Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccccc3[N+](=O)[O-])ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4[N+](=O)[O-])cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.18 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (60 mg, 0.54 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 50 mg (80%) of the title compound as a white solid. mp 130°-131°. FDMS: m/e=350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12](C3CCC=C3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[N+]1([O-])CC[O:31][CH2:30]C1.I([O-])(=O)(=O)=O.[Na+].[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>[Os](=O)(=O)(=O)=O.O.CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C:11](=[O:26])[N:12]([CH:42]([CH2:41][CH2:45][CH:30]=[O:31])[CH:43]=[O:44])[C@@H:13]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C1C=CCC1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=CCCC(C=O)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 454 mg (1.175 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperidin-2-one (Example 104, Step A) in THF (6 mL) was added water dropwise (3.5 mL) and tBuOH (0.2 mL). 4-methylmorpholine 4-oxide (207 mg, 1.763 mmol) was added followed by 4% aq. osmium(VIII) oxide (37.3 μL, 5.88 μmol). The reaction mixture was stirred at room temperature for 18 h. Sodium periodate (704 mg, 3.29 mmol) was added and the cloudy reaction mixture was stirred at room temperature for 90 min. Water (4 mL) was added and the mixture was filtered and washed with EtOAc. The filtrate was diluted with EtOAc and the layers were separated. The combined organic layers were washed with sat. Na2S2O3, sat. aq. NaCl solution, dried over Na2SO4 and concentrated in vacuo to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([F:25])[CH:24]=1>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: Nc1ccc2[nH]nc(N)c2c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Yield: 32.4 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide can be obtained as described in Example 39 from 2.1 g of 3,5-diamino-1H-indazole, 20 ml of pyridine, 20 ml of tetrahydrofuran and 1.47 g of 3,5-difluorobenzenesulfonyl chloride. 0.727 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide is thus obtained in the form of a white solid melting at 232° C. (analysis C13H10F2N4O2S % calculated C, 48.15; H, 3.11; F, 11.72; N, 17.28; O, 9.87; S, 9.89. % found C, 47.95; H, 3.14; F, 11.79; N, 17.06; S, 9.52).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)C=CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1C(=O)C=CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2-Maleimido)ethylcarbamic acid tert-butyl ester (48 mg, 0.2 mmol) was dissolved in a mixed solvent of trifluoroacetic acid and dichloromethane (30:70, 5 ml), followed by stirring at 0° C. for 2 hours, and then the reaction solution was concentrated. The thus obtained residue was dissolved in dichloromethane (20 ml), and a saturated aqueous sodium hydrogencarbonate solution (10 ml) was added thereto to separate the layers. The organic layer was dried over potassium hydrogencarbonate and filtered. The solvent was evaporated under reduced pressure to give 1-(2-aminoethyl)-3-pyrroline-2,5-dione (28 mg, 0.2 mmol, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.F[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:34][N:33]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH:42]=[CH:41][N:40]=[N:39]4)=[CH:34][N:33]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Fc1ccc(-n2ccnn2)cn1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4ccnn4)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (30 mg, 0.11 mmol) from Example 2 step 3 was dissolved in NMP (0.21 mL), DBU (24.4 mg, 0.16 mmol) was added, stirred at room temperature for 10 minutes. 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (21 mg, 0.13 mmol; from step 2 of this example) was added. Reaction was heated to 110° C. for 3 hours. The reaction was cooled down to room temperature, water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with Brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 30% ethylacetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH3:15].ClC1C=C(C=CC=1)C(OO)=[O:21].[OH-:27].[Na+]>CO.O.C(OCC)(=O)C>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH3:15])(=[O:21])=[O:27]
Reactant: [OH-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1NCC1=NCCN1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccccc1NCC1=NCCN1
Reaction time: 0.33 h

Procedure:
N-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2-(methylthio)aniline (16.8 g, 76 mmol) was stirred in methanol (250 mL) and cooled in an ice bath. A solution of m-chloroperoxybenzoic acid (37 g of ˜70 wt %) in methanol (200 mL) was added dropwise over 1 hour while the temperature of the mixture was maintained below 28° C. After 20 minutes, additional m-chloroperoxybenzoic acid (2.0 g) was added and stirring continued for 20 minutes. The reaction mixture was reduced in vacuo to a slurry (˜40 mL volume), diluted with water (250 mL) and ethyl acetate (250 mL), and treated with 10N sodium hydroxide (15 mL). The ethyl acetate phase and five additional ethyl acetate extracts (100 mL each) were combined and washed with 0.1N NaOH (50 mL). Additional 10N sodium hydroxide (10 mL) was added to the aqueous phase and two ethyl acetate extracts (100 mL each) were collected and washed with 0.1N NaOH (10 mL) and all of the ethyl acetate phases combined. Drying (MgSO4) followed by evaporation gave N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(methylsulfonyl)aniline (12.3 g, 48.5 mmol), which was dissolved in ethyl acetate (450 mL). Fumaric acid (5.6 g, 48.5 mmol) was dissolved in methanol (80 mL) and the ethyl acetate solution of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(methylsulfonyl)aniline was added to the rapidly stirred methanolic solution of fumaric acid. The mixture was stored at 4° C. for 16 hours and the resulting crystals were collected and dried in vacuo to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(methylsulfonyl)aniline as the fumaric acid salt (12.8 g, 45%).
Reaction SMILES: [SiH4].[NH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11].[CH2:16]([Cl:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Cu]>[ClH:23].[CH2:16]([N:5]([CH2:4][CH2:3][NH2:2])[CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:10][CH3:11])[O:12][CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO[Si](CCCNCCN)(OC)OC
Reactant: ClCc1ccccc1
Agent: [Cu]
Agent: [SiH4]
Product: CO[Si](CCCN(CCN)Cc1ccccc1)(OC)OC
Product: Cl

Procedure:
Example 1 was repeated except that the copper foil was pretreated with a silane solution prepared as follows. 8.8 g. of N-2-amino-ethyl-3-aminopropyltrimethoxysilane (a product of Petrarch Systems, Inc.) and 5.0 g. of benzyl chloride were charged in a reaction vessel to produce 3-(N-Benzyl-2-aminoethylamino)-propyltrimethoxysilane hydrochloride. A 1% solution of this silane in methanol was prepared, the copper foil dipped therein for 30 minutes followed by air drying and a 5-minute bake at 105° C. The copper foil was laminated to similar prepregs (2-ply, 6.12 g, 59.8% polymer uptake) as described in Example 1 and cured at 180° to 220° C. for 30 minutes under psi pressure. A 2-ply 3"×6" laminate was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH2:14]C)[CH2:6][C:5]1([CH2:18]C)[CH2:16]C.C[O:21][C:22](=O)[CH:23]=[CH2:24].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C(=O)([O-])[O-].[Zn+2].CO>[C:22]([O:1][CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:18])(=[O:21])[CH:23]=[CH2:24]
Reactant: C=CC(=O)OC
Reactant: CCC1CC(CC)(CC)N(CCO)C2CCCCC12
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CO
Product: C=CC(=O)OCCN1C2CCCCC2C(C)CC1(C)C
Temperature: 87 °C
Reaction time: 96 h

Procedure:
Following the method described in U.S. Pat. No. 3,872,161, the title compound was prepared by reacting 1 mole of 1-(2-hydroxyethyl)-2,2,4-triethyldecahydroquinoline (hereinafter referred to as HETDQ) with 3 moles methylacrylate in the presence of 0.8 gram phenothiazine and 13 grams zinc carbonate. The above mixture was heated to 87° C. in a 1 liter 3-necked flask equipped with a fractionating column. The pot temperature was gradually increased to a maximum of 164° C. while methanol and other lower boiling point liquid fractions were collected. The reaction took four days.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@@H:9]3[CH2:10][CH2:11][C@H:12]1[CH2:21][OH:22].C(O)(=O)C(O)=O>CO.O1CCCC1.O>[OH:22][CH2:21][C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH2:19][CH2:20][C:3](=[O:2])[CH2:4][C:5]=1[CH2:6][CH2:7]3
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@H](CO)CC[C@H]32)C1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@H]1CC[C@H]2CO)CC(=O)CC4
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
A solution of (14β,17α)-3-methoxyestra-2,5(10)-diene-17-methanol (Example 1, step iii; 0.30 g) in a mixture of methanol (3 ml) and tetrahydrofuran (2.1 ml) was treated with a solution of oxalic acid (0.105 g) in water (1.8 ml). After 1.5 h stirring at room temperature, the reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (14β,17α)-17-(hydroxymethyl)estr-5(10)-en-3-one (0.20 g), 1H NMR δ 3.77 (m, 1H), 3.52 (t, 1H, J=9.0 Hz), 2.74 (m, 2H), 1.09 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:18])[CH:13]2[O:14][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15](=[O:17])N)[CH:10]=2)[O:5]1.N1C=CC=C[C:20]1=[O:25].O[C:27]1C=CNC(=O)C=1.N1CCCC1=O.C1(=O)CCC(=O)C1>>[CH3:1][O:2][CH2:3][C:4]1([CH3:18])[C:13]2([CH3:27])[O:14][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]([O:25][CH3:20])=[O:17])[CH:10]=2)[O:5]1
Reactant: COCC1(C)Oc2ccc(C(N)=O)cc2C2OC21
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=c1cccc[nH]1
Agent: O=C1CCC(=O)C1
Agent: O=C1CCCN1
Product: COCC1(C)Oc2ccc(C(=O)OC)cc2C2OC21C

Procedure:
2-methoxymethyl-2-methyl-3,4-epoxy-6-carbamoylchroman and, from these epoxides with lH-2-pyridone, 4-hydroxy-1H-2-pyridone, 3-hydroxy-1,6-dihydro-3-pyridazinone (=3,6-pyridazindiol), 1-methyl-3-hydroxy-1,6-dihydro-3-pyridazinone, 2-pyrrolidinone or 1,3-cyclopentandione:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].O.O.Cl[Sn]Cl.CO.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(N)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl2.2H2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3 h at ambient temperature. To the mixture was added H2O (100 mL) and EtOAc (100 mL) resulting in the formation of a thick emulsion. To this was added sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×30 mL). The organics were combined and dried over MgSO4 before being filtered. Concentration of the filtrate in vacuo gave 2.02 g of an off-white solid. This material was used without further purification.
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH3:15])[CH:6]=1)(=O)C.[OH-].[Na+].CCOC(C)=O>O.CO>[CH3:15][C:7]1[CH:6]=[C:5]([OH:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CC(=O)Oc1cc(C)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1cc(O)c2c(c1)CCCC2
Yield: 93.7 %

Procedure:
A solution of 5,6,7,8-tetrahydro-3-methyl-1-naphthyl acetate (11.00 g) and NaOH (6.50 g) in a mixture of water (50 ml) and MeOH (150 ml) was refluxed for 5 hours. MeOH was removed under reduced pressure to give a residue. AcOEt was added to the residue and c-HCl was added dropwise under ice-cooling. The organic phase was washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 5,6,7,8-tetrahydro-3-methyl-1-naphthol as a solid (8.19 g).
Reaction SMILES: [NH:1]1[CH2:13][CH2:12][CH2:11][CH:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[F-].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:1]1[CH2:13][CH2:12][CH2:11][CH:3]([C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])[CH2:2]1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)C1CCCNC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCCN(c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of Example 437C (10.4 g, 56.1 mmol) in toluene (112 mL) was added 2-fluoronitrobenzene (6.0 mL, 56 mmol) and CsF (852 mg, 5.6. mmol). The reaction mixture was stirred under reflux conditions for 18 h, and allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with 10% HCl (2×50 mL), followed by brine (3×100 mL), then dried (Na2SO4) and evaporated in vacuo to obtain the title compound (16.5 g, 94%). MS (ESI) m/e 307 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([F:26])=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C(O)(=O)C>C(O)C>[NH2:17][C:10]1[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:7]([F:26])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(F)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(F)nc(-c2ccccc2)c(N)c1C(=O)OCC

Procedure:
In 5 ml of ethanol was dissolved 160 mg of 3,4-diethoxycarbonyl-2-fluoro-5-nitro-6-phenylpyridine, and 120 mg (5 eq.) of reduced iron was added to the solution, followed by addition of 0.5 ml (20 eq.) of acetic acid. After the mixture was refluxed for 30 minutes, the solvent was distilled off. The residue was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. After the precipitate was removed by filtration, the obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Then, the solvent was distilled off.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.O.Cl.[NH2:15][C@@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8]2([S:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[NH:15]2)[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC(=O)CC1
Reactant: N[C@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CC=C1CCC2(CC1)N[C@@H](C(=O)O)CS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
In a mixture of 3.5 ml of ethanol and 1.5 ml of water are dissolved 1.0 g of 4-(3-methylbutylidene)-1-cyclohexanone, 1.1 g of D-cysteine hydrochloride monohydrate and 0.52 g of sodium acetate. The resulting solution is stirred at ambient temperature for 2 hours. Water is added to the reaction mixture and the deposited crystal is collected by filtration. Thus, 0.81 g of (3S)-8-(3-methylbutylidene)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid is obtained as a colorless crystalline product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)[CH3:18]
Reactant: CC(C)(C)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCN(c2ccc(C(C)(C)C)cc2)CC1
Yield: 84.8 %

Procedure:
A mixture of 1-(4-tert-butyl-phenyl)-piperazine (1.09 mg; 5.0 mmol), 4-bromo-butyric acid ethyl ester (975 mg; 5.0 mmol), potassium carbonate (691 mg; 5.0 mmol) and potassium iodide (914 mg; 5.5 mmol) in acetonitrile (15 mL) is heated to reflux for 2 hours. The reaction mixture is allowed to attain room temperature and all solids removed by filtration. The filtration residue is washed with acetonitrile and the filtrate concentrated under high vacuum to afford the desired compound (1.41 g; 4.24 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN(C)CCCN
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCN(C)C)sc2Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.33 ml; 2.41 mmol; 5 eq) and N,N-dimethyl-1,3-propanediamine (0.3 ml; 2.41 mmol; 5 eq) are added successively and the reaction mixture is stirred at 0° C. for 1 hour. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (200 mg; 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=O)=[CH:4][N:3]=1.O.[NH2:20][NH2:21].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:20][N:21]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: CSc1nccc(C(=O)c2cnc(Cl)nc2Cl)n1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Temperature: 50 °C

Procedure:
To a solution of (2,4-dichloro-pyrimidin-5-yl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (9.52 g, 31.6 mmol) in THF (100 mL) was added hydrazine hydrate (2.3 g, 46 mmol) and DIPEA (5.9 g, 45.7 mmol). The mixture was heated at 50° C. for 4 hours, then concentrated to dryness. The resulting precipitate was collected by filtration and washed with water to give 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine as a yellow solid. (Yield 7.8 g, 88%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.[CH3:17][N:18]=[C:19]=[O:20].CCN(CC)CC.O>C1COCC1>[CH3:17][NH:18][C:19]([N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:16][N:15]=2)[CH2:10][CH2:11][CH2:12]1)=[O:20]
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
A solution of 6-pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (40 mg, 0.19 mmol) in 2 mL of THF is added to methyl isocyanate (16 mg, 0.28 mmol) followed by the addition of Et3N (61 mg, 0.60 mmol). The mixture is stirred at ambient temperature for 16 hrs. To the mixture is added 0.5 mL of water, stirred for 5 minutes and concentrated in vacuo. The residue is dissolved in 1 mL of DMF, filtered and purified by reverse phase HPLC to give 23 mg of the titled product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[C:8]=2[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.CN[CH:26]([NH:29][CH3:30])[CH2:27][CH3:28].[CH2:31]([N:33](CC)CC)C>>[Cl:23][C:7]1[C:8]([NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:33]([CH3:31])[CH2:28][CH2:27][CH2:26][NH:29][CH3:30])[CH:11]=[CH:10]2
Reactant: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(CC)CC
Reactant: CCC(NC)NC
Product: CNCCCN(C)c1ccc2c(NC(=O)CCC3CCCCC3)c(Cl)ccc2n1

Procedure:
Prepared according to the method of example 90(b), using N-(2,6-dichloro-5-quinolinyl)-cyclohexanepropanamide (Example 90(a)) (0.16 g), N,N′-dimethylpropanediamine (0.3 mL) and triethylamine (0.1 mL). Purification (SiO2, methanol:dichloromethane:triethylamine 5:95:0.5 followed by HPLC, Symmetry—0.1% aqueous trifluoroacetic acid:acetonitrile) gave the title compound as a solid (70 mg).