Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[N:18][N:17]=1.[CH3:26][N:27](C=O)[CH3:28].C1N=CN(C(N2C=NC=C2)=O)C=1.CNC>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23]([N:27]([CH3:28])[CH3:26])=[O:24])=[N:18][N:17]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: CNC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C)C(=O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of {5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-acetic acid (75 mg, 0.16 mmol, 1 eq) in DMF CDI (35 mg, 0.21 mmol, 1.3 eq) was added. The reaction mixture was stirred at RT under argon for 3 hrs. Then diisopropanlethylamine (352 mg, 0.41 mmol, 2.5 eq), and dimethylamine hydrichloride (40 mg, 0.41 mmol, 2.5 eq) was added and the mixture was stirred for another 2 hrs. It was then directly purified by reverse phase preparative HPLC to give the desired product (35 mg). LC/MS (Method A) [4.87 min; 483 (M+1)]
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.61 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.71 g, 46%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A solution of compound 124 (0.14 g, 0.310 mmol) in CH2Cl2 (5 mL) was treated with 40% TFA in CH2Cl2 (5 mL) at 0° C. and the resulting solution was stirred at same temperature for 3 h. The solvent was evaporated, crude was diluted with 10% cold NH4OH solution (25 mL) and precipitated solid was filtered off. Crude product was dried and purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 125 (0.095 g, 88%) as a solid. 1H NMR (DMSO-d6) δ 1.36-1.48 (m, 1H), 1.90-1.98 (m, 2H), 2.34 (s, 3H), 2.38-2.64 (m, 4H), 6.07 (brs, 1H), 6.30 (brs, 2H), 6.58 (dd, 1H, J=1.2, 8.4 Hz), 6.81 (s, 1H), 7.09 (t, 1H, J=4.2 Hz), 7.20 (d, 1H, J=2.1 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.68-7.72 (m, 2H), 10.79 (s, 1H); ESI-MS (m/z, %) 351 (MH+, 100), 119(91); ESI-HRMS calculated for C20H23N4S (MH+); calculated: 351.1637; observed: 351.1638.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:19]=1.N1C2C=CC=C(S(Cl)(=O)=O)C=2N=CC=1>>[Br:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([Cl:27])[C:18]([Cl:17])=[CH:19][C:20]=2[NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[C:4]([OH:3])=[O:16])[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Agent: O=S(=O)(Cl)c1cccc2nccnc12
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared from quinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in Example 2, Part E. HPLC: RT=9.91 min. MS (ESI−): mass calcd. for C24H16BrCl2FN4O5S, 642.28; m/z found, 639/641/643 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.49 (s, 1H), 9.00-8.93 (m, 2H), 8.62-8.57 (m, 1H), 8.37-8.32 (m, 1H), 8.20-8.12 (m, 1H), 8.05-7.97 (m, 1H), 7.93-7.88 (m, 1H), 7.73-7.67 (m, 1H), 7.65-7.61 (m, 1H), 7.41-7.33 (m, 1H), 7.25-7.15 (m, 1H), 5.00-4.90 (m, 1H), 3.38-3.28 (m, 1H), 3.18-3.10 (m, 1H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[Cl:12][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C1NCCN1CCO
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1CCCl

Procedure:
A solution of 5.00 g (38.42 mmol) of 1-(2-hydroxyethyl)imidazolidin-2-one 44-1 and 3.82 mL (52.39 mmol) of thionyl chloride in 75 mL of chloroform was stirred at reflux for 4 hours. The reaction was concentrated in vacuo to an orange oil, which was redissolved in chloroform and washed twice with water. The organic layer was dried and reconcentrated to give the crude desired product as an orange solid. The solid was used as obtained from the reaction without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[C:7]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:6]2[C:5]1=[O:18])([CH3:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[H-].[Na+]>CN(C=O)C>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[C:7]2[C:13](=[O:17])[N:14]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:15][CH2:16][N:6]2[C:5]1=[O:18])([CH3:3])[CH3:2]
Reactant: COc1c2n(c(=O)n(C(C)C)c1=O)CCNC2=O
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c(=O)n(C(C)C)c1=O)CCN(Cc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cold solution (0° C.) of 7-isopropyl-9-methoxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (0.050 g, 0.197 mmol) in DMF (1.5 mL) was added 2-(chloromethyl)quinoline hydrochloride (0.051 g, 0.237 mmol). Sodium hydride (60% suspension in mineral oil, 0.022 g, 0.868 mmol) was added. The mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without purification. HPLC RT=3.47 min (Method A); ES MS (M+H)=395.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Cl[C:14]1[N:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O.O>[CH2:21]([O:20][C:17]1[CH:16]=[N:15][C:14]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:19][CH:18]=1)[CH3:22]
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CCOc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 105 °C

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (4.0 g, 23.6 mmol) and 2-chloro-5-ethoxypyrimidine (4.12 g, 26.0 mmol) were dissolved in 40 mL of DMA, to which was added cesium carbonate (10.0 g, 30.7 mmol). The reaction was heated at 105° C. overnight. The reaction mixture was cooled to rt and diluted with 40 mL of EtOAc and 40 mL of water. The layers were separated and the aqueous phase extracted with EtOAc (30 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 340 g SNAP column, Biotage system) eluting with 15-80% EtOAc:hexanes over 11 CV to afford the title compound. LC/MS (m/z): 292 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[S:14]([OH:17])(=[O:16])=[O:15]
Reactant: BrCCc1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1c(CCBr)ccc2ccccc12
Temperature: 0 °C
Reaction time: 30 h

Procedure:
2-(2-bromoethyl)naphthalene (120 g) was stirred in an ice bath while fuming sulfuric acid (50 g) was slowly added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 30 hours, whereby 2-(2-bromoethyl)naphthalenesulfonic acid and a plurality of isomers were obtained, and then separated and purified.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]2[CH3:16])[C:11]=1[CH3:12]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (150 mg, 0.60 mmol) was slurried in N-methylpyrrolidinone (1.0 mL) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (110 mg, 0.54 mmol) and cesium carbonate (360 mg, 1.10 mmol) were added and the reaction mixture was heated at 120° C. for 2.5 h in the microwave. The reaction mixture was then diluted with water (15 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined layers were combined and washed with water (1×100 mL) and brine (1×30 mL). The organic layer was dried over magnesium sulfate and the residue was purified by medium pressure chromatography (silica gel, 0 to 15% EtOAc:hexanes) to give (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C@H:17]([N:19]1[C:28](=[O:29])[CH2:27][C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]1=[O:30])[CH3:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:18][C@H:17]([N:19]2[C:28](=[O:29])[CH2:27][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:21][C:20]2=[O:30])[CH3:16])[CH2:13][CH2:14]1
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Reactant: C[C@H](CCl)N1C(=O)CC2(CCCC2)CC1=O
Product: C[C@H](CN1CCN(c2cc(F)ccc2F)CC1)N1C(=O)CC2(CCCC2)CC1=O
Temperature: 160 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A mixture of 1-(2,5-difluorophenyl)piperazine (20 mg, 0.10 mmol) and (R)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.082 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC [reverse phase column (C18 HC), water/methanol (70:30) with 0.1% TFA to water/methanol (40:60) with 0.1% TFA gradient, UV detection at λ254 nm or λ215 nm], giving (after removal of the solvent) the title compound as a pale yellow oil (21.5 mg, 0.05 mmol, 66%): ESI-MS m/z 406 (MH+).
Reaction SMILES: C(O)CO.[NH2:5][C:6]1[N:24]=[C:23]([CH3:25])[C:22]([NH:26][C:27](=[O:29])[CH3:28])=[C:21]([CH3:30])[C:7]=1[C:8](NNS(C1C=CC=CC=1)(=O)=O)=[O:9].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)Cl>[NH2:5][C:6]1[N:24]=[C:23]([CH3:25])[C:22]([NH:26][C:27](=[O:29])[CH3:28])=[C:21]([CH3:30])[C:7]=1[CH:8]=[O:9]
Reactant: CC(=O)Nc1c(C)nc(N)c(C(=O)NNS(=O)(=O)c2ccccc2)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1c(C)nc(N)c(C=O)c1C
Temperature: 160 °C
Reaction time: 0.01 h

Procedure:
Ethylene glycol (80 ml.) is heated in an oil-bath at 170° C. until the internal temperature reaches 160° C. N1 -(2-amino-5-acetamido-4,6-dimethylnicotinoyl)-N2 -benzenesulfonyl hydrazine (8.0 g., 21.2 mmole) is added and the mixture stirred until the internal temperature returns to 160° C. Anhydrous sodium carbonate (5.6 g.) is added in one portion, heating is continued for 30 seconds and the reaction mixture cooled rapidly and poured into water (320 ml.). The product is isolated by continuous extraction with methylene chloride for about 24 hours to give 2.90 g. (66%) of crude product. Following purification by crystallization from ethanol the pure product melts at 270°-275° C. (dec.) with rapid heating.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[N:11]([C:17]([C:19]1[O:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[CH:22][CH:23]=1)=[O:18])[CH2:10][CH2:9]2.[OH-].[Na+]>ClCCl>[N:8]12[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]1)[N:11]([C:17]([C:19]1[O:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:1](=[O:3])[CH3:2])=[CH:26][CH:25]=3)=[CH:22][CH:23]=1)=[O:18])[CH2:10][CH2:9]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Reaction time: 4 h

Procedure:
Acetic acid anhydride (133 mg; 1.3 mmol) solved in dichloromethane (2 ml) was added dropwise to a mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone and dichloromethane (10 ml) at room temperature. The mixture was allowed to stir for 4 hours. Aqueous sodium hydroxide (20 ml; 1M) was added followed by extraction with dichloromethane (3×20 ml). The crude mixture was purified by silica gel chromatography, using a mixture of dichloromethane:methanol (4:1) and 2% methanol as eluent. The product was isolated as the free base. Mp. 113° C. (decomp.).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11](=[O:33])[N:12]([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][N:14]=1)([CH3:9])([CH3:8])[CH3:7].C[N:35](CCN(C)C)C.[N-]=[N+]=[N-].[Na+]>C(OCC)(=O)C.O>[NH2:35][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH2:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)([CH3:24])[CH3:25])[C:11](=[O:33])[O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[N:14][CH:15]=1
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCO)cn1
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCN)cn1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (87 μL, 1.1 mmol, 1.1 equiv) dissolved in 2 mL ethyl acetate was added to a 20 dram vial. To this stirring mixture was added a mixture of tert-butyl-2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)-carbamate (414 mg, 1.1 mmol, 1.0 equiv), TMEDA (167 μL, 1.1 mmol, 1.1 equiv), and ethyl acetate (3 mL) in a dropwise manner. The reaction was stirred for 1 h. The reaction mixture was then filtered and washed with saturated sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resultant solid was dissolved in DMF (4 mL), followed by the addition of sodium azide (139 mg, 2.1 mmol, 2.0 equiv). The reaction was stirred for 24 h, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in methanol, followed by the addition of 10% palladium on carbon (80 mg), potassium carbonate (100 mg). The reaction was stirred under 45 psi of hydrogen for 24 h, filtered, and concentrated to give tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[C:12](=[O:31])[NH:11][C:10]=3[CH:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.Cl[CH2:35][C:36]1[O:40][N:39]=[C:38]([CH2:41][O:42][CH3:43])[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]4)[C:12](=[O:31])[N:11]([CH2:35][C:36]4[O:40][N:39]=[C:38]([CH2:41][O:42][CH3:43])[N:37]=4)[C:10]=3[CH:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c2s1
Reactant: COCc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[6-(4-fluoro-2-methoxyphenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (1.0 g, compound B63) and 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole (342 mg) in dry DMF (20 ml) is added potassium carbonate (291 mg). The mixture is stirred for 2 h at 100° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo. The residue is purified by flash column chromatography [amino phase silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 (v/v)] to afford the title compound as a solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (167 mg, 0.51 mmol) and 4-bromo-benzenesulfonamide (121 mg, 0.51 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 57%). MS (ISP) 483.4 [(M+H)+]; mp 259-261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[S:14]([CH2:24][N+:25]#[C-:26])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[C-]#N.[Na+]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[O:7][CH:26]=[N:25][C@@H:24]2[S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
In a manner analogous to Preparation 1, 4-chloro-3-(trifluoromethyl)benzaldehyde (0.31 g, 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 404.5 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23]([NH2:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>C(O)(C)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH:32][C:23]([CH3:25])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:24])=[N:3][C:4]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Solvent: CC(C)O
Product: Cn1c(NC(C)(C)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Temperature: 25 °C

Procedure:
2-Chloro-3-methyl-6-(4-pyridyl)-5-(4-fluorophenyl)-4(3H)-pyrimidinone (5.43 g, 17.2 mmol) and cumyl amine (4.65 g, 34.4 mmol) were combined in dry isopropyl alcohol (ca. 40 mL) and the mixture was heated at reflux for 48 h. The reaction was cooled to RT, the solvent was evaporated in vacuo and the residue was partitioned between sat. aq. NaHCO3 and CHCl3. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (1% MeOH/NH3:CHCl3) to provide the product as a tan solid; MS: m/z (M+H)+ 415; C25H23FN4O requir. 414.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH:8]=[CH:9][NH:10]2)=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].S(Cl)([Cl:20])=O>CN(C=O)C>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 7-methoxy-6-methoxycarbonyl-1,4-dihydroquinolin-4-one (5.4 g, 23 mmol), DMF (0.4 ml) and thionyl chloride (75 ml) was heated at reflux for 2 hours and then stirred at ambient temperature for a further 2 hours. The excess thionyl chloride was removed by evaporation and by azeotroping with toluene. The residue was suspended in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried by passing through phase separating paper and the solvent was removed by evaporation. The residue was suspended in ether, collected by filtration, washed with hexane and dried to give 4-chloro-7-methoxy-6-methoxycarbonylquinoline (4.06 g, 70%) as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[O:11])=[CH:8][CH:7]=1>C(NCCCC)CCC>[CH2:12]([N:13]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:14][CH2:19][CH2:18][CH3:17])[CH2:10][CH2:9][CH3:8]
Reactant: Cc1cccn2cc(C(=O)c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cn3cccc(C)c3n2)cc1
Yield: 197.7 %

Procedure:
A mixture of 2-(4-chloropropoxybenzoyl)-8-methylimidazo-[1,2-a]pyridine (2,4 g, 6.0 mmol) in dibutylamine (30 ml) was stirred at reflux for 8 hours. The excess dibutylamine was removed by distillation and the resulting oil was flash chromatographed (silica gel, acetone) to give the free base of the title compound (2.5 g, 100% yield) as a thick oil. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the title compound in methanol, concentrated and recrystallized from methanol-acetone, mp 159° C. to 161° C. IR(KBr): 3420, 1650cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ8.89 (s, 1H), 8.72 (d, J=6.6 Hz, 1H), 8.15 (d, J=8.9 Hz, 2H), 7.89 (d, J=7.3 Hz, 1H), 7.48 (t, J=6.9 Hz, 1H), 7.21 (d, J= 8.9 Hz, 2H), 4.29 (t, J=7 Hz, 2H), 3.26 (m, 6H), 2.73 (s, 3H), 2.33 (m, 2H), 1.79-1.35 (m, 8H), 1.02 (m, 6H).