Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A solution of 2-benzyloxyphenol (6.01 g, 30 mmol) in anhydrous N,N-dimethylformamide (25 mL) was treated with anhydrous potassium carbonate (7.6 g, 55 mmol), then with 4-fluoronitrobenzene (3.53 g, 25 mmol), and heated to 90° C. for 5 h under nitrogen. The solution was cooled to room temperature, diluted with dichloromethane (50 mL), and treated with DOWEX® 550A OH anion exchange resin (10 g) which had been washed dry with methanol. The mixture was stirred for 3 h, filtered, and the filtrate concentrated in vacuo (exhaustively at end to remove DMF). The residue was chromatographed on silica gel (eluted with 2:1 hexane/ethyl acetate) to afford 4-(2-benzyloxyphenoxy)nitrobenzene (6.40 g, 66%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J13) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (362 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][CH:6]([CH3:13])[NH:7]2.[S:15]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](Cl)=[O:28])([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][CH:6]([CH3:13])[N:7]2[C:27](=[O:28])[C@@H:26]1[CH2:30][CH2:31][CH2:32][N:25]1[S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)Cl)cc1
Reactant: CC1CC(=O)c2c(ccc(F)c2Cl)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N2c3ccc(F)c(Cl)c3C(=O)CC2C)cc1
Reaction time: 0.33 h

Procedure:
36.7g of (+)-5-chloro-6-fluoro-2-methyl-4-oxo1,2,3,4-tetrahydroquinoline was dissolved in 34.3 g of pyridine and 400 ml of dichloromethane. Then, a solution of N-tosyl-L-prolyl chloride (prepared from 92.4 g of N-tosyl-L-proline and 74.5 ml of thionyl chloride) in 70 ml of dichloromethane was added thereto at room temperature over a period of 20 minutes. After completion of the addition, the resulting mixture was stirred for 15 minutes and then heated under reflux for 20 minutes. This reaction mixture was allowed to cool, washed successively with dilute hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water, and then dried. Thereafter, the solvent was evaporated under reduced pressure to obtain a residue comprising a mixture diastereomers of 5-chloro-6-fluoro-2-methyl-4-oxo-1-(N-tosyl-L prolyl)-1,2,3,4-tetrahydroquinoline. This residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (10:1) as the eluent, and then subjected to thin-layer chromatography [using chloroform-ethyl acetate (10:1) as the developing solvent]. Fractions having an Rf value of 0.47 were collected and concentrated under reduced pressure to obtain 36.8 g of (+)-5-chloro-6-fluoro-2-methyl-4-oxo-1-(N-tosyl-L-prolyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:15])=[O:24])[C:7]=1[C:8]#[N:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: CSc1cccc(NS(N)(=O)=O)c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(NS(N)(=O)=O)c1C#N

Procedure:
The mixture of 2-sulfamoylamino-6-(methylthio)benzonitrile (Example 104a) (48 mg, 0.2 mmol) and MCPBA (69 mg, 0.4 mmol) in dichloromethane (16 mL) was heated refluxed overnight. After cooling down, the precipitation was collected by filtration, rinsed with dichloromethane, dried in the air to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.83 (s, 3H), 7.35 (brs, 2H), 7.72-6.69 (m, 2H), 7.92 (t, J=8.0 Hz, 1H), 9.87 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:34]([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([C:28]([O:30]CC)=[O:29])[NH:25][C:24]=4[CH:33]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:34]([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([C:28]([OH:30])=[O:29])[NH:25][C:24]=4[CH:33]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(NC(=O)C(C(C)C)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: COc1cn(C(C(=O)Nc2ccc3nc(C(=O)O)[nH]c3c2)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
130 mg (237 μmol) of ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-1H-benzimidazole-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 56 mg (44% of theory)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:2]1.[CH:35](=O)[CH3:36]>>[CH2:35]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:4]1)[CH3:36]
Reactant: CC=O
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CNC3)cc2)n1
Product: CCN1CC(Oc2ccc(Sc3ccc(Sc4nncn4C)nc3C(=O)Nc3nc(C)ns3)cc2)C1

Procedure:
Starting from 3-{[4-(azetidin-3-yloxy)phenyl]thio}-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Example 2 (step 2) and using acetaldehyde, the entitled compound was obtained as a yellow solid in the same method as in Example 2 (step 3) or in accordance with the method or by combining it with an ordinary method.
Reaction SMILES: [BH4-].[Na+].[Br:3]/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C>[Br:3]/[CH:4]=[CH:5]/[CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)/C=C/Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)/C=C/Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled mixture of 20 g. of sodium borohydride in 800 ml. of anhydrous ethanol is added 160 g. of crude 1-bromo-trans-1-octen-3-one (Example 992) over a period of 0.5 hour. The mixture is stirred for 2 hours with ice cooling and is then partitioned between ice water and benzene. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated to an oil. Distillation gives the product as an oil, b.p. 66°-68°C. (0.025 torr.).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].O.C(=O)([O-])[O-].[K+:38].[K+]>CO>[K+:38].[C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 1 h

Procedure:
A 100 mg (0.23 mM) quantity (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (Preparation 6, 5Ba) is stirred at room temperature under nitrogen in 3 mL MeOH. Added 0.1 mL water and 43 mg (0.31 mM) potassium carbonate. After 1 hour, TLC shows no starting material left. Stored in freezer overnight. The next morning the solvent is evaporated to give (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (6Ba). The residue is partitioned between methylene chloride and water containing 0.9 mL 1N HCl. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated. This leaves (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (7Ba) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl.C(OCC)(=O)C>[C:31]([NH:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(CN)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of benzyl tert-butyl (3-aminopropane-1,2-diyl)biscarbamate (8.0 g, 25 mmol) and triethylamine (7.9 g, 78 mmol) in DCM (100 mL) was added acetic anhydride (2.8 g, 27 mmol) at 0° C. After 1 hour, the reaction mixture was diluted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on silica gel to give benzyl tert-butyl [3-(acetylamino)propane-1,2-diyl]biscarbamate. MS ESI calc'd. for C18H28N3O5 [M+H]+ 366. found 366. 1H NMR (400 MHz, CD3OD) δ 7.34-7.30 (m, 5H), 5.01 (s, 2H), 3.59-3.51 (m, 3H), 2.87-2.77 (m, 2H), 2.0 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]=[CH:7][CH:8]([CH3:16])[CH2:9][CH:10]=[CH:11][CH:12]([CH3:15])[CH2:13][CH3:14])[CH:3]=[O:4]>O1CCCC1.[Pd]>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])[CH:3]=[O:4]
Reactant: CCC(C)C=CCC(C)C=CCC(C)C=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(C)CCCC(C)CCCC(C)C=O
Yield: 92.8 %

Procedure:
22 g (0.1 mole) of 2,6,10-trimethyl-dodeca-4,8-dien-1-al are dissolved in 20 ml of tetrahydrofuran, 1 g of a palladium/charcoal catalyst (1%) is added and hydrogenation is carried out at 70° C until the absorption of hydrogen has ceased. The catalyst is then filtered off, the solvent distilled off and the residue is fractionated through a descending condenser. 21 g of 2,6,10-trimethyl-dodecan-1-al are obtained (yield, 93% of theory). B.p. = 80° - 81° C at 0.3 mm Hg; nD25 = 1.4456. Odor: bitter, greener and more aldehyde-like orange scent.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([CH3:42])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:40])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:10][C:9]=1[CH3:41])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:42][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:25]2[S:29][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=3)=[N:27][C:26]=2[CH3:40])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:10][C:9]=1[CH3:41])([CH3:6])[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2OC)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1CN(Cc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
To a solution of example 94 (520 mg, 0.85 mmol) in EtOH (20 mL) was added 1N NaOH (2.5 mL, 3 eq.) and the reaction was stirred at 80° C. for 1 h. When all of the starting material had disappeared, the reaction cooled, evaporated to dryness, taken up with 1 N HCl and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed eluting with CH2Cl2 (100%) then CH2Cl2/MeOH (95/5) to afford the title compound as a yellow oil (80 mg, 16%).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([C:6]1[C:7]([OH:13])=[CH:8][CH:9]=[CH:10][C:11]=1[OH:12])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19](Cl)=O.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19]1[O:13][C:7]2[C:6]([C:4](=[O:5])[CH:3]=1)=[C:11]([OH:12])[CH:10]=[CH:9][CH:8]=2
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3c(O)cccc3o2)cc1OC
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (19.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2,6-dihydroxyacetophenone (6.6 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 3,4-dimethoxybenzoyl chloride (6 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 3′,4′-dimethoxy-5-hydroxyflavone. 1H NMR (250 MHz, CDCl3): δ=4.00 (d, 6 H), 6.60–7.60 (md, 7 H), 12.65 (s, 1 H); 13C NMR CDP (250 MHz, CDCl3): δ=54.71 (s), 103.48 (s), 105.57 (s), 107.45 (s), 109.76 (s), 118.93 (s), 122.24 (s), 133.80 (s), 147.93 (s), 151.06 (s), 159.39 (s), 163.17 (s), 182.04 (s); EI-MS (70 eV) m/e (rel. abund.)=298; UV (2-propanol): λ=248 nm, 342.5 nm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC(=O)C1C=C(OCC)C([Cl:46])=C(OCC)C=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[Cl:46][C:28]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=3)[CH2:10][CH2:9]2)=[CH:26][C:27]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 257) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 463.3 (MH+).
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH2:10]([SH:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C>[CH2:10]([S:12][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])[CH3:11]
Reactant: O=[N+]([O-])c1cc[nH]c1Cl
Reactant: CCS
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1[nH]ccc1[N+](=O)[O-]
Temperature: 175 °C

Procedure:
Using a microwave chemical reactor (CEM Explorer Microwave System manufactured by CEM Corporation, 3100 Smith Farm Road, Matthews N.C., 28106-0200), 0.1 gram (0.70 millimole) of 2-chloro-3-nitropyrrole (prepared in Steps D-F of Example 1), 0.5 mL (excess) of ethylmercaptan and 0.2 mL of ethyldiisopropylamine (excess) in 5 mL of acetonitrile were placed in an appropriate 10 mL vile. The vile was sealed and placed in the reaction chamber of the microwave chemical reactor. At 150 watts of power, the microwave reactor was brought to 100° C. during a five-minute period, where it was maintained for a 30-minute period. In a like manner the reactor was brought to 150° C. where it was maintained for a 30-minute period, and finally to 175° C. where it was maintained for a 30-minute period, after which time the reaction was considered to be complete. Upon completion of the reaction the microwave reactor was cooled, and the vile containing the reaction mixture was removed from the reactor and absorbed onto silica gel. The silica gel-reaction mixture combination was then subjected to column chromatography. Elution was accomplished using 33% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.03 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated.
Reaction SMILES: [CH2:1]([S:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.[NH2:32][NH2:33]>C(O)CC>[CH2:1]([S:23][CH2:24][CH2:25][C:26]([NH:32][NH2:33])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NN
Reactant: CCCCCCCCCCCCCCCCCCCCCCSCCC(=O)OCC
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCSCCC(=O)NN
Temperature: 25 °C

Procedure:
22.1 Grams of ethyl 3-(docosylthio)propionate, 150 ml of n-propanol and 12.5 g of hydrazine monohydrate were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 20 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 17.2 g of the desired product. m.p. 106° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26]C(=O)C(F)(F)F)[CH2:22][CH2:21]4)=[O:19])=[CH:13][C:12]=3[CH:33]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:33][C:12]=3[CH:13]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N2CCC(NC(=O)C(F)(F)F)CC2)CCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N2CCC(N)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbonyl)-4-trifluoroacetamidopiperidine (1.6 g) dissolved in methanol (100 ml) was added a 1 N aqueous solution of sodium hydroxide (7 ml), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and was then extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbonyl)piperidine (compound 76) (1.1 g) as colorless prisms.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:29])[CH:22]=[C:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].CI.[C:32](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:29])[CH:22]=[C:23]4[CH2:28][CH2:27][N:26]([CH3:32])[CH2:25][CH2:24]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: O=C([O-])[O-]
Reactant: C#Cc1cccc(Nc2ncnc3ccc(NC(=O)C=C4CCNCC4)cc23)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: C#Cc1cccc(Nc2ncnc3ccc(NC(=O)C=C4CCN(C)CC4)cc23)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(4-(3-ethynylphenylamino)quinazolin-6-yl)-2-(piperidin-4-ylidene)acetamide (20 mg, 0.046 mmol), methyl iodide (8.0 mg, 0.056 mmol), anhydrous potassium carbonate (17 mg), and acetonitrile (5 mL) were placed in a one-neck flask (50 mL). The reaction mixture was stirred at room temperature for 24 hours. After reaction completion, the solution was filtered, and evaporated in vacuo to give a solid. The solid was purified by TLC (silica gel plate, thickness 5 mm, chloroform:methanol=95:5). MS: 398 (M+1).