Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13]([O:15]C)=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:26]=2)[C:21]([CH2:33][C:34]([NH2:36])=[O:35])=[CH:20]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:15])[NH:36][C:34](=[O:35])[C:33]=3[C:21]3[C:22]4[C:27](=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:24][CH:23]=4)[N:19]([CH3:18])[CH:20]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(Cl)ccc12
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCCC3)cc21
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)NC2=O)c2ccc(Cl)cc21
Yield: 39.1 %

Procedure:
3-(6-Chloro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (70 mg, 37%) was prepared from methyl (6-chloro-1-methyl-1H-indol-3-yl)glyoxylate (98 mg, 0.39 mmol) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-acetamide (100 mg, 0.39 mmol).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:42])[C:4]([S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH2:15][C:16]1C=CC(OCCN2CCOCC2)=C[CH:17]=1)[CH2:5]/[CH:6]=[C:7](\C)/CCC=C(C)C>CO.[Pd]>[OH:1][NH:2][C:3](=[O:42])[C:4]([S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:32])=[O:33])([CH2:15][CH2:16][CH3:17])[CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(S(=O)(=O)C(C/C=C(\C)CCC=C(C)C)(Cc2ccc(OCCN3CCOCC3)cc2)C(=O)NO)cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide (326 mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)30 ; 1H NMR (300 MHz, CDCl3): δ0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9 Hz, 2H), 7.76 (d,J=9 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[C:18]([S:22]([NH2:24])=[O:23])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CO.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4](/[C:5](/[C:7]2[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:24]\[S:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:23])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1ncccc1C(=O)c1cccc(Br)c1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccnc1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Titanium(IV)ethoxide (1 M solution in THF, 18.7 mL) was added to a solution of 3-(3-bromobenzoyl)pyridine-2-carbonitrile (2.680 g, 9.334 mmol) and tert-butylsulfinamide (1.244 g, 10.27 mmol) in anhydrous THF (10 mL) under an atmosphere of argon. The mixture was heated at 50° C. for 70 h. After cooling to room temperature the mixture was diluted with methanol (20 mL) and 100 drops of water was added. The resulting mixture was allowed to stand for about 1 h and then filtered through a pad of sodium sulfate. The filter cake was taken up in saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The mixture was stirred over night, the phases were separated and the aqueous phase was extracted with dichloromethane. The extracts were combined with the filtrate from above, dried over sodium sulfate and evaporated. Purification by column chromatography using a gradient of increasing concentration of acetonitrile in dichloromethane (0-20%) gave 2.52 g (69% yield) of the title compound. 1H NMR (CDCl3) δ 8.81 (d, 1H), 7.76 (m, 2H), 7.68 (m, 1H), 7.62 (dd, 1H), 7.43 (d, 1H), 7.32 (t, 1H), 1.39 (br. s., 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[C:17]2[O:16][C:15]([CH2:18][CH2:19][C:20]#[CH:21])=[N:14][C:13]=2[CH:12]=[C:11]([F:22])[CH:10]=1>>[Br:8][C:9]1[C:17]2[O:16][C:15]([CH2:18][CH2:19][C:20]#[C:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:14][C:13]=2[CH:12]=[C:11]([F:22])[CH:10]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cc(F)cc(Br)c2o1
Product: Fc1cc(Br)c2oc(CCC#Cc3ccccn3)nc2c1
Yield: 45.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (131 mg, 0.83 mmol) and 7-bromo-2-(but-3-ynyl)-5-fluoro-benzo[d]oxazole (223 mg, 0.83 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 130 mg (0.38 mmol, 45%) of 7-bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][CH3:7].[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11]>>[CH3:8][C:9]([CH3:14])([C:10](=[O:12])[CH2:11][CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][CH3:7])[CH3:13]
Reactant: CC=CC=CCCl
Reactant: CC(=O)C(C)(C)C
Product: CC=CC=CCCC(=O)C(C)(C)C
Yield: 100 %

Procedure:
According to the procedure described in Example 2, from 19.4 g of 1-chloro-2,4-hexadiene and 17.4 g of 3,3-dimethyl-butan-2-one there are obtained 30 g of crude 2,2-dimethyl-6,8-decadien-3-one which are subjected to a fractional distillation.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([O:11][C:12](=[O:18])[NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[O:16][CH2:15][C@H:14]([NH:13][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:18])[CH3:17]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](COC(=O)N(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N,N-Dimethylcarbamoyl chloride (0.12 mL, 0.0013 mol) was added to a solution of tert-butyl[(1R)-2-hydroxy-1-methylethyl]carbamate (0.150 g, 0.856 mmol), 4-dimethylaminopyridine (0.02 g, 0.2 mmol) and pyridine (0.14 g, 1.7 mmol) in methylene chloride (3.0 mL). The mixture was stirred overnight, diluted with EtOAc and washed with 1N HCl, saturated NaHCO3 and brine. The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.CCOCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH3:7][N:5]1[CH:6]=[C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:3]=[N:4]1
Reactant: Cn1cc(Br)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-methylpyrazole (15 g, 38.5 mmol) in ether (150 mL) n-Butyllithium (2.5M in hexanes, 17 mL, 42.4 mmol) was added at −78° C. After the reaction solution was stirred at −78° C. for 30 minutes, tributyltin chloride (11.5 mL, 42.4 mmol) was added. It was stirred at −60° C. for 1 hour and warmed to room temperature, at which it was stirred for 1 more hour. Then, it was diluted with ethyl acetate (300 mL) and washed with water (200 mL) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel with hexanes/ethyl acetate=10/1 as eluant to get 1-methyl-4-tributylstannylpyrazole as a white wax. 1H NMR (CDCl3, 300 MHz): δ7.42 (s, 1H), 7.23 (s, 1H), 3.93 (s, 3 H). 1.28-1.55 (m, 18 H), 0.91 (t, J=15 Hz, 9 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:23]4[NH:22][C:21]5[CH2:26][CH2:27][N:28]([CH2:30][C:31]6[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=6)[CH2:29][C:20]=5[C:19]=4[CH:18]=3)=[O:16])[CH2:10][CH2:9]2)[CH:2]=1.[H-].[Na+].[C:43](Cl)(=[O:45])[CH3:44]>CN(C=O)C>[C:43]([N:22]1[C:23]2[CH:24]=[CH:25][C:17]([C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:9][CH2:10]3)=[O:16])=[CH:18][C:19]=2[C:20]2[CH2:29][N:28]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)[CH2:27][CH2:26][C:21]1=2)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCN(Cc2cccnc2)CC1)c1ccc2[nH]c3c(c2c1)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3cc(C(=O)NC4CCN(Cc5cccnc5)CC4)ccc31)CN(Cc1ccc(C(F)(F)F)cc1)CC2
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 11, 50 mg, 0.09 mmol) in DMF (1.0 mL), NaH (60%, 5 mg, 0.13 mmol) was added at room temperature. The resulting brown reaction mixture was allowed to stir for 20 min, cooled down to −25° C. and acetyl chloride (7 μL, 7.7 mg, 0.1 mmol) was added. The reaction mixture was then allowed to warm up to room temperature over 1 h and poured over ice-cold saturated NaHCO3 solution to give a brown precipitate which was collected and purified by reverse phase HPLC. The purified material was triturated with ethyl ether to provide 5-acetyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 20) as its bistrifluoroacetate salt as a white solid (31%). 1H NMR (CD3OD, 300 MHz) 8.73 (d, J=1.7 Hz, 1H), 8.70 (dd, J=5.1, 1.5 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.07 (dt, J=7.4, 1.7 Hz, 1H), 7.97 (s, 1H), 7.87-7.79 (m, 5H), 7.61 (dd, J=8.0, 5.0 Hz, 1H), 4.69 (s, 2H), 4.53 (s, 2H), 4.45 (s, 2H), 4.26-4.14 (m, 1H), 3.77 (br s, 2H), 3.64-3.52 (m, 4H), 3.28-3.20 (m, 2H), 2.80 (s, 3H), 2.26 (d, J=14.4 Hz, 2H), 1.99 (br s, 2H) ppm; MS (ES) 590 (M+H).
Reaction SMILES: [CH:1]([CH:3]=C)=O.C(O[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:13]([O:12][CH:8]([O:9][CH2:10][CH3:11])[CH:1]=[CH2:3])[CH3:14]
Reactant: CCOC(OCC)OCC
Reactant: C=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=CC(OCC)OCC
Temperature: 5 °C
Yield: 48 %

Procedure:
After 10 ml of acrolein commercially available from Aldrich, Co. is dissolved in 50 ml of anhydroust ethanol, 19 ml of triethylorthoformate and p-toluene sulfonic acid are added to the solution, and the resulting mixture is allowed to reflux under a nitrogen atmosphere for 5 hours. After that, the resulting solution is cooled to a temperature of 5° C., extracted with diethyl ether, washed with 5% sodium bicarbonate (NaHCO3) aqueous solution, dried with anhydrous magnesium sulfate (MgSO4), and then evaporated under a reduced pressure to remove ethanol. Next, the material is fractionally distilled, thereby giving 8.4 g of 3,3-diethoxy-1-propene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[CH2:48][C:47](=[O:49])[O:46][C:44](=[O:45])[CH2:43]1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:47](=[O:49])[CH2:48][C:42]([CH3:50])([CH3:41])[CH2:43][C:44]([OH:46])=[O:45])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CC(C)(C)CC(=O)O)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
To a mixture of 181 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 0.114 mL of triethylamine, and 3.0 mL of THF was added 64 mg of 3,3-dimethylglutaric anhydride at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by stirring, extracting with chloroform, and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 266 mg of 5-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,3-dimethyl-5-oxopentanoic acid as a crude product. ESI+: 587
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[C:8]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25](Cl)=[C:20]3[CH:19]=[CH:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>C(O)C>[C:8]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]([NH:1][CH:2]4[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]4)=[C:20]3[CH:19]=[CH:18]2)(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCC(O)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 3-Amino-cyclopentanol (about 2.5 g) in ethanol (50 mL) were added 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (7 g, 20.4 mmol) and diisopropylethylamine (DIPEA) (7.2 g, 60 mmol), then the reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was purified by column chromatography (Hexanes/ethyl acetate=3:1) to give 7.4 g (76%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol. 1H NMR (400 MHz, CDCl3) δ: 9.56 (s, 1H), 9.54 (s, 1H), 8.19-8.16 (m, 2H), 7.62-7.56 (m, 4H), 6.82-6.81 (m, 1H), 4.56-4.50 (m, 2H), 2.25-1.96 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:38][S:39]([O-:41])=[O:40].[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][S:39]([CH3:38])(=[O:41])=[O:40])=[N:6][CH:7]=1
Reactant: OCCc1ccc(Br)cn1
Reactant: CS(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCc1ccc(Br)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
The product of Step 1 of Example 6 (940 mg, 4.65 mmol) in dimethylformamide (5 mL) at 5° C. is treated with triphenylphosphine (1710 mg, 6.5 mmol) and N-bromosuccinimide (1.24 g, 7.0 mmol) then stirred for 1 hour. Sodium methanesulfinate (980 mg, 9.3 mmol) and tetrabutylammonium iodide (175 mg, 0.45 mmol) are added and the mixture heated at 70° C. for 1 hour then cooled to room temperature, diluted with ethyl acetate (25 mL), washed with water (25 mL) and brine (25 mL), dried over MgSO4, filtered, concentrated, and the crude material purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (570 mg): m/z (Cl) 265 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](Cl)=[N:7][C:6]=2[CH:16]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C1(C)C=CC=CC=1>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]3)=[N:7][C:6]=2[CH:16]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1ccc2c(c1)N=C(Cl)c1cscc1O2
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N=C(N1CCN(CCO)CC1)c1cscc1O2

Procedure:
7-Methyl-10-chloro-thieno[3,4-b][1,5]benzoxazepine (Example 7) is reacted with 20 ml. of N-(2-hydroxyethyl)-piperazine in 20 ml. of dry toluene as described in Example 1, giving the base compound which is further reacted with fumaric acid, giving the desired product as the fumarate salt, m.p. 178°-180° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:27])[C:21]([NH:23]CC=C)=O)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH:33]1[CH:38]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:34]=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl>ClCCl>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:27])([CH2:38][CH:33]=[CH2:34])[C:21]#[N:23])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCNC(=O)C(C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C=CCC(C)(C#N)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
The 3-aza-claisen reaction was carried out according to the method of Walters et al. (1991) Tetrahedron Lett. 2: 179-182. Amide 49.3 (15.9 g, 36.2 mmol) and PPh3 (21 g, 80 mmol) were dissolved in anhydrous dichloromethane (160 mL). Et3N (12 g, 119.5 mmol) and CCl4 (18.4 g, 119.5 mmol) were added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated brine (250 mL). The organic phase was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (25% ethyl acetate in hexanes) to yield 12.3 g of 49.4. 1H NMR (400 MHz) (CDCl3) δ 7.73 (4H, s); 7.70 (1H, s); 7.61-7.51 (3H, m); 7.41 (2H, d, J=8.9 Hz); 7.05 (2H, d, J=8.9 Hz); 5.76-5.72 (1H, m); 5.21-5.17 (4H, m); 2.71-2.59 (2H, m); 1.72 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(O)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 4-Chloro-3-nitro-phenol (2.0 g, 11.52 mmol), 4-hydroxythiophenol (1.45 g, 11.52 mmol) and cesium carbonate (11.26 g, 34.56 mmol) in N,N-dimethylformamide (25 mL) was heated to 100° C. for 4 hours. After cooling to room temperature, 1N aqueous Hydrochloric acid (150 mL) was added and the resultant solution extracted with ethyl acetate (2×100 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the crude title compound which was purified by chromatography on silica gel using hexanes/ethyl acetate as eluent to obtain the title product as a bright orange solid (1.35 g, 45%).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=1[O:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[O:23][CH3:24])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CC(=O)O)ccc1Oc1ccc(N)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 4-fluoro-3-nitroaniline (3.45 g, 22.1 mmol), 4-hydroxy-3-methoxyphenylacetic acid (4.03 g, 22.1 mmol) and cesium carbonate (18.0 g, 55.3 mmol) in methylsulfoxide (40 mL) was heated to 120° C. (external temperature, oil bath) overnight. After 16 h the reaction was poured into water and the pH adjusted to <4 by addition of citric acid. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark brown oil. The product was isolated by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient, to afford an orange foamy solid. LC-MS ESI (neg.) m/z: 317.0 (M−H). 1H NMR (400 MHz) (CDCl3) δ 7.27 (d, J=8.4 Hz, 1H); 6.93 (s, 1H); 6.84-6.79 (m, 4H); 5.90 (br s, 2H); 3.85 (s, 31H); 3.63 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N2CCNCC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCNCC4)cc3)cc2)cc1)c1ccc(N2CCNCC2)cc1

Procedure:
Compound 317 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-piperazinobenzoate. [M+H]+ calcd for C35H37N6O3: 589.29; found: 589.07.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:23]([CH2:24][CH3:25])=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19]O)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:26])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:46]=[N+:47]=[N-:48].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:46]([CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:23]([CH2:24][CH3:25])[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:26])[CH2:15][C@@H:16]1[OH:17])=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1NC(=O)c1ccccc1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)nc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.1 %

Procedure:
A mixture of 1.436 g of N-benzoyl-2'-deoxy-5-ethylcytidine, 1.072 g of triphenylphosphine, 1.304 g of sodium azide and 1.360 g of carbon tetrabromide in 16 ml of dimethylformamide was stirred at room temperature for 20 hours. 8 ml of methanol were added, the mixture was stirred for 30 minutes and then evaporated. The residue was suspended in 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed with water and evaporated. The residue was subjected to flash chromatography on a column of silica gel using ethyl acetate for the elution, there being obtained 1 g of 5'-azido-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in the form of a white crystalline solid of melting point 125°-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)[CH:5]=[CH:6][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)[CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Nc1cccc(C2=NNC(=O)C3CC23)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 40 %

Procedure:
6.0 g (29.8 millimoles) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 33), 3.5 g (44.6 millimoles) of acetyl chloride and 100 ml of anhydrous toluene are kept at 80° C. for 6 hours. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from methanol. 2.9 g (40% of theory) of 2-(m-acetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 200°-202° C.