Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>O>[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:41][CH:40]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N(C)C)cc4)cc23)CC1
Yield: 6.1 %

Procedure:
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.097 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (40 mg, 0.289 mmol) in water (1.2 mL). To this mixture was added [4-(dimethylamino)phenyl]boronic acid (65 mg, 0.386 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (1 mg, 0.002 mmol). The vial was capped and the reaction was reacted in a CEM microwave for 10 min at 160° C. The reaction was concentrated under a stream of nitrogen at 80° C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified through a 1 g silica SPE cartridge eluting with dimethyl sulfoxide (4 mL). The dimethyl sulfoxide was concentrated in a Genevac at 65° C. for 3 h, and the residue was reconstituted in dimethyl sulfoxide (1 mL) and filtered through an acrodisc. The solution of crude product was then purified on the Agilent MDAP (UV 214 selection). The purified product was passed through a polymer-bound carbonate SPE cartridge to afford 2.7 mg of the title compound (6.2%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=4)[C:23]3=[O:38])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>CC(O)=O>[Cl:1][C:12]1[C:13]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=4)[C:23]3=[O:38])[CH2:20][CH2:21]2)=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cn1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(Cl)nc4Cl)CC3)C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
N-Chlorosuccinimide (0.013 g, 0.098 mmol) was added to a suspension of (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(6-(methylsulfonyl)pyridin-3-ylamino)pyrrolidin-2-one (0.034 g, 0.075 mmol) in AcOH (0.3 mL). The mixture was stirred at ambient temperature for 1 hour and then at 50° C. for 1 hour. Acetic acid was removed with a stream of nitrogen. The residue was vigorously stirred in a mixture of 10% Na2S2O3 (1 mL) and EtOAc (1 mL) for 40 minutes. The mixture was partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). Solids which did not dissolve were collected by filtration of the suspension through a 0.45 μm nylon membrane to provide (S)-1-(1-(3,5-dichloropyrazin-2-yl)piperidin-4-yl)-3-(6-(methylsulfonyl)pyridin-3-ylamino)pyrrolidin-2-one (0.011 g, 0.023 mmol, 30%). Mass spectrum (apci) m/z=485.0 (M+H) 487.0. Optical purity of the product was not determined.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](SC)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C([C:37](OO)=[O:38])C=1.S(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([O:38][CH3:37])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Agent: C[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
131 mg (0.293 mmol) of 4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 101 mg (0.586 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of methanol and excessive amounts of 565 mg (2.93 mmol) of sodium methoxide (28% methanol solution) was added at room temperature and stirred at 60° C. for 6 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21](=[O:37])[NH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH:26]=[CH:27][CH:28]=1)=[O:5]>C(O)=O>[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21](=[O:37])[NH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=1)=[O:5]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(CC(=O)OC(C)(C)C)c2)s1
Solvent: O=CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(CC(=O)O)c2)s1
Reaction time: 24 h
Yield: 79.2 %

Procedure:
tert-Butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)ureido)phenylacetate (0.92 g) was dissolved in formic acid (20 ml), and the solution was allowed to stand at room temperature for one day. The reaction mixture was concentrated, and the obtained residue was recrystallized from ethyl acetate and isopropyl ether to give 0.66 g of 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)ureido)phenylacetic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[CH:7][N:8]=2)[N:3]=1.[NH2:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:29]=2[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][N:12]([C:6]3[CH:5]=[C:4]4[C:9]([CH:10]=[CH:11][C:2]([C:32]5[CH:33]=[CH:34][C:28]6[O:27][C:26]([NH2:25])=[N:30][C:29]=6[CH:31]=5)=[N:3]4)=[N:8][CH:7]=3)[CH2:13]2)[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(C2CN(c3cnc4ccc(Cl)nc4c3)C2)CC1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CCN(C2CN(c3cnc4ccc(-c5ccc6oc(N)nc6c5)nc4c3)C2)CC1
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine (C-10) (220 mg, 0.636 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (135 mg, 0.763 mmol, 1.2 eq), Pd(PPh3)4 (73 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (202 mg, 1.908 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (30 mL) and water (9 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1:5 MeOH-DCM) to afford the desired product 5-(7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2-yl)benzo[d]oxazol-2-amine (72) (120 mg, 42.5% yield). 1H NMR (300 MHz, DMSO-d6) δ: 8.35 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.87 (d, J=6.3 Hz, 1H), 7.48 (s, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 4.12 (m, 2H), 3.85 (m, 2H), 3.36 (m, 1H), 3.23 (m, 4H), 2.47 (m, 1H), 2.37 (m, 4H), 0.95 (d, J=6.9 Hz, 6H); ESI-MS m/z: 444.21 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[C@H:12]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.C1(C(N)C2CCCCC2)CCCCC1>CN1CCCC1=O>[C@H:12]1([NH:21][C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Fc1cnc(C(F)(F)F)nc1
Reactant: N[C@@H]1CCc2ccccc21
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ncc(N[C@@H]2CCc3ccccc32)cn1
Yield: 101.5 %

Procedure:
0.20 g (1.20 mmol) of 5-fluoro-2-(trifluoromethyl)pyrimidine, 0.225 g (1.69 mmol) of (1R)-2,3-dihydro-1H-inden-1-amine and 0.50 g (2.41 mmol) of dicyclohexylmethylamine in 1.5 ml of 1-methyl-2-pyrrolidone are heated in a closed cuvette in the microwave at 180° C. for 120 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives 0.34 g of N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2-(trifluoromethyl)pyrimidine-5-amine (melting point 123.7° C., yield 96% at a purity of 95%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:12]1.[CH:25]1[C:30]([O:31][C:32](Cl)=[O:33])=[CH:29][CH:28]=[C:27]([Cl:35])[CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:35][C:27]1[CH:28]=[CH:29][C:30]([O:31][C:32]([N:9]([CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]#[C:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:16]2)[CH3:8])=[O:33])=[CH:25][CH:26]=1
Reactant: CNC[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
A solution of 7.70 g (corresponds to 9.63 mmol) of crude trans-methanesulfonic acid 3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester trifluoro-acetate in 60 ml methylenechloride was treated at 0° C. with 1.61 ml (11.56 mmol) 4-chlorophenylchloroformate and then during 3 minutes with 8.25 ml (48.17 mmol; 5 equivalents) of Huenig's base. The reaction was stirred 45 hours at room temperature and extracted with aqueous 10% KHSO4/ether (3×). The organic phases were washed with aqueous 10% NaCl and dried over sodium sulfate to yield 5.3 g of crude trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester as dark brown oil, MS: 414 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:15](O)[CH2:16][CH2:17][CH3:18]>>[CH3:18][C:17]1[CH:16]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]2[N:4]=[CH:5][C:6]([C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:8])=[C:2]2[N:1]=1
Reactant: CCCCO
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Product: Cc1cc(-c2ccccc2)n2ncc(C(=O)c3ccccc3)c2n1

Procedure:
A mixture of 0.01 mole of 1-(3-phenyl)butan-1,3-dione and 0.01 mole of (3-amino-1H-pyrazol-4-yl)phenyl-methanone in 25 ml of n-butanol was refluxed for 8 hours. The solvent was removed and the product isolated as described in Example 1, giving the desired product as crystals, mp 165°-166° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C-:11]#[N:12].[K+].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6]([OH:9])([C:11]#[N:12])[CH2:5][CH2:4]1
Reactant: CN(C)N1CCC(=O)CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)N1CCC(O)(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A solution of 6.0 g 1-dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) in 30 ml of dichloromethane is added to a mixture of 4.1 g potassium cyanide and 10.6 g sodium hydrogencarbonate in 30 ml of water. The resulting mixture is stirred at room temperature for 3 hours, then extracted with ethyl acetate, the organic layer dried over sodium sulfate, and the solvent evaporated. 4.8 g 1-Dimethylamino-4-hydroxy-piperidine-4-carbonitrile is obtained. 1H-NMR (CDCl3): 3.95 ppm (s, broad, 1H), 2.90 ppm (m, 2H), 2.68 ppm (m, 2H), 2.40 ppm (s, 6H), 2.15 ppm (m, 2H), 1.95 ppm (m, 2H).
Reaction SMILES: C(OC([CH:8]1[S:20][C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.Cl.CN.[CH2:27]([N:29](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:29][C:21]([CH:9]1[CH:10]2[C:11]3([CH:19]=[CH:18][CH:17]=[CH:16][C:12]3=[N:13][CH2:14][CH2:15]2)[S:20][CH2:8]1)=[O:23]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C1SC23C=CC=CC2=NCCC3C1C(=O)O
Agent: CN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C1CSC23C=CC=CC2=NCCC13
Temperature: 50 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In 5 ml of dimethylformamide were dissolved 0.32 g of 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid, 0.08 g of methylamine.hydrochloride, and 0.17 ml of triethylamine, and after adding dropwise thereto 5 ml of a dimethylformamide solution of 0.33 g of diphenylphosphorylazide under ice-cooling and further adding dropwise thereto 2 ml of a dimethylformamide solution of 0.17 ml of triethylamine, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 50 ml of ethyl acetate and the mixture was washed thrice with 10 ml of an aqueous 5% citric acid solution, thrice with an aqueous 5% sodium hydrogencarbonate solution and then twice with a saturated sodium chloride solution, and thereafter dried with sodium sulfate. After filtering away sodium sulfate, 5 ml of a mixture of 1N hydrochloric acid in ethyl acetate were added to the filtrate and the mixture was heated to 50° C. for one hour. Then, the reaction mixture was allowed to stand overnight in a refrigerator and crystals thus deposited were collected by filtration to provide 0.23 g (yield of 65%) of N-methyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboamide. (See Table 11, Table 12).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.CI.[C:23](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:23])[CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CC1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1C

Procedure:
28.6 g 8-chloro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one in 100 ml dimethylformamide is stirred with 18 g methyl iodide and 14 g anhydrous potassium carbonate for 2 hours on a boiling water bath. The reaction mixture is poured into 500 ml water and extracted with ether several times. The ethereal extracts are washed with water and dried over sodium sulfate. Upon distilling off the solvent, the crystalline residue is recrystallized from acetic acid ethyl ester. The yield is 24.5 g having an m.p. = 113°-114° C (82% of the theory).
Reaction SMILES: Cl/[C:2](=[C:4]1\[C@H:5]2[C@@H:7]([CH2:8][C:9]\1=O)[C:6]2([CH3:12])[CH3:11])/[CH3:3].[C:13]([CH2:15][S:16]C(=O)C)#[N:14]>C1COCC1.[OH-].[Na+]>[CH3:11][C:6]1([CH3:12])[C@@H:7]2[CH2:8][C:9]3[C:4]([C@H:5]12)=[C:2]([CH3:3])[S:16][C:15]=3[C:13]#[N:14]
Reactant: CC(=O)SCC#N
Reactant: C/C(Cl)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C#N)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
A solution of (1S, 5R)-2-(1-chloro-(E)-ethylidene)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (997 mg, 5.40 mmol) and thioacetic acid S-cyanomethyl ester (746 mg, 6.48 mmol) in THF (37 mL) is treated with 2 N aq. NaOH (10.8 mL). The resulting mixture is stirred vigorously at rt for 2 h. Another portion of thioacetic acid S-cyanomethyl ester (100 mg, 0.87 mmol) and 2 N aq. NaOH (2 mL) is added and stirring is continued for 1 h. The reaction mixture is diluted with 2 N aq. NaOH and extracted twice with DCM. The organic extracts are dried over Na2SO4 and evaporated. The remaining brown oil is dissolved in THF (30 mL) and treated with 2 N aq. NaOH (3 mL). The mixture is heated to 90° C. for 4 h before it is diluted with 2 N aq. NaOH and extracted with DCM. The organic extracts are dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Phenomenex Aqua 30×75 mm, gradient 10 to 95% acetonitrile in water containing 0.5% formic acid) to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopro-pa[a]pentalene-4-carbonitrile (650 mg) as a brown oil; LC-MS: tR=1.06 min, [M+1+CH3CN]+=245.11; 1H NMR (CDCl3): δ 2.90 (dd, J=5.9, 18.8 Hz, 1H), 2.68 (d, J=18.8 Hz, 1H), 2.38 (s, 3H), 1.96-1.88 (m, 2H), 1.13 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([O:10][C:8]([C:4]1[NH:5][C:6]([CH3:7])=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([F:26])([F:25])[F:14])[C:3]=1[CH3:13])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(-c2ccccc2C(F)(F)F)c1C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (3.42 g, 20 mmol) in carbon tetrachloride (40 mL) was added a solution of bromine in carbon tetrachloride (10 mL) dropwise at 20° C. After the addition was complete, stirring was continued for 2 h. The reaction mixture was diluted with DCM, washed with aqueous NaHCO3 and water, and then dried over Na2SO4. Evaporation of solvent gave ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate as a solid (4.8 g), which was used in the next step without purification. 1H-NMR (CDCl3): δ 9.36 (1H, s), 4.30 (2H, q), 228 (3H, s), 2.26 (3H, s), 1.36 (3H, t). To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (2.4 g, 10 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium (2.3 g, 1 mmol). After stirring 15 min, the reaction mixture was charged with 2-(trifluoromethyl)-benzeneboronic acid (2.4 g, 12.5 mmol) and sodium carbonate (in 5 mL of water). The reaction mixture was heated to reflux overnight with stirring. After cooling, the reaction mixture was then diluted with water and extracted with DCM. The combined extracts were washed with water and dried over Na2SO4. Evaporation of solvent gave a crude material, which was purified by chromatography on silica gel column eluting with EtOAc-hexane (1:1) to give the title compound (1.5 g). MS (ES): 312 (MH+);
Reaction SMILES: Br[C:2]1[C:3]([NH:15][CH2:16][C:17]([C:31]([F:34])([F:33])[F:32])([OH:30])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[OH:29])([CH3:21])[CH3:20])=[C:4]2[C:9](=[C:10](Br)[CH:11]=1)[N:8]=[C:7]([NH:13][CH3:14])[CH:6]=[CH:5]2>[Pd]>[F:28][C:26]1[CH:25]=[CH:24][C:23]([OH:29])=[C:22]([C:19]([CH3:20])([CH3:21])[CH2:18][C:17]([C:31]([F:32])([F:33])[F:34])([OH:30])[CH2:16][NH:15][C:3]2[CH:2]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH3:14])=[N:8]3)[CH:27]=1
Reactant: CNc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)c(Br)cc(Br)c2n1
Agent: [Pd]
Product: CNc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Yield: 60.1 %

Procedure:
45 mg (0.07 mmol) of 1-(6,8-dibromo-2-(methylamino)quinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol and 50 mg of 10% Pd—C are stirred in 2 ml for 90 minutes under hydrogen atmosphere. The batch is filtered and concentrated by evaporation. Column chromatography on silica gel with ethyl acetate-MeOH yields 19 mg of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1(O)[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[CH2:9]1.S(=O)(=O)(O)O>C(O)C.[Pd]>[CH:12]1([CH:10]2[CH2:11][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])[CH2:9]2)[CH2:14][CH2:13]1
Reactant: Nc1ccccc1C1(O)CC(C2CC2)C1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1ccccc1C1CC(C2CC2)C1
Reaction time: 5.5 h

Procedure:
1.22 g (0.006 mol) 1-(2-aminophenyl)-3-cyclopropylcyclobutanol (prepared as described in Example 9) was dissolved in 40 ml of ethanol, 1.72 g sulphuric acid (96%) were added and after addition of 250 mg of 10% Pd on charcoal, the mixture was hydrogenated for 5.5 hours at room temperature. After removal of the catalyst, ethanol was distilled off in a water jet vacuum and the residue purified by flash chromatography over silica gel (eluent: hexane/ethyl acetate 5:1). Yield: 0.94 g (82% of theory) of a cis/trans mixture of 2-(3-cyclopropylcyclobutyl)phenylamine in the form of a yellow oil (MS: M+-peak of 187).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[CH:12]1[C:24]2[CH:23]([C:25](O)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:12]1[C:24]2[CH:23]([C:25]([CH:8]3[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]3=[O:7])=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C2c3ccccc3-c3ccccc32)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (2.5 g, 16.01 mmol), 9-fluorenylcarboxylic acid (5.05 g, 24.01 mmol), 4-dimethylaminopyridine (0.98 g, 8.00 mmol) in dry CH2Cl2 (15 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (3.30 g, 16.01 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (50 ml) and the combined solution was washed with 2 N HCl solution (5 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from recrystallised from MeOH giving 5-(9-fluorenyl-carbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 5 (2.85 g, 69%).