Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:3]2[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (250 mg, 0.56 mmol), 4-phenoxyphenylboronic acid (133 mg, 0.62 mmol), Pd(PPh3)4 (100 mg) and Na2CO3 (150 mg, 1.41 mmol) in dioxane/H2O (40/10 ml) was stirred at 100° C. for 4 h. The reaction mixture was concentrated and purified by Pre-TLC to obtain (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (150 mg, 55% in yield).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:1]([OH:3])(=[O:5])=[O:2])[CH:7]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cccnc1
Yield: 50 %

Procedure:
Fischer (Ber., Vol. 15, 62 (1882) described already in 1882 the sulfonation of pyridine with concentrated sulfuric acid at 300° to 350° C. and after a reaction time of 24 hours, pyridine-3-sulfonic acid could be isolated with a yield of 50%. Subsequent investigations had the goal to produce the acid under milder reaction conditions in a shorter reaction time with a higher yield.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:23]([OH:25])[CH3:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:26])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)C>[C:23]([C:22]1[C:13]([O:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:14][C:15]([F:26])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:25])[CH3:24]
Reactant: COC(=O)c1cc(C(C)O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)=O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a mixture of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate (0.76 g, 2.10 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (1.34 g, 3.20 mmol). The reaction mixture was stirred for 1 hour at ambient temperature and then quenched by addition of saturated sodium bicarbonate solution (5 mL) and saturated sodium thiosulfate solution (5 mL). Dichloromethane (30 mL) was added and the mixture was stirred for 16 hours at ambient temperature. The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue, which re-dissolved in a mixture of diethyl ether and dichloromethane (30 mL, 1:1). Insoluble material was filtered off, and the filtrate was concentrated in vacuo to yield the title compound as a colorless oil (0.75 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 1H), 6.62 (d, J=12.8 Hz, 1H), 3.78 (s, 3H), 3.55 (s, 2H), 2.55 (s, 3H), 1.97-1.90 (m, 3H), 1.72-1.53 (m, 12H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.Cl[C:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=[C:23]([S:32][CH3:33])[N:22]=1>O1CCCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([NH:10][C:25]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:22]=[C:23]([S:32][CH3:33])[N:24]=2)=[N:12]1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Nc1n[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 86.8 %

Procedure:
N,N-diisopropylethylamine (19.4 g) and 3-aminoindazole (6.66 g) were added to a tetrahydrofuran (0.2 L) solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (12.22 g), and stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue and the precipitated solid was collected through filtration, washed with distilled water and ethyl acetate in that order, and dried to give the title compound as a white solid (14.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH3:30])[C:26](S)=[N:27][N:28]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.OO>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH3:30])[CH:26]=[N:27][N:28]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](c1ccc(-c2nnc(S)n2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: OO
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(-c2nncn2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-[3-mercapto-4-methyl-1,2,4-triazol-5-yl]phenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol (0.6 g, 1.4 mmol) in acetic acid (10 ml) was heated under reflux and treated with aqueous hydrogen peroxide (30%, 0.5 ml, 8 mmol) dropwise. After a further 0.5 hour at reflux, the mixture was cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and saturated sodium bicarbonate solution (20 ml). The organic phase was washed with brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 106.2 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (50.0 g, 0.32 mol), ethylamine (33.5 g, 0.74 mol), and xylenes (85 mL) was heated at 105° C. in a sealed vessel for three hours. After cooling, the solvent was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, dried (sodium sulfate), and concentrated in vacuo to give 56.8 g of the title compound as a brown oil, suitable for use in the next reaction.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:16][NH2:17])([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N=C=N.[Cl:21][C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>ClCCl>[Cl:21][C:22]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:23]=1[C:24]([NH:17][CH2:16][C:9]1([CH2:12][CH:13]([CH3:14])[CH3:15])[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]1)=[O:25]
Reactant: CCS(=O)(=O)N1CCC(CN)(CC(C)C)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Cl
Agent: N=C=N
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(C(F)(F)F)cc2Cl)(CC(C)C)CC1
Reaction time: 0.5 h

Procedure:
In a large glass container with a Teflon cap was placed 1-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methanamine (5) (670 mg, 2.55 mmol). This was dissolved in dichloromethane (50 ml) and PS-carbodiimide resin (5.11 mmol) was then added along with 2-chloro-4-(trifluoromethyl)benzoic acid (688 mg, 3.06 mmol). The lid was sealed and the bottle was shaken for 0.5 hours. The resin was filtered off and washed with EtOAc (3×25 ml). The organics were concentrated in vacuo to give an off white solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 2-chloro-N-{[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methyl}-4-(trifluoromethyl)benzamide (7) as a white solid. Calculated HRMS 469.1534 Found 469.15333. 1H NMR (300 MHz D6DMSO): δ 8.85 (s, 1 H), 7.95 (s, 1 H), 7.79 (d, J=7.8 Hz, 1 H), 7.60 (d, J=8.1 Hz, 1 H), 3.34 (s, 2 H), 3.21 (s, 4 H), 3.05 (q, J=7.2 Hz, 2 H), 1.75 (m, 1 H), 1.51 (m, 4 H), 1.29 (d, J=4.8 Hz, 2 H), 1.21 (t, J=7.5 Hz, 3 H), 0.94 (s, 3 H), 0.91 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:8]2[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)cc1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (35 mL) was added sodium hydride (60% in oil, 483 mg) at room temperature, and the mixture was stirred for 1 hr. 4-Methylphenylsulfonyl chloride (1.92 g) was added, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, 1 mol/L hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:3), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 1.95 g, 60%).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=O)[CH:2]=[CH2:3].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH2:16]([N:19]1[C:11](=[O:13])[CH:6]2[CH:5]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:7]2[CH:8]=[CH:9]3)[C:14]1=[O:15])[CH2:17][N:18]1[C:11](=[O:13])[CH:6]2[CH:5]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:7]2[CH:8]=[CH:9]3)[C:14]1=[O:15]
Reactant: NCCN
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C1C(=O)N(CCN3C(=O)C4C5C=CC(CC=C)(C5)C4C3=O)C(=O)C12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
204 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are initially taken and 30 g of ethylenediamine are added dropwise, with stirring. The temperature rises to 130° C. The temperature is increased to 180° C.; in the course of this 14 ml of water distil off. Heating is then continued for a further 2 hours at 200° C. and under a pressure of 9.3 Pa. This gives 210 g of a yellow resin, solid at room temperature and having a softening point of 56° C., measured on a Kofler heated stage.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.ClCC1C=CC(OCC2C=CC(Cl)=CC=2Cl)=C([N+]([O-])=O)C=1.[NH:47]1[CH:51]=[CH:50][N:49]=[CH:48]1.[H-].[Na+].S(=O)(=O)(O)O.N1C=CN=C1CC1C=CC(C2(Cl)C=CC(COCC3C=CC(Cl)(C4C=CC(CC5NC=CN=5)=CC=4[N+]([O-])=O)CC=3Cl)=C(Cl)C2)=C([N+]([O-])=O)C=1>CN(C)C=O.CCOCC>[NH:47]1[CH:51]=[CH:50][N:49]=[C:48]1[CH2:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(CO)ccc1OCc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cc(CCl)ccc1OCc1ccc(Cl)cc1Cl
Agent: O=[N+]([O-])c1cc(Cc2ncc[nH]2)ccc1C1(Cl)C=CC(COCC2=C(Cl)CC(Cl)(c3ccc(Cc4ncc[nH]4)cc3[N+](=O)[O-])C=C2)=C(Cl)C1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cc2ncc[nH]2)ccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
5.5 g. of 4-hydroxy-3-nitrobenzaldehyde is reacted with 6.7 g. of 2,4-dichlorobenzyl chloride analogously to Chem. Abstr. 71 (1969) 30232, thus obtaining 5.2 g. of 4-(2,4-dichlorobenzyloxy)-3-nitrobenzaldehyde, m.p. 172°-174°. Of this product, 0.9 g. is dissolved in methanol/dioxane and reduced with 500 mg. of sodium borohydride, yielding 580 mg. of 4-(2,4-dichlorobenzyloxy)-3-nitrobenzyl alcohol, m.p. 126°-127°. 450 mg. of this product is heated with 5 ml. of thionyl chloride for 5 minutes to 100°. After the residual thionyl chloride has been removed under vacuum, the remainder is vacuum-filtered with ethanol, thus producing 400 mg. of (4-chloromethyl-2-nitrophenyl)-(2,4-dichlorobenzyl)-ether, m.p. 147°-149°. 300 mg. of this ether is added to a solution of 68 mg. of imidazole in 3 ml. of dimethylformamide, which was agitated with the addition of 30 mg. of sodium hydride suspension (80%) for 1 hour at room temperature, and the mixture is stirred for another hour at room temperature. Then, the mixture is combined with 1N sulfuric acid and the thus-precipitated product is vacuum-filtered, dissolved in methanol/chloroform, and extracted with 1N sodium hydroxide solution. The chloroform phase is washed with water, dried, and evaporated. Recrystallization from cyclohexane/benzene yields 260 mg. of [4-(4-(1-imidazolylmethyl)-2-nitrophenyl]-(2,4-dichlorobenzyl)-ether, m.p. 120°-124°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([O:14]C)=[O:13])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[OH-].[Na+].C(O)C>O>[CH3:1][O:2][C:3]1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1
Reactant: COC(=O)c1cc2c(cc1OC)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1C(=O)O)OCO2
Yield: 85.7 %

Procedure:
A mixture of methyl 6-methoxy-1,3-benzodioxole-5-carboxylate (3 g, 14 mmol), prepared as in Example 1, 20% sodium hydroxide (50 mL) and ethanol (25 mL) was heated 1 hour at reflux and then diluted with water, washed with diethyl ether (2×), treated with concentrated hydrochloric acid and cooled in an ice-bath. The solids were collected, washed with water (2×) and dried under vacuum at 70° C. to give 6-methoxy-1,3-benzodioxole-5-carboxylic acid (2.3 g, 12 mmol), m.p. 151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[F:13]
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Reaction time: 2 h

Procedure:
10 g of 7-chloro-6-fluoro-2H-isoquinolin-1-one (60) were suspended in 100 mL of DMF. 19.75 g of cesium carbonate and 7.55 mL of p-methoxy benzyl chloride were added successively and the mixture was stirred for 2 h. The mixture was poured on ice/water and the formed precipitate was filtered off, washed with water and dried in vacuum to give 13.67 g of the title compound. Rt=1.96 min (Method B). Detected mass: 318.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=O)=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:36]([O:43][CH2:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][CH3:50])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[Si:36]([O:43][CH2:44][CH2:45][CH2:46][N:47]([CH2:48][CH2:49][CH3:50])[C:33]([C:11]1=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1)=[O:35])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CCCNCCCO[Si](C)(C)C(C)(C)C
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI(+) m/z 689 detected.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:22]([NH:24][N:25]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:26]([C:29](=O)[CH2:30][N:31]1C(=O)C2C(=O)C=CC=C2C1=O)(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.NN>C(O)C>[NH2:31][CH2:30][CH2:29][S:26]([N:25]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:48][CH:49]([CH3:51])[CH3:50])(=[O:28])=[O:27]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)C(=O)CN1C(=O)C2=CC=CC(=O)C2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A solution of 0.46 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(1,3-dioxo-2-phthalimidoethansulphonyl)-4-methylvalerohydrazide in 10 ml of ethanol was treated with 4.5 ml of hydrazine hydrate and stirred at room temperature for 2 hours. Evaporation gave a residue which was triturated with ethyl acetate and filtered. The filtrate was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulphate. The residue was purified by column chromatography on silica gel using methanol/dichloromethane (5:95) for the elution to give 0.26 g of (E)-2′-(2-aminoethanesulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale yellow gum.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]1[C:18]2=[C:19]3[C:25](=O)[CH2:24][CH2:23][C:20]3=[N:21][CH:22]=[C:17]2[O:16][CH2:15]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:14]1[C:18]2=[C:19]3[C:20]([CH2:23][CH2:24]/[C:25]/3=[CH:3]\[C:1]#[N:2])=[N:21][CH:22]=[C:17]2[O:16][CH2:15]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCc2ncc3c(c21)CCO3
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C/C=C1\CCc2ncc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (757 mg, 4.27 mmol) in tetrahydrofuran (20 mL) was added 65% sodium hydride (137 mg, 3.71 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The mixture was added to a solution of 1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-one (500 mg, 2.85 mmol) in tetrahydrofuran (10 mL) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by recrystallization (ethyl acetate) to give the title compound (337 mg, yield 60%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[O:16][C:15]([C:14]3[N:13]=[CH:12][N:11]([CH3:28])[C:10](=[O:29])[C:9]=3[OH:8])=[N:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O

Procedure:
Reaction of 5-benzyloxy-6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-3-methyl-3H-pyrimidin-4-one and a 1:1 mixture of TFA/CH2Cl2 gave the debenzylated product in reasonable yield. Results are summarized below.
Reaction SMILES: [C:1]([C:5]([O:7][CH2:8][C:9]([NH2:11])=[S:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19](C(=O)CCl)[C:18]=2[CH:17]=1)=O.BrCC(C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)=O>>[C:5]([O:7][CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:16]2[CH:29]=[CH:28][C:27]3[S:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]=3[CH:17]=2)[N:11]=1)(=[O:6])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc2c(c1)N(C(=O)CCl)c1ccccc1S2
Reactant: CC(C)(C)C(=O)OCC(N)=S
Agent: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Product: CC(C)(C)C(=O)OCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 63.2 %

Procedure:
This compound is prepared according to a protocol identical to that described for Stage 350.3 of Example 350, respectively using 2-(tert-butylcarbonyloxy)thioacetamide and 2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl]ethanone instead of intermediate 1.2 and bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expected compound is obtained in the form of a greenish solid with a yield of 63.2%. Melting point: 120.0-122.0° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>O1CCCC1.O>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36](/[C:35](/[C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:37]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cccnc1)c1cccs1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCC/C=C(/c1cccnc1)c1cccs1
Temperature: 85 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
Sodium hydride (60% in oil, 10 g, 0.25 mole) was added to dimethyl sulfoxide (250 ml) under argon and the mixture was stirred at 85° C. for an hour. The mixture was then cooled to room temperature and 5-carboxypentyltriphenylphosphonium bromide (52 g, 0.11 mole) was added gradually with the temperature being maintained at 40° C. The resulting mixture was stirred for 10 minutes, and a solution of 2-nicotinoylthiophene (20 g, 0.11 mole) in tetrahyrofuran (60 ml) was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes, and water (300 ml) was added. The aqueous solution was extracted twice with toluene (300 ml) to remove the neutral substance. The aqueous layer was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as eluant and the eluate was concentrated. The resulting oily product was dissolved in ethyl acetate and the solution was allowed to stand overnight to give (Z)-7-(3-pyridyl)-7-(2-thienyl)-6-heptenoic acid (9 g, 29%). Mp 93°-94° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)(C)C)(C)C)[C:5]2=[N:6][CH:7]=1.[C-:18]#[N:19].[K+]>[Cu].[Pd].CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]2[C:7](=[CH:9][CH:10]=1)[NH:6][N:19]=[CH:18]2)#[N:8]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Agent: [Cu]
Agent: [Pd]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]ncc2c1

Procedure:
Compound 19 can be cyanated with, for example, KCN in heating DMF in the presence of a catalyst such as, copper or palladium to provide the 5-cyano azaindole 46.