Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)[CH3:5].[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33](O)=[O:34])=[C:31]([CH3:39])[N:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:34])=[C:31]([CH3:39])[N:30]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-pyridin-3-ylmethyl-amine (0.78 g, 2.12 mmol) was dissolved in DCM (10 mL). 6-Chloro-2,4-dimethyl-nicotinic acid (474 mg, 1.2 eq.), HOBT (430 mg, 1.5 eq.), DIPEA (760 μL, 2 eq.), and EDCI (612 mg, 1.5 eq.) were added sequentially. The mixture was stirred at room temperature for 6 h, and then quenched with saturated NaHCO3 (20 mL). The pH of the equilibrated aqueous was adjusted to 8 with 1N HCl, and the mixture was extracted with DCM (200 mL in 5 extracts). The combined organic was dried (Na2SO4) and concentrated. The residue was purified with flash chromatography on 150 mL silica using a gradient of 5%→10% MeOH in EtOAc containing 1% NH4OH as the eluent to give 6-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (0.88 g, 77%) as light brown foam. 1H NMR (δ, CDCl3): 8.66 (1 H, d, br, J=5.7 Hz), 8.51 (1 H, s), 8.44 (1 H, d, J=4.8 Hz), 7.61 (1 H, d, J=8.1 Hz), 7.20 (1 H, dd, J=7.8, 4.8 Hz), 7.01 (1 H, s), 6.73 (2 H, d, J=9.0 Hz), 6.62 (2 H, d, J=9.0 Hz), 3.88 (2 H, s, an overlapping 1H, m), 3.71 (3 H, s), 3.33 (2 H, pentet, J=13.5 Hz), 2.80 (3 H, m), 2.51 (3 H, s, an overlapping 1 H, m), 2.30 (3 H, s), 2.12 (1 H, t, J=11.4 Hz), 1.82-1.66 (3 H, m), 1.60-1.46 (1 H, m), 1.11 (1 H, qd, J=12.3, 3.6 Hz), 0.99 (3 H, d, J=6.6 Hz), 0.92 (1 H, qd, J=12.0, 3.0 Hz); 13C NMR (δ, CDCl3): 167.2, 155.4, 152.9, 150.2, 148.9, 148.1, 147.5, 142.5, 135.7, 134.8, 123.3, 122.5, 117.8, 114.6, 60.5, 58.1, 55.6, 52.1, 47.5, 43.6, 40.1, 30.7, 29.4, 22.1, 18.8, 13.4; ES-MS m/z 536.5 (M+1). Anal. Calcd. for (C30H38N5ClO2) 0.2(H2O): C, 66.76; H, 7.17; N, 12.98; Cl, 6.57. Found: C, 66.80; H, 7.00; N, 12.86; Cl, 6.55.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:4][C:3]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)c(Cl)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Benzyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (20.8 g, 54.7 mmol) and N-chlorosuccinimide (8.04 g, 60.2 mmol) were dissolved in N,N-dimethylformamide (339 mL) and allowed to stir overnight. The reaction was diluted with water, extracted with diethyl ether, washed with saturated aqueous sodium chloride then dried over MgSO4, filtered and the solvent evaporated. The mixture was purified by silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give an orange oil (13.7 g, 62%). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 6.95 (s, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.61 (d, J=8.0 Hz, 2H), 5.18 (d, J=12.1 Hz, 1H), 5.10 (d, J=12.3 Hz, 1H), 4.98 (d, J=8.2 Hz, 1H), 4.71 (d, J=5.3 Hz, 1H), 4.54 (m, 1H), 3.97 (m, 2H), 2.96 (m, 2H), 1.43 (s, 9H); LCMS found for C21H25ClN2NaO4 (M+Na)+: m/z=427.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:14][CH2:15][CH2:16][OH:17])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzenesulfonyl chloride (1.17 g, 4 mmol) in CH2Cl2 (3 mL) was added to a solution of 2-aminoethanol (0.36 mL, 6 mmol) and triethylamine (1.67 mL, 12 mmol) in CH2Cl2 (12 mL) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 884 mg (70%) of 4-bromo-2,5-difluoro-N-(2-hydroxyethyl)benzenesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, 1H, Ja=7.2 Hz, Jb=6.0 Hz), 7.47 (dd, 1H, Ja=8.7 Hz, Jb=5.1 Hz), 5.39-5.14 (m, 1H), 3.78-3.64 (m, 2H), 3.26-3.10 (m, 2H), 1.73 (bs, 1H); LRMS (ESI), m/z 314/316 (M−H).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4](Cl)(Cl)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.S(=O)(=O)(O)O.[CH3:23][OH:24]>>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:24][CH3:23])=[O:1])[CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1cccc(CC(Cl)(Cl)Cl)c1
Reactant: [OH-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)Cc1cccc(C(F)(F)F)c1
Yield: 94 %

Procedure:
Fifty ml. of methanol, 4.9 g. of sodium hydroxide and 6.0 g. of 1,1,1-trichloro-2-(3-trifluoromethylphenyl)ethane were combined, and stirred under reflux for 6 hours. The mixture was cooled overnight, and was then made acid with 2.5 ml. of concentrated sulfuric acid. It was stirred under reflux for 1 hour more, cooled and filtered. The solids were washed with 100 ml. of methanol. Thirty ml. of water was added to the filtrate, and the aqueous layer was separated and washed 3 times with 20 ml. portions of dichloromethane. All of the organics were combined, and washed with two 15 ml. portions each of water and saturated sodium chloride. The organics were then dried over sodium sulfate and evaporated under vacuum to obtain 4.6 g. of an oil, which was found to contain 94% of the desired product by vapor phase chromatography.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[CH2:14][NH:15][C:16]([C:18]1[S:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:17].[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:12]1[CH2:13][C:9](=[O:8])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:11]1)=[O:33]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@@H]1CNCC1=O)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1

Procedure:
81.3 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-4-oxo-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale brown solid. MS 489.0 ([M+H]+)
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH2:8][NH:7]2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>C(O)C>[NH:4]1[C:5]([CH:6]2[CH2:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH2:8][N:7]2[C:26]([S:28][CH3:29])=[S:27])=[N:1][N:2]=[N:3]1
Reactant: S=C=S
Reactant: c1ccc2c3c([nH]c2c1)CNC(c1nnn[nH]1)C3
Reactant: CI
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2CC1c1nnn[nH]1

Procedure:
In the same manner as described in Example 53, (3RS)-3-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-β-carboline (0.257 g), triethylamine (0.23 ml), carbon disulfide (0.05 ml), 70% ethanol (4 ml) and methyl iodide (0.055 ml) are reacted and treated. The product is crystallized from chloroform to give the title compound (75 mg), m.p. 203°-205° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([O:34][CH3:35])[N:4]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:42][S:39]([CH:36]5[CH2:38][CH2:37]5)(=[O:41])=[O:40])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([O:34][CH3:35])[N:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Yield: 52.1 %

Procedure:
The acid 18g (1.2 g, 2 mmol) was reacted with cyclopropane sulfonamide (73 mg, 0.6 mmol), EDAC (115 mg, 0.6 mmol) and DBU (215 mg, 1.4 mmol) in dry DCM (3 ml) according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (185 mg, 70%), (M+H)+592.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[C:30]([S:34]([NH:1][CH2:2][C:3]2[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]3[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]3=[N:7][C:8]=2[CH2:9][CH3:10])(=[O:36])=[O:35])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
345(a) 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (0.1 mmol) was dissolved in DCM (3 mL), followed by the addition of Et3N (10 mg, 0.1 mmol). The resultant solution was stirred overnight. The solution was then purified using a Gilson to give 2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[O:6].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl.CCOCC>[C:25]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[O:6])(=[O:27])[CH3:26]
Reactant: CCCCCOc1ccc(C=O)cc1O
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCOc1ccc(C=O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
3-Hydroxy-4-pentyloxy-benzaldehyde (0.750 g., 3.6 mmol, 1 equiv. ) is dissolved in 10 mL of methylene chloride. Diisopropyl ethyl amine (0.840 g., 6.5 mmol, 1.8 equiv. ) is then added, and the mixture is cooled to 0° C. Acetyl chloride (0.340 g., 4.32 mmol, 1.2 equiv. ) dissolved in 2 mL of methylene chloride is added slowly, and the reaction is stirred at 0° C. for 20 min., followed by stirring 30 min. at room temperature. The mixture is diluted with ether, and washed twice with water, dilute HCl, then brine. The organic phase is dried (MgSO4), and evaporated. Trituration with ether affords 3-acetoxy-4-pentyloxy-benzaldehyde (0.750 g., 3.0 mmol, 83%) as a white solid: UVmax (EtOH) 232 nm (ε=17514), 276 nm (ε=12951), 208 nm (ε=10508), 314 nm (ε=10472 ); 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H, CHO), 7.45-7.40 (m, 2H, ArH), 6.95 (d, J=8 Hz, 1H, ArH), 4.15 (t, J=7 Hz, 2H, OCH2R), 2.03 (s, 3H, CH3CO), 1.90-1.85 (m, 2H, OCH2CH2R), 1.57-1.40 (m, 4H, pentyl), 0.95 (t, J=7 Hz, 3H, RCH3); 13C NMR (75 MHz, CDCl3) δ 191.07 (C=O), 151.31, 146.17, 130.39, 124.56, 113.99, 110.85, 69.27, 28.67, 28.04, 22.38, 13.96; IR (KBr) 2950, 1750, 1680, 1600, 1580, 1510, 1230, 1250 cm-1 ; MS (DCI) m/e 251 (MH+). Anal. Calcd for C14H18O4 : C, 67.20; H, 7.20. Found: C, 66.92; H, 7.62.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:42]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[O:42]1[CH:46]=[CH:45][C:44]([CH2:47][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]4\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]5[C:4]\4=[CH:3][C:2]([I:1])=[CH:11][CH:10]=5)=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)=[CH:43]1
Reactant: O=Cc1ccoc1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(Cc3ccoc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.2 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), furan-3-carbaldehyde (0.214 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 45 mg (81%) of the title compound as an orange solid. MS (ESI) m/z 555.4 (M+H)+1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.BrC1C([F:42])=CC(C(F)(F)F)=CN=1>>[F:42][C:30]1[C:25]([NH:24][CH2:23][C@@H:3]2[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])=[N:26][CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cc2F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 490 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=2)[CH2:10]1)([CH3:6])([CH3:5])[CH3:4].[CH3:27][C:28](OC(C)=O)=[O:29].O.NN>CN(C=O)C>[NH2:22][C:21]1[C:20]2[CH:19]=[N:18][C:17]([S:23][CH3:24])=[N:16][C:15]=2[N:14]([C@H:11]2[CH2:12][CH2:13][C@H:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:26])[CH3:25])[CH2:10]2)[C:28](=[O:29])[CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)n1
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(N)cc(=O)n([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.7 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 303 mg, 7.59 mmol) was added in one portion, under argon atmosphere, to a mixture of 4-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbonitrile (658 mg, 1.81 mmol) in anhydrous DMF (10 mL) and the resulting mixture was stirred at RT for 30 min. Anhydrous Ac2O (2.56 mL, 27.1 mmol) was added dropwise, over a period of 35 min, and the reaction mixture was stirred for additional 10 min. The resulting mixture was quenched with NH4Cl (sat'd aq, 50 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was dissolved in MeOH (15 mL), and hydrazine hydrate (0.877 mL, 18.08 mmol) was added dropwise. The resulting mixture was heated at 85° C. in a microwave reactor for 50 min. The solvent was evaporated under reduced pressure and water was added to the residue. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (3×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH) to afford 800 mg of 5-amino-8-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](C)=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7](C3C=CC(Cl)=CC=3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB(C2C=CC(C(OC)=O)=CC=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[CH:12]1[N:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:23][C:6]=3[N:7]=[CH:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Agent: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C1=Nc2ccccc2-n2cnnc2C1
Temperature: 120 °C

Procedure:
A mixture of 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine,5,6-dihydro-1-methyl-8-bromo-6-(4-chloro-phenyl) (Compound 13; 60 mg, 0.15 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (81 mg, 0.30 mmol), and cesium carbonate (98 mg, 0.30 mmol) in dioxane (2 mL) and water (1 mL) was heated at 120° C. for 20 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The solid was filtered and the filtrate was concentrated to give a residue. To the residue, ethyl acetate (30 mL) was added and the mixture was washed with brine (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford 4H-[1,2,4]Triazolo[4,3-a][1,5]benzodiazepine, 5,6-dihydro-1-methyl-8-(4-carboxy-phenyl)-6-(4-chloro-phenyl) as a white solid (30 mg, 47%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)[C:18]3=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[C:16]=2[C:48]#[N:49])=[CH:11][C:10]=1[CH3:50])C1C=CC=CC=1.C1CC=CCC=1>[Pd].CO.C(Cl)Cl>[C:48]([C:16]1[C:17]([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)=[C:18]2[C:23]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[N:22][NH:21][C:19]2=[N:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:50])[CH:11]=1)#[N:49]
Reactant: Cc1cc(-c2nc3[nH]nc(-c4ccco4)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1=CCC=CC1
Solvent: CO
Product: Cc1cc(-c2nc3[nH]nc(-c4ccco4)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)ccc1O
Yield: 49.9 %

Procedure:
To a solution of 2.12 g (3.2 mmol) of tert-butyl 4-(4-(6-(4-(benzyloxy)-3-methylphenyl)-5-cyano-3-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate in a MeOH/CH2Cl2 mixture are added 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene. The mixture is refluxed for 18 h, then 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene are added, and the mixture is refluxed for an additional 24 h, 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene are added and the mixture is again refluxed for 24 h. The mixture is then concentrated, dissolved in dichloromethane, filtered on Celite, then concentrated. The residue is purified by chromatography on silica (MeOH gradient in dichloromethane: 0 to 3%) to give 0.92 g (50%) of tert-butyl 4-(4-(5-cyano-3-(furan-2-yl)-6-(4-hydroxy-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate in the form of yellow crystals.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([O:23][CH3:24])=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:11]([OH:19])[C:12]#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:36]=[CH:35][C:30]([CH2:31][N:32]=[N+:33]=[N-:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[OH:19][CH:11]([C:9]1[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:23][CH3:24])=[CH:7][C:8]=1[N+:20]([O-:22])=[O:21])[C:12]1[N:34]=[N:33][N:32]([CH2:31][C:30]2[CH:35]=[CH:36][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C#CC(O)c1cc(OC(C)C)c(OC)cc1[N+](=O)[O-]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(O)c2cc(OC(C)C)c(OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
1.5 N butyl lithium (22.6 ml, 33.8 mmol) was added to a solution of diisopropylamine (5.0 ml, 36.0 mmol) in tetrahydrofuran (75 ml) under an argon atmosphere at −78° C., and the mixture was stirred for one hr. Ethyl propiolate (2.9 ml, 28.2 mmol) and a solution of 5-isopropoxy-4-methoxy-2-nitrobenzaldehyde (4.5 g, 18.8 mmol) in tetrahydrofuran (50 ml) were then added thereto in that order, and the mixture was stirred at −78° C. for additional 1.5 hr. A solution of acetic acid (5.9 ml, 102 mmol) in tetrahydrofuran (20 ml) was added to the reaction solution. Water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7.27 g). The resultant ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate was dissolved in toluene (60 ml). 4-Methoxybenzyl azide (9.2 g, 56.4 mmol) was added to the solution. The mixture was heated at 100° C. with stirring overnight. The reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give a 1:1 mixture (7.01 g, 75%) of ethyl 4-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (a-2: high polar product (MP)).