Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:30]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)NC3CCCC3)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 22 mg (0.20 mmol, 1.0 eq.) of cyclopentyl isocyanate were reacted according to General Method 4. Yield: 70 mg (83% of theory)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2].[SiH](CC)(CC)[CH2:35]C.FC(F)(F)C(O)=O>C(Cl)CCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:35])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CC[SiH](CC)CC
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccccc1-c1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(COC(C)=O)CSC23)cs1
Yield: 73 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8o (193 mg, 0.288 mmol), Et3SiH (0.461 mL, 2.88 mmol), and trifluoroacetic acid (0.887 mL, 11.5 mmol) in dry ClCH2CH2Cl (7 mL) at 0° C. under nitrogen to give 9o (106 mg, 73%) as a white solid after crystallization from THF/CH2Cl2 /hexane. mp 178° C. (dec); IR (KBr) 3550-2800 (br), 3278, 1785, 1735, 1667, 1256 cm-1 ; 1H NMR (DMSO-d6) δ1.98 (3H, s, CH3), 3.45 (1H, d, J=18.1 Hz), 3.59 (1H, d, J=18.1 Hz), 3.74 (2H, s, CH2), 3.96 (3H, s, CH3), 4.65 (1H, d, J=12.8 Hz), 4.96 (1H, d, J=12.8 Hz), 5.07 (1H, d, J=4.8 Hz), 5.71 (1H, dd, J=8.1 and 4.8 Hz), 7.04 (1H, t, J=7.5 Hz), 7.19 (1H, d, J=8.3 Hz), 7.37-7.42 (1H, m), 7.41 (1H, s), 8.22 (1H, d, J=7.5 Hz), 9.06 (1H, d, J=8.1 Hz, NH), 13.62 (1H, br s, CO2H); FDMS m/z 504 (M+ +1); Anal. Calcd for C22H21N3O7S2 : C, 52.48; H, 4.20; N, 8.34. Found: C, 52.72; H, 4.27; N, 8.10
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)cc1Br
Reaction time: 4.5 h
Yield: 78.3 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (45.7 g), ethylene glycol (27.39 g), p-toluenesulphonic acid (0.225 g) and dry toluene (110 cm3) was heated at the reflux temperature under a Dean and Stark trap. After 4.5 hours, approximately 12 cm3 of water had collected in the trap, and analysis of the reaction mixture by gas liquid chromatography indicated that no starting aldehyde was present. The mixture was sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a yellow oil, which was purified bydistillation under reduced pressure to give 2-(3-bromo-4-fluorophenyl)-1,3-dioxolane (43.56 g), boiling point 68°-106° C. at 0.004 mmHg.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]([CH:35]2[CH2:37][CH2:36]2)[C:7]([C:9]2[N:32]([CH2:33][CH3:34])[C:12]3=[N:13][C:14]([NH:21][C:22]4[S:23][C:24]([CH3:31])=[C:25]([C:27]([O:29]C)=[O:28])[N:26]=4)=[C:15]4[N:19]=[CH:18][N:17]([CH3:20])[C:16]4=[C:11]3[CH:10]=2)=[O:8])[CH2:5][CH2:4]1.Cl>C(O)C>[CH:35]1([N:6]([CH:3]2[CH2:4][CH2:5]2)[C:7]([C:9]2[N:32]([CH2:33][CH3:34])[C:12]3=[N:13][C:14]([NH:21][C:22]4[S:23][C:24]([CH3:31])=[C:25]([C:27]([OH:29])=[O:28])[N:26]=4)=[C:15]4[N:19]=[CH:18][N:17]([CH3:20])[C:16]4=[C:11]3[CH:10]=2)=[O:8])[CH2:36][CH2:37]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)OC)c(C)s3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)O)c(C)s3)nc21
Temperature: 60 °C
Yield: 56.9 %

Procedure:
1N Aqueous NaOH (0.962 mL, 0.962 mmol) was added to a suspension of methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylate (example 41, 0.19 g, 0.385 mmol) in ethanol (2 mL) and the mixture was heated at 60° C. for 2 h. The reaction was cooled to room temperature and acidified with 1N HCl to pH 4. The reaction mixture was concentrated and the residue triturated 5× with methanol. The combined methanol washes were concentrated, and the remaining solid washed 3× with 2:1 ether/dichloromethane provided 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylic acid (105 mg, 57% yield).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: C1CNCCN1
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Temperature: 25 °C

Procedure:
1,2-Epoxy-3-octadecyloxypropane (5.0 g, 15.3 mmol) is added to a mixture of piperazine (1.94 g, 22.5 mmol) and anhydrous potassium carbonate (100 mg) in dimethyl formamide (60 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (125 mL). The undissolved material is filtered in vacuo, and the filtrate is concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine.
Reaction SMILES: [OH:1][CH:2]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:3][N:4]1[C:9]2=[N:10][C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13](=[O:14])[N:8]2[CH2:7][CH2:6][CH2:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:3][N:4]1[C:9]2=[N:10][C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13](=[O:14])[N:8]2[CH2:7][CH2:6][CH2:5]1
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c(-c2ccncc2)nc2n1CCCN2CC(O)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(Cc1ccccc1)CN1CCCn2c1nc(-c1ccncc1)c(-c1cccc(C(F)(F)F)c1)c2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 9-(2-hydroxy-3-phenyl-propyl)-2-pyridin-4-yl-3-(3-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (50 mg, 0.1 mmol) in CH2Cl2 (5 mL) was treated with the Dess Martin Periodinane (450 mg, 1.1 mmol). After the mixture was stirred at room temperature for 5 hr, the mixture was washed with NaHCO3 (aq). The organic residue was loaded to a silica column and eluted with 0-4% (2N NH3-MeOH)/CH2Cl2. The product (4) was collected as a yellow solid (35 mg, 70%). M+1 505.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[CH2:10]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](O)=[O:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:25]([C@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])=[O:26])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NC(=O)c1cccn1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccn1NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carboxamide (6.00 g, 48.0 mmol) and (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (14.3 g, 57.5 mmol) was dissolved in THF (480 mL). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.0 g, 57.5 mmol). The reaction was stirred overnight at rt then concentrated in vacuo. The residue was dissolved in CH2Cl2 (400 mL), washed with water (3×400 mL) and brine (400 mL), then dried (MgSO4), filtered, and concentrated in vacuo to give slightly impure 11A (17.65 g, >100%). 11A had an analytical HPLC retention time=2.103 min (Phenomenex Luna 3.0×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=357.
Reaction SMILES: C([O:4][CH:5]1[O:25][C@H:24]([C:26](=S)[O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:11](OC2C=CC=CC=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[C:8]([O:7][C@@H:6]1[CH2:11][C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:25][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(=S)[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](Oc2ccccc2)[C@@H]1OC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)C[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 135.5 %

Procedure:
1,2,4,6-tetra-O-acetyl-3-O-phenylthiono-glucopyranose (5.2 g) was dissolved in toluene (50 mL) and added to tributyl tin hydride (6.7 mL) and azobisisobutryonitrile (AIBN) (2.8 g). The reaction mixture was heated for 1 to 3 hours at 80° C. to provide for 3-deoxy-2,4,6-tri-O-acetyl-glucopyranose (4.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[CH:6]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([S:34]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH3:24])[CH:6]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C)S(=O)(=O)c2ccc(OC)cc2)c1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-methoxybenzenesulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][CH3:22])=[CH:17][C:16]3=[O:23])[C:7]=2[CH:24]=1)#[N:2].N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([O:14][C:31](=[O:33])[CH3:32])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][CH3:22])=[CH:17][C:16]3=[O:23])[C:7]=2[CH:24]=1)#[N:2]
Reactant: CCOC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2OC(C)=O)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-ethoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran (0.5 g) in 25 ml of methylene chloride at 0° C. was added pyridine (0.415 g) and acetic anhydride (0.56 g), and the mixture stirred at room temperature for 5 days. The reaction mixture was then stirred with a mixture of 50 ml of water and 40 ml of methylene chloride. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and solvent removed under reduced pressure. The residue was triturated with ether followed by pentane to give 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-acetyloxy-4-(4-ethoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 156° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8](=O)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5].CO>C1COCC1>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5]
Reactant: CCOC(=O)[C@@H]1CCC(C)C(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC(C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
To a solution of (S)-5-methyl-6-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (10 g, 35 mmol) in THF (150 mL) was added borane dimethylsulfide complex (49 mL, 49 mmol). The reaction mixture was stirred at 0° C. for 1 h, and then stirred at 40° C. for 3 h. Methanol was added and the reaction mixture was concentrated, washed with 1 M HCl, and extracted with EtOAc/water to give the oil layer, which was dried, and concentrated. The crude product was purified by silica gel chromatography (20:1 petroleum ether:EtOAc) to provide the title intermediate (2 g, 21% yield). (m/z): [M−100+H]+ calcd for C14H25NO4 172.18 found 172.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH:16]2[CH2:21][CH2:20][N:19](OC(C)(C)C)[C:18](=C=O)[CH2:17]2)[NH:11][C:10]2=[N:29][NH:30][CH:31]=[C:9]12>O1CCOCC1.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[NH:11][C:10]2=[N:29][NH:30][CH:31]=[C:9]12
Reactant: CC(C)(C)ON1CCC(C2=C(C#N)C(c3ccccc3Cl)c3c[nH]nc3N2)CC1=C=O
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1ccccc1Cl
Yield: 139.7 %

Procedure:
4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-6-(1-t-butoxy-carbonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (2.0 g) was added to 4N-HCl dioxane solution (20 mL) at 0° C. and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure and the residue was washed by ethanol, and the precipitated crystals were collected by filtration to give the title compound (1.2 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:70]=[CH:69][C:62]([CH2:63][N:64]2[CH2:67][CH:66]([OH:68])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:68][CH:66]1[CH2:65][N:64]([CH2:63][C:62]2[CH:69]=[CH:70][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:60][CH:61]=2)[CH2:67]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (27 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.04 mL, 0.20 mmol), 1-(4-methylaminomethyl-benzyl)-azetidin-3-ol hydrochloride (29 mg, 0.11 mmol) and DCM (10 mL).
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[C:20]4[C:12]([C:13]5[C:18]([N:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:24]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[CH:23]=[CH:22][CH:27]=[C:26]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=5[NH:19][C:20]4=3)[C:5]3[C:6]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:25]=1
Reactant: c1ccc2c(c1)N=c1c-2ccc2c1=Nc1ccccc1-2
Reactant: Brc1cccc(-c2ccc(-c3ccccc3)cc2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(-c3cccc(-n4c5ccccc5c5ccc6c7ccccc7[nH]c6c54)c3)cc2)cc1
Yield: 67.5 %

Procedure:
Indolo[2,3-a]carbazole (9.8 g) was dissolved in 150 ml of dry toluene under nitrogen. 12.9 g of 3-bromo-p-terphenyl, 0.65 g of tris(dibenzylideneacetone) dipalladium, 0.46 g of tri-t-butylphosphine and 40.3 g of potassium orthophosphate were added and heated to reflux for 16 h. After the completion of reaction, the reaction was quenched with water. The reaction mixture was then extracted using ethyl acetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using ethyl acetate/hexane (1:9) as eluent, yielded 12.6 g of N-(1,1′:4′,1″-terphenyl-3-yl)indolo[2,3-a]carbazole.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][NH:29][CH2:30][CH3:31].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH2:30]([N:29]([CH3:28])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:31]
Reactant: CCNC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Yield: 89.4 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), N-methylethanamine (174 ul, 2.02 mmole), N-ethyldiisopropylamine (564 ul, 3.23 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4-ethyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (149 mg, 89.4%) as a white solid. Mp.: 201-3° C. MS: m/z=413.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][C:3]=1[Br:11].Cl[CH2:13][C:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[CH2:16]([C:14]1[N:7]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([Br:11])[CH:4]=2)[S:8][CH:13]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=S)c1ccc(N)c(Br)c1
Reactant: O=C(CCl)Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br
Yield: 68 %

Procedure:
A mixture of 4-amino-3-bromobenzthioamide (1.66 g, 7.18 mmol) and 1-chloro-3-phenylacetone [Tarhouni, R. et al., Tetrahedron Letters, 835 (1984)](1.36 g, 8.07 mmol, 1.1 eq) in absolute ethanol (18 mL) was heated at reflux under nitrogen for 2.5 hours. The resulting reaction mixture was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and a saturated solution of sodium hydrogen carbonate (20 mL). The ethyl acetate layer was removed, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residual solid was chromatographed using silica gel (approximately 175 g) and elution with an ethyl acetate gradient in hexanes [1:4 to 1:1] to afford the title compound (68%) as a pale yellow solid: top, 110°-115° C.; 13C NMR (CDCl3) δ 166.8, 157.1, 145.6, 139.1, 130.7, 129.1, 128.6, 126.9, 126.4, 125.4, 115.3, 113.2, 109.2, 38.0. Anal. calcd for C16H13BrN2S: C, 55.66; H, 3.79; N, 8.11. Found: C, 55.36; H, 3.71; N, 7.92.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (75 mg, 0.19 mmol), glycine (1.87 g, 24.9 mmol) and NaOMe solution (37.5 mL, 18.8 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was further purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as an off-white solid. MS: (+) m/z 444.11 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:28])([C:24]([O:26]C)=[O:25])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:28])([C:24]([OH:26])=[O:25])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@]1(C(=O)O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R,3S)-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52j, (0.035 g, 0.083 mmol) dissolved in MeOH (5 mL) and water (1 mL) was added LiOH (0.004 g, 0.168 mmol). The reaction was allowed to stir for 2 days at room temperature and then concentrated to dryness. The residue was washed with ethanol. The combined ethanol washings were concentrated in vacuo, yielding 30 mg of desired product as an off white solid.