Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[S:25](Cl)([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([N:20]=[C:8]([NH:9][C:10]1[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=1)[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:28]2[C:40]3[C:32](=[C:33]([N:34]([CH3:36])[CH3:35])[CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:24][CH:23]=1)#[N:22]
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(CNC(=NC#N)Nc4ccncc4)cc3)cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (400 mg, 1.50 mmol) and dansyl chloride (405 mg, 1.50 mmol) were combined in pyridine (15 mL). An exothermic reaction occurred and the suspension became homogeneous. This solution was shaken at room temperature for 12 hours. The reaction mixture was then diluted with ethyl acetate (80 mL) and washed with water (40 mL×3). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a solid product which was purified by HPLC (yield=60%). 1H NMR (DMSO-d6, ppm): 10.73 (s, 1H), 9.09 (bs, 1H), 8.57 (d, 2H), 8.44 (d, 2H), 8.36 (d, 1H), 8.21 (d, 1H), 7.61 (m, 3H), 7.50 (s, 2H), 7.27 (d, 1H), 7.17 (d, 2H), 7.03 (d, 2H), 4.38 (d, 2H).
Reaction SMILES: C(OC([NH:8][N:9]([CH2:23][CH:24]([OH:41])[CH:25]([NH:33]C(OC(C)(C)C)=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:42]>O1CCOCC1>[ClH:42].[ClH:42].[ClH:42].[NH2:33][CH:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:24]([OH:41])[CH2:23][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[NH2:8]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccc(-c2ccccn2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NC(Cc1ccccc1)C(O)CN(N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
The Boc-aza-isostere (7) (1.2 g, 2.1 mmol) was taken up in 1,4-dioxane (16 mL), and stirred at room temperature, under nitrogen. After five minutes, 4N HCl (12 mL) was added via syringe. There was immediate precipitate formation, and the mixture was stirred at room temperature, under nitrogen. After approximately 18 hours, the dioxane was removed under reduced pressure. The yellow residue was azeotroped with toluene (3×25 mL), and then dried under high vacuum. After 6 hours under high vacuum, 0.92 g (91%) of (8) was obtained as a yellow solid. 1H NMR (CD3OD) δ 8.87 (d, 1H), 8.69 (m, 1H), 8.42 (d, 1H), 8.06 (m, 3H), 7.80 (d, 2H), 7.28 (m, 6H), 4.25 (m, 3H), 3.13 (m, 2H), 2.88 (d, 2H); MS (M)+=472.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][N:16]4[C:23]=3[N:24]=2)=[O:9])[N:4]=[C:3]1[C:25]([O:27]CC)=[O:26].[OH-].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][N:16]4[C:23]=3[N:24]=2)=[O:9])[N:4]=[C:3]1[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)c1nc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)nc1C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a suspension of ethyl 1-methyl-4-{[(6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepin-2-yl)carbonyl]amino}-1H-imidazole-2-carboxylate (Example 28, 160 mg, 0.40 mmol) in methanol (3 mL) is added 2M aqueous NaOH (0.4 mL). The mixture is stirred at 60° C. for 3 h and is then cooled to room temperature. The methanol is removed in vacuo and the aqueous mixture is acidified to pH 5 with 1N aqueous HCl. The resulting solid is collected by filtration and dried in vacuo to afford the title compound as a yellow solid (130 mg, 87%). LCMS: 369.20 (M+H+). (System V)
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:16][CH:15]=2)[CH2:11][C:12]1=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2
Product: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O

Procedure:
Prepared from 5-hexanoyl-2-indolinone and acetic anhydride
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([NH:58][CH3:59])=[CH:54][CH:53]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1>ClCCl>[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N:58]([CH3:59])[C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])=[CH:56][CH:57]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
A mixture of 2,4-dimethyl-thiazole-5-carboxylic acid (18.1 mg, 0.11 mmol) in dichloromethane (3.0 mL) at 25° C. was treated with triphenylphosphine (33 mg, 0.13 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (19.9 mg, 0.15 mmol). This mixture was stirred at 0° C. for 20 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with N-chlorosuccinimide (5.0 mg, 0.04 mmol) and 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with dichloromethane (100 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 5:95 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with chloroform (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with chloroform (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 2,4-dimethyl-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (30.2 mg, 45.8%) as a white solid: EI-HRMS m/e calcd for C30H29N6O3FS (M+H)+ 573.2079, found 573.2083.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)=[C:6]1[CH3:25])[CH2:2][CH2:3][CH3:4].[CH2:26]([N:28]([CH2:40][CH3:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:30]=1)[CH3:27]>>[CH2:36]([N:35]([CH2:38][CH3:39])[C:31]1[CH:30]=[C:29]([N:28]([CH2:26][CH3:27])[CH2:40][CH3:41])[CH:34]=[CH:33][C:32]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:20])[O:19]1)[CH3:37]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Product: CCCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
In a manner similar to that described in part B above, 3.35 g (0.01 mole) of 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-benzoic acid and 2.42 g (0.011 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted to obtain 3-[2,4-bis(diethylamino) phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)phthalide (Formula III: R°=R1 =R2 =R3 =Y1 =H; R=CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; R6 =(CH2)3CH3), as tan-colored crystals which melted at 78°-80° C. A toluene solution of the product spotted on silica gel developed an intense blue-black-colored image.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([C:7]([F:10])([F:8])[F:9])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)c(C(F)(F)F)nn1C
Yield: 54.5 %

Procedure:
3-(4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.11 mmol) was treated with 4-chlorophenyl isocyanate (0.02 g, 0.13 mmol, 1.2 equiv.) in CH2Cl2 (4.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 41 (0.03 g, 0.06 mmol, 56% yield) as a white solid: LCMS m/z (%)=459 (M+H35Cl, 100), 461 (M+H35Cl37Cl, 84), 463 (M+H37Cl, 10). 1H NMR (400 MHz, MeOH-d4) δ: 7.59 (dd, J=8.0, 4.0 Hz, 1H), 7.41 (dd, J=8.0, 8.0 Hz, 2H), 7.40 (dd, J=8.0, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.17 (d, J=12.0 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: CS(O[CH:6]([CH3:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH:6]([CH3:16])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:18]=[N-:19]
Reactant: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 85 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN3 (7.7 g, 118.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were washed with saturated NaHCO3 (2×200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. 1HNMR (CDCl3): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH2), 2.9 (m, 1H, CH2), 1.49 (s, 9H, CH3 1.2 (d, 3H, CH3).
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClC(Cl)C(Cl)Cl.CCOCC>[CH3:8][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([CH:4]=1)[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)C(Cl)Cl
Product: Cc1cccc(C(=O)CCC(=O)O)c1
Temperature: 60 °C

Procedure:
This compound was prepared by the method of Raval et al., J. Univ. Bombary, 7, Pt. 3, 184 (1983); CA 33, 3779 (1989). p-Cresol (4.0 g, 37 mmol) and succinic anhydride (3.4 g, 34 mmol) were combined in 1,1,2,2-tetrachloroethane (40 mL) and the mixture was heated to 60° C. Aluminum chloride (9.5 g, 71 mmol) was then added to the solution at a rate of 2 g/20 min. Once this was complete the reaction was heated to 135° C. for 30 min. After cooling, water and ether (30 mL of each) were added and the aqueous layer was extracted with 3×20 mL of ether. The combined organic fractions were dried and the remaining residue was purified by flash silica chromatography to yield 2.2 g (28.5%). 1H NMR δ 7.62 (s, 1H), 7.30 (d, 1H), 6.85 (d, 1 H), 3.32 (t, 2H), 2.35 (t, 2H), 2.22 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[C:13]([CH2:15][OH:16])[N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:32]([O:16][CH2:15][C:13]1[N:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[NH:11][C:12]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(CO)c(Sc2cccc(Cl)c2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)[nH]c1Sc1cccc(Cl)c1
Yield: 78.3 %

Procedure:
To a solution of 700 mg (1.8 mmol) of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methanol (46) in methylene chloride (14 ml), was added 1.29 g (12.8 mmol) of triethylamine, and then, 1.00 g (12.8 mmol) of acetyl chloride was added dropwise under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 15 minutes, and added to a cooled saturated aqueous sodium hydrogen carbonate solution to neutralize and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of methanol, to which was added 5 ml of 50% aqueous acetic acid, and the mixture was stirred at room temperature for1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2) to give 602 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methyl acetate as oil (yield 78%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:27][OH:28])=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1>>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:30][O:1][C:2]2[C:3]([CH2:27][OH:28])=[C:4]([CH2:9][NH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)=[O:12])[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:32][CH:33]=1)#[N:38]
Reactant: Cc1ncc(CNC(=O)c2ccc(-c3ccc(C#N)cc3)cc2)c(CO)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc(CNC(=O)c2ccc(-c3ccc(C#N)cc3)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 75.5 %

Procedure:
The coupling of 4′-cyano-biphenyl-4-carboxylic acid (5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (64) (650 mg, 1.7 mmol) and α-bromo-p-tolunitrile (375 mg, 1.9 mmol), as described in Example 3, gave 4′-cyano-biphenyl-4-carboxylic acid (5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amide (65) (627 mg, 74% yield).
Reaction SMILES: [Br-].[K+].BrBr.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH3:16].C(=O)(O)[O-:18].[Na+]>O.[Pd].C(O)(C)(C)C>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:18])[N:11]2[CH3:16]
Reactant: COc1cccc2c1ccn2C
Reactant: O=C([O-])O
Agent: [Pd]
Agent: BrBr
Agent: [Br-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cccc2c1CC(=O)N2C
Reaction time: 0.5 h

Procedure:
To a solution of potassium bromide (3986 mg, 33.5 mmol) in water (26.5 ml) was added bromine (0.863 ml, 16.75 mmol). A separate flask containing 4-methoxy-1-methyl-1H-indole (900 mg, 5.58 mmol) was charged with t-butanol (20.00 ml) and water (20.0 ml). To this flask was added 22.5 mL of bromine solution dropwise. The mixture was permitted to stir for approximately 30 minutes and then was neutralized with saturated aqueous sodium bicarbonate and quenched with saturated aqueous sodium thiosulfate. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in 50 mL EtOH and 5 mL of AcOH. The solution was then charged with 10% palladium on carbon (1.2 g, 1.13 mmol). The atmosphere over the reaction mixture was evacuated and the reaction was placed under an atmosphere of hydrogen gas via a balloon. The reaction was stirred for 18 hours. The reaction mixture was then filtered through a plug of Celite® and the filtrate was then concentrated to approximately 25% of its original volume. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 4-methoxy-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 178.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH2:22])[C:10]=12.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.O>[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[C:10]=12
Reactant: O=C(O)c1cccnc1
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cccnc1
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
Triethylamine (“TEA”; 0.50 mL, 3.61 mmol) was added to 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.17 g, 0.72 mmol), nicotinic acid (0.18 g, 1.44 mmol) and BOP-Cl (0.37 g, 1.44 mmol) in DCM (10 mL). The mixture was stirred for 30 minutes, and water was added (10 mL). The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (80 mg, 0.2 mmol, 32% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([C:21](=[O:23])[CH3:22])[CH:29]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(C)=O)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 11 mg, 10%; LC/MS tr 1.46 min; MS(ES+) m/z 378 (M+H)
Reaction SMILES: CC(C)C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C(C)C)[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29]C=O)[N:25]=[C:26]([O:27]C)[C:21]=3[C:20]([Cl:32])=[C:19]2[Cl:33])[CH2:7]1)=O>[OH-].[Na+]>[NH2:29][C:24]1[NH:25][C:26](=[O:27])[C:21]2[C:20]([Cl:32])=[C:19]([Cl:33])[N:18]([C@@H:8]3[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]3)[C:22]=2[N:23]=1
Reactant: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(c(Cl)c(Cl)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 95.5 %

Procedure:
A suspension of compound (49) (200 mg, 0.4 mmol) in 2N aq. NaOH (8 ml) is boiled under reflux for 3 h. After the solution has been neutralized with conc. ACOH, the reaction product is filtered, washed with water and dried. Colorless crystals (128 mg, 96%) are obtained after crystallizing from CH3CN. 1H-NMR ([D6 ] DMSO): δ=2.22 (m, Hα --C(2')), 2.92 (m, Hβ --C(2')), 3.52 (m, H--C(5')), 3.72 (m, H--C(4')), 4.33 (m, H--C(3')), 4.81 (t, 5'-OH), 5.22 (d, 3'-OH), 6.35 (dd, H--C(1')), 6.46 (br., NH2), 10.75 (s, NH).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:8]([NH:50][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 2-amino-4-methylthiazole-5-carboxylic acid (5.20 g, 32.9 mmol) and N,N-diisopropylethylamine (15 mL, 86.70 mmol) in N,N-dimethylformamide (40 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (8.18 g, 42.7 mmol). The resulting mixture was stirred for 30 min, then 1-hydroxybenzotriazole hydrate (5.78 g, 42.7 mmol) was added, followed by the addition of benzylamine (4.3 mL, 39.3 mmol). The reaction mixture was stirred at ambient temperature for 2 days, then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 60% yield (4.90 g): 1NMR (300 MHz, DMSO-d6) δ 7.36-7.25 (m, 5H), 5.79 (br s, 1H), 5.36 (br s, 2H), 4.54 (d, J=5.7 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 248.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:17][C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19]>>[NH2:20][C@@H:18]([CH3:19])[CH2:17][N:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=2[F:10])=[N:15]1
Reactant: N#Cc1ccc(-c2ccn[nH]2)c(F)c1Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Product: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Yield: 53.8 %

Procedure:
The title compound was prepared from 2-chloro-3-fluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.075 g, 0.34 mmol) and (S)-tert-butyl (1-hydroxypropan-2-yl)-carbamate (0.059 g, 0.34 mmol) using the method of Example 34(c) to afford 0.051 g of the title product. 1H NMR (400 MHz; CDCl3): δ 1.15 (d, 3H), 1.34 (bs, 2H), 3.49 (m, 1H), 3.95 (dd, 1H), 4.16 (dd, 1H), 6.79 (dd, 1H), 7.48 (m, 1H), 7.52 (d, 1H), 8.07 (m, 1H).