Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH2:6]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]([S:34][CH3:35])=[CH:19]2)[CH2:7][CH2:8][CH2:9][CH2:10]CCCCC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:24]1[CH:23]=[C:22]2[C:6](=[CH:7][CH:8]=1)[CH:16]=[C:19](/[CH:18]=[CH:17]/[C:21]1[C:20]([S:34][CH3:35])=[CH:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:17]=3)[CH:22]=1)[C:20]([S:34][CH3:35])=[CH:21]2)[CH2:16][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCc1ccc2cc(OS(=O)(=O)C(F)(F)F)c(SC)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1ccc2cc(/C=C/c3cc4ccc(CCCCCCCCCC)cc4cc3SC)c(SC)cc2c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 257.7 %

Procedure:
Pd(PPh3)4 (322 mg, 0.29 mmol, 7 mol %) was added to a DMF (40 ml) solution of 6-decyl-3-methylthio-2-(trifluoromethanesulfonyloxy)naphthalene (compound (4)-81) (1.9 g, 4.1 mmol) and 1,2-bis(tributylstanyl)ethylene (compound (5)-05). The mixture was heated and stirred at 90° C. for 17 hours in a dark place, diluted with water, and extracted with chloroform. The extracted solution was dried with MgSO4, and condensed. The residue was refined by column chromatography (silica gel, developed with dichloromethane) to obtain trans-1,2-bis(6-decyl-3-methylthionaphthalen-2-yl)ethylene (compound (6)-64) (2.3 g, quantitative) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.CON(C)[C:26](=[O:28])[CH3:27].[NH4+].[Cl-]>C1COCC1>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CON(C)C(C)=O
Reactant: CC(C)Oc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc(OC(C)C)nc1
Temperature: -66 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A round-bottomed flask was charged with 5-bromo-2-iso-propoxypyridine (IM1) (5.00 g, 23.1 mmol) in THF (100) under N2 and cooled in an acetone/dry-ice bath to −66° C. (internal temperature). A solution of 2.5 M n-butyllithium in hexane (10.1 mL, 25.3 mmol) was added drop wise over 10 minutes at keeping the internal temperature below −55° C. The mixture was stirred at −65° C. for 15 minutes. N-methoxy-N-methylacetamide (3.07 mL, 28.9 mmol) dissolved in THF (10 mL) was then added drop wise over 10 minutes while keeping the internal temperature below −65° C. After stirring for 1 h the mixture was allowed to reach room temperature. The mixture was poured into saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (3.20 g, 77%) sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([NH:19][C@@H:20]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[CH3:21])=[O:18])[S:14][C:11]=2[NH:12][N:13]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH2:36][OH:37]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([NH:19][C@@H:20]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[CH3:21])=[O:18])[S:14][C:11]=2[N:12]([CH2:35][CH2:36][OH:37])[N:13]=1
Reactant: Cc1noc([C@@H](C)NC(=O)c2cc3c(-c4ccc(F)cc4F)n[nH]c3s2)n1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc3c(-c4ccc(F)cc4F)nn(CCO)c3s2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
3-(2,4-Difluorophenyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide (203.5 mg, 0.523 mmol) and potassium carbonate (331.5 mg, 2.40 mmol) were dissolved in N,N-dimethylformamide (5.20 ml) at 25° C. 2-Iodoethanol (69 μL, 0.885 mmol) was added. The reaction was heated to 50° C. and stirred for 4 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (10 mL), and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with saturated aqueous ammonium chloride (2×10 mL) and saturated aqueous sodium chloride (1×10 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 40 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-100%). The title compound (129.6 mg, 0.299 mmol, 57.2% yield) was recovered as a light yellow/white solid. The undesired regioisomer, 3-(2,4-difluorophenyl)-2-(2-hydroxyethyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-2H-indazole-6-carboxamide (33.1 mg, 0.076 mmol, 14.61% yield), was recovered as a light yellow/white solid. Title compound: HRMS [M+1] found=434.1091. 1H NMR (400 MHz, CDCl3): δ 7.99-7.89 (m, 1H); 7.61 (d, J=3.7 Hz, 1H); 7.01-6.91 (m, 2H); 6.80 (d, J=7.8 Hz, 1H); 5.60-5.51 (m, 1H); 4.39-4.34 (m, 2H); 4.15 (d, J=5.4 Hz, 2H); 2.90 (s, 1H); 2.40 (s, 3H); 1.70 (d, J=7.1 Hz, 3H). Regioisomer: HRMS [M+1] found 434.1095.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@@H:27]2[N:31]3[C:32](=[O:45])[CH:33](P(=O)(OCC)OCC)[CH2:34][CH2:35][CH2:36][C@@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]>O1CCCC1.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C@@H:27]2[N:31]3[C:32](=[O:45])/[C:33](=[CH:8]/[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[CH2:34][CH2:35][CH2:36][C@@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CCOP(=O)(OCC)C1CCC[C@@H]2CC[C@H](c3ccc(F)c(F)c3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CCC[C@@H]3CC[C@H](c4ccc(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
Lithium hydroxide (0.0668 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.20 g) and diethyl [(3R,9aR)-3-(3,4-difluorophenyl)-5-oxooctahydropyrrolo[1,2-a]azepin-6-yl]phosphonate (0.25 g) in tetrahydrofuran (1 mL) and ethanol (4 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added to ice-sodium bicarbonate water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.20 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:32])[CH:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:15][CH2:14][CH:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:32]
Reactant: CC(C)[Si](OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cnccc2c1)C(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401) in THF cooled to 0° C. was added TBAF and this solution was stirred for 3 h at 0° C. The mixture was poured into EtOAc/NH4Cl(sat) washed with NH4Cl(sat). The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (0-10% MeOH/CH2Cl2) gave pure 3-hydroxy-N-(isoquinolin-6-yl)-2-phenylpropanamide (E402).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[C:41]1([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[ClH:58].O1CCOCC1>>[ClH:58].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:38])([F:39])[F:40]
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Reactant: OCCCCCCCCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O)OCCCCCCCCCCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
984 mg (1.74 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 2.12 g (8.68 mmol) of 10-phenyl-1-decyl alcohol were mixed, 17.4 mL (69.6 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 50° C. for 4 hours.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[H-].[Na+].Cl[C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][N:12]=1>O1CCCC1>[NH2:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][O:4][C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][N:12]=1
Reactant: CCCC(N)CO
Reactant: Clc1noc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(N)COc1noc2ccccc12
Yield: 88.1 %

Procedure:
A solution of 2.86 g of 2-amino-1-pentanol in 2 ml of tetrahydrofuran is added to a suspension of 2.24 g of 60% (w/w) sodium hydride in 20 ml of tetrahydrofuran at 20°-25° C. and they are refluxed for two hours. Subsequently, under reflux, a solution of 4.3 g of 3-chloro-1,2-benzoisoxazole in 30 ml of tetrahydrofuran is added and refluxed for a further one hour. After cooling, the solvent is removed by distillation under reduced pressure. Ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and thereafter purified by a silica gel column chromatography [eluant:chloroform:methanol=20:1], to obtain 5.38 g of oily 3-(2-aminopentyloxy)-1,2-benzoisoxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN
Reactant: COc1ccc2c(c1)CC(=O)CC2
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNC1CCc2ccc(OC)cc2C1
Yield: 61 %

Procedure:
A solution of 7-methoxy-2-tetralone (32 mmol. 5 g), n-propylamine (60 mmol. 5 mL), acetic acid (60 mmol. 4 mL), molecular sieves 3A (5 g) in ethanol (25 mL) was stirred at room temperature for 2.5 hrs. The solution was filtered on paper in a Paar bottle and the reduction was carried out with PtO2 (100 mg) as the catalyst, under 30 PSI of hydrogen. When the pressure dropped to 6 PSI (30 min.), the catalyst was removed by elution onto a column (celite 545) with chloroform. The eluent was concentrated under vacuum. The residue, a brown oil, was converted to solid by formation of hydrogen chloride salt in ether/HCl. Several recrystallizations in ether/methanol (60/40) afforded the final product (1) as white crystals (4.28 g, 61% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)c(OCC2CC2)c1
Reaction time: 6 h
Yield: 84 %

Procedure:
To a stirred solution of ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100 mL) was added Pd(OH)2 (2 g). The mixture was hydrogenated under a H2 atmosphere for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield 7.5 g of the desired product as an oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: Cl
Product: O=C(O)CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Yield: 62.9 %

Procedure:
The solution of tert-butyl 2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetate (40 mg, 0.116 mmol) in HCl-1 M (5 ml, 165 mmol) was stirred at the 50° C. for 24 hours. The solution was evaporated. The oil was suspended in acetonitrile, sonicated and filtered. 2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetic acid (25 mg, 0.073 mmol, 63.0% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.30-7.38 (m, 2H), 7.17-7.29 (m, 3H), 4.13 (s, 2H), 3.74 (dd, J=1.52, 3.79 Hz, 2H), 3.11-3.29 (m, 4H), 3.05 (dt, J=4.14, 7.64 Hz, 1H), 2.61 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.15 (d, J=14.91 Hz, 3H), 1.73 (d, 2H), 1.62 (ddd, J=4.29, 6.63, 10.55 Hz, 1H), 1.37-1.49 (m, 1H); LC-MS Rt=0.39 min; MS (ESI): 289.3 [M+H]+.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C([BH3-])#N.[Na+]>>[CH:12]1([NH:6][C:5]2[CH:7]=[CH:8][CH:2]=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc(I)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: c1ccc(NC2CC2)cc1

Procedure:
4-Iodoaniline (F-0) is reductively alkylated with [(1-ethoxycyclopropyl)oxy]trimethylsilane and sodium cyanoborohydride to give the N-cyclopropyl aniline (F-1). Treatment with diethyl ethoxymethylenemalonate in pyridine affords the enamine (F-2) which is cyclized with polyphosphoric acid to the quinoline (F-3). Treatment with p-chlorobenzylamine at elevated temperature converts the ester to the amide (F-4). Palladium catalyzed coupling of the iodide with propargyl alcohol affords F-5. Reaction with platinum and hydrogen gas affords the saturated propyl alcohol (F-6).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH2:21][CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:21]([C:4]1[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:7]=[N:6][C:5]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH3:22]
Reactant: C1CCNCC1
Reactant: CCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)c1
Product: CCc1cc(N2CCCCC2)nnc1Cn1ccnc1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-4-ethyl-3-[2-(3-fluoro-phenyl)-imidazol-1-ylmethyl]-pyridazine (55.3 mg, 0.17 mmol) and piperidine (5 mL) is heated at 110° C. for 5 hours. Excess piperidine is removed and the residue is purified by PTLC to give the title compound. LC-MS (M+1) 366.2 (retention time: 0.91 min).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[N:7]=[C:6]([C:18]([F:21])([F:19])[F:20])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:35])[CH3:2]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1SCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1S(=O)CC
Yield: 90.2 %

Procedure:
To a 0° C. solution of 4.8 g (0.012 mol) of product of Example 33 in 30 ml of CH2Cl2 was added 4.08 g (0.024 mol) of MCPBA. The reaction was monitored by TLC. The reaction mixture was filtered, washed with NaHCO3, dried (MgSO4) and concentrated in vacuo to give 4.56 g of solid which was purified by HPLC using 8% ethyl acetate/cyclohexane to elute the first fraction (1.52 g) followed by 15% ethyl acetate/cyclohexane to elute 1.46 g of the desired product. Recrystallization of the 1.46 g solid in hot hexane afforded 0.88 g (17.4%) of product as a white solid; mp 87°-88.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)O)cc2o1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)N(C)C)cc2o1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-6-carboxylic acid (150 mg, 0.343 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (125 mg, 1.03 mmol) and EDC (99 mg, 0.514 mmol). The mixture is stirred for 15 m at RT, and dimethylamine hydrochloride (42 mg, 0.514 mmol) is added. The reaction is stirred for 18 h and quenched with aqueous NH4Cl (5.0 mL). The organic layer is loaded onto a silica gel column and purified with 50% EtOAc/Hex to afford the title compound (125 mg, 79%). MS (ES) m/e: 465.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:74][C:75]([CH3:79])([CH3:78])[CH2:76][NH2:77]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:77][CH2:76][C:75]([CH3:79])([CH3:78])[CH3:74])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC(C)(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2,2-dimethyl-1-propanamine (8.65 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.8 mg, 50%). LC-MS m/z 643 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].B.C1COCC1>>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Agent: B
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc([C@@H](O)CBr)cc1

Procedure:
The title compound was prepared from N-[4-(2-bromoacetyl)phenyl]methanesulfonamide (0.23 g, 0.82 mmol )(which was obtained in Example 111), and 1M BH3/THF solution (10.35 mL, 10.5 mmol) in substantially the same manner, as described in Example 103 and was obtained as a white solid (1.75 g, 72% yield); MS (ES) m/z: 293 (M)+; 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, 2H), 2.95 (s, 3H), 3.53 (m, 1H), 3.55 (m, 1H), 4.73, (m, 1H), 5.75 (d, 1H), 7.14 (d, 2H), 9.74 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21

Procedure:
To a mixture of 8.17 g (0.05 mole) of N-ethylcarbazole and 3.7 g (0.025 mole) of phthalic anhydride in 112 g of chlorobenzene, 6.65 g (0.05 mole) of aluminum chloride was added in small increments at ambient temperature after which the mixture was warmed in the range of 50°-70° C. for two hours. The reaction mixture was poured onto ice and rendered acidic by the addition of 10 percent hydrochloric acid. The chlorobenzene layer was separated and steam-distilled to remove the chlorobenzene. The residue was extracted with 10 percent aqueous sodium hydroxide, filtered to remove the insolubles and then acidified with dilute hydrochloric acid. The solid which separated was collected by filtration, washed with water and dried to obtain 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid (Formula VII: R°=R1 =R2 =R3 =H; R8 =CH2CH3) melting over the range 120°-130° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C
Temperature: 65 °C
Yield: 56 %

Procedure:
To a solution of ethyl 2-chloro-4-methyl-1,3-thiazole-5-carboxylate (X-1) (0.25 g, 1.22 mmol) and phenol (0.15 g, 1.61 mmol) in acetone (3 mL) was added K2CO3 (0.25 g, 1.81 mmol). The mixture was heated for 18 h at 65° C. Additional K2CO3 (0.25 g) was added and the mixture was continued to heat at 70° C. for 24 h. Upon cooling, water was added (10 mL). The mixture was extracted with Et2O. The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a white solid (0.18 g, 56%). 1H NMR (CDCl3) δ 7.44 (m, 2H), 7.33-7.27 (m, 3H), 4.26 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).