Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:24]I.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:10]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH3:24])[CH2:15][CH2:16]2)=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1N1CCC(O)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CCN(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)CC1
Reaction time: 24 h

Procedure:
2-Chloro-3-(4-hydroxypiperidin-1-yl)-4-methylsulfonylbenzoic acid (0.70 g, 2.1 mmol) was added with stirring to a suspension of 0.25 g (6.3 mmol) of sodium hydride in a mixture of 0.40 mL (6.4 mmol) of methyl iodide and 10 mL of dry tetrahydrofuran. The mixture was heated to reflux and stirred for 24 hr. The resulting mixture was treated with water, acidified with 1N aqueous hydrochloric acid and extracted several times with dichloromethane. The organic layers were combined and dried over magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was rinsed with petroleum ether to obtain 0.70 g (96 percent of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]
Reactant: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)C[C@@H](C)C2)c1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(OCOC)c(C2CC(C)CC2C(=O)OC)c1
Yield: 100 %

Procedure:
To a suspension of 10% palladium on carbon (0.5 g) in methanol (40 mL) add a solution of 2-(2,5-Bis-met oxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol) in methanol (10 mL). Place the mixture under hydrogen (60 psi) at 40° C. for twelve hours. Purge the reaction with nitrogen and filter through celite. Concentrate the filtrate in vacuo to yield 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methyl ester (2.47 g, 7.1 mmol, 100%) as a clear oil. 1H NMR (δ, 400 MHz, CDCl3): 6.98 (d, 1H, J=8.8 Hz), 6.85 (d, 1H, J=8.8), 6.81 (dd, 1H, J=3.2, 8.8 Hz), 5.15 (s, 2H), 5.10 (d, 1H, J=6.6 Hz), 5.07 (d, J=6.6 Hz), 3.77-3.67 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.38-3.31 (m, 1H), 3.15 (s, 3H), 2.19-2.03 (m, 2H), 1.96-1.68 (m, 3H), 1.19 (d, 3H, J=6.2 Hz). HRMS calcd. 339.1808; found (electrospray, M+1) 339.1818.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1
Reactant: COCc1ccc(CO)c(N)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCc1ccc(C=O)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a mixture of (2-amino-6-methoxymethyl-pyridin-3-yl)methanol (260 mg, 1.5 mmol) described in Manufacturing Example 26-1-5 and methylene chloride (15 mL) was added manganese dioxide (1.3 g, 15 mmol), which was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=3:2) to obtain the title compound (210 mg, 81%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([C:9]2[CH:18]=[C:17]3[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[C:3]([C:2]([F:21])([F:20])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Oc1ccnc2cc(-c3ncccc3C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccnc1-c1ccc2c(Cl)ccnc2c1

Procedure:
Reflux 7-[3-(trifluoromethyl)pyridin-2-yl]quinolin-4-ol (145 mg) for 2 hours in POCl3 (2 mL). Evaporate the solvent, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry-over Na2SO4, concentrate under vacuum to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([C:28]#[CH:29])([O:18][C:19]([O:21]C3C=CC=CC=3)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[CH2:37]([NH:44][C:19]([O:18][C:15]1([C:28]#[CH:29])[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:17][CH2:16]1)=[O:21])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C#CC1(OC(=O)Oc2ccccc2)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: C#CC1(OC(=O)NCc2ccccc2)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 10 h
Yield: 75.7 %

Procedure:
9.8 g of 1-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-ethynyl -4-phenoxycarbonyloxypiperidine are stirred with 9 ml of benzylamine at 42° C. under nitrogen for 30 minutes, then at room temperature for 10 hours. Thereafter, benzene is added to the reaction mixture and washed first with an aqueous sodium hydroxide solution of 1 ml/liter concentration, then with water and dried over anhydrous magnesium sulfate. After evaporating the solution under reduced pressure, the residue is boiled in hexane and after filtration it is recrystallization from diisopropyl ether to give the title product in 75.7% yield, m.p.: 94°-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:13]=2)[N:8]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:7]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:5])[CH3:2].[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>CCOC(C)=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>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:43]3[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=3)[CH:13]=2)[N:8]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:7]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(OS(=O)(=O)C(F)(F)F)ccc2n1-c1ccc(C(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
A mixture 2-ethoxycarbonylmethyl-1-(4-isopropylphenyl)-5-trifluoromethane-sulfonyloxyindole-3-carboxylic acid ethyl ester (133 mg, 0.25 mmol, see step (a) above), 4-trifluoromethylphenylboronic acid (142 mg, 0.75 mmol), K2CO3 (276 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) and anhydrous dioxane (10 mL) was stirred at 90° C. for 4 h. The mixture was diluted with EtOAc (30 mL), washed with saturated NaHCO3 (aq, sat) dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 102 mg (76%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:8])CC1)#[N:2].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[C:1]([CH2:3][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:39]3[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]3)=[CH:19][C:18]=2[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:8])#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccc(F)cc2)CC1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(S(=O)(=O)[C@H]3C[C@@H](COc4ccc(F)cc4)[C@H](C(=O)NCC#N)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(4-fluoro-phenoxymethyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 145) and 1-ethyl-piperazine. Yellow oil. MS (EI): 563.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl-].[Cl-].[CH3:6][C:7]([CH3:30])([CH3:29])[CH2:8][C:9]1[N:10]=[C:11]([CH:14](F)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][NH+:23]=3)=[CH:18][CH:17]=2)[NH2+:12][CH:13]=1>O1CCCC1>[CH3:6][C:7]([CH3:30])([CH3:29])[CH2:8][C:9]1[N:10]=[C:11]([CH:14]([NH:3][CH2:1][CH3:2])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[NH:12][CH:13]=1
Reactant: CCN
Reactant: CC(C)(C)CC1=C[NH2+]C(C(F)Cc2ccc(-c3cccc[nH+]3)cc2)=N1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCNC(Cc1ccc(-c2ccccn2)cc1)c1nc(CC(C)(C)C)c[nH]1
Temperature: 25 °C

Procedure:
Ethylamine (2 M in tetrahydrofuran) (excess) was added to an ambient temperature solution of 2-(4-{2-[4-(2,2-dimethylpropyl)-1H-imidazol-1-ium-2-yl]-2-fluoroethyl}phenyl)pyridinium dichloride (for synthesis see Example 2) (10 mg, 0.03 mmol) in tetrahydrofuran (3 mL). After stirring at ambient temperature until no further reaction (LCMS), the reaction mixture was concentrated. Preparative plate chromatography eluting with 40% methanol/ethyl acetate afforded the title compound. (M+H) found: 363.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])[CH:5]=[N:6][CH:7]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[C:10]([F:18])=[CH:11][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:13][C:14]=2[F:15])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cc(F)c(Oc2cncc(Cl)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4cncc(Cl)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl.O=O.[CH3:12][OH:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:2]3[C:7]([C:12](=[O:13])[C:3]=2[CH:4]=1)=[CH:6][C:5]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:12](=[O:13])[C:4]=1[CH:3]=3
Reactant: Cc1ccc(N)cc1
Reactant: CO
Agent: Cl
Agent: O=O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
1 Mole of 1,4-cyclohexanedione-2,5-di(methyl carboxylate), methanol whose weight was 10 times the weight of the 1,4-cyclohexanedione-2,5-di(methyl carboxylate), 2.53 mol of p-toluidine and 0.1 mol of hydrochloric acid were allowed to react at 65°-100° C. for 3 hours while they were substantially not in contact with oxygen, and the formed product was recovered by filtration and washed. This product was further heated to 250°-268° C. in a dimethylnaphthalene isomer mixture while it was substantially not in contact with oxygen, and the resultant product was recovered by filtration and washed. Added thereto were ethylene glycol monoethyl ether whose amount was 7 times the weight thereof and 50% caustic soda in such an amount that was 18% based on the total amount of the mixture. Then, sodium m-nitrobenzenesulfonate was added for oxidation, and the formed product was recovered by filtration and washed to give a crude 2,9-dimethylquinacridone having a purity of at least 99%. The crude 2,9-dimethylquinacridone obtained in this Referential Example was used in the following Examples.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([OH:23])=O)=[CH:9][CH:10]=2)[N:5]=1)=[O:3].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:2]([NH2:1])=[O:3])[CH:13]=2)=[CH:19][CH:18]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)N3CCCC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
2-(Aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3, 50.0 mg, 0.161 mmol, 1.0 equiv), pyrrolidine (11.5 mg, 0.161 mmol, 1.0 equiv.), BOP (93.0 mg, 0.209 mmol, 1.3 equiv.), and TEA (0.0670 mL, 0.483 mmol, 3 equiv) were dissolved into DMF (1.0 mL) and stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-Fluorophenyl)-7-(pyrrolidin-1-ylcarbonyl)quinoline-2-carboxamide (5-4, 50.0 mg, 85.0%) as a colorless solid. 1H NMR (500 MHz, CDCl3): δ 8.324 (d, J=1.47 Hz, 1H); 8.273 (s, 1H); 8.251 (br s, 1H); 8.026 (d, J=8.78 Hz, 1H); 7.762 (dd, J1=8.54 Hz, J2=1.71 Hz, 1H); 7.501-7.529 (m, 2H); 7.246-7.286 (m, 2H); 6.750 (br s, 1H); 3.765 (tr, J=6.95 Hz, 2H); 3.567 (tr, J=6.68 Hz, 2H); 2.055 (quint, J=6.78 Hz, 2H); 1.962 (quint, J=6.65 Hz, 2H). LRMS m/z (M+H)+ 364.1 found, 364.1 required.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:26]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)=[N:27][N:28]4[CH:33]=[C:32]([C:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(Cl)(Cl)(Cl)[Cl:52]>O1CCCC1>[Cl:52][C:33]1[N:28]2[N:27]=[C:26]([C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)[C:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:18][CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]=3)=[C:29]2[CH:30]=[CH:31][C:32]=1[C:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (4.1 mL, 29 mmol) in tetrahydrofuran (25 mL) was added butyllithium (17 mL, 1.6 M in hexanes, 28 mmol) dropwise. The resultant solution was stirred at 0° C. for 10 minutes then cooled to −78° C. The reaction mixture was transferred via syringe to a cold (−78° C.) solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (4.86 g, 9.35 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at −78° C. for 30 minutes. Carbon tetrachloride (3.6 mL, 37 mmol) was added and the resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured onto ice. After the ice had melted, the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.37 g, 46%) as a yellow solid. Rf 0.36 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.08 (d, 1H), 7.85 (d, 1H), 7.67 (m, 2H), 7.15 (t, 2H), 6.33 (d, 1H), 5.15 (d, 1H), 4.36 (m, 1H), 3.46 (q, 6H), 2.10 (m, 2H), 1.81–1.53 (m, 6H), 1.26 (t, 9H); MS m/z 554 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=O)=[CH:5]2)[CH2:3][CH2:2]1.C([N:22](CC)CC)C.ClC(OCC)=O.N>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([NH2:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: CCOC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (1.00 g, 3.77 mmol) was dissolved in dimethylformamide (15 ml), added with triethylamine (0.788 ml, 5.66 mmol) and ethyl chloroformate (0.538 ml, 5.66 mmol) under ice cooling, and stirred for 1 hour. The reaction mixture was warmed to room temperature, stirred for 30 minutes, and further stirred at 0° C. for 1 hour. The reaction mixture was added with concentrated aqueous ammonia (0.75 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (1.23 g, quantitative) as white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11].[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CO)CCCCCCCBr
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of ethyl 9-bromo-2,2-dimethylnonanoate (example 103, step a) (1.27 g) in dry diethyl ether (40 mL) at 0° C. under N2 was added diisobutylaluminium hydride (1 M in toluene, 9.5 mL) dropwise. The reaction mixture was stirred at 0° C. for 1.25 h then quenched by addition of saturated potassium sodium tartrate solution (150 mL). The mixture was stirred for 15 min then extracted with ethyl acetate (×3) then the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 0.56 g.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:20][C:13]1[C:14]2[O:15][CH2:16][CH2:17][O:18][C:19]=2[C:10]([C:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)c2c1OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CCC(=O)CC2)c2c1OCCO2
Yield: 93.9 %

Procedure:
To the mixture of Compound 2a (1.2 g, 3.6 mmol) obtained in Step A of Example 2 and p-toluenesulfonic acid monohydrate (1.2 mg, 0.0063 mmol) were added water (70 mL) and toluene (140 mL ), followed by refluxing for 4 hours. The mixture was allowed to cool, the mixture was extracted with toluene, and the extract was washed with a saturated aqueous solution of sodium bicarbonate and then with brine. The mixture was dried over sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 16 (0.88 g, 94%) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([C:13]([F:12])([F:22])[F:23])[CH:15]=1
Reactant: COC(=O)[C@@]1(C)CCCN1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@]1(C)CCCN1Cc1cccc(C(F)(F)F)c1
Yield: 47.3 %

Procedure:
The title compound (D10) (47 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride (D3) (60 mg, 0.33 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.076 ml, 0.50 mmol). (Na2CO3: 3 eq; Reaction time: 8 hrs; 60° C.).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:23]([CH3:34])[CH:22]=1)[C:6]1[C:7]([CH3:19])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([N:5]([CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:23]([CH3:34])[CH:22]=1)[C:6]1[C:7]([CH3:19])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Ethyl (4-{[butyl(2,4′-dimethyl-1,1′-biphenyl-3-yl)amino]methyl}-2-methylphenoxy)acetate (12.7 g, 27.6 mmol) was dissolved in THF (210 mL) and water (70 ml) was added, followed by 2M aq. NaOH (61 mL, 122 mmol). The reaction was stirred at room temperature for 1/2 hr and then evaporated to give a white slurry. The suspension was diluted with water (100 mL) and pH adjusted to pH7 with 2M aq HCl. EtOAc (200 mL) the aqueous layer was separated and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (200 mL), dried (Na2SO4) and concentrated In vacuo to give the title compound as a white foam (11.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])#[N:2].OO.Cl([O-])=[O:15].[Na+]>O.C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]([OH:15])=[O:9])#[N:2]
Reactant: N#Cc1ccc(F)c(C=O)c1
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
NaH2PO4 (87 mg, 0.724 mmol) in water (3.5 mL) was added to a solution of 5-cyano-2-fluorobenzaldehyde (500 mg, 3.35 mmol) in acetonitrile (7 mL), followed by 30% H2O2 (0.31 mL). Sodium chlorite (434 mg, 4.8 mmol) in water (3.5 mL) was added dropwise to this reaction mixture at 0° C. The mixture was stirred at room temperature for 1 h, quenched with aqueous sodium sulfite solution at 0° C. and then acidified with 1.5N HCl solution. The aqueous solution was extracted with EtOAc and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-cyano-2-fluorobenzoic acid (500 mg, yield 90%). 1H NMR (300 MHz, DMSO-d6) δ 13.79 (br s, 1H), 8.30-8.27 (dd, J=6.6 Hz, 2.2 Hz, 1H), 8.17-8.12 (ddd, J=8.6 Hz, 4.4 Hz, 2.3 Hz, 1H), 7.60-7.53 (dd, J=10.5 Hz, 8.8 Hz, 1H). MS (ESI) m/z: Calculated for C8H4FNO2: 165.02. found: 163.6 (M−H)−.