ccnc(Cl)c1
Product: Nc1ccc(Oc2ccnc(Cl)c2)nc1
Yield: 34.8 %

Procedure:
Using a procedure analogous to Example A1, 5-amino-2-hydroxypyridine (10.15 g, 92 mmol) and 2,4-dichloropyridine (13.64 g, 92 mmol) were combined to provide 6-(2-chloropyridin-4-yloxy)pyridin-3-amine (7.09 g, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (m, 1H), 7.61 (m, 1H), 7.26 (m, 1H), 7.0 (s, 1H), 6.97-6.94 (m, 2H), 5.4 (brs, 2H); MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13]1([CH:23]2[CH2:25][O:24]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[ClH:26]>CC(C)=O.C(OCC)(=O)C>[ClH:26].[CH3:7][N:8]([CH2:10][CH2:11][O:12][CH2:25][CH:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[OH:24])[CH3:9]
Reactant: CN(C)CCO
Reactant: c1ccc2c(C3CO3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCOCC(O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 13.2 g of potassium tert-butoxide and 47.2 ml of 2-(N,N-dimethylamino)ethanol was heated to 80° C. Thereto was dropwise added 40.0 g of 2-(1-naphthyl)oxirane in 3.5 hours. The resulting mixture was stirred for 1.5 hours at 80°-85° C. The reaction mixture was cooled and added to a mixture of 100 ml of ethyl acetate and 100 ml of ice water. The resulting mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation to obtain a fraction having a boiling point of 152°-163° C./0.6-0.8 mmHg. The oily product obtained was dissolved in 200 ml of acetone. Into the solution was blown hydrogen chloride gas with ice cooling. The resulting crystals were collected by filtration, washed with acetone, and dried to obtain 22.7 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride (compound No. 228).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:41])=[CH:28]\[CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[C:21]=1[CH3:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:30][CH2:29]/[CH:28]=[C:27](\[C:22]1[C:21]([CH3:42])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:25]([CH3:26])=[CH:24][CH:23]=1)/[CH3:41]
Reactant: C/C(=C/CN1C(=O)c2ccccc2C1=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Agent: NN
Solvent: O
Solvent: CCO
Product: C/C(=C/CN)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Yield: 90.8 %

Procedure:
To a suspension of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-1-methyl-3-phthalimido-1-propenyl)benzene (94 mg) in ethanol (1 ml) was added hydrazine monohydrate (16.4 mg), and the mixture was refluxed for 1 hour. After cooling, the insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added dichloromethane, and the insoluble material was filtered off. The filtrate was concentrated in vacuo to give 3-((Z)-3-amino-1-methyl-1-propenyl)-1-tert-butyldiphenylsilyloxymethyl-2,6-dimethylbenzene (66 mg) as pale yellow amorphous.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1>C(O)CCC.C(N(CC)CC)C>[NH:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5ccccc5[nH]4)CC3)nc(N)c2cc1OC
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To 5.14 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride in 100 ml butanol, 11 ml of triethylamine was added. The mixture was stirred for 15 min and 2.65 g of 2-chloro-1H-benzimidazole was added. The mixture was refluxed for 18 hr and evaporated. Water was added to the residue and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate and evaporated. The residue was crystallized from methanol to give 3.5 g of the title compound, which was recrystallized from methanol: mp>250° C.; ir (nujol mull) 3360 and 3180 cm-1 ; uv max (MeOH) 341 (ε=6,300), 284 (ε=28,500) and 251 nm (ε=66,800); nmr (DMSO-d6) ε 3.5 (m, 4H), 3.8 (m, 4H), 3.8 (s, 3H), 3.84 (s, 3H), 7.1 (m, 8H) and 10.7 (s, 1H); and Anal. Calcd for C21H23N7O2. 1/2 H2O: C, 60.86% H, 5.79% N, 23.67% and Found: C, 60.87% H, 5.98% N, 23.65%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][NH:13][CH2:12][C@@H:11]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:31]([O:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][N:13]([C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[O:32])[CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(3S,4R)-4-({[Tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-3-yl]pyridine and N,N-diisopropylethylamine were dissolved in THF, methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added in one portion thereto at room temperature and stirred for 3 hours, and then the reaction solution was concentrated under a reduced pressure. Work-up and purification of the residue was carried out in the standard method to produce 4-(methoxycarbonyl)phenyl (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-pyridin-3-ylpyrrolidine-1-carboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:23]5[CH2:24][N:19]6[CH2:20][CH:21]([CH2:25][CH:17]4[CH2:18]6)[CH2:22]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:34])C=1>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][C:13]([O:15][C@@H:16]4[CH:17]5[CH2:18][N+:19]6([O-:34])[CH2:20][CH:21]([CH2:22][CH:23]4[CH2:24]6)[CH2:25]5)=[N:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cc2cc(-c3cnc(OC4C5CC6CC4CN(C6)C5)s3)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: [O-][N+]12CC3CC(C1)C(Oc1ncc(-c4ccc5[nH]ccc5c4)s1)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 28A (105 mg, 0.30 mmol) in methanol (4 mL) was treated with 3-chloroperbenzoic acid (mCPBA; 70-75%; 71.0 mg, 0.30 mmol; Aldrich) and stirred at ambient temperature for 4 hours. The resulting material was purified by preparative HPLC [Waters® XTerra RP18 column, 5μ, 30×100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.70-2.02 (m, 2H), 2.10-2.29 (m, 1H), 2.29-2.47 (m, 1H), 2.58-2.78 (m, 2H), 3.57-3.67 (m, 5H), 5.32 (t, J=3.3 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 7.27-7.31 (m, 2H), 7.36-7.42 (m, 1H), 7.66 (d, J=1.3 Hz, 1H). MS (DCI/NH3) m/z=368 (M+H)+.