Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([O:15][CH2:16][CH2:17][OH:18])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[C:27]([C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])([Cl:37])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[C:38]([C:27]([N:11]1[C:12](=[O:13])[CH:14]([O:15][CH2:16][CH2:17][OH:18])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:10])([Cl:37])[C:28]([NH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:29])(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)C(=O)C(Cl)(Br)C(=O)Nc1ccccc1
Reactant: O=C1NC(=O)N(Cc2ccccc2)C1OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C(Cl)(C(=O)Nc1ccccc1)N1C(=O)C(OCCO)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
51.5 g of 1-benzyl-5-(2-hydroxyethoxy)hydantoin and 20 g of triethylamine were dissolved in 500 ml of methylene chloride, and a solution of 34.8 g of α-bromo-α-pivaloyl-2-chloroacetanilide in 200 ml of methylene chloride was dropwise added thereto in about 1 hour. After completion of the dropwise addition, the solution was stirred for 2 hours. Then, the reaction solution was washed twice with 300 ml of dilute hydrochloric acid, and twice with 300 ml of water. After drying the reaction solution with sodium sulfate, it was concentrated and purified by silica gel chromatography to obtain 42.2 g of oily α-pivaloyl-α-(1-benzyl-5-(2-hydroxyethoxy)hydantoin-3-yl)-2-chloroacetanilide. (Yield: 84%)
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([N:21]([CH3:22])[C:33]([CH:30]3[CH2:32][CH2:31]3)=[O:34])[C:18]([O:23][CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(NC)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)C3CC3)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of Compound 252 (150 mg, 0.37 mmol) in dry THF (3 mL) was added cyclopropylcarbonyl chloride (34 μL, 0.37 mmol) at 0° C. Slowly the temperature was raised to room temperature and stirred for an additional hour. Reaction was quenched with aqueous NaHCO3 solution and extracted with EtOAc, washed with brine, dried over Na2SO4 and finally purified preparative HPLC to provide Compound 253 (132 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.63 (br. d, J=8.1 Hz, 2 H) 0.80 (br. s., 2 H) 1.18 (t, J=7.45 Hz, 3 H) 1.48 (td, J=8.02, 3.92 Hz, 1 H) 2.27 (s, 3 H) 3.26 (s, 3 H) 3.41 (q, J=7.45 Hz, 2 H) 3.98 (s, 3 H) 7.17 (s, 1 H) 7.54 (s, 1 H) 7.88 (t, J=7.71 Hz, 1 H) 8.04 (d, J=8.08 Hz, 2 H) 8.14 (s, 1 H) 8.31 (d, J=1.26 Hz, 1 H) 12.31 (s, 1 H); [M+H] calc'd for C26H28N3O4S, 478.2; found, 478.3.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])(=[O:35])[CH3:34]
Reactant: CC(=O)NCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 89 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-acetylamino-ethyl)-amide (44 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N-(2-amino-ethyl)-acetamide (34 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 494. 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (s, 1H), 7.98 (m, 2H), 7.81 (s, 1H), 7.64 (d, 1H), 7.51 (br, 1H), 7.35 (m, 1H), 7.25 (d, 1H), 3.62 (s, 3H), 3.22 (t, 4H), and 1.81 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH:23]=O)[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+]>CO>[C:23]([C@H:13]1[O:12][CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14]1)#[CH:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Dimethyl (1-diazo-2-oxpropyl)phosphonate (3.90 mL, 26.0 mmol) was added to tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-formylmorpholine-4-carboxylate (Example 1, step 6) (7.78 g, 21.6 mmol) and K2CO3 (5.98 g, 43.3 mmol) in anhydrous MeOH (216 mL) at ambient temperature. The reaction was stirred for 2 hours then filtered and concentrated in vacuo. Saturated aqueous KH2PO4 was added and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (750 g) eluting with a gradient of 0-30% EtOAc/hexanes afforded the title compound (4.60 g, 12.9 mmol, 60% yield) as a colorless oil, MS (ESI): m/z=256.01 (M+H-Boc).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])=[O:8])[N:6]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nccc3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=488.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O.[NH2:20][NH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:12][C:13](=[O:15])[NH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NNC(=O)C2)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
To an ethanol solution of ethyl 3-(3-methyl-4-nitro-phenyl)-3-oxo-propionate (3.0 g), hydrazine monohydrate (0.9 g) and a small amount of p-toluenesulfonic acid were added and the mixture was refluxed for 5 hours. After cooling, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 5-(3-methyl-4-nitro-phenyl)-2,4-dihydro-pyrazol-3-one (2.6 g). mp; 218-219° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([CH2:25][C:26](=[O:32])[O:27]C(C)(C)C)[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([N:8]([CH2:25][C:26]([OH:32])=[O:27])[CH2:7][C:6]([OH:33])=[O:5])=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)CCCCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(CC(=O)O)C(=O)CCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl 6-[bis(2-tert-butoxy-2-oxoethyl)amino]-6-oxohexanoate (5.9 g, 12.73 mmol) in CH2Cl2 (30 mL) at room temperature was added TFA (30 mL, 12.73 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated. The residue was purified by flash chromatography on C18 reverse phase silica gel to give the title compound. LC-MS Method A: m/e=486 [M+1]; Rt=2.53 min. 1H NMR (CD3OD) δ 7.30 (m, 5H), 5.06 (s, 2H), 4.81 (s, 4H), 4.19 (s, 2H), 4.07 (s, 2H), 2.34 (q, 4H, J=7.03).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:29][CH:28]([NH:30]C(=O)OC(C)(C)C)[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH2:30][CH:28]1[CH2:29][N:26]([C:24]([NH:23][C:20]2[N:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:25])[CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)azetidin-3-ylcarbamate (Example 14; 10 mg, 0.019 mmol) was dissolved in 0.5 mL 50% TFA in DCM and stirred at ambient temperature for 2 hours. The reaction is concentrated, treated with ether, and concentrated again to yield the final product salt form as a white solid. MS (apci) m/z=414.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].[NH:24]1[CH:28]=[CH:27][N:26]=[N:25]1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:25]1[N:26]=[CH:27][CH:28]=[N:24]1)[N:6]2[CH3:16]
Reactant: Cn1c(Br)nc2c(N)nc(CCCCO)nc21
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(-n2nccn2)nc2c(N)nc(CCCCO)nc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)butan-1-ol (1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added Cs2CO3 (5.9 g, 18.24 mmol) and then 1H-1,2,3-triazole (1.2 g, 1.0 ml, 17.2 mmol). The mixture was stirred overnight at 90° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: Clc1cccc(Cl)n1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc(OCc2ccsc2)n1

Procedure:
To a solution containing 3-thiophenemethanol (1.17 g, 0.010×1.0 mol) and sodium hydride (0.39 g, (ca.60% in mineral oil), 0.010×1.0 mol) in tetrahydrofuran, 2,6-dichloropyridine (1.5 g, 0.010 mol) was added and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:67][NH:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>ClCCl>[CH2:69]([N:68]([CH3:67])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[CH:17]=1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Reactant: CNCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
The compound (0.10 g) prepared in step (c) was dissolved in dichloromethane (2 ml). A BOP reagent (0.10 g) and diisopropylethylamine (0.052 ml) were added to the solution. The mixture was stirred at room temperature for 30 min. N-Methylbenzylamine (0.039 ml) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give 0.072 g (57.3%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: O=C(O)c1cnccn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnccn1

Procedure:
To a solution of pyrazine-2-carboxylic acid (100 g) in ethanol (EtOH, 1000 ml) was added conc. sulfuric acid (45 ml) at room temperature. After refluxing for 8 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (AcOEt, 1500 ml) and water (H2O, 1000 ml), and sodium hydrogencarbonate (NaHCO3) was added to adjust the pH of the mixture to 8. The aqueous layer was extracted with AcOEt (1000 ml), and the combined organic layer was washed with brine and dried over magnesium sulfate (MgSO4). The solution was concentrated in vacuo, and the residue was crystallized from hexane (1000 ml) to give 111.2 g of ethyl pyrazine-2 carboxylate.
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:24]([O-:26])=O)=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:43][C:44]([F:48])([F:47])[CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][C:24]([NH:46][CH2:45][C:44]([F:48])([F:47])[F:43])=[O:26])=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCC(F)(F)F
Reactant: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)[O-])c3ccccc3)c2=O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)NCC(F)(F)F)c3ccccc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.5 %

Procedure:
To a solution of 200 mg (0.43 mmol) of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenylpropanoate, 0.3 mL (1.7 mmol) of DIEA and 30 μL (0.43 mmol) of 2,2,2-trifluoroethylamine in 1 mL of DCM are added, at 0° C., 207 mg (0.64 mmol) of TBTU. The medium is stirred for 12 hours at room temperature. A further 0.3 mL of 2,2,2-trifluoroethylamine is then added and the medium is heated at 40° C. for 6 hours. The medium is taken up in 20 mL of DCM, washed successively with water (2×10 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure, and then purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 32 mg of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenyl-N-(2,2,2-trifluoroethyl)propanamide are thus obtained in the form of a powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14]OCC2C=CC=CC=2)[CH2:9][CH2:8]1.[CH3:24][O:25][C:26](=O)[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34]NCC1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:35][CH:34]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Reactant: COC(=O)CCCC1CCNCC1
Product: COC(=O)CCCC1CCN(CCCOCc2ccccc2)CC1
Yield: 40 %

Procedure:
Following the same procedure described for the preparation of compound 3a, the compound 3b was synthesized in 40% yield from compound 2 as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 1.21 (m, 4H), 1.42 (m, 1H), 1.49 (m, 2H), 1.83 (d, 2H), 1.93 (m, 2H), 2.31 (m, 2H), 2.69 (m, 2H), 2.99 (m, 2H), 3.35 (m, 2H), 3.60 (m, 5H), 4.50 (m, 2H), 7.28 (m, 5H). m/z (ESI): 334 [C20H31NO3+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:14]2[B:15]([OH:18])[O:16][CH2:17][C:13]=2[CH:12]=1)[C:5]#[N:6].[CH:21]1(I)[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C=O.[H-].[Na+]>O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[C:5]#[N:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: IC1CCCC1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of 3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.500 g, 1.87 mmol), cyclopentyl iodide (0.65 mL, 5.61 mmol), and N,N-dimethylformamide (30 mL) under a nitrogen balloon was cooled to 0° C. on an ice water bath. Sodium hydride (0.224 g, 5.61 mmol) was added and then the reaction was stirred for 5 minutes on the ice water bath. The reaction was then stirred at room temperature for 2 hours. More cyclopentyl iodide (0.22 mL, 1.87 mmol) was added and the reaction was cooled to 0° C. on an ice water bath. Sodium hydride was added (0.075 g, 1.87 mmol) and the reaction was stirred at 0° C. for 5 minutes. The reaction was then stirred at room temperature for another 2 hours. Water was added to quench excess sodium hydride and the reaction was then neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 3-(cyclopentyloxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.396 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (m, 2H), 1.38 (m, 2H), 1.50 (m, 2H), 1.73 (m, 2H), 4.86 (m, 2H), 6.84 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 9.06 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:32][C:33]([CH3:40])([C:36]([F:39])([F:38])[F:37])[C:34]=1[CH3:35])#[N:29]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([CH3:40])([C:36]([F:39])([F:37])[F:38])[O:32][C:31](=[C:41]([C:42]#[N:43])[C:44]#[N:45])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)cc2)c(OC)c1
Temperature: 50 °C
Reaction time: 9 h
Yield: 38.9 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 500 mg (1.37 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 380 mg (1.50 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 50° C. for 9 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 320 mg of a black powder (yield: 38.9%; mp: 175-177° C.)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Temperature: 65 °C
Yield: 63.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (1.1 g, 3.1 mmol, from Example 47, Step 2), piperazine (0.40 g, 4.7 mmol) and cesium carbonate (2.8 g, 8.7 mmol) in tetrahydrofuran (20 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with water, and extracted with dichloromethane. The organic phases were combined, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 15% methanol in dichloromethane) to give the desired product (0.57 g, 63%). LCMS calculated for C15H17ClN3O (M+H)+: m/z=290.1; Found: 290.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].[C:32]1([Mg]Cl)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (350 mg, 0.85 mmol) obtained in Step 1 was dissolved in THF, and phenylmagnesium chloride (0.064 mL, 0.93 mmol) was added thereto, followed by stirring for 1 hr at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 475 mg of the titled compound (yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1C(=O)N([Br:29])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[C:15]([Br:29])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CC2c3sccc3C(C)C2C1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1

Procedure:
A solution of the product from step i) (204 mg, 0.81 mmol) in AcOH (2 ml) and CHCl3 (2 ml) was treated with NBS (152 mg, 0.85 mmol) at 22° C. for 30 minutes. Next, the reaction was carefully quenched with sat. NaHCO3 (10 ml), extracted with EtOAc (2×75 ml) and the combined organic layers were dried (MgSO4). The crude product was filtered through a plug of silica gel using hexanes:EtOAc (50:50) to give the subtitle compound. MS calculated for C13H16BrNO2S+H 330, observed 332.