Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.I[CH2:8][CH2:9][OH:10].C(N(CC)CC)C>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:8][CH2:9][OH:10])=[N:2]1
Reactant: Sc1nc[nH]n1
Reactant: OCCI
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCCSc1nc[nH]n1
Yield: 34.7 %

Procedure:
A solution of 1H-1,2,4-triazole-3-thiol (14.7 g, 145 mmol), 2-iodoethanol (25.0 g, 145 mmol) and triethylamine (14.7 g, 145 mmol) in ethanol (400 mL) was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with water and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (10%-100% ethyl acetate/hexane) to give the title compound as a colorless oil (7.30 g, 35%).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[CH3:8][C:9]([CH3:18])([CH3:17])[C:10](=O)[CH2:11][C:12](OC)=[O:13].C[O-].[Na+].O>CO.C(O)(=O)C>[CH3:8][C:9]([C:10]1[N:7]=[CH:5][N:6]=[C:12]([OH:13])[CH:11]=1)([CH3:18])[CH3:17]
Reactant: N=CN
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Formamidine acetate (2.172 g, 20.86 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (3.0 g, 18.96 mmol) were added to a mixture of sodium methoxide (2.203 g, 40.8 mmol) in methanol (20 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. Water (5 mL) and acetic acid (2.2 mL) were added and the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting solid was triturated with ethyl acetate, filtered and washed with a small volume of ethyl acetate. The solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (1.66 g);
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH2:13][CH2:14][CH3:15])[CH:5]=1.[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8](=[NH:9])[O:18][CH2:16][CH3:17])=[C:6]([O:12][CH2:13][CH2:14][CH3:15])[CH:5]=1
Reactant: CCCOc1cc(OC)ccc1C#N
Reactant: CCO
Agent: Cl
Product: CCCOc1cc(OC)ccc1C(=N)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride gas was passed through a solution of 4-methoxy-2-propoxy-benzonitrile (280 mg, 1.464 mmol) in anhydrous ethanol (20 mL) at 0° C. After 1 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a stopper. After stirring at room temperature for 2 d, the reaction vessel was cooled to 0° C. and the stopper was removed. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford crude ethyl 4-methoxy-2-propoxy-benzimidate hydrochloride. It was dissolved in ethanol (10 mL), and meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (412 mg, 1.464 mmol) and triethylamine (308 μL, 2.194 mmol) were added. The reaction mixture was heated at reflux for 4 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 70% ethyl acetate in hexanes to afford 4,5-bis-(4-chloro-phenyl)-2-(4-methoxy-2-propoxy-phenyl)-4,5-dihydro-1H-imidazole (303 mg, 46%). HR-MS (ES, m/z) calculated for C25H25N2O2Cl2 [(M+H)+] 455.1288, observed 455.1293.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].C[Sn](C)(C)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)c1nccs1
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(-c2nccs2)cc(NC(C)=O)c1Cl
Yield: 29.6 %

Procedure:
A solution of methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (1.0 g, 4.05 mmol), 2-(trimethylstannyl)thiazole (2.9 g, 17.3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.6 mmol) in tetrahydrofuran (75 mL) was heated under reflux for four hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was dried (MgSO4) and concentrated. The crude product was purified by column chromatography (50% ethyl acetate in hexane) to give methyl 4-acetamido-3-chloro-6-(2-thiazolyl)pyridine-2-carboxylate (0.38 g, 1.2 mmol), mp 187-8° C.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.O1CCCC1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:21]>C(O)(=O)C>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)([OH:21])[CH2:19][CH3:18])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(C(F)(F)F)c1

Procedure:
To a Grignard reactant prepared from 1.46 g. of magnesium turnings and 13.5 g. of 3-trifluoromethyl-bromobenzene in 34 ml. of dry tetrahydrofurane a solution of 9.61 g. of 4-benzyloxy-propiophenone in 50 ml. of dry tetrahydrofurane is added dropwise, under moderate reflux. The reaction mixture is slightly boiled for a further hour. The progress of the reaction can be monitored by thin layer chromatography. After termination of the reaction the reaction mixture is cooled and poured onto a mixture of glacial acetic acid and ice. The solvent phase is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo. 15 g. of the named compound are obtained, which can be recrystallized from n-heptane. Melting point: 50°-51° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([CH:9]=1)[CH:7]=O.B(F)(F)F.CCOCC.C[Si](C)(C)[O:26][C:27]1[CH2:30][CH2:29][C:28]=1[O:31][Si](C)(C)C.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([CH:7]2[C:27](=[O:26])[CH2:30][CH2:29][C:28]2=[O:31])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1OC(F)(F)F
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(=O)C1c1cc(Br)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 5-bromo-2-trifluoromethoxybenzaldehyde (2.0 g, 7.43 mmol) in anhydrous dichloromethane (40 ml) at room temperature is added boron trifluoride etherate (1.13 ml, 8.92 mmol) then 1,2-bis(trimethylsiloxy)cyclobutene (2.86 ml, 11.2 mmol). The mixture is stirred at room temperature for 23 hours, followed by addition of distilled water (1.2 ml) and additional boron trifluoride etherate (14.1 ml, 112 mmol). After stirring for 24 hours at room temperature the reaction mixture is then quenched with saturated aqueous ammonium chloride solution (50 ml) and extracted with dichloromethane (2×50 ml). The crude product is extracted into 0.5 M aqueous potassium carbonate solution (×3), then the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid. Final extraction with dichloromethane (×3) is followed by washing with brine then drying over magnesium sulfate. Filtration then concentration in vacuo gives a crude product which is purified by preparative reverse phase HPLC to afford 2-(5-bromo-2-trifluoromethoxyphenyl)cyclopentane-1,3-dione.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][NH:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1.CCN(CC)CC>C(Cl)Cl>[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41]([N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:10]2[CH:29]=[CH:30][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)=[CH:8][CH:9]=2)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(Oc3ccc(F)cc3)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 3-((4-(4-fluorophenoxy)benzylamino)methyl)benzylcarbamate (0.72 g, 1.64 mmol) in CH2Cl2 (15 mL) added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (0.45 g, 1.72 mmol) and Et3N (0.68 ml, 4.91 mmol). The reaction mixture was stirred at 0° C. under nitrogen for 1.5 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and saturated NaHCO3 solution. The organic layer was washed successively with brine, 1 N HCl, brine, and concentrated after drying over MgSO4 to give viscous solid (0.99 g, 82%). 1H NMR (CDCl3): δ 9.10 (bs, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.40 (d, J=2.8 Hz, 1H), 7.28-7.17 (m, 1H), 7.14-6.90 (m, 9H), 6.85 (d, J=8.3 Hz, 2H), 4.36 (m, 4H), 4.23 (m, 2H), 1.46 (s, 9H); MS (ESI): (M+H)+=605.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C(OCC)(OCC)[O:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl.C(O)CO>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:14][CH2:15][CH2:16][O:3]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: ClCCl
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 m mol), ethylene glycol (5 ml, 89 m mol), triethyl orthoformate (2.96 g, 20 m mol), and p-toluenesulfonic acid (0.086 g, 0.5 m mol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., (lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[OH-:16].[Na+].O.Cl>O1CCOCC1>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([OH:16])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(O)nc(NCCC)n1
Temperature: 140 °C
Yield: 74.8 %

Procedure:
A vial was charged with 6-chloro-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (XXXIV) (800 mg, 3.48 mmol), NaOH (696 mg, 17.40 mmol), water (3 mL) and 1,4-dioxane (3 mL). The reaction mixture was heated at 140° C. for 30 min under microwave irradiation. The mixture was acidified with 1N HCl to pH 5, precipitate were filtered, washed with water. The product was dissolved in 50% trifluoroacetic acid (30 mL), the indissoluble residue was filtered off. The filtrate was neutralized with saturated NaHCO3 solution, the formed precipitate was filtered, washed with water, acetone and dried to give 550 mg (75%) of 4,6-bis(propylamino)-1,3,5-triazin-2-ol (CLXXVIII). 400 MHz 1H NMR (DMSO-d6+CF3COOD, ppm) 3.18-3.34 (4H, m), 1.45-1.59 (4H, m), 0.86 (6H, t). ESI-MS (m/z): 212 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:19](=[O:21])[CH3:20])[N:10]=2)[N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cn2nc(Cl)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazin-2-amine (18 g, 106.5 mmol) in DCM (180 mL) was added triethylamine (10.8 g, 106.5 mmol), DMAP (1.32 g, 1.06 mmol), and acetic anhydride (6 g, 106.5 mmol) sequentially at rt. The reaction mixture was stirred for 5 h at rt and the precipitate was filtered and washed with 50 mL of methanol to afford the title compound (15 g, 66%). 1H NMR (DMSO-d6, 300 MHz): δ 7.3 (d, 1H), 8.02 (d, 1H), 8.25 (s, 1H). LCMS (M+1) 211 (99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([O:14][CH:15]=[CH:16][C:17](Cl)=[O:18])[CH3:13]>C(OCC)C>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[NH:1][C:17](=[O:18])[CH:16]=[CH:15][O:14][CH2:12][CH3:13])=[O:6]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CCOC=CC(=O)Cl
Solvent: CCOCC
Product: CCOC=CC(=O)Nc1cccc(C(=O)OC)c1
Yield: 63.8 %

Procedure:
To a solution containing 29.5 g of methyl m-aminobenzoate in 300 ml of diethyl ether, 11.53 g of β-ethoxyacrylic acid chloride was added dropwise at 17°-27° C. under stirring condition. After the addition was finished, the reaction mixture was further stirred at a room temperature for 1 hour, then the crystals thus precipitated were collected by filtration. The crystals were washed with ether, and the crude crystals were dissolved in chloroform, then the chloroform solution was washed with 0.5N-hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The chloroform solution was dried and then chloroform was removed by distillation, and the residue thus obtained was purified by a silica gel column chromatography, then recrystallized from methanol to obtain 13.63 g of m-methoxycarbonyl-N-(β-ethoxyacryloyl)aniline in the form of colorless prism-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35](N(OC)C)=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:44].[Li+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35]([OH:36])=[O:44])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide (0.57 g, 0.089 mmol) in a mixture of methanol (1.0 mL) and tetrahydrofuran (THF) (3.0 mL) was added a solution of lithium hydroxide (0.075 g, 0.179 mmoL) in water (1.0 mL). The mixture was stirred at room temperature for 48 hours. Solvent was removed to dryness. Residue was dissolved into a mixture of dichloromethane (20 mL) and 1.0 N HCl (1.0 mL). Organic layer was separated, washed with water (5 mL×4), dried over sodium sulfate and concentrated to dryness. The residue was dried further under high vacuum at 45° C. for 24 hours to provide 0.45 g (85%) as a yellow solid. M.p.=190-195° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.16(bs, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78-7.83 (m, 1H), 7.77-7.74 (m, 2H), 7.68-7.65 (m, 2H), 7.58 (t, J=8.0 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.17 (d, J=6.8 Hz, 1H), 6.37 (d, J=5.2 Hz, 1H), 3.92 (br. s, 1H), 3.75-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.49-2.43 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H). LCMS: 596 [M+H].
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([O-])(C)[CH3:15].[K+].C1COCC1.C(Br)C=C>O>[CH2:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:2]=1[I:1])[CH:14]=[CH2:13]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: O
Product: C=CCNc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a mixture of 2-iodo-4-trifluoromethyl-aniline (5 g, 17.4 mmol), KOt-Bu (2.05 g, 18.3 mmol) and THF (200 mL) at −78° C., is added allyl bromide (2.21 g, 18.3 mmol). The resulting mixture is warmed to rt and stirred for 18 h. Water is added, and the mixture is extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-50% EtOAc in heptane to afford allyl-(2-iodo-4-trifluoromethyl-phenyl)-amine (1.9 g, 33%). MS 328 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.45 (d, 1 H), 5.88-6.02 (m, 1H), 5.33 (d, 1 H), 5.25 (d, 1H), 4.72(broad s, 1H), 3.90 (s, 2H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][N:17]([CH2:27][CH2:28][NH:29]C(=O)C3C=CC=CC=3)[C:16]=2[CH:38]=1.O.Cl>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][N:17]([CH2:27][CH2:28][NH:29][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:16]=2[CH:38]=1
Reactant: COc1ccc2c(c1)N(CCNC(=O)c1ccccc1)CC(c1ccccc1)O2
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)N(CCNC(=O)Nc1ccccc1)CC(c1ccccc1)O2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.011 mol of phenyl isocyanate are added to a suspension of 0.01 mol of the amine hydrochloride obtained in Example 24 (before acylation) in 5 cm3 of pyridine. After stirring for 1 hour at 80° C., the reaction mixture is poured into iced water and then acidified with 1N HCl. The precipitate formed is suction-filtered off, washed, dried, and then recystallised to yield the title product.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:4](=[O:3])[N:29]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:22][CH2:21]3)[CH2:7][CH2:8]2)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: Nc1cccnc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C1N(c2cccnc2)CCC12CCN(S(=O)(=O)c1ccccc1)CC2
Yield: 26.3 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (0.9 molar, 1.88 ml) and 3-amino-pyridine (0.069 g) to give the desired 8-benzenesulfonyl-2-pyridin-3-yl-2,8-diaza-spiro[4.5]decan-1-one (0.055 g) as a white solid. MS (ESI): 372.13 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: OC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 339 (M+H+, 45), 257 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)=[O:25])[CH:19]=2)=[CH:16][CH:17]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH2:12][C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)=[O:25])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: CN1CCCN(C(=O)c2cccc(-c3ccc(C=C4C(=O)Nc5ccc(Cl)cc54)o3)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCCN(C(=O)c2cccc(-c3ccc(CC4C(=O)Nc5ccc(Cl)cc54)o3)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one (24 mg) in methanol (4 ml) was added sodium borohydride (8 mg). The reaction was stirred at room temperature for 5 min. Water was added and the product was extracted with dichloromethane, dried with sodium sulfate and concentrated under vacuum to give 5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methyl)indolin-2-one as orange powder. LCMS (ES): >95% pure, m/z 464 [M+1]+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: Cc1nccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nccnc1NN
Temperature: 90 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Hydrazine hydrate (9.66 mL, 311.14 mmol) was added to 2-chloro-3-methylpyrazine (CAS no. 95-58-9) (8 g, 62.23 mmol) in ethanol (25 mL). The resulting solution was stirred at 90° C. for 16 hours. The resulting solution was evaporated to dryness and the crude product was purified by crystallisation from toluene (125 mL) to afford 2-hydrazinyl-3-methylpyrazine (6.2 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 2.24 (3H, s), 7.61 (1H, d), 7.61 (1H, d), 7.87 (1H, d).