Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(OCC)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1O
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Temperature: 180 °C

Procedure:
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid is filtered, washed with hexanes, and dried to yield 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4chlorobenzylamine (4.0 mL) are heated at 180° C. for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting solid is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]([C:20](=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:19])[CH3:18]>>[CH2:25]([O:24][C:22]([C:21]1[C:20]([CH:17]([CH3:19])[CH3:18])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:23])[CH3:26]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1 step A using (2-amino-5-chlorophenyl)(phenyl)methanone and ethyl 3-isopropyl-3-oxopropanoate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:5].[H][H]>O1CCCC1.C(O)CC>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:3]=1[C:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:5]
Reactant: [H][H]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Solvent: CCCO
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Temperature: 25 °C
Yield: 94.6 %

Procedure:
In a stirred autoclave, 0.1 g of a catalyst prepared according to Example H1 is added to a solution of 10 g of allyl 2-(2-chloro-5-nitrobenzoyloxy)-2-methylpropionate in 80 ml of tetrahydrofuran and 20 ml of n-propanol, 6 mg (0.1 mol %) of FeCl2 4H2O are added in addition and the mixture is hydrogenated for 7 hours at a temperature of 140° C. and at a hydrogen pressure of 20 bar. After cooling to room temperature and flushing the stirred autoclave with nitrogen, the catalyst is filtered off. 117.3 g are obtained of a solution having a content of 7.26% of allyl 2-(2-chloro-5-aminobenzoyloxy)-2-methylpropionate (yield: 94.6% of theory).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.C(O)(C)C.C(=O)=O.[N:16]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[C:17]=[O:18]>C1COCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:17]([NH:16][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C=NC1CCCCC1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N[C@H]1CC[C@H](NC(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of trans-1,4-diaminocyclohexane (6.15 g, 0.054 mol) in dry THF (500 mL) was cooled to −40° C. in a cooling bath (isopropyl alcohol/dry ice) under inert atmosphere. Isocyanatocyclohexane (6.75 g, 0.054 mol) in dry THF (100 mL) was added slowly under heavy stirring. The resulting mixture was stirred for another 24 h at room temperature. The precipitating white solid was filtrated, suspended in water and acidified to pH 2 (HCl). The emerging clear solution was again filtrated and the filtrate was brought to pH 8 (NaOH) whereupon trans-1-(4-aminocyclohexyl)-3-cyclohexylurea precipitated as a white solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:14]([O:15]C(=O)C)[C@H:13]([O:19]C(=O)C)[C@@H:12]([CH2:23][N:24]=[N+:25]=[N-:26])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]>CO>[C:1]([NH:4][C@H:5]1[C@@H:14]([OH:15])[C@H:13]([OH:19])[C@@H:12]([CH2:23][N:24]=[N+:25]=[N-:26])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCO[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Solvent: CO
Product: C=CCO[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Allyl 2-acetamido-3,4-di-O-acetyl-6-azido-2,6-dideoxy-α-D-mannopyranoside, prepared as described above, (0.5 rag) was dissolved in 10 mL methanol containing 0.2M MeONa. After five minutes, Dowex 50 cation exchange resin was added to the mixture to neutralize. The resin was filtered and the filtrate was concentrated to yield allyl 2-acetamido-6-azido-2,6-dideoxy-α-D-mannopyranoside (99 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH3:22][CH:23]1[CH2:28][CH:27]([CH3:29])[CH2:26][NH:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:25]1[CH2:26][CH:27]([CH3:29])[CH2:28][CH:23]([CH3:22])[CH2:24]1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CC1CNCC(C)C1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(N3CC(C)CC(C)C3)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 93.2 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (from Example 7a, Step 2) (0.5 g, 1.54 mmole) and 3,5-dimethylpiperidine (0.17 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The solution was maintained at 90° C. for 48 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by Biotage silica chromatography with 30% methylene chloride in hexane to give light yellow oil (0.6 g, 93%). GCMS m/z 417.00 (M+). 1H NMR (CDCl3/300 MHz) 7.61 (s, 1H), 7.18 (s, 1H), 6.60 (s, 1H), 5.67 (q, 1H, J=7.0 Hz), 4.67 (m, 2H), 3.40 (m, 2H), 2.18 (m, 2H), 1.86 (m, 2H), 1.31 (m, 3H), 1.04 (m, 1H), 0.90 (m, 6H), 0.68 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:43])=[CH:9][C:10]([CH3:42])=[C:11]([CH:13]([S:18][CH:19]([C:24]3[CH:29]=[C:28]([N:30]4[C:34]([NH2:35])=[N:33][C:32]([C:36]([F:39])([F:38])[F:37])=[N:31]4)[C:27]([F:40])=[CH:26][C:25]=3[CH3:41])[C:20]([F:23])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15])[CH:12]=2)[N:5]=[C:4]([C:44]([F:47])([F:46])[F:45])[N:3]=1.ClC1C=CC=C(C(OO)=[O:56])C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:43])=[CH:9][C:10]([CH3:42])=[C:11]([CH:13]([S:18]([CH:19]([C:24]3[CH:29]=[C:28]([N:30]4[C:34]([NH2:35])=[N:33][C:32]([C:36]([F:39])([F:37])[F:38])=[N:31]4)[C:27]([F:40])=[CH:26][C:25]=3[CH3:41])[C:20]([F:21])([F:22])[F:23])=[O:56])[C:14]([F:17])([F:16])[F:15])[CH:12]=2)[N:5]=[C:4]([C:44]([F:47])([F:46])[F:45])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1C(SC(c1cc(-n2nc(C(F)(F)F)nc2N)c(F)cc1C)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1C(S(=O)C(c1cc(-n2nc(C(F)(F)F)nc2N)c(F)cc1C)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
1.9 g of [5-(5-amino-3-trifluoromethyl-1,2,4-triazolyl)-4-fluoro-2-methylphenyl]2,2,2-trifluoroethyl sulfide was dissolved in 100 ml of chloroform, and 1.0 g of m-chloroperbenzoic acid was added at 0° C., followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent ethyl acetate:hexane:triethylamine=50:50:1) to obtain 1.8 g of [5-(5-amino-3-trifluoromethyl-1,2,4-triazolyl)-4-fluoro-2-methylphenyl]2,2,2-trifluoroethyl sulfoxide as pale yellow crystals (melting point 236 to 238° C.).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH2:13]=[C:14]1[C:27](=[O:28])[N:17]2[C@@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][CH2:20][C@@H:16]2[CH2:15]1>C1COCC1>[C:21]1([C@@H:18]2[N:17]3[C:27](=[O:28])[C:14]4([CH2:7][CH2:13]4)[CH2:15][C@H:16]3[CH2:20][O:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)[O-]
Reactant: C=C1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N2[C@H](CO[C@@H]2c2ccccc2)CC12CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Trimethylsulfoxonium iodide [Me3S(O)I] (1.5 eq) and anhydrous THF (12 vol) were charged to a reactor. Cooled to 10˜20° C. and then added t-BuOK (1.5 eq). The resulting mixture was warmed to 60±5° C. and stirred for 1 h. Cooled down back to 10˜20° C. and then dropwise added a solution of (3R,7aS)-6-methylene-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(1H)-one (1.0 eq) in THF (3 vol) while maintaining the temperature at 60±5° C. The completion of reaction was monitored by HPLC every hour until the conversion >99% (system purity was 55%˜60%). The reaction mixture was then cooled to 15˜20° C., filtered and washed the cake with EtOAc (2 vol). The combined filtrate was washed with brine (3 vol) and the aqueous phase was back-extracted with EtOAc (3 vols). The combined organic phase was concentrated to about 3 vol under vacuum below 45° C. Add silica gel (1 wt/wt) and continued to concentrate to almost dryness. The solid residue was purified by silica gel (2 wt/wt) chromatography eluting with petroleum ether (PE) followed by EtOAc/PE=1:10 (v/v). The yield was about 40% (97.1% HPLC purity). ESI MS m/z (M+H)+ 230.16.
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3cnn(-c4ccccc4)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(1-phenyl-1H-pyrazol-4-yl)quinoxaline-6-carboxylate (80 mg, 0.20 mmol) in methanol (25 ml) and chloroform (5 ml) was added sodium hydroxide (24 mg, 0.60 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (15 ml), and the pH adjusted to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(1-phenyl-1H-pyrazol-4-yl)quinoxaline-6-carboxylic acid (56 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C1C(=O)N([Cl:18])C(=O)C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][C:6]=1[Cl:18]
Reactant: COC(=O)c1cc(Br)co1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(Cl)o1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of methyl 4-bromo-2-furancarboxylate (1.4 g, 6.83 mmol) and NCS (0.912 g, 6.83 mmol) in N,N-dimethylformamide (13.7 ml) was stirred in a sealed tube for 1 h at 100° C. After 1 h, the solution was partitioned between DCM-H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (2-10% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2-furancarboxylate (1.348 g, 5.12 mmol, 75% yield) as a white solid: LCMS (ES) m/e 238, 240, 242 (M, M+2, M+4)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3](=[O:20])[CH2:4][C:5]([CH3:19])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([CH3:18])[O:17][CH2:16][CH2:15][O:14]2)[CH:8]=1)[CH3:6].[Na].[I-].[CH3:25][S+](C)(C)=O>CS(C)=O>[CH3:19][C:5]([C:7]1[CH:8]=[C:9]([C:13]2([CH3:18])[O:14][CH2:15][CH2:16][O:17]2)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH2:4][C:3]1([C:2]([F:1])([F:21])[F:22])[CH2:25][O:20]1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(C2(C)OCCO2)c1
Reaction time: 2 h

Procedure:
To a solution of 1,1,1-trifluoro-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]pentan-2-one (0.56 g, 1.8 mmol) in anhydrous DMSO (2.3 mL) was added the sodium ylide of trimethylsulfoxonium iodide (2.6 mL of a 0.8M solution in DMSO) over 5 minutes. The mixture was stirred 2 hours, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried over sodium sulfate. The solution was concentrated in vacuo to afford the yellow oil, 2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-2-methyl-[1,3]dioxolane, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[N+:20]([O-])([OH:22])=[O:21].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N+:20]([O-:22])=[O:21]
Reactant: CN1CCN(c2ncccc2C(=O)NCCO)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2ncccc2C(=O)NCCO[N+](=O)[O-])CC1
Reaction time: 4 h

Procedure:
To a solution of 1.27 g of compound 7 prepared in Examples 2-10 in 13 ml of acetonitrile was added dropwise a mixture of 2.0 g of fuming nitric acid and 1.4 g of acetic anhydride while maintaining the temperature below -10° C. The mixture was stirred for 4 hours, then poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed twice with water and once with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated to give N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide (compound 17). The product was dissolved in ethanol, and to the solution was added under ice-cooling hydrogen chloride-saturated ethanol. The hydrochloride thus formed was recrystallized from ethanol to give 1.32 g of N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl) nicotinamide dihydrochloride (compound 18)(yield 66%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1ccccc1Cl
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (4.3 g.), sodium hydroxide (1.1 g.) and water (50 ml.) was refluxed under heating for 5 hours with stirring. The reaction mixture was left to cool at ambient temperature and washed with diethyl ether. To the aqueous solution was added diethyl ether, and the mixture was adjusted to ph 4 with 5% sulfuric acid. The diethyl ether layer was separated, washed with water and dried over magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue (3.4 g.) was crystallized with a mixture of benzene and n-hexane to give 2[2-amino-3-(2-chlorophenoxy)phenyl]acetic acid (1.9 g.). mp 86° to 90° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2=[N:16]O)([OH:3])=[O:2].[H][H]>CO.N.[Ni]>[NH2:16][CH:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8]1
Reactant: CC1(C)CC(=NO)c2cc(C(=O)O)ccc2O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)CC(N)c2cc(C(=O)O)ccc2O1

Procedure:
35.2 g (0.15 mol) of 6-carboxy-2,2-dimethyl-4-chromanone oxime are dissolved in 300 ml of methanol by addition of 600 ml of concentrated aqueous ammonia and, after addition of a few grams of Raney nickel catalyst, hydrogenated at 80° C. for 10 hours under 100 atm hydrogen pressure. After filtering off the catalyst, approximately ¾ of the solvent is distilled off in a rotary evaporator. The crystalline precipitate of 4-amino-6-carboxy-2,2-dimethylchroman is filtered off.
Reaction SMILES: [CH:1]1([C:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]1([C:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([O:31][CH2:30][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: OCC1CCCC1
Reactant: CC(O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Product: CC(O)(CNC(=O)c1cnc(OCC2CCCC2)c(-c2ccc(Cl)cc2)n1)C1CC1

Procedure:
The title compound was prepared in analogy to example 26 starting from 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid (-2-cyclopropyl-2-hydroxy-propyl)-amide and replacing ethylenglycolmonomethylether by cyclopentylmethanol. MS (ISP) (M+H+)=430.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:21])/[C:16](OCC)=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[C:15](\[CH3:21])/[CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(Cc2cccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C/C(=C\c1ccc(Cc2cccnc2)cc1)CO
Yield: 72.3 %

Procedure:
In 33 ml of anhydrous tetrahydrofuran was dissolved 6.5 g of ethyl (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylacrylate, and to the resulting solution was added 0.66 g of lithium aluminum hydride in small portions at room temperature. Further, the resulting mixture was subjected to reaction at the same temperature for one hour, and thereafter, 30 ml of ethyl acetate and then 2.5 ml of water were added in small portions with water-cooling. The insolubles were removed by filtration, and thereafter, the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (3:1 by volume)], to obtain 4.0 g (yield 72.3%) of colorless, oily (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl alcohol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:33][C:34]2[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:24][CH:23]4[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[N:14]=2)=[N:10][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([C:15]1[N:14]=[C:13]([NH:12][C:9]3[C:8]([O:33][C:34]4[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:7][C:6]([S:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][N:10]=3)[S:17][N:16]=1)[CH2:24]2
Reactant: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
tert-Butyl 3-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (256 mg, 0.438 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (2 mL) was added. The reaction was stirred at ambient temperature for 15 minutes. The reaction was concentrated and redissolved in CH2Cl2 and washed with saturated aqueous. NaHCO3, dried over sodium sulfate, filtered and concentrated to afford 3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (193 mg, 0.398 mmol, 91.0% yield) as a crude yellow solid.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[C:9]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:22](C)[CH:21]=3)(=[O:19])=[O:18])=[C:10]3[N:15]([CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[ClH:1].[C:2]1([C:8]2[C:9]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:25]=3)(=[O:18])=[O:19])=[C:10]3[N:15]([CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(S(=O)(=O)c2c(-c3ccccc3)cn3ccccc23)ccc1OCCCNC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)cn3ccccc23)cc1

Procedure:
2-Phenyl-1-{4-[3-(tert-butylamino)propyloxy]-3-methylbenzenesulphonyl}indolizine hydrochloride (SR 33485 A) (Example 25) M.p. b 181° C. (methanol)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[S:22][CH:23]=2)=[N:10]1.C1COCC1.[OH-].[Na+]>CO.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[S:22][CH:23]=2)=[N:10]1
Reactant: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a mixture of methyl 4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (32.0 mg) obtained in Example 36 in methanol (2 mL)/THF (2 mL)/water (2 mL) was added 8 M aqueous sodium hydroxide solution (0.026 mL) at 0° C. The reaction mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (31.1 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C([O-])([O-])=O.[K+].[K+].C(C(C)=O)C(C)C>CN1CCCC1=O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1
Reactant: ICCC1Cc2ccccc2C1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)CC(CCN1CCN(c3cccc4[nH]ccc34)CC1)C2
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of 4-(piperazin-1-yl)-1H-indole (1.5 g), 2-(2-iodoethyl)indane (2.0 g), K2CO3, methyl isobutyl ketone (150 ml), and N-methylpyrrolidone (10 ml) was boiled under reflux for 3 h. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:2) to give a crystalline compound, which was recrystallized (ethyl acetate) to give the title compound (1.2 g, 47%).