Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30](C)C(=O)C.C([O-])(O)=O.[Na+]>O.[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:29]([C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1)#[N:30]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CC(=O)N(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C#N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 135 °C

Procedure:
To 20 mL microwave vial containing a mixture of 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.25 g, 0.564 mmol), zinc cyanide (0.066 g, 0.564 mmol), zinc (7.37 mg, 0.113 mmol), and dppf (0.063 g, 0.113 mmol) was added N,N-Dimethylacetamide (DMA) (5.0 mL). The suspension was stirred with degassing under nitrogen for 5 min. Next added PdCl2(dppf)-CH2Cl2 adduct (0.046 g, 0.056 mmol). The reaction contents were sealed and stirred with heating at 135° C. (heat block) for 16 h. The reaction mixture was allowed to cool to RT, diluted with 80 mL of water, and adjusted to pH˜8 with sat NaHCO3. The contents were stirred for 30 min, filtered, and the filter cake was washed with water. The collected solid was dried under hi vacuum for 4 h. The crude product was dissolved in DCM/MeOH followed by addition of silica gel, and concentrated in vacuo to dryness. The contents were purified by silica gel chromatography (dry loaded; eluent: 2-65% gradient of 10% methanol in dichloromethane and dichloromethane). The product was concentrated from MTBE and dried in hi-vac oven for 6 h at 45° C. to afford the title compound as 0.190 g (85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.75 (m, 2H) 1.83-1.93 (m, 2H) 1.94-2.06 (m, 2H) 2.10-2.19 (m, 5H) 2.21 (s, 3H) 4.35 (d, J=4.80 Hz, 2H) 5.31 (t, J=7.07 Hz, 1H) 5.89 (s, 1H) 7.91 (d, J=1.26 Hz, 1H) 8.51 (s, 1H) 8.60 (s, 1H) 8.66 (t, J=4.93 Hz, 1H) 11.54 (s, 1H); LC-MS (ES) m/z=390.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]([NH:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[S:8])=[O:5].[C:16](=O)([O-])[O-].[Na+].[Na+].IC>O1CCCC1>[CH3:16][S:8]/[C:7](=[N:6]\[C:4](=[O:5])[CH:3]=[C:2]([CH3:15])[CH3:1])/[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=CC(=O)NC(=S)N1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CS/C(=N\C(=O)C=C(C)C)N1CCCCC1
Reaction time: 60 h
Yield: 150.5 %

Procedure:
A mixture of 3-methyl-N-(piperidine-1-carbonothioyl)but-2-enamide (3.21 g, 14.2 mmol, Eq: 1.00), sodium carbonate (1.58 g, 14.9 mmol, Eq: 1.05) and iodomethane (10.1 g, 4.43 ml, 70.9 mmol, Eq: 5) in tetrahydrofuran (100 ml) was stirred for 2.5 days under reflux. The mixture was evaporated, 30 ml of ethyl acetate was added and the mixture was filtrated, the filtrate was evaporated affording 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-piperidin-1-yl-meth-(Z)-ylideneamide (5.137 g, 151%) as an orange-brown semi-solid. MS: m/z=241.2 (M+H+)
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C1C(=O)N(C)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC(C)C1C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac)-3-isopropyl-1-methyl-1,3-dihydro-indol-2-one (4.5 g) (J. Chem. Soc. Chem. Commun. 1986, 115-116) in concentrated sulfuric acid (7 ml) is added drop-wise a mixture of nitric acid (65%, 1.7 ml) and concentrated sulfuric acid (2.8 ml) at 0° C. over a period of 30 min. The reaction mixture is stirred at this temperature for 30 min and then poured into ice-water. The precipitate is collected by filtration and washed with water to give the title compound (3.4 g).
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13]C(=O)OC(C)(C)C)[CH2:7]1)[CH2:4][F:5].Cl>O1CCOCC1>[F:5][CH2:4][CH:3]([N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1)[CH2:2][F:1]
Reactant: CC(C)(C)OC(=O)NCC1CN(C(CF)CF)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: NCC1CN(C(CF)CF)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 252A (538 mg) in dioxane (4 mL) was treated with 4.0M HCl in dioxane solution (1.8 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[CH:10]2.[CH3:17][C:18](N(C)C)=[O:19]>>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:18](=[O:19])[CH3:17]
Reactant: Cn1ccc2cc(F)ccc21
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cn(C)c2ccc(F)cc12
Reaction time: 0.17 h

Procedure:
Phosphoryl chloride (1.1 ml) was added dropwise to ice-cooled dimethylacetamide (10 ml) and the resulting solution was stirred at ca.0° for 10 min. A solution of 5-fluoro-1-methyl-1H-indole (1.3 g) in dimethylacetamide (5 ml) was added, and the resulting solution was stirred at 100° for 2 h, then cooled, and partitioned between sodium carbonate (2N; 100 ml) and ethyl acetate (2×50 ml). The combined organic extracts were washed with water (50 ml), dried and evaporated in vacuo to give a solid which was purified by FCC eluting with hexane:ethyl acetate (1:1) to give the title compound (0.48 g), m.p. 158°-160°.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10](O)=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH2:41]([OH:52])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].[ClH:53].O1CCOCC1>>[ClH:53].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:52][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:38])([F:40])[F:39]
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Reactant: CCCCCCCCCCCO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCCOC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
704 mg (1.24 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 1.30 mL (6.26 mmol) of 1-undecyl alcohol were mixed, 12.4 mL (49.6 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 45° C. for 4 hours.
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[C:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1)=[O:4].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.N1C=CC=CC=1>>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][S:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([Cl:19])([Cl:18])[Cl:1])[CH2:13]2)(=[O:16])=[O:15]
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(Cl)(Cl)Cl
Temperature: 60 °C
Yield: 71.4 %

Procedure:
2-(2,2,2-Trichloro-acetyl)-2,3-dihydro-1H-isoindole-5-sulfonyl chloride (0.25 g, 0.7 mmol), was added to a stirring solution of 2-aminothiazole (0.07 g, 0.7 mmol) and pyridine (57 μl, 0.7 mmol) and heated to 60° C. for 1 h. The reaction mixture was then partitioned between CH2Cl2 and aqueous 1N HCl solution. The organic layer was concentrated in vacuo and purified via silica gel chromatography (3% MeOH in CH2Cl2) to give the sulfonamide as a tan solid (200 mg, 0.5 mmol, 67% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=426.0; tR=2.88 min.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][O:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:41]3[CH2:42][CH2:43][CH:38]([CH2:37][O:36][CH3:35])[CH2:39][CH2:40]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COCC1CCNCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COCC1CCN(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)CC1

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-methoxymethyl-piperidine trifluoroacetate and N-ethyldiisopropylamine in chloroform. [α]D20=+23.0° (c=1.04, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2Cl)cc1-c1c(Br)cnn1C
Yield: 69.1 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 2,4-dichlorophenyl isocyanate (0.021 g, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 3 (0.036 g, 0.076 mmol, 69%) as a white solid. LCMS m/z (%)=469 (M+H79Br35Cl35Cl35, 60), 471 (M+H79Br35Cl37Cl&81Br35Cl35Cl, 100), 473 (M+H81Br35Cl37Cl79Br37Cl37Cl, 54), 475 (M+H81Br37Cl37Cl, 4). 1H NMR (400 MHz, acetone-d6) δ: 8.81 (s, 1H), 8.36 (d, J=9.0 Hz, 1H), 7.91 (s, 1H), 7.69 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.4, 9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10]C(=O)[C:8]2=[O:13].[OH:16]O.Cl>[OH-].[Na+].O>[F:14][C:2]([F:1])([F:15])[C:3]1[C:11]([NH2:10])=[C:7]([CH:6]=[CH:5][CH:4]=1)[C:8]([OH:13])=[O:16]
Reactant: OO
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
7-Trifluoromethylisatin (10 g, 46 mmol) was dissolved in 5% sodium hydroxide solution (83 ml). To this was added dropwise over 30 minutes a solution of 50% hydrogen peroxide (7.4 ml) in water (4.6 ml); the temperature rose to 50°. The solution was stirred an additional 30 minutes, acidified (conc. HCl) to pH 1-2, and the tan product was filtered.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C:10]1[N:11]=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:13][C:14]=1[CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][OH:19]>N1C=CC=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:19][CH2:18][CH2:17][CH2:16][CH:15]([C:14]1[S:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:11][C:10]=1[CH3:9])[OH:20])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.2 %

Procedure:
tert-Butyl-dimethylsilyl chloride (115 mg, 0.76 mmol) was added in one portion to a stirred solution of [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butane-1,4-diol (212 mg, 0.64 mmol) in pyridine (2 ml) at 0° C. The solution was naturally warmed to ambient temperature and stirred for 14 h. Pyridine was removed under reduced pressure and the residue dissolved in ethyl acetate. The solution was washed with 1 M aqueous HCl solution and two times with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, n-heptane/ethyl acetate) to give 120 mg (0.27 mmol, 42%) of the title compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C(N(CC)C(C)C)(C)C>>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: NCC1CCCCO1
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1ccc(NCC2CCCCO2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (step C of Example 2), 2-aminomethyltetrahydropyran (Sciences Chimiques 1972, 3, 685-688) and N,N-diisopropylethylamine.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[C:22]([CH3:24])=[CH2:23].C(#N)C>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH2:24][CH:22]=[CH2:23])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: C=C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication 88/08424, 2.78 g), 2-bromopropene (1.87 g), anhydrous potassium carbonate (3.3 g) and acetonitrile (100 ml) is refluxed for 36 hr. The mixture is cooled and then diluted with dichloromethane and aqueous potassium carbonate solution. The phases are separated and the organic phase is washed with saline and than concentrated in vacuo. Purification by flash column chromatography (2% methanol/chloroform) provided of the title compound. Capillary GC analysis (HP1 column, initial temperature at 100° for 1 min, then programmed to rise 20° per minute to 250°) gave a peak at 6.06 (96%) minutes.
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][N:4]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:4]2[CH:5]=[N:6][C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)=[N:3]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Cl)n2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 2-(3-chloro-[1,2,4]triazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.65) (0.17 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.032 g, 16%). MS (ISP) 398.1 [(M+H)+]; mp 244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35]>CC(N(C)C)=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCc2ccccc2O)cc(OC)c1
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(CCc2ccccc2OCCC2CCCN2C)cc(OC)c1
Yield: 80.4 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3,5-dimethoxyphenyl)ethyl]phenol (prepared as described in Preparation 27), 1.30 g of potassium t-butoxide and 1.06 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.15 g (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14](=[O:17])(=[O:16])[NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([Cl:28])[CH:23]=[CH:24][C:25]=1[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([N:15]2[CH:19]=[C:20]3[C:25]([CH:24]=[CH:23][C:22]([Cl:28])=[CH:21]3)=[CH:26]2)(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=S(=O)(N1CCN(Cc2ccccc2)CC1)n1cc2ccc(Cl)cc2c1

Procedure:
In ethanol (5 ml), 1-benzyl-4-sulfamoylpiperazine (251 mg) was dissolved. To the resulting solution, 3,4-bis(bromomethyl)-1-chlorobenzene (293 mg) and potassium carbonate (204 mg) were added, followed by heating under reflux for 3.5 hours. After cooling, the precipitate was filtered off. The filtrate was then distilled under reduced pressure and the residue was purified by chromatography on a silica gel column (dichloromethane˜ethanol:dichloromethane=1:100), whereby the title compound (222 mg, 58%) was obtained.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[C:13]([Br:14])=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])(=O)[CH3:2].C(O)COCCO.O.NN.[OH-].[K+]>O>[CH2:1]([C:4]1[S:5][C:6]2[C:13]([Br:14])=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[CH3:2]
Reactant: CC(=O)c1sc2c(Br)cccc2c1C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCc1sc2c(Br)cccc2c1C
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
8.6 g (32 mmol) of 2-acetyl-3-methyl-7-bromobenzothiophene and 175 ml of diethylene glycol are placed in a 500 ml three-necked flask equipped with a distillation system. The mixture is stirred at 30° C. for 5 minutes and 4.2 ml (56 mmol) of hydrazine monohydrate are added dropwise. The mixture is heated at 40° C. for 5 minutes and 4.3 g (76.6 mmol) of powdered potassium hydroxide are added. The temperature is brought to 110° C. for 40 minutes and then to a 160° C. for 100 minutes, in order to allow the water present in the reaction mixture to be distilled off. The mixture, once cooled, is then poured onto crushed ice and extraction is carried out with ethyl acetate (3×200 ml). The organic phases are combined, washed with 200 ml of a saturated sodium bicarbonate solution and 2×200 ml of water, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solvent: cyclohexane). 7.62 g (Yield: 84%) of 2-ethyl-3-methyl-7-bromobenzothiophene are obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#N)C=C>>[CH2:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:2]=[CH:1]1
Reactant: C=Cc1ccccc1
Reactant: C=CC#N
Product: C1=Cc2ccccc2C1

Procedure:
A terpolymer of a weight ratio of 70:25:5 styrene:acrylonitrile:indene was prepared by emulsion polymerization using the following ingredients:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:16][C@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[O:9])[C@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2ccnn2)c(C(=O)O)c1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-n2ccnn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 5-methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 459, [M+1]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([OH:26])[CH2:28]1)=[O:13])[CH2:8]2
Reactant: OC1CCCNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCCC(O)C1

Procedure:
5-(3-Hydroxy-piperidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-hydroxypiperidine. Mass spectrum (ES) MH+=421.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][C:12]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]indole-1-carboxylate (100 mg, 0.1696 mmol) and piperazine (146.1 mg, 1.696 mmol) in DMF (2 mL) was heated at 100° C. for 30 minutes and then allowed to cool to ambient temperature. The reaction was diluted with EtOAc/water and the organic layer washed further with water (2×), dried (MgSO4) and concentrated in vacuo. The material was used crude in the next step (quantitative yield assumed). MS (ES+) 595.09