Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([OH:20])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[O:23]1[CH2:27]CC[CH2:24]1>C(N(CC)CC)C.COCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([O:20][CH2:24][O:23][CH3:27])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Oc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Agent: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: COCOc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-(benzyloxy)phenyl)isoxazol-3-ol (1.38 g) in tetrahydrofuran (30 ml), 2.15 ml of triethylamine and 0.51 ml of methoxymethyl chloride were added, and the reaction solution was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-0:100)) to afford the title compound as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[C:11]3[C:12](=[N:22][N:23]([CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=4)[N:24]=2)[CH:13]=[C:14]([C:19](O)=[O:20])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[OH:20][CH2:19][C:14]1[C:15]2[CH2:16][S:17][N:18]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]3=[N:24][N:23]([CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=4)[N:22]=[C:12]([C:11]=23)[CH:13]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(C(=O)O)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1c(C)cnc(Cn2nc3cc(CO)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Reaction time: 2 h
Yield: 72 %

Procedure:
4-[(tert-Butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-carboxylic acid (50 mg) was dissolved in tetrahydrofuran (1 ml) under cooling in an ice bath. N-Methylmorpholine (13 μl) and ethyl chloroformate (12 μl) were added, followed by stirring for two hours. Subsequently, sodium borohydride (12 mg) and methanol (1 ml) were added to the reaction solution, and the mixture was stirred for three hours while gradually returning to room temperature. A 10% citric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound as an oil (35 mg, 72%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CS(C)=O>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step B (0.28 mmol), and 3-aminomethylpyridine (0.59 mmol), in dimethylsulfoxide (1.5 mmol) and acetonitrile (2.5 mL) was stirred at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The material was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane. (0.103 g; 75%), m.p. 169-171° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:24])=[N:4][CH:3]=1>[Pd].CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:24])=[N:4][CH:3]=1
Reactant: CCN(CC)c1nc(/C=C/c2nc3c(C)ncc(C)n3n2)n(C)n1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1nc(CCc2nc3c(C)ncc(C)n3n2)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of (E)-5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-N,N-diethyl-1-methyl-1H-1,2,4-triazol-3-amine (62 mg, 190 μmol, Eq: 1.00) and palladium on carbon 10% (10.1 mg, 9.5 μmol, Eq: 0.05) in methanol (15 ml) was stirred for 5 hours at 25° C. under hydrogen atmosphere. The catalyst was filtered off, the filtrate was evaporated affording {5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-diethyl-amine (62 mg, 99.4%) as a light yellow viscous oil. MS: m/z=329.5 (M+H+)
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].C(N(CC)CC)C.[Si:17]([O:24][CH2:25][CH:26](O)[CH2:27][N:28]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[C:35]2[C:30]([N:31]([CH3:47])[C:32](=[O:46])[N:33]([CH3:45])[C:34]2=[O:44])=[CH:29]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH3:1][S:2]([O:5][CH:26]([CH2:27][N:28]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[C:35]2[C:30]([N:31]([CH3:47])[C:32](=[O:46])[N:33]([CH3:45])[C:34]2=[O:44])=[CH:29]1)[CH2:25][O:24][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:18])[CH3:19])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonic anhydride (0.679 g, 3.90 mmol) in 1,2-dichloroethane (3.0 mL) was added dropwise to a solution of DMAP (0.016 g, 0.130 mmol), triethylamine (0.544 ml, 3.90 mmol) and 6-(3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.6 g, 1.300 mmol) in 1,2-dichloroethane (10 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours, then diluted with water (10 mL). The phases were separated and the aqueous phase was extracted with DCM (3×10 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]=3[CH2:27][CH2:28][CH3:29])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>CO>[C:30]1([N:25]2[C:26]([CH2:27][CH2:28][CH3:29])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:36])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:23]=[N:24]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)OC)ccc3c2)cnn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
1 N NaOH (431 μL, 0.431 mmol) was added under nitrogen to a solution at room temperature of (6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (170 mg, 0.359 mmol), prepared in the previous step, in 25 mL of MeOH plus 10 mL of water. After the addition the reaction was stirred at room temperature for 18 h (overnight). The reaction was acidified with 1 N HCl and then concentrated under reduced pressure to remove the MeOH. The solid present was collected by filtration and dried under reduced pressure to give the title compound (146 mg, 92%) as an off-white solid, mp 175-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:22])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)c1cc(CN)on1
Product: CC(C)c1cc(CNC(=O)c2ncc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 41, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example W) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN 543713-30-0) as starting materials; LC-MS (UV peak area/ESI) 98.43%, 455.0 (M+H)+.
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14]1([CH3:38])[CH:19]=[CH:18][C:17]([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:16][CH:15]=1>>[C:14]1([CH3:38])[CH:15]=[CH:16][C:17]([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([N:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]4[CH2:1][CH2:2][CH2:3][C@@H:4]4[CH2:13]3)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: c1ccc2c(c1)NC[C@H]1CCCN21
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@H]4CCCN4c4ccccc43)cc2)cc1
Yield: 31.7 %

Procedure:
The same procedures used in Example 1 were repeated using (3aR)-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 15 and 4-[[2-(4-tolyl)benzoyl)amino]benzoic acid to give the title compound after recrystallization from ethyl acetate-hexane. Yield 31.7%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH2:29][CH3:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[CH2:29]([NH:28][C:11]1[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[F:27])=[O:19])=[CH:16][N:17]=2)[N:14]=[C:9]([NH:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][C:39](=[O:40])[NH:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH2:7][CH2:6]2)[CH:10]=1)[CH3:30]
Reactant: CCNc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCNc1cc(N[C@H]2CC[C@H](NC(=O)Nc3ccc(F)cc3)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To suspension of 82B (20 mg, 0.048 mmol) in THF was added 4-fluorophenylisocyanate (6.54 μL, 0.058 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced and MeOH (1 mL) was added. The mixture was sonicated and the solid was collected by filtration, rinsed with a small amount of MeOH and dried under vacuum to give 8-(ethylamino)-6-((trans-4-(((4-fluorophenyl)carbamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (20.8 mg) as an off white solid. HPLC Rt=3.176 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=550.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH2:13]3)=[O:7])=[CH:4][CH:3]=1.[OH-:20].[Na+]>O>[NH2:15][C:16]1[C:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:20])=[O:17]
Reactant: O=C1Cc2cccc(C(=O)c3ccc(F)cc3)c2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(F)cc1

Procedure:
A mixture of 1.5 g. (0.006 mole) of 7-(4-fluorobenzoyl) indolin-2-one in 50 ml. of 3N sodium hydroxide was refluxed under nitrogen for 45 min. The solution was cooled, diluted with an equal volume of water, filtered, and the filtrate was extracted two times with 50 ml. of ether. The aqueous basic solution was treated dropwise with glacial acetic acid until a heavy yellow precipitate formed. The precipitate was filtered off, washed thoroughly with water and air-dried. The yield was 1.1 g. (68%); m.p. 136°-137° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7](=[NH:9])S.[OH-].[Na+].[NH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]1>O>[NH:12]([CH2:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]1)[C:7]([NH2:9])=[NH:6]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N=C(N)S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Isothiourea sulfate (21.2 g) was dissolved in water (40 ml) and a 2N solution of sodium hydroxide (46 ml) was dropwise added under ice-cooling. The mixture was stirred at said temperature for 30 minutes and trans-4-aminomethylcyclohexanecarboxylic acid dissolved in boiling water (100 ml) was dropwise added and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was cooled and the resultant crystals were collected by filtration. The crystals were thoroughly washed with cold water and dried to give 18.5 g of trans-4-guanidinomethylcyclohexanecarboxylic acid, melting point 325° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9](=[N:12][N+:13]([O-:15])=[O:14])[S:10][CH3:11])=[CH:5][N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>N1C=CC=CC=1>[C:16]([N:8]([CH2:7][C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)[C:9](=[N:12][N+:13]([O-:15])=[O:14])[S:10][CH3:11])(=[O:18])[CH3:17]
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture consisting of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea, 1.15 g acetic anhydride and 25 ml pyridine was stirred at room temperature for 3 hours. The reaction mixture was added into an aqueous hydrochloric acid solution (concentrated hydrochloric acid 20 ml, water 50 ml, ice 10 g) for separation into layers. The resultant aqueous layer was extracted with 120 ml of chloroform, while the resultant organic layers were combined together, dried over magnesium sulfate and concentrated to afford 1.15 g of N-acetyl-N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea as a brown crystal, mp 77-78° C. 1H-NMR(CDCl3): 7.50 (1H, s), 4.80 (2H, s), 2.52 (3H, s), 2.26 (3H, s)
Reaction SMILES: C(C(O)C1C=CC2OCOC=2C=1)CC.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:34]([CH:37]([N:47]=[N+:48]=[N-:49])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1)[CH2:35][CH3:36]>C1(C)C=CC=CC=1>[CH2:34]([C@@H:37]([N:47]=[N+:48]=[N-:49])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1)[CH2:35][CH3:36]
Reactant: CCCC(N=[N+]=[N-])c1ccc2c(c1)OCO2
Agent: CCCC(O)c1ccc2c(c1)OCO2
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCC[C@@H](N=[N+]=[N-])c1ccc2c(c1)OCO2

Procedure:
tR : α-propyl-piperonyl alcohol, 5.9 min.; toluene, 7.8 min.; (PhO)2P(O)N3, 9.3 min.; olefin side-product, 10.6 min.; α-propyl-piperonylazide, 11.4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(Cl)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(Cl)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-chlorophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]>CC(C)=O>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:20])\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Solvent: CC(C)=O
Product: CCOC(=O)/C(C)=C\c1cc(OC)c(OCOC)c2c(CC)cccc12
Yield: 42.3 %

Procedure:
15.6 g of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate was dissolved in 300 ml of acetone and irradiated for 2 hours with light from a high pressure mercury lamp through a Pyrex filter. The solvent was evaporated and the resultant residue was purified by silica gel column chromatography (3% ethyl acetate/hexane) to obtain 6.6 g of the titled compound as a yellow oil. At the same time, 9.0 g of a mixture of E and Z isomers was obtained.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH:10]=[O:11])[N:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:13][C:14](=[O:17])/[CH:15]=[CH:16]/[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH:10]=[O:11])[N:3]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(C=O)nc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1nc(C=O)ccc1OC

Procedure:
Under the conditions of example 16 H, a solution of 20 g of 2-iodo-3-methoxypyridine-6-aldehyde in 100 ml of dimethylformamide is reacted with 33.5 ml of acrylic acid methyl ester in the presence of 1.73 g of palladium acetate, 26.1 g of potassium carbonate and 23.8 g of tetrabutylammonium bromide, worked up, and the crude product is chromatographed on silica gel with hexane/0-50% ethyl acetate. 11.66 g of 3-(6-formyl-3-methoxy-2-pyridyl)-(2E)-2-propenoic acid methyl ester of melting point 132°-134° C. is obtained.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])N)=[N:6][CH:5]=1.[H-].[Na+].CI.C[N:20]([CH:22]=O)[CH3:21]>>[CH3:22][N:20]([CH3:21])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:14])=[O:2])=[CH:5][N:6]=1)(=[O:12])=[O:13]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(S(N)(=O)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)cn1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
1st step: To a stirred solution of 6-sulfamoyl-nicotinic acid methyl ester (250 mg, 1.15 mmol) in DMF (10 mL) at 0° C. was added NaH (53 mg, 55%, 1.20 mmol). After 10 minutes, MeI (0.079 mL, 1.26 mL) was added. Stirring was continued for one hour before the reaction was quenched upon addition of H2O. The product was extracted with EtOAc, the combined organic layers were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1/2) afforded 51 mg of the title compound (19%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([C:26]#[N:27])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[NH2:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[C:21]([C:26]#[N:27])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
[(S)-1-(7-Cyano-6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (563 mg, 1.47 mmol) was dissolved in hydrochloric acid in dioxane (10 mL, 4M) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to yield the title compound as an off-white solid (523 mg, 100%). LCMS (Method C): RT=1.75 min, [M+H]+=282.
Reaction SMILES: [B](F)F.[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14](F)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(OCC)C>CS(C)=O>[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1
Reactant: C1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: F[B]F
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 8 h
Yield: 60.5 %

Procedure:
0.11 g (0.00032 mole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate (IV) (prepared as described in Preparation 7) was dissolved in 0.5 ml of dimethyl sulfoxide, and 0.11 g (0.0012 mole) of anhydrous piperazine was added to the resulting solution. The mixture was then allowed to stand at room temperature overnight, after which it was poured into 50 ml of diethyl ether. The yellow crystals which precipitated were collected by filtration and dissolved in 30 ml of 80% aqueous ethanol and 5 ml of triethylamine, and the resulting solution was heated under reflux for 4 hours. The reaction mixture was then filtered while hot to remove insoluble material, and the filtrate was concentrated by evaporation under reduced pressure to give a crystalline substance, which was washed with ethanol to afford 0.07 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless powdery crystals, melting at 177°-178° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:33])[CH2:10]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:8][C@H:9]1[C@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:33])[CH2:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CCCCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
(−)-methyl(11R, 15S, 13E)-11-tert-butyldimethylsilyloxy-15-hydroxy-9-oxoprost-13-en-1-oate (481 mg, 1.0 mmol) was dissolved in 5 ml of a mixed solvent (ethyl acetate/water/tetrahydrofuran 6:3:1) and stirred at 40° C. for 2 h. The reaction mixture was poured into a saturated aqueous sodium carbonate cooled with ice and extracted with ethyl acetate (100 ml) two times. The combined organic layer was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove solvent. The residue was purified by silica gel column chromatography [ethyl acetate/hexane (2/1)] to give 312 mg (85% yield) of prostaglandin E1 methyl ester;