Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]2)[C:34]([F:45])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]4)[C:34]([F:45])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
A microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (2.13 g, 4.93 mmol) and (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone in DME (22.2 mL) and aqueous Na2CO3 (5.13 mL of 2 M solution, 10.26 mmol) solution. The mixture was deoxygenated with nitrogen for 20 min. To the reaction mixture was added tetrakis triphenylphosphane palladium (0.47 g, 0.41 mmol). The reaction was sealed and heated to 120° C. for 30 min. The reaction was diluted with ethyl acetate (40 mL), filtered through Celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification via silica gel chromatography using 10-80% EtOAc/hexanes gradient afforded (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 64a.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([F:34])[CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[C:24]([F:34])[CH:23]=1)[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 39.9 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (131 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)—N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (82.3 mg, 0.182 mmol, 39.9% yield) as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.08 (m, 3 H) 1.77-1.96 (m, 3 H) 2.04-2.18 (m, 1 H) 2.35-2.43 (m, 4 H) 2.93-3.07 (m, 4 H) 3.13-3.23 (m, 2 H) 3.28-3.38 (m, 3 H) 3.47-3.57 (m, 1 H) 3.88-3.95 (m, 1 H) 6.92 (d, J=2.02 Hz, 1 H) 6.97 (t, J=8.84 Hz, 1 H) 7.47-7.57 (m, 3 H) 8.28 (t, J=5.56 Hz, 1 H) 10.37 (s, 1 H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][N:12](CC(OC(C)(C)C)=O)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:33](NN)([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([N:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:14][CH:13]=[N:12]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)NN
Agent: Cl
Product: CC(C)(C)n1nccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the major isomer (80%). ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) δ 8.32 (d, 2H), 7.7 (d, 2H), 7.48 (d, 1H), 6.25 (d, 1H), 1.42 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][C:3]=1[CH3:16].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.O.[OH-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH2:19])=[O:9])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(C)(C)C(N)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propionic acid (500 mg) is dissolved in 10 mL of tetrahydrofurane, 1,1′-carbonyldimidazole (217 mg) and 30% ammonium hydroxide water solution are added and the reaction mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated under vacuum, ethyl acetate is added and the organic solution is washed with a 10% HCl water solution. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound. Yield: 300 mg.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:43]([C:45]1[CH:46]=[C:47]([N:51]=[C:52]=[O:53])[CH:48]=[CH:49][CH:50]=1)#[N:44].[N-]=C=O>CN(C=O)C>[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:52](=[O:53])[NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([C:43]#[N:44])[CH:46]=4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)N2CCCC2c2cccc(C(=O)Nc3ccc4c(c3)CN(C(=O)OCc3ccccc3)CC4)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
To a solution of 7-(3-pyrrolidin-2-yl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl (238 mg, 0.387 mmol) in DMF (5 mL) add Et3N (0.082 mL, 0.581 mmol) followed by 3-cyanophenyl isocyanate (69 mg, 0.464 mmol). Stir the solution at room temperature for 48 h. LCMS analysis indicates the presence of starting material. Add more isocyanate (69 mg, 0.464 mmol) and stir the reaction at room temperature 24 h more. Quench the reaction with sat. NH4Cl (100 mL) and extract with EtOAc (2×150 mL). Wash the organic layers with water (100 mL), dry (Na2SO4) and concentrate to an oil. Purify the crude product by silica gel chromatography eluting with 10% to 75% EtOAc/hexane to afford 186 mg 7-{3-[1-(3-cyanophenylcarbamoyl)-pyrrolidin-2-yl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a solid foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][CH2:8][C:7](=O)[CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[S:9][CH2:8][C:7]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:6]=3[C:5]=2[CH:4]=1
Reactant: CCCNCCC(=O)OC
Reactant: COc1ccc2c(c1)CC(=O)CS2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN1CCC(=O)C2=C1CSc1ccc(OC)cc12

Procedure:
The starting material is prepared as follows: A mixture of 7.5 g 6-methoxythiochroman-3-one [J. Org. Chem. 34, 1566 (1969)], 5.8 g of methyl 3-(propylamino)-propionate and 0.8 ml of trifluoroacetic acid in 80 ml of toluene is heated under reflux for 22 hours in a Dean Stark apparatus. Additional 0.8 ml portions of trifluoroacetic acid are added after 2, 5, and 16 hours. The solvent is removed, the residue is taken up in ether and the product is extracted with 3N hydrochlorid acid. After neutralization the aqueous layers are extracted with ethyl acetate, the organic layer is dried and the solvent is removed. The product is crystallized from a small volume of methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzothiopyrano[3,4-b]pyridin-1-one, m.p. 108°-110°.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH:10]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CNC
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H-chromene (4.4g., 0.012 moles) was dissolved in a solution of dimethylamine in ethanol (28ml., ~40% solution) and left to stand at room temperature for 48 hours. Removal of solvent gave the title product as an orange oil which was converted to the hydrochloride salt. Recrystallization from acetone gave a white solid (3.13g., 64%) m.p. 185-187° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[CH3:14][C:15]1[C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:18]([CH3:32])[O:17][N:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[C:19]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([N:7]([C:6]3[CH:12]=[CH:13][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[C:18]([CH3:32])[O:17][N:16]=1
Reactant: CCc1ccc(NCC(C)C)cc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cc1
Reaction time: 16 h
Yield: 83 %

Procedure:
To 4-ethyl-N-isobutylaniline (50 mg, 0.282 mmol) in pyridine (1 mL) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (94 mg, 0.310 mmol) and the reaction stood at room temperature, in air, for 16 hours. The crude was then purified by MDAP (Method F), to provide 103.6 mg of desired product. LCMS (M+1) 443, RT 1.39 mins.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]1[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:12]([C:9]1[S:8][C:7]([C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:11][CH:10]=1)(=[O:14])=[O:13]
Reactant: Cc1occc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccoc3C)s2)c1Br
Yield: 53.1 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-(2-methylfuranyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methyl isoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10% MeOH/CHCl3, gave 45 mg of the pure sulfonamide as a brown semisolid, 54% yield, m.p. 123-124° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>O1CCCC1>[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:11](=[O:13])[C:10]2[CH:14]=[C:6]([S:3]([N:2]([CH3:1])[CH3:17])(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=2[O:15][CH3:16])=[CH:38][CH:37]=1
Reactant: CN(C)CCOc1ccc(CN)cc1
Reactant: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)NCc1ccc(OCCN(C)C)cc1
Yield: 91.4 %

Procedure:
To a cooled suspension of 3.20 g of 5-dimethylaminosulfonyl-2-methoxybenzoic acid in 10 ml of tetrahydrofuran were successively added dropwise 1.25 g of triethylamine and 1.34 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes and then a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was dried and evaporated. The residue was washed with isopropyl ether to give 4.10 g of colorless crystals, which were recrystallized from a mixture of ethyl acetate and ether to give colorless needles, m.p. 99.5°-100.5° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>O>[C:9]([C:8]1[C:3]([CH2:2][Cl:14])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1cccnc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cccnc1CCl
Temperature: 25 °C

Procedure:
165.5 g (0.98 mol) of 2-hydroxymethyl-3-pyridinecarboxamide are heated together with 270 ml of phosphorus oxychloride to 90-100° C. for 1 hour. The reaction mixture is cooled to room temperature and subsequently added dropwise to approx. 800 ml of water at 50-60° C. After the phosphorus oxychloride has been hydrolyzed, the mixture is neutralized with sodium hydroxide solution with cooling, in the course of which the product precipitates out. It is filtered off, washed with 300 ml of water and subsequently dried at 35-40° C.
Reaction SMILES: O.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.N#N.[C:20]([C@@:25]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H:29]([CH2:30][OH:31])[C@@H:27](O)[CH2:26]1)(=O)[CH:21](C)C.C(Cl)(=O)C1C=CC=CC=1>>[C:30]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:2]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]2)[C:11](=[O:12])[N:13]=1)(=[O:31])[C:29]1[CH:21]=[CH:20][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CC(C)C(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: N#N
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Product: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1

Procedure:
This compound was prepared from 2'-deoxycytidine monohydrate by the same procedure used for the preparation of N2 -isobutyryl-2'-deoxyguanosine except that 9.0 mL (77.5 mmol, 5.17 equiv.) of benzoyl chloride was used instead of isobutyric anhydride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1)#[N:2].C(Cl)[Cl:13].CO.N>CO.Cl.[Pd]>[ClH:13].[ClH:13].[C:9]([C:6]1[N:7]=[CH:8][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1)(=[O:10])[NH2:11]
Reactant: N#Cc1ccc(C(N)=O)nc1
Reactant: ClCCl
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: CO
Product: NCc1ccc(C(N)=O)nc1
Reaction time: 5 h

Procedure:
67 g (0.46 mol) of 5-cyanopyridine-2-carboxamide (Chem. Ber. 117 (1984) 1259) were suspended in 1 l aqueous methanol (1/1) and 84.7 ml (1.9 equivs.) of conc. HCl, 21,4 g of 10% strength Pd/C were added and hydrogenation was carried out in a shaken vessel at room temperature for 5 h (H2 uptake: 23.2; l theory: 22.3 l). The product dissolved during the hydrogenation (and the catalyst changed from gray to black). TLC (CH2Cl2/MeOH 9/1, NH3-saturated) revealed only traces of starting material.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (22%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH3:20][CH:21]([CH3:49])[CH2:22][C:23]([C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)=[O:24]>>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:23]([C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=1)([OH:24])[CH2:22][CH:21]([CH3:49])[CH3:20])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)CC(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 77.9 %

Procedure:
6-Bromo-2-tert-butyldimethylsilyloxynaphthalene (33.7 g) and 3-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-butanone (31.5 g) were used as the starting materials. By the same procedure described in Reference example 1, the titled compound (40.6 g) was obtained as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>[Cu].O>[N:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1cc(Br)cs1
Agent: [Cu]
Solvent: O
Product: O=Cc1cc(-n2ccnc2)cs1
Temperature: 60 °C

Procedure:
In a three-necked-20-l-reaction bulb aquipped with a thermometer, a reflux cooler and a KPG-stirrer, 1.911 kg (10 mole) of 4-bromothiophen-2-aldehyde, 4.084 kg (60 mole) of imidazol of 99% purity and 0.065 kg (about 1 mole) of powderous copper metal are added to 10 l of water. The reaction mixture is stirred and boiled to reflux for 5 hours. After cooling the reaction mixture to 60° C., the reaction mixture is extracted several times with a total of 26 l of chloroform. The combined chloroform solutions are washed three times mit 15 l of water. The washed chloroform phase is mixed with 10 l of water and then brought to a pH of smaller than 1 by the addition of about 750 ml of 25% hydrochloric acid with vigorous stirring. The aqueous acidic phase is added with 30 l of chloroform at 40° C. Subsequently, about 600 g of NaHCO3 is added thereto slowly with vigorous stirring, until the aqueous phase reaches a pH larger than 7.5. In order to extract completely the precipitated product, the chloroform phase is separated and the aqueous phase is again extracted with 20 l of chloroform. The combined chloroform phases are evaporated to a final volume of about 4 l and is added to 9 l of petrol ether (b.p. 40° to 60° C.) with vigorous stirring. The resulting precipitate is filtered off with suction and is dried at 50° C.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 68 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-heptyl chloroformate. Yield: 68% of theory, C37H46N6O6 (670.8); Rf value: 0.56 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=671; (M+H+Na)++=347.4.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[C:8](Cl)=[C:9]2[CH:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[N:11][CH:12]=1>>[Br:6][C:7]1[C:8]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[C:9]2[CH:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[N:11][CH:12]=1
Reactant: CNCCO
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(Br)cnc21
Product: CN(CCO)c1c(Br)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 145 °C

Procedure:
2-(Methylamino)ethanol (1.5 ml) was added to 5-bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine obtained by the method described in WO 2008/150914 (700 mg), and the mixture was heated under reflux at 145° C. for 18 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (472 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34](O)=[C:33]([F:38])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([F:38])[CH:32]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-fluoro-4-hydroxy benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White foam (81%). MS (Turbo Spray): m/z=543.0 [M+H].