Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[CH:22][CH:21]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[CH:33][CH:34]=2)[CH2:14][CH2:13]1)([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)C(C)NC(=O)c1ccc(CN(C(=O)OC(C)(C)C)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)NC(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl trans-4-{[N-(tert-butoxycarbonyl)-N-(4-tert-butylcyclohexyl)amino]methyl}benzoylaminopropanoate (19.5 g, 41.1 mmol) was dissolved in a mixture of TFA (200 mL) and dichloromethane (200 mL), while cooling on an ice bath. The ice bath was removed and the mixture allowed to stir at room temperature for 30 min. Solvent was removed by rotary evaporation, and the crystalline residue recrystallized from ethyl acetate/heptane. Yield: 14.8 g (74%).
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].O[O:17][S:18]([O-:20])=O.[K+].[C:22](OCC)(=O)C.CCCCCC>CC(C)=O>[CH3:22][S:18]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[C:6]([NH2:8])=[O:7])(=[O:20])=[O:17]
Reactant: CCOC(C)=O
Reactant: O=S([O-])OO
Reactant: CSc1cc(C(N)=O)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)c1cc(C(N)=O)cc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
In a 500-mL, 3-neck round-bottomed flask equipped with an 100-mL pressure-equalizing addition funnel fitted with an nitrogen inlet, and a rubber septum, 3-(methylthio)-5-(trifluoromethyl)benzamide (8.0 g, 1.0 eq.), in acetone (70 mL). Oxone (36.5 g, 2 eq.) was added at RT. The reaction was stirred for 12 h. The progress of the reaction was followed by TLC analysis on silica gel with 30% ethyl acetate-hexane as mobile phase and visualization with UV, SM Rf=0.30 and Product Rf=0.20. Reaction was stirred for 12 h and white solid (Oxone salts) was separated by filtration on a Büchner funnel and washed with acetone (100 mL). The combined acetone layer was concentrated by rotary evaporation (40° C., 20 mmHg) to afford 7.0 g of off white solid. The resulting crude compound off white (7 g) was subjected to further stage Yield (90.4%); Mass: (ES+) 267.89 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.O>CN(C)C=O>[I:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(I)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(I)cc3)c2cc1OC
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1.00 mmol), potassium carbonate (152 mg, 1.10 mmol) and 4-iodophenol (244 mg, 1.10 mmol) in dimethylformamide (4 ml) was heated at 110° C. for 2 hours before the reaction was allowed to cool to ambient temperature. The reaction was poured into water and the solid which had precipitated was collected by suction filtration and washed with a mixture of diethyl ether (10 ml), ethyl acetate (10 ml) and isohexane (10 ml). Drying of this material yielded, yielded 4-(4-iodophenoxy)-6,7-dimethoxyquinazoline (340 mg, 83% yield) as a white solid:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)(O)C1CCNCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure K, 2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid was coupled with 2-(piperidin-4-yl)propan-2-ol to give 569. LCMS m/z: 533.3 (M+H+)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[O:24][C:23]2[CH:25]=[C:26]([F:37])[C:27]([C:29]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)=[O:30])=[CH:28][C:22]=2[O:21]1>ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[O:24][C:23]2[CH:25]=[C:26]([F:37])[C:27]([C:29]([N:31]3[CH2:36][CH2:35][S:34](=[O:9])[CH2:33][CH2:32]3)=[O:30])=[CH:28][C:22]=2[O:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1CCSCC1
Solvent: ClCCl
Product: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1CCS(=O)CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of m-chloroperbenzoic acid (74 mg, 0.3 mmol) in dichloromethane (1.2 mL) was added to a cooled (−20° C.) solution of [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone (Example 136) (153 mg, 0.3 mmol) in dichloromethane (1.7 mL). The reaction mixture was stirred at −20° C. for 3 h, quenched with 5% aqueous sodium thiosulfate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and the volatiles were removed under vacuo. Purification by flash chromatography afforded the title product as a white foam (141 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:17](N1C=CN=C1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:18]>C1COCC1.ClCCl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([NH:1][C:17]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[O:18])=[N:6][C:5]=2[CH3:7])=[CH:9][CH:10]=1)(=[O:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1ccc(-c2sc(N)nc2C)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1
Temperature: 50 °C

Procedure:
A solution of 1-[4-(2-Amino-4-methyl-thiazol-5-yl)-phenyl]-ethanone (0.57 g, 2.45 mmol) is dissolved in a mixture of THF (10 ml) and dichloromethane (20 ml) and heated in an oil bath set to 50° C. Carbonyldiimidazole is added (0.64 g, 3.92 mmol) and the reaction mixture heated at 50° C. for a further 2 hours in which a pale yellow precipitate forms. After cooling to room temperature the precipitate is filtered, washed with dichloromethane and dried under high vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[SH:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([N:12]1[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[S:20][CH:4]1[C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[OH:1])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Nc1cc(Cl)ccc1S
Solvent: CO
Product: COc1ccc(O)c(C2Sc3ccc(Cl)cc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 34.9 %

Procedure:
A solution of 2-hydroxy-5-methoxybenzaldehyde (10.0 g, 65.7 mmol) in methanol (20 ml) was added to a solution of 2-amino-4-chlorothiophenol (10.5 g, 65.7 mmol) in methanol (20 ml) under a nitrogen stream at room temperature, the mixture was stirred at room temperature for 50 minutes, and then the precipitated crystals were filtered off. Acetic anhydride (20 ml, 212 mmol) was added to the obtained crystals, the mixture was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. Methanol (60 ml), water (10 ml) and potassium carbonate (5.0 g) were added to the residue, the whole was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. Ethyl acetate (300 ml) and 1 N-hydrochloric acid (200 ml) were added to the residue, and the whole was extracted. The organic layer was washed with saturated brine (150 ml), dehydrated with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=3/1) to give 7.7 g (60%) of the target compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:3][CH2:4][CH2:5][C:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:37](OC(=O)C)(=[O:39])[CH3:38].O>N1C=CC=CC=1.CCOCC>[C:10]([O:9][C:7](=[O:8])[C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]([O:1][C:37](=[O:39])[CH3:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@H](O)CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Temperature: 60 °C

Procedure:
Di-tert.-butyl 2-[4-(S)-hydroxynonyl]-2-(6-ethoxycarbonylhexyl)malonate (39.0 g., 0.076 mole) is dissolved in pyridine (50 ml.). Acetic anhydride (8.2 g., 0.08 mole) is added dropwise during 15 minutes and the mixture is stirred and heated at 60° C. for 3 hours. The mixture is then cooled and treated with 300 ml. water. The oily product is taken up in ether, washed with 5% hydrochloric acid, two portions of water and brine, and dried over sodium sulfate. Distillation of the ether in vacuo leaves the title compound as a residual oil weighing 41 g.
Reaction SMILES: C(O[C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7]3[C@:8]4([O:27][C:6]1=3)[O:26][C@H:9]4[C@@H:10]1[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[CH2:15][CH3:16])(=O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C[C:46](C)=[O:47]>>[O:27]1[C:6]2=[C:7]3[C@:21]([CH3:24])([CH2:22][CH2:23][CH2:5]2)[C@@H:20]2[C@H:10]([C@H:11]4[C@:17]([CH3:25])([CH2:18][CH2:19]2)[C@@H:14]([CH:15]([CH:46]=[O:47])[CH3:16])[CH2:13][CH2:12]4)[C@@H:9]2[O:26][C@:8]123
Reactant: CC(C)=O
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 48 %

Procedure:
In 5 ml of acetone was dissolved 24.3 mg (0.05 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α- diepoxypregn-4-en-3β-yl acetate, followed by addition of 2.5 mg (0.01 mmole) of pyridinium p-toluenesulfonate. The mixture was refluxed for 2 hours. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. To the residue was added methylene chloride and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to recover 9.6 mg of 3β-acetoxy-1α,2α;6α,7α-diepoxypregn-4-ene-20-carbaldehyde (yield: 48%).
Reaction SMILES: N1(C(N2C=CN=C2)=S)C=CN=[CH:2]1.[CH:13]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]2[NH2:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([C:38]([NH:40][NH2:41])=[O:39])[CH:35]=[CH:34][C:32]=2[N:33]=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH:13]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]2[NH:20][C:2]1[O:39][C:38]([C:36]2[CH:35]=[CH:34][C:32]3[N:33]=[C:29]([C:23]4[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=4[Cl:21])[NH:30][C:31]=3[CH:37]=2)=[N:40][N:41]=1
Reactant: NC1CC2CCC1C2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(NC4CC5CCC4C5)o3)cc2[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Add di-imidazol-1-yl-methanethione (72 mg, 0.403 mmol) to a solution of bicyclo[2.2.1]hept-2-ylamine (48 uL, 0.403 mmol) in DMF (1 mL) and stir for 3 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (100 mg, 0.310 mmol) and DMF (1 mL) to the reaction. Heat the mixture to 80° C. for 1.5 hr. Add EDCI (119 mg, 0.620 mmol) and heat for 1 hr. Allow the reaction to cool to room temp and dilute with water (15 mL). Collect the resulting precipitate by filtration. Suspend the solid in boiling ACN. Allow the suspension to cool to room temp and then 4° C. Filter to collect the white solid. Suspend the solid in 1 N NaOH (3 mL) and stir for 20 min. Filter and wash the solid with 1 N NaOH, water, and Et2O. Dry the solid in a vac oven to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) ppm 1.17-1.35 (m, 3 H) 1.42-1.49 (m, 1 H) 1.50-1.64 (m, 3 H) 1.87 (ddd, J=12.98, 8.05, 2.08 Hz, 1 H) 2.33 (br. s., 1 H) 2.40 (d, J=4.04 Hz, 1 H) 3.54 (dd, J=7.77, 2.84 Hz, 1 H) 7.55-7.63 (m, 3 H) 7.77 (d, J=8.34 Hz, 1 H) 7.92 (dd, J=8.53, 1.20 Hz, 1 H) 8.17 (s, 1 H); MS (m/z) 439.9 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[N:14]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>ClCCl.CO>[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][S:2]([C:5]2[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([N:22]3[CH2:23][CH2:24][CH:19]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:20][CH2:21]3)=[O:9])[CH:6]=2)(=[O:4])=[O:3])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cccc(S(=O)(=O)Nc2ccc(F)cc2)c1)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.178 g, 0.746 mmol) in anhydrous dichloromethane (10 mL) was added 4-(pyrrolidin-1-yl)piperidine (0.115 g, 0.746 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.277 g, 2.61 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 4-fluoroaniline (0.83 g, 7.5 mmol) was added. The mixture was stirred at room temperature overnight. Then methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then methanol/ethyl acetate=1:10) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (m, 2H), 1.73 (m, 6H), 1.93 (m, 2H), 2.63 (m, 4H), 2.96 (m, 2H), 4.25 (m, 1H), 7.08 (m, 4H), 7.62 (m, 3H), 7.79 (m, 1H); MS (ESI) m/z 432 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14](C)[C:13]=1C.[CH2:21]([OH:23])[CH3:22]>>[C:21]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][N:15]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:17]=1[CH3:16])(=[O:23])[CH3:22]
Reactant: CCO
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCOc1ccnc(COC(C)=O)c1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
15 ml of acetic anhydride was added to 25 g of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide to obtain a solution. This solution was stirred at 90° C. for 2 hours, followed by the addition of ethanol. The obtained mixture was distilled under a reduced pressure to obtain 4-(2-acetoxyethoxy)-2-acetoxymethyl-3-methylpyridine.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=[CH:10][C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].BrCCCC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH2:4][CH2:11][CH3:10]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCBr
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate B19, vide infra) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K2CO3 as base. MS (ISP): 209.1 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](B(O)O)=[C:19]([F:27])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:21]1[CH:22]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:18]=[C:19]([F:27])[C:20]=1[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(Br)s1
Reactant: CCCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cc(F)c(-c3ccc(C)s3)c(F)c2)cc1

Procedure:
A mixture of 5.50 g (31.0 mmol) of 2-bromo-5-methylthiophene, 9.0 g (32.6 mmol) of 4′-propyl-3,5-difluoro-4-biphenylboronic acid, 1.83 g (1.58 mmol) of tetrakis(triphenylphosphine)palladium(0) and 36 ml of 2 N sodium carbonate soln. in 90 ml of toluene/ethanol (1:2) is heated under reflux for 16 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to completion. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). Further purification is carried out by recrystallisation from ethanol and n-heptane; 2-(3,5-difluoro-4′-propylbiphenyl-4-yl)-5-methylthiophene (PUS-3-1) is obtained as a colourless solid (m.p. 75° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].[H][H]>[Pd].CO>[OH:29][CH:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)[C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)[N:6]=[N:7][CH:2]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(O)c4cc(C)c5[nH]c(=O)oc5c4)cnn3)CC1)C(=O)N2

Procedure:
A mixture of 0.25 g (0.40 mmol) 3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 0.10 mL (0.71 mmol) TEA and 50 mg palladium on charcoal (Pd/C 10%) in MeOH was hydrogenated for 3 h at 50° C. in a hydrogen atmosphere of 50 psi. After filtration of the reaction mixture the filtrate was evaporated down to approx. 3 mL and mixed with a little ice water. The precipitate formed was suction filtered and dried. The residue contained the desired product in the mixture and was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=S)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.[C:19]([NH:22][NH2:23])(=O)C.[CH2:24](O)CCC>>[CH3:24][C:15]1[CH:16]=[CH:17][C:10]2[N:9]3[CH:19]=[N:22][N:23]=[C:8]3[C:7]3[CH2:6][CH2:5][CH:4]=[C:3]4[CH:2]=[CH:1][N:12]([C:13]=34)[C:11]=2[CH:14]=1
Reactant: S=C1Nc2ccccc2N2CCc3cccc1c32
Reactant: CC(=O)NN
Reactant: CCCCO
Product: Cc1ccc2c(c1)-n1ccc3c1=C(CCC=3)c1nncn1-2
Yield: 65 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin6-thione (4.5 g), acetic hydrazide (4 g) and n-butanol (200 ml) were combined and refluxed overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (2% methanol/dichloromethane) to yield 3.2 g (65%) of product. Recrystallization from ethanol gave the analytical sample, mp 237°-238° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:27]2C=CC=[CH:31][C:26]=2N=N1.[C:43]([O:46]CC)(=[O:45])[CH3:44]>C(Cl)Cl>[CH2:8]([O:46][C:43](=[O:45])[CH2:44][CH:26]([CH3:31])[CH3:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(C)=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (example 1) (905 mg, 2.08 mmol) in methylene chloride (18 mL) were added sequentially triethylamine (0.72 mL, 5.14 mmol), benzylamine (0.25 mL, 2.29 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.01 grams, 2.28 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using a 2:5:16 ratio of methylene chloride/ethyl acetate/hexane affording 2-(R)-2-[benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as a clear oil, 933 mg (86%).
Reaction SMILES: C(S)C.[H-].[Na+].[H][H].C[O:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]=[CH:15][N:16]3[CH:22]=[CH:21][CH:20]=[C:17]3[C:18](=[O:19])[C:12]=2[CH:11]=1.Cl>CN(C)C=O>[OH:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]=[CH:15][N:16]3[CH:22]=[CH:21][CH:20]=[C:17]3[C:18](=[O:19])[C:12]=2[CH:11]=1
Reactant: COc1ccc2ccn3cccc3c(=O)c2c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=c1c2cc(O)ccc2ccn2cccc12

Procedure:
Ethanethiol (0.62 g., 10 mmoles), dissolved in dimethyl formamide (10 ml.) is added to a suspension of sodium hydride (0.5 g. of 50% oil dispersion) in dry dimethyl formamide (5 ml.). The mixture is stirred until all hydrogen has evolved and 9-methoxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one (2.26 g., 10 mmoles) is added. The solution is refluxed for a period of 3 hours. The cooled reaction mixture is acidified with 0.2N HCl and extracted with chloroform. The organic layer is washed with water, dried over sodium sulfate and concentrated to yield 9-hydroxy-11-H-pyrrolo[2,1-b] [3]benzazepin-11-one.