Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][N:8]([CH3:37])[C:9]1[CH:36]=[CH:35][C:12]([CH:13]([C:23]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.OC1C=CC2C(=CC=CC=2)C=1N=NC1C=C(S(O)(=O)=O)C=CC=1O>>[CH3:22][N:20]([CH3:21])[C:17]1[CH:16]=[CH:15][C:14]([C:13]2([C:12]3[CH:11]=[CH:10][C:9]([N:8]([CH3:7])[CH3:37])=[CH:36][CH:35]=3)[C:23]3[C:24](=[CH:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=3)[C:25](=[O:27])[O:26]2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccc(O)c(N=Nc2c(O)ccc3ccccc23)c1
Agent: [Na+]
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
In accordance with the process of Example 1, the aqueous solution containing a sodium carbonate and 2-[4,4'-bis-(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid and cobalt complex of 1-[(2-hydroxynaphthyl)azo]-2-hydroxybenzene-5-sulfonic acid [I], was heated at 90° C. and 36 wt. parts of air was fed into it under vigorously stirring during 15 hours and the precipitate was separated by a filtration and washed with a dilute aqueous solution of sodium hydroxide and with water to obtain 39.4 wt. parts of 3,3-bis-(4-dimethylaminophenyl)-6-dimethylaminophthalide having a melting point of 181° to 183° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4]>N1C=CC=CC=1>[CH2:1]([O:5][C:4]1[CH2:3][CH2:2][C:1]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Solvent: c1ccncc1
Product: CCCCOC1=C(OCCCC)CC1
Yield: 12.2 %

Procedure:
In a reactor flask purged with nitrogen gas, 1.4 g (2.0 mmol) of the compound No. 40 obtained in Example 2, 0.50 g (2.2 mmol) of 3,4-dibutoxy-3-cyclobutene, 4.0 g of butanol, and 0.24 g of pyridine were charged, and the resulting mixture was stirred at room temperature for 15 hours, at 50° C. for 4 hours, and at 75° C. for 21 hours. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified with a column (silica gel, chloroform:acetone=10:1) to obtain 0.92 g of a brown amorphous product (yield: 70%). The brown amorphous product was subjected to the 1H-NMR analysis. The brown amorphous product was identified as the aimed product of compound No. 50. The result of the 1H-NMR analysis is shown below.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C@@H:9]([NH:13][C:14]1[C:19]([CH2:20][C:21]2[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[C:34]([O:36]C)=[O:35])=[CH:23][C:22]=2[O:40][CH3:41])=[C:18]([CH3:42])[N:17]=[C:16]([NH2:43])[N:15]=1)[CH2:10][CH2:11][CH3:12])(=O)C>CO>[NH2:43][C:16]1[N:15]=[C:14]([NH:13][C@@H:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][OH:6])[C:19]([CH2:20][C:21]2[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[C:34]([OH:36])=[O:35])=[CH:23][C:22]=2[O:40][CH3:41])=[C:18]([CH3:42])[N:17]=1
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@H]2C(=O)OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@H]2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 88.7 %

Procedure:
1M-sodium hydroxide (2 mL) was added to a solution of the product (60 mg) from step (vi) in methanol (2 mL) and the mixture was stirred at RT for 9 h. The reaction mixture was concentrated, diluted with water and washed with chloroform. The aqueous layer was neutralized with 2M-hydrogen chloride and extracted with chloroform/EtOH (3/1). The combined organic layer was dried and concentrated. The residue was diluted with chloroform, filtered, concentrated under reduced pressure to afford the sub-title compound (48 mg) as a white solid; 1H NMR (CDCl3); 6.79 (1H, d), 6.48 (1H, d), 6.38 (1H, dd), 6.17 (1H, br s), 5.24 (1H, br s), 4.20-3.97 (3H, m), 3.85 (3H, s), 3.70-3.58 (1H, m), 3.55 (2H, s), 3.48-3.34 (2H, m), 3.32-3.15 (2H, m), 3.05-2.80 (1H, m), 2.75-2.55 (1H, m), 2.35 (3H, s), 2.30-2.07 (4H, m), 2.05-1.85 (2H, m), 1.85-1.70 (1H, m), 1.48-1.34 (1H, m), 1.33-0.98 (4H, m), 0.77 (3H, t); LC-MS: m/z 516.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:5]=1[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)([CH3:3])[CH3:2].O.NN>CO>[CH:25]([C:18]1[CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][NH2:7])([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(C)C)c(CN2C(=O)c3ccccc3C2=O)c(C(C)C)c1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C(C)C)c(CN)c(C(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of N-(2,4,6-triisopropylbenzyl)phthalimide (4.62 g, 13.7 mmol), hydrazine hydrate (0.5 mL), and methanol (150 mL) was heated on the steambath for 3 hours, at which time 0.3 mL more hydrazine hydrate was added. The reaction mixture was allowed to stand overnight at room temperature. Methanol (150 mL) was added and heated on the steambath. The methanol was removed on the rotary evaporator without heating. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (1×200 mL and 1×100 mL), the extracts were combined, dried (magnesium sulfate), filtered, and concentrated. The residue was filtered through silica using ethyl acetate as eluant. The product was obtained as an oil, 1.93 g, (65%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[S:13][C:14]([Br:17])=[CH:15][N:16]=1)(=O)OCC)C.O=[C:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1.[Cl-].[NH4+]>[Br:17][C:14]1[S:13][C:12]([CH:11]=[C:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[N:16][CH:15]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ncc(Br)s1)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=Cc2ncc(Br)s2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (60% in mineral oil, 122 mg, 3.06 mmol) in THF (10 mL) was cooled to 0° C., and diethyl[(5-bromo-1,3-thiazol-2-yl)methyl]phosphonate (769 mg, 2.448 mmol) in THF (2 mL) was added dropwise and subsequently stirred at 0° C. for 30 minutes. Ethyl 4-oxocyclohexanecarboxylate (417 mg, 2.448 mmol) in THF (2 mL) was then added, and allowed to warm to room temperature over 2 h. Then, the reaction was diluted with saturated ammonium chloride and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-10% ethyl acetate in hexanes) to afford ethyl 4-[(5-bromo-1,3-thiazol-2-yl)methylidene]cyclohexanecarboxylate as a yellow oil. MS ESI calc'd. for C13H17BrNO2S [M+H]+ 330, 332. found 330, 332. 1H NMR (600 MHz, CDCl3) δ 7.62 (s, 1H), 6.34 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.41-3.33 (m, 1H), 2.60-2.52 (m, 1H), 2.47-2.40 (m, 1H), 2.31-2.19 (m, 2H), 2.12-2.02 (m, 2H), 1.80-1.63 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:32][CH2:33][CH2:34][Cl:35])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(OCCCCl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
100 mg (0.292 mmol) of the compound of Example 44A are provided in 3 ml of dry DMF, 76.6 mg (0.554 mmol) of potassium carbonate and 133 mg (0.846 mmol) of 1-bromo-3-chloropropane are added, and the mixture is heated under reflux for 4 h. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 42 mg of the title compound with 49% purity (17% of theory) are obtained.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].S(O)(=O)(=O)C.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1([CH2:25][N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[CH2:24][O:23]1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]([OH:23])([CH2:24][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: O=C(O)CCS
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCSCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 5 °C
Reaction time: 19 h

Procedure:
3-Mercaptopropionic acid (1.2 g, 1.1 equiv.) was dissolved in dimethylformamide (50 ml) and cooled to 5° C. in an ice bath. Sodium hydride (1.6 g of a 50% dispersion in oil, 3.3 equiv.) was added in portions over 10 minutes, followed by 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane mesylate (3.6 g). After stirring overnight (19 hours) the mixture was poured onto ice (200 ml) and extracted with methylene chloride (3×50 ml). The aqueous layer was adjusted to pH3 with hydrochloric acid (5N) and extracted with methylene chloride (3×50 ml). The organic extracts were combined, washed with saturated sodium chloride solution (2×50 ml), dried (Na2SO4), and evaporated under reduced pressure to a gum, 5.6 g.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[C:67]([Cl:68])=[CH:66][CH:65]=[CH:64][N:63]=3)[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:52][C:53]2[N:58]=[CH:57][N:56]=[C:55]3[N:59]([C:62]4[C:67]([Cl:68])=[CH:66][CH:65]=[CH:64][N:63]=4)[N:60]=[CH:61][C:54]=23)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)[C@H](COCCO)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.790 mL, 0.79 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AB4) (576 mg, 0.79 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (1 mL), diluted with DCM (10 ml) and poured onto a phase separator. The organic layer was collected and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. The resulting product decomposed to an extent during evaporation and so was re-purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to afford the product (82 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 2.49-2.56 (1H, m), 3.69-3.85 (4H, m), 4.14-4.25 (2H, m), 6.08 (1H, t), 7.45-7.50 (1H, m), 7.67-7.72 (1H, m), 7.98-8.04 (1H, m), 8.15-8.28 (2H, m), 8.47 (1H, s), 8.58-8.65 (2H, m), 8.99 (1H, s); m/z (ES+) (M+H)+=490.35; HPLC tR=1.82 min.
Reaction SMILES: [H-].[Na+].C(S)C.[H][H].C[O:9][C:10]1[C:11](OC)=[CH:12][C:13]2[S:19](=O)[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:21]=1>CN(C)C=O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[S:19][CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:21]=1
Reactant: COc1cc2c(cc1OC)S(=O)CCCC2
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ccc2c(c1)C=CC=CS2

Procedure:
Sodium hydride (8.8 g of a 50% w/w dispersion in oil) was added over 30 minutes to a solution of ethanethiol (20.8 g) in dry dimethylformamide at 0°. After evolution of hydrogen had ceased additional ethanethiol (8.8 ml) was added followed by 7,8-dimethoxy-2,3,4,5-tetrahydro-1-benzothiepin-1-oxide. The mixture was heated at reflux for 3 hours, cooled and the solvent was removed in vacuo. The residue was taken up in water (100 ml) and extracted with diethyl ether (2×100 ml). The aqueous solution was acidified with conc. hydrochloric acid, saturated with solid sodium chloride and extracted with chloroform (2×100 ml). The organic extract was dried (Na2SO4) and the solvent was removed in vacuo to give a cream coloured solid. This material was chromatographed on a silica gel column eluting with methylene chloride/methanol mixtures (gradient 0 to 3% v/v methanol) to give the 7-hydroxybenzothiepin (20.7 g), m.p. 165°-166°. Further elution of the column gave, after recrystallisation from methanol, the isomeric 8-hydroxybenzothiepin (2.25 g), m.p. 173°-175°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([CH:16]3[CH2:17][CH2:18][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 120 °C

Procedure:
8-Chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (product from Example 24A) (4.18 g, 13 mmol) was dissolved in toluene (175 mL). Ethyl chloroformate(11.6 g, 110 mmol, 10.2 mL) was then added and the reaction mixture was heated to ˜120° C. overnight. All volatiles were stripped off and the crude product was purified on silica gel column eluting with 50% EtOAc-hexanes to give the title compound as a white solid(MH+ 385).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[F:8].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1F)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 15.1 g (58.1 mmol) of 3-chloro-2,4-difluoro-(trifluoroacetamido)-benzene in 80 mL of H2SO4 kept in an ice-bath was added dropwise 10 mL of HNO3. Solid precipitate was observed during addition of HNO3. The mixture was stirred in an ice-bath for 4 h, then added to 600 mL of ice-water. The precipitate was filtered, washed with water, and dried to leave an almost colorless solid (16.8 g, 95%); mp 124-125° C.; 1H NMR (CDCl3), 7.69 (dd, 1), 8.936 (mb, 1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.O=[C:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=[O:36])[CH2:26][CH2:25]1>>[O:36]=[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]1[CH:27]1[CH2:28][CH2:29][CH:24]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:25][CH2:26]1
Reactant: O=C1CCC(n2ccccc2=O)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(n3ccccc3=O)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide and 1-(4-oxo-cyclohexyl)-1H-pyridin-2-one using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.C(N(CC)CC)C.[C:18](OCC)(=[O:24])[C:19](OCC)=[O:20]>>[OH:20][C:19]1[C:18]([OH:24])=[N:10][C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCN(CC)CC
Product: COc1ccc2nc(O)c(O)nc2c1
Temperature: 25 °C

Procedure:
A mixture consisting of 20 g. (0.114 mole) of 4-methoxy-o-phenylenediamine and 11 g. (0.114 mole) of triethylamine dissolved in 200 ml. of diethyl oxalate was refluxed overnight for a period of approximately 16 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.) and filtered to remove the desired product. After washing with ethanol, there were ultimately obtained 14.8 g. (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline, m.p. >300° C. Mass Spectrum: m/e, 192 (P).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.NC(C(O)=O)CCSC.CS(O)(=O)=O.O>CC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: O
Solvent: CC(C)=O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Temperature: 25 °C

Procedure:
A solution of 50 g (0.12 mol) of podophyllotoxin I, prepared in 50 ml of acetone, is added with stirring at ordinary temperature to a mixture consisting of 100 g (0.67 mol) of D,L-methionine, of 500 ml (7.7 mol) of methanesulfonic acid and of 10 ml of water. The temperature rises to approximately 40° C. and stirring is maintained for 2 h with return to ambient temperature. The mixture is then poured onto ice in order to obtain a precipitate which is extracted with ethyl acetate (3×700 ml). The organic phases are washed with an NaHCO3 solution and then separated by settling, dried over Na2SO4, filtered and evaporated under reduced pressure in order to obtain 4'-demethylepipodophyllotoxin, existing in the form of a white solid. 45 g (Yd 94%) are obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]#[C:9]Br.[OH-].[Na+]>>[N:1]1([C:9]#[N:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CBr
Reactant: C1CCCNCC1
Agent: [Na+]
Agent: [OH-]
Product: N#CN1CCCCCC1

Procedure:
In the manner given in Example 1, hexahydroazepine is treated with cyanogen bromide and aqueous sodium hydroxide to give 1-hexahydroazepinecarbonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[N+:9](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-:10]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[NH:10][N:9]=1)=[O:13])[CH3:16]
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccn2)[nH]n1
Temperature: 85 °C
Reaction time: 36 h
Yield: 45.2 %

Procedure:
A mixture of 2-ethynylpyridine (10.3 g), ethyl diazoacetate (11.6 g), and toluene (100 ml) was stirred at 85° C. for 36 hours. The resulting mixture was rotavaped and the residue recrystallized with ethanol (50ml) to afford 9.81 g of 5-(2-pyridinyl)pyrazole-3-carboxylic acid ethyl ester as tan crystallines, mp 103°-105° C. NMR: 1.43 (t, 3H), 4.40 (q, 2H), 7.32 (s, 1H, 4-pyrazolyl H), 7.30, 7.78, 8.66 (3 m, 4H, pyridinyl H's).
Reaction SMILES: [OH:1][CH:2]([CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]>[Cl-].[Ca+2].[Cl-]>[C:2]([CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)(=[O:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: OC(c1ccccc1)C1CCCC1[c-]1cccc1
Agent: [Fe+2]
Agent: [Ca+2]
Agent: [Cl-]
Product: O=C(c1ccccc1)C1CCCC1[c-]1cccc1
Reaction time: 1 h
Yield: 22.3 %

Procedure:
1-(α-Hydroxybenzyl)-2-ferrocenyl cyclopentane (360 mg; 1 mmole) was added to a suspension of chromium trioxide dipyridine complex (1.6g; sixfold excess) in calcium chloride dried methylene chloride (25 ml) at room temperature with stirring for 1 hr. The suspension was filtered, the organic solution was washed with 2N NaOH (2 × 100 ml), 2N HCl (2 × 100 ml) and water (2 × 100 ml), and dried (Na2SO4) to yield a pale brown oil which crystallized on trituration with petroleum ether. Recrystallization from petroleum ether (bp 40°-60°) gave the desired product as a yellow solid (80 mg; 22%) mp 109°-110° IR:γ max 1670 cm-1 'HNMR:δ 7.7 and 7.4 (multiplets 5H); 4.0 (s, 5H); 4.1 - 3.9 (m; 4H); 3.5 (m, 1H); 2.0 (m; 7H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:28][C:11]3=[N:12][C:13]([N:18]([CH2:23][CH2:24][CH2:25]C=C)[S:19]([CH3:22])(=[O:21])=[O:20])=[C:14]([CH:16]=[CH2:17])[CH:15]=[C:10]3[C:9]=2[C:29]([NH:31][CH3:32])=[O:30])=[CH:4][CH:3]=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C(Cl)Cl>[CH3:32][NH:31][C:29]([C:9]1[C:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][CH2:25][CH2:24][CH2:23][N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]3=[N:12][C:11]=2[O:28][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:30]
Reactant: C=CCCCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1C=C)S(C)(=O)=O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)/C=C\CCCN3S(C)(=O)=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C=CCCCN3S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-(pent-4-enyl)methylsulfonamido)-5-vinylfuro[2,3-b]pyridine-3-carboxamide (5.0 mg, 1 eq.), Hoveyda-Grubbs catalyst 2nd generation (0.7 mg, 0.1 eq.) and methylene chloride (0.55 ml) was degassed and stirred in a microwave reactor at 100° C. for 15 min. The reaction mixture was diluted with EtOAc, filtered through a 0.2 μM PTFE syringe filter and concentrated to yield the crude title compound which was used without purification in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O:21][C:22]1[C:33]([CH2:34][CH:35]=O)=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[O:28][CH2:29][C:24]=2[CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:20][O:21][C:22]1[C:33]([CH2:34][CH2:35][N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:13]=4)[CH:9]=[CH:10]3)[CH2:15][CH2:16]2)=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[O:28][CH2:29][C:24]=2[CH:23]=1
Reactant: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1cc2c(cc1CC=O)N(C)C(=O)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)COC(=O)N5C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
80 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 83 mg of (6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)acetaldehyde were dissolved in 6 ml of methylene chloride. Thereafter, 0.04 ml of acetic acid and 99 mg of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate), so as to obtain 141 mg of the subject compound.