Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:25]=[CH:24][C:14]([NH:15]C(=O)C2C=CC=CC=2)=[N:13][C:11]1=[O:12]>N>[CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:25]=[CH:24][C:14]([NH2:15])=[N:13][C:11]1=[O:12]
Reactant: C=C1[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@H](CO)[C@H]1O
Agent: N
Product: C=C1[C@H](n2ccc(N)nc2=O)O[C@H](CO)[C@H]1O
Yield: 96.1 %

Procedure:
A solution of 139 mg (0.5 mmol) of 2'-deoxy-2'-methylidene-4-N-benzoylcytidine in 10 ml of methanolic ammonia was stirred at room temperature for 6 hours to cause reaction and the solvent distilled off under reduce pressure. The residue was developed through a silica gel column (1.6×10 cm, 20% ethanol-chloroform being used as a solvent for elution), fractions containing the desired compound collected, 2 ml of 1N hydrochloric acid added, and the solvent distilled off under reduced pressure. The residue was crystallized from acetone-methanol to obtain 115 mg (yield 83%) of 2'-deoxy-2'-methylidenecytidine.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[Mg+2].[Cl-]>O1CCCC1.COCCO>[CH2:22]([O:21][C:19]([C:18]1[C:9]2=[C:8]3[C:13](=[CH:12][CH:11]=[CH:10]2)[CH2:14][CH2:15][CH:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:7]3[CH:17]=1)=[O:20])[CH3:23]
Reactant: c1ccc2c(c1)CCC(C1CCCC1)N2
Reactant: CCOC(=O)C(=O)CBr
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2C1CCCC1
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 2-cyclopentyl-1,2,3,4-tetrahydroquinoline (4.0 g, 20 mmol) in tetrahydrofuran (15 ml) was added ethyl bromopyruvate (˜90% purity; 1.38 ml, 9.9 mmol) and the reaction stirred for 15 h. The resulting precipitate was filtered and washed with tetrahydrofuran (20 ml). The filtrate was evaporated in vacuo. The resulting residue was dissolved in tetrahydrofuran (10 ml) and 2-methoxyethanol (10 ml) and the solution added dropwise to a refluxing solution of magnesium (II) chloride (1.05 g, 11 mmol) in 2-methoxyethanol (10 ml). The reaction mixture was refluxed for 2 h and then a further portion of magnesium (II) chloride (1.05 g, 11 mmol) added and refluxing continued overnight. The reaction was cooled and the solvent removed in vacuo. The resulting brown oil was dissolved in dichloromethane (150 ml) and washed with 2 M HCl (50 ml), saturated potassium carbonate (50 ml) and brine (50 ml). The organics were dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography using 33-67% (v/v) dichloromethane in heptane to give 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (1.45 g, 4.9 mmol).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40]S)[CH3:37]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:36][N:38]([CH2:42][CH3:43])[CH2:39][CH3:40])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CCS
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCN(CC)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(C)=O)CC2)s1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])[N:20]([CH2:35][CH2:36][O:37][CH3:38])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1.OC1C2N=NNC=2C=CC=1.[NH:50]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:51]([C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH:52]([CH3:54])[CH3:53].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[C:65]([O:64][C:62](=[O:63])[NH:50][CH:51]([C:55](=[O:56])[NH:57][CH2:58][C:59](=[O:60])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])[N:20]([CH2:35][CH2:36][O:37][CH3:38])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1)[CH:52]([CH3:53])[CH3:54])([CH3:66])([CH3:68])[CH3:67]
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(C(=O)N3CCOCC3)cccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)CNC(=O)C(NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(C(=O)N3CCOCC3)cccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indol-3-yl]-methanone hydrochloride (100 mg, 0.18 mmol) was dissolved in DMF (2.6 mL) under nitrogen and stirred at 0° C. for 5 min. To this was added sequentially hydroxybenzotriazole (77 mg, 0.57 mmol), BOC-Val-Gly-OH (59 mg, 0.21 mmol), triethylamine (0.05 mL, 0.36 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg, 0.21 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (30 mL). The brine was back extracted with ethyl acetate (2×30 mL) and the organic fractions were combined and washed with 10% citric acid (2×30 mL), sat sodium bicarbonate solution (2×30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by SiO2 column chromatography using 5% MeOH/CH2Cl2 as the eluent to afford (1-{[(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-methyl]-carbamoyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (100 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.40-7.30 (m, 2H), 7.28-7.21 (m, 2H), 7.18-7.10 (m, 1H), 7.08-7.00 (m, 1H), 6.98-6.85 (m, 1H), 5.00-4.90 (br s, 1H), 4.30 (t, 2H), 3.85-3.70 (br m, 2H), 3.73 (t, 2H), 3.47 (s, 2H), 3.33 (s, 3H), 3.20-2.90 (br m, 2H), 1.90-1.60 (br m, 6H), 1.30-1.24 (m, 10H), 1.80-1.70 (br m, 6H); 19F NMR (282 MHz, CDCl3) δ −57.60 (s, 1F); MS m/z: [M+H]+=779.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([O:32]CC3C=CC=CC=3)=[O:31])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.[H][H]>[Pd].CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=[O:31])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH2:28][CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OCc2ccccc2)cc1CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC

Procedure:
A mixture of 350 mg (0.60 mmol) (R)-1-benzyloxycarbonyl-2-(3,4-diethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30 mL MeOH was hydrogenated in the presence of 50 mg Pd/C (5%) at RT and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent was eliminated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH3:14]
Reactant: CC(C)(C)c1cc(I)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(Br)cc(I)cc1C(C)(C)C

Procedure:
A solution of 2-bromo-6-tert-butyl-4-iodophenol (5.0 g, 14.08 mmol) in acetone (50 mL) was treated with potassium carbonate (2.92 g, 21.13 mmol) and dimethylsulfate (1.95 g, 15.49 mmol) at reflux for 16 hours, cooled and concentrated. The residue was dissolved in ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified on an Isco 40 g silica cartridge eluting with 2% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([O-:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](=[CH2:21])[CH3:20].O>O1CCOCC1.S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][NH2:17])[C:13]([O:15][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(S)-(benzyloxycarbonyl)amino-3-aminopropionate (Fluka) (5.25 g, 22 mmol) in dioxane (75 mL) and conc. sulfuric acid (9 mL) was cooled to 0° C. and treated with 100 mL isobutylene in a Fisher Porter high pressure apparatus. The reaction was allowed to warm to room temperature and was stirred for 24 h. The reaction was vented, then poured into water (200 mL) to give an acidic solution that was extracted with ether (2×50 mL). The aqueous layer was carefully basified with conc. NaOH to pH 11-12 and extracted with 3×150 mL EtOAc. The EtOAc was removed in vacuo and the residue was azeotroped with toluene and dried under vacuum to give 4-1 as an oil. Rf (5% MeOH/CHCl3 saturated with NH3) 0.31. 1H NMR (400 MHz, CDCl3) δ7.3 (m, 5H), 5.6 (bs, 1H), 5.1 (s, 2H), 4.22 (bs, 1H), 3.05 (m, 2H), 1.45 (s, 9H), 1.4-1.2 (b, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:25](O)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[CH3:25])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde, MeMgBr was added (in THF at 0° C.) to give an ethanol derivative, which was oxidized to the title compound as in Example 15, Step 11.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].I[CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].O>CN(C)C=O>[S:1]([CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: O=C1N[C@H](CI)[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CSC[C@H]1NC(=O)[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
1.5 g of potassium thiocyanate were added at 75° C. with stirring to a mixture of 1.78 g of the product of Step A in 5 ml of dimethylformamide and the mixture was stirred for 31/2 hours and was poured into water. The mixture was vacuum filtered and the product was washed with water and dried. The product was empasted with hot isopropyl ether, vacuum filtered and dried to obtain 1.25 g of racemate of cis 4-thiocyanatomethyl-3-phthalimido-2-oxo-azetidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].C(S)CC.Br[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[Br:25].[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:23]([F:29])([F:28])[C:24]([Br:25])([F:27])[F:26]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)(F)Br)c(Cl)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 190 %

Procedure:
Into a pressure bottle was placed 15.0 g (0.086 mole) 2-chloro-4-nitrophenol, 11.9 g (0.086 mole) potassium carbonate, 1.5 g (0.02 mole) propanethiol, 33.7 g (0.13 mole) 1,2-dibromotetrafluoroethane and 115 ml of N,N-dimethylformamide. The pressure bottle was sealed and the mixture stirred at 50° C. for 48 hours. The pressure bottle was cooled to room temperature, opened, and the contents poured into a separatory funnel. Approximately 200 ml of a 2N sodium hydroxide solution was added to the separatory funnel. The resultant mixture was extracted with four 300 ml portions of diethyl ether. The extracts were combined and washed with two 100 ml portions of a 2N sodium hydroxide solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving an oil. The reaction described above was repeated three additional times. The residual oils from the four runs were combined and purified by column chromatography on silica gel, eluting with n-heptane: toluene (95:5), to yield 57.6 g of 3-chloro-4-(2-bromo-1,1,2,2-tetrafluoroethoxy)nitrobenzene as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]([Cl:14])([Cl:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9]>O.CC(C)=O>[Cl:6][C:7]([Cl:14])([Cl:13])[C:8]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:12])=[O:9]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NCCCO
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCCO)NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
3.75 g of 3-aminopropanol are dissolved in a mixture of 10 g of water and 10 g of acetone. 9.4 g of trichloroacetyl isocyanate are subsequently added dropwise. After a slightly exothermic reaction, the mixture is stirred for 1 hour at room temperature, then refluxed for 2.5 hours. Concentration in a rotary evaporator gives 7.7 g of an oily phase, which is taken up in acetone and subjected to column chromatography on silica gel using cyclohexane/ethyl acetate (1:1) as eluent.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH:38]3[CH2:40][CH2:39]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:34]2[CH:33]=[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:41])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)[CH:37]=[CH:36][N:35]=2)[CH2:40][CH2:39]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M268) (298 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (179 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9](C(C)(C3C=CC=CC=3)C)[CH:10](O)[C:6]=2[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(ccnc2Br)C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2ccnc(Br)c21
Yield: 33.5 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-bromo-1-hydroxy-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (239 mg, 0.688 mmol) was dissolved in nitromethane (12 mL), and the solution was treated with trifluoroacetic acid (1.17 mL, 15.1 mmol) and triethylsilane (0.440 mL, 2.75 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1) to obtain 4-bromo-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (49.1 mg, yield 34%).
Reaction SMILES: Cl[C:2]([CH3:16])([CH3:15])[CH:3]([N:13]=[O:14])[CH2:4][C:5]1[N:6]=[C:7]([N+:10]([O-:12])=[O:11])[NH:8][CH:9]=1.[NH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][NH2:21]>C(#N)C>[NH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][NH:21][C:2]([CH3:16])([CH3:15])[C:3](=[N:13][OH:14])[CH2:4][C:5]1[N:6]=[C:7]([N+:10]([O-:12])=[O:11])[NH:8][CH:9]=1
Reactant: CC(CN)CN
Reactant: CC(C)(Cl)C(Cc1c[nH]c([N+](=O)[O-])n1)N=O
Solvent: CC#N
Product: CC(CN)CNC(C)(C)C(Cc1c[nH]c([N+](=O)[O-])n1)=NO
Reaction time: 0.5 h

Procedure:
3-Chloro-3-methyl-1-(2-nitroimidazolyl)-2-nitrosobutane (1.5 g, 6.09 mmol, Example 1) was added portionwise over a period of 30 minutes to a stirred solution of 1,3-diamino-2-methylpropane (3.0 g, 34.10 mmol) in dry acetonitrile (30 mL) at 50° C. After the addition the reaction mixture was allowed to remain at 50° C. for an additional 30 minutes. The reaction mixture was then cooled and solvent was removed on a rotary evaporator to a give a paste. This was crystallized from dichloromethane-ether to afford the title product as a light yellow solid; yield: 1.36 g (75%); mp. 102-104° C. (decomp); 1H NMR (CDCl3) δ 0.89 (d, 3H, CH3), 1.22 [s, 6H, C(CH3)2], 1.51 (m, 1H, CH3CH), 2.25 (d, 2H, CH2NH2), 2.65 (m, 2H, NHCH2), 5.31 (s, 2H, imi-CH2), 7.03 & 7.21 (2s, 2H, imi-H). MS m/e 299 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O-]CC.[K+]>CCOCC.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C)cc1
Agent: [Ru+2]
Agent: CC[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1ccc(C(C)O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.33 mol %) were dissolved in ether (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 40° C. After the mixture was cooled to room temperature, p-methylacetophenone (0.8 mmol), ether (2 mL) and a solution of potassium ethoxide in i-propanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 12 h under H2 (10 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-methylphenyl)ethanol was obtained and the ee value (ee=99.3%) was measured by GC analysis.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([S:12](Cl)(=O)=O)=[CH:11][C:4]=2[NH:3]1.Cl.[Sn].C(OCC)(=O)C>O1CCOCC1>[SH:12][C:10]1[CH:9]=[CH:8][C:5]2[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[CH:11]=1
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Agent: Cl
Agent: [Sn]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1COc2ccc(S)cc2N1
Yield: 16.1 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (5.8 g, 20.2 mmol), was added the hydrogen chloride in 1,4-dioxane (30 mL) followed by tin powder (12 g, 10.1 mmol). The resulting mixture was heated under reflux for 2 hours. After this time, the solvent of the reaction mixture was removed under vacuum to give the crude residue. The resulting residue was treated with ethyl acetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude material was purified by silica gel chromatography using a 60:40 mixture of hexane and ethyl acetate as eluent to afford the title product as a white solid (0.59 g, 16% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.82 (1H, s), 6.86 (2H, m), 6.81 (1H, m), 5.40 (1H, s), 4.53 (2H, s).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:32]([O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40]([C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:26](=[O:28])[CH2:25][NH:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([S:15](=[O:17])(=[O:16])[NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1)=[O:46])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: O=C(NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared from [4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid and L-proline benzyl ester hydrochloride according to the method described in Example 1.1/d. MS (EI) 614.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:34][CH2:35][CH2:36][OH:37])[CH:10]=3
Reactant: OCCCBr
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) produced in Example 102 was suspended in dimethyl sulfoxide (40 ml). After adding potassium carbonate (540 mg), the mixture was stirred at room temperature for 30 minutes, and 3-bromo-1-propanol (0.3 ml) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (100 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (177 mg, 72%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9].[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CC(=CCBr)CCC(C)=C(C)C
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC(C)=C(C)C

Procedure:
1-bromo-3,6,7-trimethyl-2,6-octadiene and 6-hydroxy-2,3-dihydrobenzofuran are reacted to form 6-[(3,6,7-trimethyl-2,6-octadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point 124°-126° C./0.001 mmHg; nD20 = 1.5412;