Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([O:12][C:13]1[C:31]([F:32])=[CH:30][C:29]([N+:33]([O-])=O)=[CH:28][C:14]=1[CH2:15][N:16](C)[C:17](=O)OCC1C=CC=CC=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][CH2:9][C@@H:10]([O:12][C:13]1[C:14]([CH2:15][NH:16][CH3:17])=[CH:28][C:29]([NH2:33])=[CH:30][C:31]=1[F:32])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1c(F)cc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCc1cc(N)cc(F)c1O[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a degassed solution of 33B (573 mg, 1.131 mmol) in MeOH (10 mL), was added 10% Pd—C (50 mg, 0.047 mmol). The mixture was evacuated and flushed with H2 (3×), then was stirred under an atmosphere of H2 for 8 h. The mixture was filtered and concentrated to give 33C (382 mg, 1.115 mmol, 99% yield) as a pale brown oil. MS (ESI) m/z: 343.1 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 6.40 (1H, d, J=1.8 Hz) 6.33 (1H, dd, J=12.5, 2.8 Hz) 4.20 (1H, sxt, J=5.7 Hz) 3.62-3.79 (4H, m) 3.53 (2H, br. s.) 2.40 (3H, s) 1.25 (3H, d, J=6.3 Hz) 0.89 (9H, s) 0.05 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([C:15]2[NH:1][C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cccc2nc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2,3-diaminobenzoate (3.0 g) in methanol (60 mL) was added 1 N hydrochloric acid (0.6 mL) and benzaldehyde (1.7 mL), and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under a reduced pressure, to the solution of the obtained residue in dichloromethane was added silica gel. The solvent was evaporated under a reduced pressure, and the resulting residue was heated at 100° C. for 1 hour. By purifying the reaction mixture by a silica gel column chromatography (eluent:hexane/ethyl acetate), the title compound was obtained as crystal (1.8 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[C:35]4[CH2:40][CH2:39][CH2:38][CH2:37][N:36]4[C:41]=3[Cl:42])[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[C:35]4[CH2:40][CH2:39][CH2:38][CH2:37][N:36]4[C:41]=3[Cl:42])[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4n(c3Cl)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(C)cc(-c3nc4n(c3Cl)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 208 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(N)c1

Procedure:
A mixture of 7 g of 4-methoxy-2-nitrophenol, 50 ml of ethyl acetate and 1.3 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for 3.3 hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 2-amino-4-methoxyphenol. This is used in the following reaction without purification.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].C1CCN2C(=NCCC2)CC1>>[CH3:10][CH:8]([S:5]([NH:4][CH2:3][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:15][CH:16]=1)[CH3:1])(=[O:6])=[O:7])[CH3:9]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNS(=O)(=O)C(C)C)cc1
Yield: 72 %

Procedure:
Scheme Va, step C: {2-[4-(2-Aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.15 g, 0.53 mmol, prepared in example 12), isopropylsulfonyl chloride (0.1 mL, 0.58 mmol) and DBU (0.1 mL, 0.61 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the title compound, [(methylethyl)sulfonyl]{2-[4-(2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]propyl}amine, (0.149 g, 72%) as a white crystalline solid. Electron spray M.S. 391 (M*+H). Analysis for C17H30N2O4S2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][O:28][CH2:27][CH2:26][C:11]=3[N:12]([C:14](N[C@@H](C(C)(C)C)C(NC)=O)=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[N:35]=1>>[C:36]([C:34]1[N:35]=[C:31]([NH:30][C:14]([N:12]2[C:11]3[CH2:26][CH2:27][O:28][CH2:29][C:10]=3[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[N:13]2)=[O:15])[S:32][CH:33]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Reactant: CC(C)(C)c1csc(N)n1
Product: CC(C)(C)c1csc(NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)n1

Procedure:
Compound 56 was prepared according to the procedure described for the synthesis of compound 28 by replacing tert-leucine methylamide with 2-amino-4-tert-butylthiazole. LCMS (+ESI) m/z=419.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[N:10]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2Cc1cccc(OC)c1
Reaction time: 4 h

Procedure:
366.5.0 mg (0.929 mmol) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 15 mL DMF. Sequentially 192.6 mg (1.394 mmol) K2CO3 and 156.1 μl (1.394 mmol) 1-bromomethyl-3-methoxy-benzene were added and the resulting mixture was stirred for 4 h at 80°. The mixture was diluted with 300 mL toluene and washed with 50 mL of a saturated NaHCO3-solution. The product was not completely soluble in toluene, so ethyl acetate had to be added. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) (separation of isomers) to give 1-(3-Methoxy-benzyl)-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a light brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[OH:30][CH2:31][CH2:32][CH2:33][NH2:34]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:33][CH2:32][CH2:31][OH:30])=[O:20])=[O:5]
Reactant: NCCCO
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCCCO

Procedure:
The title compound was prepared from the product of Example 45A and commercially available 3-hydroxypropylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (s, 6H), 1.47 (s, 6H), 1.56-1.65 (m, 2H), 3.18-3.25 (m, 2H), 3.37-3.44 (m, 2H), 4.43 (t, J=4.8 Hz, 1H), 7.67-7.80 (m, 3H), 8.01 (t, J=5.3 Hz, 1H), 11.57 (br s, 1H). MS (ESI+) m/z 489 (M+H)+. Anal. calcd. for C22H24F4N2O4S: C, 54.09; H, 4.95; N, 5.73. Found: C, 53.87; H, 4.86; N, 5.64.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]1[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=2[F:21])[N:11]=[C:10]([CH3:22])[C:9]=1[C:23]#[N:24].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]1[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:21])[N:11]=[C:10]([CH3:22])[C:9]=1[C:23]#[N:24]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2-c2c(C)ccn2C)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Temperature: 25 °C
Yield: 53.7 %

Procedure:
5-(1,3-Dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (20 mg, 0.06 mmol) was dissolved in CH2Cl2 (3 mL) and BBr3 (1 M solution on DCM, 0.3 mL, 0.3 mmol) was added and stirred at room temperature over night. The reaction was quenched using water and extracted with CH2Cl2. Concentration and purification using preparative HPLC gave 5-(1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (10 mg, 53%). Also 5-(5-bromo-1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (7 mg) was isolated.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:15]>ClCCl>[NH:1]1[C:5]2=[N+:6]([O-:15])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide 507 is prepared by reacting 7-azaindole 1 with an oxidizing agent (e.g. m-chloro-peroxybenzoic acid) in an appropriate solvent (e.g. dichloromethane). After stirring at room temperature for 30 minutes to one hour, compound 507 is collected by filtration.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: COCC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O=[CH:2][CH2:3][N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8].[C:13]1([C@H:19]([NH:21][CH2:22]C(O)=O)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([C@H:19]([N:21]2[C@@H:2]3[C@@H:11]([CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:3]3)[CH2:12][CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](NCC(=O)O)c1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@H]2CCN([C@H](C)c3ccccc3)[C@H]2C1
Yield: 38.5 %

Procedure:
A mixture of ethyl N-(2-oxoethyl)-N-prop-2-enylcarbamate (Intermediate 41, 466 g, 2.7 mol) and 2-{[(1R)-1-phenylethyl]amino}acetic acid (Intermediate 43A, 490 g, 2.7 mol) in toluene (4 L) was refluxed overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. Purification by FCC, eluting with 10:1 petrol-EtOAc, gave the title compound (300 g, 38%) as red oil; 1H NMR: (CDCl3) 1.10-1.40 (8H, m), 1.55 (1H, m), 1.90 (1H, m), 2.45 (1H, m), 2.77 (1H, m), 3.20-3.65 (5H, m), 4.10-4.20 (2H, m), 7.25-7.38 (5H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C1CCN2C(=NCCC2)CC1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-cyanophenol (6.55 g, 55.0 mmol) in anhydrous acetonitrile (50 mL) at ~0° C. under argon was added DBU (9.04 mL, 60.45 mmol). After the solution had cooled to ~0° C., 3-chloro-3-methyl-1-butyne (5.13 g, 50 mmol) was added followed by cupric chloride dihydrate (9.62 mg, 0.056 mmol). After stirring at ~0° C. for 5 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (50 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (2×50 mL), 1N NaOH (2×50 mL), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a nearly colorless oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (7.25 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]2[CH:35]=[N:34][NH:33][C:30]2=[N:31][CH:32]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:30]4=[N:31][CH:32]=[C:27]([CH3:26])[CH:28]=[C:29]4[CH:35]=[N:34]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1cnc2[nH]ncc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (136 mg, 318 μmol), 5-methyl-1H-pyrazolo[3,4-b]pyridine (42.4 mg, 318 μmol) in dioxane (3.5 mL) was added sodium tert-butoxide (67.3 mg, 700 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.3 mg, 31.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-30% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.96 (dd, J=2.0, 1.0 Hz, 1H), 5.72 (s, 2H), 3.52-3.59 (m, 2H), 2.54 (s, 3H), 1.60 (s, 9H), 0.88-0.97 (m, 3H), −0.04 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:17]=[N:18][CH:19]=1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: Clc1cncc(Cl)n1
Product: COc1cc(CNc2cncc(Cl)n2)cc(OC)c1
Yield: 91 %

Procedure:
In a procedure analogous to Example 21, reaction of 3,5-dimethoxybenzylamine and 2,6-dichloropyrazine furnished the product (91%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.O>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:1]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=[CH:3]2)#[N:11]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cccc(C#N)c21
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 1H-indole-7-carbonitrile (2.0 g, 14.08 mmol, 1.0 equiv.) in dry DMF (10 ml) was added at 0° C. to a suspension of NaH (0.845 g, 21.12 mmol, 1.5 equiv. 60% in mineral oil) in DMF (10 ml), and the mixture was stirred for 30 min. Ethyl bromoacetate (1.9 ml, 16.9 mmol, 1.2 equiv.) was added at 0° C., and stirring was carried out for 1 h at RT. When the reaction was complete (TLC monitoring), the mixture was cooled and diluted with water (60 ml). Extraction with ethyl acetate (3×80 ml) was carried out, and the combined organic phases were washed with sat. NaCl solution (2×100 ml), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, 8-10% ethyl acetate/hexane) and the desired product was isolated in the form of a yellow solid. Yield: 80% (2.6 g, 11.37 mmol)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: N#Cc1csc(Br)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C#N)cs3)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared as described for Example 321 from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and 2-bromo-1,3-thiazole-4-carbonitrile (prepared as described in J. Am. Chem. Soc. 1952, 74, 5799).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([O:15][C@H:13]1[CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][CH2:11][C@@H:12]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Yield: 71.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107a by using the (1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (774 mg, 2.49 mmol) prepared in Example 160a, triethylamine (2.08 mL, 14.9 mmol), benzoyl chloride (1.45 mL, 12.6 mmol) and dichloromethane (8.0 mL), to yield the title compound (739 mg, 72%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K8) (172 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (176 mg).