Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=2[CH:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC[B-](F)(F)F
Reactant: O=Cc1cc2cc(Br)ccc2o1
Agent: [K+]
Product: CCCCc1ccc2oc(C=O)cc2c1
Yield: 89.5 %

Procedure:
The compound was synthesized as in Example 3.1, using 5-bromo-2-formylbenzofuran (500 mg, 2.22 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (546 mg, 3.33 mmol) in place of hexylboronic acid to give 5-butyl-2-formylbenzofuran (402 mg, 90%). Used without further characterization.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 2-chlorosulfonyl-5-(2-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyoxyphenyl)thiophene-2-sulfonamide in 32% yield, m.p. 114°-117° C.
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.C([Li])(CC)C.[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27]C=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].CI>C1COCC1>[C:14]([Si:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:4]([CH3:5])=[C:25]([F:29])[C:24]=1[F:30])([CH3:20])[CH3:19])([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)c(F)c1F
Reaction time: 0.33 h
Yield: 105.3 %

Procedure:
To a solution of TMEDA (3.9 mL, 3.0 g, 26 mmol) in THF (33 mL) at −78° C. was added sec butyllithium (20 mL, 1.3 M in hexane, 26 mmol). After stirring for 20 minutes, a solution of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane (6.0 g, 23 mmol) in 17 mL of THF was added dropwise. After stirring for 1 hour, the solution was added dropwise to a solution of methyl iodide (8 mL) in THF (40 mL) at −20° C. After stirring for 18 hours, the mixture was quenched with saturated aqueous NH4Cl, extracted 3× into ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, giving 6.6 g of tert-butyl-(2,3-difluoro-4-methyl-benzyloxy)-dimethyl-silane as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.07 (app. t, 1H, J=7.2 Hz), 6.89 (app. t, 1H, J=7.3 Hz), 4.74 (s, 2H), 2.26 (d, 3H, J=1.9 Hz), 0.87 (s, 9H), 0.07 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: COC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: COC1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 4-methoxypiperidine (27 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (16 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 1.59-1.75 (m, 2 H) 1.98-2.12 (m, 2 H) 3.31 (s, 3 H) 3.41-3.58 (m, 3 H) 3.97-4.15 (m, 2 H) 6.35 (d, J=2.27 Hz, 1 H) 7.40 (s, 1 H) 7.60 (m, J=8.34 Hz, 2 H) 7.99 (m, J=8.59 Hz, 2 H) 8.08 (d, J=2.27 Hz, 1 H) 10.88 (s, 1 H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[CH3:9][N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][C:17]([C:19]3[N:20]=[C:21]([CH:31]=O)[NH:22][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[CH:18][C:12]2=[N:11]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:1][N:2]([CH3:3])[CH2:31][C:21]1[NH:22][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)=[C:19]([C:17]2[CH:16]=[CH:15][C:13]3=[N:14][N:10]([CH3:9])[N:11]=[C:12]3[CH:18]=2)[N:20]=1
Reactant: CNC
Reactant: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3nn(C)nc3c2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(CN(C)C)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
2M solution of dimethylamine in tetrahydrofuran (189 μl, 0.378 mmol) was dissolved in 2 ml anhydrous methanol. Glacial acetic acid was added until approximately pH 4. 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde (20 mg, 0.063 mmol) was added and the reaction stirred at room temperature for 3 hours. Sodium cyanoborohydride (6 mg, 0.095 mmol) was added and the reaction stirred at room temperature overnight. 1M solution of sodium hydroxide in water was added until the reaction pH was 8 and the organic solvent was then removed by rotary evaporation. The residue was dissolved in water and extracted three times with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified on Biotage Flash 12S silica gel column using chloroform/methanol gradient system (95:5 to 80:20, respectively) as eluent to afford dimethyl-[4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-ylmethyl]-amine (6 mg, 28% yield). HPLC tR=3.29 min, LC-MS=348 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[N:12]([CH2:22][C:23]([O:25]CC)=[O:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cn1c(SCc2ccc3ccccc3n2)nc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCc3ccc4ccccc4n3)n(CC(=O)O)c2-c2ccc(OC)cc2)cc1

Procedure:
Starting substances: 423 mg (0.8 mmol) of Z26 from Example 125; 2 ml (4 mmol) of 2 N NaOH
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[N:4]=1.Cl.[Cl:20][C:21]1[CH:37]=[CH:36][C:24](/[CH:25]=[CH:26]/[S:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[ClH:20].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[S:27]([N:30]2[CH2:35][CH2:34][N:33]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([C:5]4[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=4)=[CH:18][CH:17]=3)[CH2:32][CH2:31]2)(=[O:28])=[O:29])=[CH:36][CH:37]=1
Reactant: Nc1cc(-c2ccc(C(=O)O)cc2)nc(N)n1
Reactant: O=S(=O)(/C=C/c1ccc(Cl)cc1)N1CCNCC1
Agent: Cl
Product: Nc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)/C=C/c4ccc(Cl)cc4)CC3)cc2)nc(N)n1

Procedure:
In the same manner as in Example A-21, a reaction was conducted using 4-(2,4-diamino-6-pyrimidyl)benzoic acid hydrochloride and 1-[(E)-4-chlorostyrylsulfonyl)piperazine hydrochloride obtained in Referential Example 31 as starting materials, whereby the title compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8](=[O:43])[C@@H:9]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.Br[C:45]1[CH:46]=[C:47]2[CH2:53][N:52]([CH3:54])[C:51](=[O:55])[C:48]2=[N:49][CH:50]=1>O.C(#N)C>[NH2:7][C:8](=[O:43])[C@@H:9]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:45]2[CH:46]=[C:47]3[CH2:53][N:52]([CH3:54])[C:51](=[O:55])[C:48]3=[N:49][CH:50]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: CN1Cc2cc(Br)cnc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cnc2C1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
Potassium carbonate (176 mg) in water (2 mL) was added to (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 329 mg), 3-bromo-6-methyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (Example 32, step (ii), 144 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (12 mL) at 20° C. under nitrogen. The resulting solution was stirred at 80° C. for 90 min. The reaction mixture was cooled and filtered and the filtrate diluted with ethyl acetate, and washed with water. The aqueous was then extracted with dichloromethane and the combined organics dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with methanol/ethyl:acetate (15:85 to 25:75). Pure fractions were evaporated to dryness to afford the sub-titled compound (278 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.[CH2:35]([NH:37][C:38](=[O:51])[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1)[CH3:36]>>[CH2:35]([NH:37][C:38](=[O:51])[C:39]1[CH:40]=[CH:41][C:42]([N:45]2[CH2:46][CH2:47][N:48]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:49][CH2:50]2)=[CH:43][CH:44]=1)[CH3:36]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 90 °C

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (800 mg, 3.43 mmol) was added (cyanomethyl)trimethylphosphonium iodide (1000 mg, 4.12 mmol) and DIEA (1797 μl, 10.29 mmol) and N-ethyl-4-(piperazin-1-yl)benzamide (800 mg, 3.43 mmol)). The vial was heated to 90° C. for 16 hours. The crude reaction was cooled to RT and filtered. The resulting solid were collected and suspended in EtOH (24 mL), heated to reflux, then cooled to RT and filtered. The resulting material was rinsed with EtOH to give a white solid.
Reaction SMILES: C[S-].[Li+].CCOCC.CCCCCC.[C:15]([C:19]1[CH:20]=[C:21]([C:26]([CH3:37])=[CH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([C:19]1[CH:20]=[C:21](/[C:26](/[CH3:37])=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=Cc1ccc(C(=O)O)cc1)c1ccc(O)c(C(C)(C)C)c1
Agent: C[S-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc(O)c(C(C)(C)C)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1.84 g of lithium methanethiolate are added to 2 g (5.67 mmol) of the E ester obtained in Example 33(b) in 40 ml of DMF. The reaction mixture is stirred under nitrogen at 120° C. for 4 h. After the same treatment as in Example 8, followed by a chromatography in the ether/hexane eluent (80/20), 1.69 g of a mixture of E and Z isomers of 4-[-2-(3-tert-butyl-4-hydroxyphenyl)propenyl]benzoic acid are isolated in the respective proportions (83:17). A recrystallization from the hexane/ether mixture gives 225 mg of the expected derivative which melts at 209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.I([O-])(=O)(=O)=[O:23].[Na+]>CC(C)=O.O.[Ru](=O)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH3:6])=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3)c3cc(Cl)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 23.4 %

Procedure:
A stirred suspension of 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline (2.94 g., 0.01 mole) in acetone (110 ml.) is cooled in an ice-bath and treated slowly with a solution prepared by adding sodium periodate (2 g.) to a stirred suspension of ruthenium dioxide (200 mg.) in water (35 ml.). The mixture becomes dark. Additional sodium periodate (8 g.) is added during the next 15 minutes. The ice bath is removed and the mixture is stirred for 45 minutes. Additional sodium periodate (4 g.) is added and the mixture is stirred at ambient temperature for 18 hours and filtered. The solid is washed with acetone and the combined filtrate is concentrated in vacuo. The residue is suspended in water and extracted with methylene chloride. The extract is dried over anhydrous potassium carbonate and concentrated. The residue is chromatographed on silica gel (100 g.) with 10% methanol 90% ethyl acetate; 50 ml. fractions are collected. The product is eluted in fractions 10-20 and is crystallized from ethyl acetate to give: 0.405 g. of melting point 168°-169.5° C. and 0.291 g. of melting point 167.5°-169° (23.4% yield) of 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone. The analytical sample has a melting point of 168° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:31]([C:32](=[O:35])[NH:33][CH3:34])=[C:30]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[O:29][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22]CC)=[O:21])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:31]([C:32](=[O:35])[NH:33][CH3:34])=[C:30]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[O:29][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([OH:22])=[O:21])[S:11]([CH3:14])(=[O:12])=[O:13])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(CCCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(C(=O)O)S(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C

Procedure:
To ethyl 6-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-(methylsulfonyl)hexanoate was added 1 mL 50% NaOH and 3 mL EtOH. Stirred at RT ON Removed organic solvent on vac. Added 10 mL EtOAc. Added 20 mL conc. NH4OH and 5 mL 1N HCl and extracted with EtOAc. Washed with brine. Dried over Na2SO4, and conc. on vac. To give 6-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-(methylsulfonyl)hexanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:36])[C:16](=[O:35])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:24][C:25](=[O:34])[C:26]4[C:31]([CH:32]=3)=[C:30]([CH3:33])[CH:29]=[CH:28][CH:27]=4)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:36][N:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:16](=[O:35])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:24][C:25](=[O:34])[C:26]3[C:31]([CH:32]=2)=[C:30]([CH3:33])[CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCNCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
To 4-({methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.35 mmol) in CH2Cl2 (5 mL) was added 4M HCl/dioxane (2 mL) and the reaction mixture stirred at RT for 4 h. The solvent was removed in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-piperidin-4-ylmethyl-benzamide as a pale orange solid (44 mg, 33%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].[CH3:11][NH:12][NH2:13].Cl>CCO>[NH2:8][C:7]1[N:12]([CH3:11])[N:13]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CC(C)(C#N)C(=O)CC#N
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(C)(C)C#N)cc1N
Yield: 24.9 %

Procedure:
A solution of 2,2-dimethyl-3-oxo-pentanedinitrile (9 g, 66 mmol) and methyl-hydrazine (3 g, 66 mmol) in EtOH (100 mL) was treated with cone HCl (16.5 mL, 198 mmol) and the resulting mixture was refluxed overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 2-(5-amino-1-methyl-1 H-pyrazol-3-yl)-2-methylpropanenitrile (2.7 g, 25% yield), 1H NMR (300 MHz, CDCl3): δ 5.56 (s, 1 H), 3.63 (s, 3 H), 1.67 (s, 6 H); MS (ESI) m/z: 165.2 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]([O:15][CH2:16][CH2:17]O)[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.O>N1C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]([O:15][CH2:16][CH2:17][Cl:3])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1
Reactant: N#CC(OCCO)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#CC(OCCCl)c1cccc(Br)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.23 mL) was added dropwise to a solution of (3-bromophenyl)-(2-hydroxyethoxy)acetonitrile (3.62 g) in pyridine (12.1 mL) at 50° C., and the mixture was stirred at 60° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (elution solvent:heptane:ethyl acetate=9:1→8:2) to obtain 3.21 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+].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>[C:40]1([C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Reactant: OB(O)c1ccccc1
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: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(-c5ccccc5)c4)c3)ncnc21
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80° C. in oil bath for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][N:19]=1>>[CH2:24]([C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1)[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: CCc1ccnc(N)c1
Product: CCc1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 27 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-4-ethylpyridine instead of 2-amino-3-methylpyridine, to the title compound (33 mg, 27%) which was obtained as a yellow oil. MS: m/e=304.0 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH:9]1C(O)=O)([O:3][C:4](C)(C)[CH3:5])=[O:2].Cl.C(OC(=O)[C@H](CS)N)C.C(N(CC)CC)C.BrC(Br)C>C1COCC1>[CH2:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1)=[O:2])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Agent: CC(Br)Br
Agent: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCSCC1
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Boc-thiomorpholine-3-carboxylic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF was added cysteine ethyl ester hydrochloride (1.15 g, 6.18 mmol), triethylamine (4.17 mL, 30 mmol) and dibromoethane (2.51 mL, 6.2 mmol). After stirring for 1 hour and refluxing for 16 hours, the solids were removed by filtration. The solvent was removed in vacuo and the residue was chromatographed on silica to give thiomorpholinecarboxylic acid ethyl ester (0.94 g, 87%). The ester (15.3 g, 95 mmol) was dissolved in dioxane/water (1/1) and di-t-butyldicarbonate (24 g, 110 mmol) and LiOH were added. After stirring for 3 hours, the solvent was removed in vacuo and the pH was adjusted to 3 with KHSO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to give 17.4 g (78%) 4-Boc-thiomorpholine-3-carboxylic acid: 1H NMR (CDCl3) δ 1.45 (m, 9), 2.45 (m, 1), 2.71 (m, 1). 2.93 (m, 1), 3.10 (m. 1), 3.29 (m, 1), 4.11 (m, 1), 4.19 (m, 1), 5.20 (m, 1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[Cu][C:12]#[N:13]>CN(C)C=O>[NH2:8][C:6]1[N:7]=[C:2]([C:12]#[N:13])[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1
Reactant: COc1cc(N)nc(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc(N)nc(C#N)c1
Temperature: 220 °C
Yield: 29.3 %

Procedure:
To a solution of 0.40 g 6-bromo-4-methoxy-pyridin-2-ylamine in 8.0 ml dimethylformamide was added 0.265 g copper(I) cyanide and the mixture was heated to 220° C. under microwave irradiation for 6 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and washed with water and brine, dried over magnesium sulfate dihydrate and purified by chromatography on silica gel with heptane : ethyl acetate to yield 0.086 g of the title compound as greenish solid MS (ISP) M+H+=183.1