Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[C:14](=[O:20])[CH:15](I)[CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[C:14](=[O:20])[CH:15]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C(I)CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (4R*,10aS*)-4-(4-fluorophenyl)-7-iodooctahydropyrido[1,2-a]azepin-6-one (208 mg) with triethyl phosphite (2 mL) was stirred at 120° C. for 1.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 213 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].CO.[CH3:36][NH:37][CH3:38]>C1COCC1>[CH3:36][N:37]([CH3:38])[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8]
Reactant: CNC
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Step 4): A mixture of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (13.4 g, 30 mmol) and 2.0M MeOH solution of dimethylamine (45 ml, 90 mmol) in THF (100 ml) was refluxed for 22 hours. The resulting solution was evaporated to give 5-dimethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as yellow powders, 14.1 g (99.6%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2([CH3:34])[CH:13]([C:14]([O:16]CC(Cl)(Cl)Cl)=[O:15])[N:12]3[C:22](=[O:33])[CH:23]([NH:24][C:25](=[O:32])[CH2:26][N:27]4[CH:31]=[N:30][N:29]=[N:28]4)[C@H:11]3[S:10]2)=[N:5][N:4]=[N:3]1.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2([CH3:34])[CH:13]([C:14]([OH:16])=[O:15])[N:12]3[C:22](=[O:33])[CH:23]([NH:24][C:25](=[O:32])[CH2:26][N:27]4[CH:31]=[N:30][N:29]=[N:28]4)[C@H:11]3[S:10]2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1(C)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1nnnc1SCC1(C)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)O
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
2,2,2-Trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) acetamido]-penam-3-carboxylate (0.6 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.9 ml) and zinc powder (0.8 g) under cooling at -15° C. and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off and the filtrate was poured into 5% hydrochloric acid (20 ml) and then extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was crystallized from ether to give 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) acetamido]penam-3-carboxylic acid (0.25 g). mp. 152° to 154° C.
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]([CH2:31][CH2:32][CH3:33])=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[C:13]([C:14]1[N:15]=[C:16]([CH2:31][CH2:32][CH3:33])[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:10]=1[I:11])#[N:12]
Reactant: ICI
Reactant: CCCc1nc(C#N)c(N)n1CCOCCNC(=O)OC(C)(C)C
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C#N)c(I)n1CCOCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 66 %

Procedure:
A solution of isoamylnitrite (96 mL, 715 mmol), diiodomethane (475 mL), and chloroform (240 mL) was heated to 80° C. over a period of one hour. A solution of tert-butyl 2-[2-(5-amino-4-cyano-2-propyl-1H-imidazol-1-yl)ethoxy]ethylcarbamate (64.3 g, 191 mmol) in chloroform (240 mL) was added dropwise over a period of 115 minutes. During the addition the reaction temperature was decrease to 74° C. The reaction was allowed to cool to 50° C., and the chloroform was removed under reduced pressure. The resulting liquid was diluted with a small volume of dichloromethane and was purified by chromatography on silica gel (eluting sequentially with hexanes and ethyl acetate) and dried under high vacuum at 60° C. for eight hours to provide 56.3 g (66%) of tert-butyl 2-[2-(4-cyano-5-iodo-2-propyl-1H-imidazol-1-yl)ethoxy]ethylcarbamate as a dark orange oil containing a small amount of diiodomethane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:31][NH2:32].[CH2:33](O)[CH3:34]>>[CH3:4][C:16]1[CH:15]=[C:17]([CH:18]=[CH:33][CH:34]=1)[CH:22]=[N:31][NH:32][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH:16]=[C:4]2[N:3]=1
Reactant: Cc1ccccc1-c1cc2nc(Cl)cc(N3CCOCC3)n2n1
Reactant: NN
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4C)cc3n2)c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-2-(2-methyl-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (72.1 mg, 0.219 mM) and then potassium carbonate (32.8 mg, 0.241 mM) and hydrazine monohydrate (106 μL, 2.19 mM) were added to the suspension. This suspension was stirred at 150° C. for 20 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined together and then dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (25.4 μL, 0.219 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to give the title compound (11.2 mg, overall yield of these two steps: 12%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[C:14]([C:15](Cl)=[O:16])=[C:13]([CH3:18])[O:12][N:11]=1.C([N:21]([CH2:24][CH3:25])CC)C.[C:26]([OH:29])(=O)[CH3:27]>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[C:14]([C:15]([NH:21][CH:24]2[CH2:25][CH2:18][CH2:13][CH:14]([CH2:10][C:26](=[O:29])[CH2:27][C:8]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:15]2)=[O:16])=[C:13]([CH3:18])[O:12][N:11]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(=O)O
Agent: Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NC1CCCC(CC(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A compound from preparation 88 (3.0 g; 9.05 mmol) was dissolved in excess, neat acetic acid saturated with HCl(g) (20 mL). After 30 min of stirring at room temperature, in air, the solution was concentrated to dryness by rotary evaporation. Acetic acid was removed from the resultant solid by consecutive dissolution in, and drying from, acetonitrile (thrice) and then diethyl ether (once). The resulting white powder was dissolved in anhydrous dichloromethane (400 mL) under a nitrogen atmosphere. First was added 3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (2.74 g; 9.99 mmol; 1.1 equiv), and then 4-N,N-dimethylaminopyridine (114 mg; 0.93 mmol; 0.1 equiv) and finally triethylamine (5 mL; 36.3 mmol; 4 equiv). The reaction solution was stirred 17 h and then quenched with saturated NaHCO3(aq). The organic layer was washed with saturated NaHCO3(aq) (twice), saturated NaCl(aq) (once), dried with Na2SO4(s), filtered, and concentrated to dryness by rotary evaporation. The resulting oil was dissolved in dichloromethane and purified by column chromatography on a 6×15 cm silica gel bed in dichloromethane. Dichloromethane (1 L) was followed by a 2% tetrahydrofuran/dichloromethane (v/v) mobile phase. A white solid (3.93 g; 95%) was obtained. TOF-MS(ES) calc'd: [M+H]+=469.1694 m/z. Found: 469.1692 m/z.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH3:31])([CH3:30])[CH:24]=[C:23]2[CH3:32])=[O:18])([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.ClCCl>[C:1]([N:26]1[C:27]2[C:22](=[CH:21][C:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[CH:29][CH:28]=2)[C:23]([CH3:32])=[CH:24][C:25]1([CH3:31])[CH3:30])(=[O:3])[CH3:2]
Reactant: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reaction time: 18 h

Procedure:
Acetyl chloride (11.1 ml) and acetic anhydride (11.1 ml) were added dropwise to a solution of 6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (8.5 g) in pyridine (22 ml) and dichloromethane (212 ml). After stirring for 18 h, the reaction mixture was washed with 2 M HCl and water. The organic layer was dried (MgSO4); filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=8/2 (v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[CH2:9][C:8]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Brc1cnc2c(c1)NCC21CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6′-bromo-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine] (89 mg, 0.33 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (90 mg, 0.33 mmol) and hydrochloric acid in 1,4-dioxane (83 μL, 0.330 mmol) in NMP (2.0 mL) and heating in the microwave at 150° C. for 2 h. After purification 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] was obtained as a yellow film. Mass Spectrum (ESI) m/e=505 [(M+1) (79Br)] and 507 [(M+1) (81Br)].
Reaction SMILES: C1(C)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[O:10]=O.[C:12]([OH:15])(=[O:14])[CH3:13]>C([O-])(=O)CCC.[Co+2].C([O-])(=O)CCC.[Co]>[C:7]([OH:8])(=[O:10])[C:4]1[CH:3]=[CH:2][C:13]([C:12]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=O
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Co]
Agent: CCCC(=O)[O-]
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 115 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
A stock solution consisting of 1000 g of glacial acetic acid, 26 g of cobalt butyrate (cobalt concentration 0.50% by weight based on the weight of the solvent) and 200 g of p-tolualdehyde was charged into the same reactor as that used in Example 1 at a rate of 160 ml/hr. The reaction solution was throughly mixed by the stirrer and air was blown therein while the temperature of the inside of the reactor was maintained at 115° C. The reaction was carried out at a reaction pressure of 30 kg/cm2 (i.e. a partial pressure of oxygen of 6 kg/cm2). The vapor phase portion was withdrawn from the reaction system at a rate of 80 l/hr. The value of toluic acid/cobalt in the reaction solution at a steady state was 1.10 and the average residence time of the reaction solution was 150 minutes. As a result, terephthalic acid having an acid value of 671 and a purity of 99.2% was obtained in a yield of 95.0% by mole.
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=1>CN(C1C=CN=CC=1)C.ClCCl>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:26][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][C:17]=1[N+:27]([O-:29])=[O:28])[C:22]([CH3:24])([CH3:25])[CH3:23])=[O:11]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, (1S)-camphanic acid chloride (1.68 g, 7.77 mmol) was added to a solution of (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (2.17 g, 6.47 mmol) and DMAP (1.18 g, 9.7 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred overnight at room temperature and then washed with saturated NaHCO3 solution (60 mL) and water (60 mL). The organic phase was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.94 g, 88%, 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) for diastereomers: δ 8.23 (m, 1 H, Ph-H), 7.90 (m, 1 H, Ph-H), 7.31 (m, 1 H, Ph-H), 6.56 and 6.51 (2 s, 1 H, Ph-CH), 2.38 (m, 1H), 2.07-1.9 (m, 2H), 1.69 (m, 1H), 1.13, 1.11, 1.07, 1.04, 1.02, 0.87 (6 s, 9 H, CH3×3), 0.96 (s, 9 H, (CH3)3C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([CH3:13])[N:12]=1.[CH3:20][N:21]=[C:22]=[S:23]>O1CCCC1>[CH3:13][C:11]1[N:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22]([NH:21][CH3:20])=[S:23])[NH:9][C:10]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1nc(-c2ccccc2N)[nH]c1-c1cccnc1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccccc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.8 g) in tetrahydrofuran (10 ml) was added methyl isothiocyanate (0.33 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for one hour, and refluxed for 20 hours. The resulting precipitate was collected by filtration, and washed with tetrahydrofuran and diethyl ether to give 4-methyl-2-[2-(3-methylthioureido)phenyl]-5-(3-pyridyl)imidazole (0.71 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.B(Br)(Br)Br.N1C2C(=[CH:25][C:26]([OH:30])=CC=2)C=CC=1.BrC[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.CC(C)=O>[O:13]1[CH2:25][CH2:26][O:30][CH:12]1[C:11]1[CH:2]=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH2:15][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCOC(=O)CBr
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc2ncc(C3OCCO3)cc2c1

Procedure:
The masked aldehyde 3-(1,3-dioxolan-2-yl)-quinolin-6-ol LPO 55016 was obtained via a similar method as for SSA 48104 from 2-chloro-6-hydroxyquinoline-3-carbaldehyde LPO 50188A. LPO 50188A itself was prepared by treatment of 2-chloro-6-methoxyquinoline-3-carbaldehyde by boron tribromide (BBr3) in dichloromethane. Finally quinolin-6-ol LPO 55016 was O-alkylated by treatment with ethyl 2-bromoacetate and cesium carbonate as a base in acetone for 2 hours at 85° C. to yield ethyl 2-((3-(1,3-dioxolan-2-yl)quinolin-6-yl)oxy)acetate LPO 55070A (reaction scheme 2). The masked aldehyde 3-(1,3-dioxolan-2-yl)-8-(trifluoromethyl)quinolin-5-ol LPO 50180C was prepared by radical trifluoromethylation of dioxolane TTA 46034 using a methodology developed by Langlois B. et al., Tetrahedron Lett., (32), 51, 7525-7528, 1991 and modified by Baran P. et al., PNAS, 108, 35, 14411-14415, 2011 (reaction scheme 2).
Reaction SMILES: CCN(CC)CC.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:21][C:22]1[S:26][C:25]([NH:27][C:28]([CH:30]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:29])=[N:24][CH:23]=1>CC(N(C)C)=O>[Cl:21][C:22]1[S:26][C:25]([NH:27][C:28]([CH:30]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([N:11]3[CH2:12][CH2:13][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:10]3)(=[O:46])=[O:45])=[CH:42][CH:43]=2)[CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:29])=[N:24][CH:23]=1
Reactant: O=C(Nc1ncc(Cl)s1)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)Nc3ncc(Cl)s3)cc2)CC1
Reaction time: 16 h

Procedure:
NEt3 (278 μL, 2.0 mmol) and tert-butyl piperazine-1-carboxylate (373 mg, 2.0 mmol) were added to a stirred solution of 4-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-(tetrahydropyran-4-yl)ethyl]benzenesulfonyl chloride (Preparation 60, 449 mg, 1.0 mmol) in anhydrous DMAc (4 mL). The mixture was stirred for 16 h, then the solvents were removed in vacuo. The residue was dissolved in EtOAc (50 mL) to give a solution that was washed with H2O (15 mL), saturated aqueous Na2CO3 (15 mL), and brine (15 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 7:3 to 1:1) gave tert-butyl 4-{4-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-(tetrahydropyran-4-yl)ethyl]benzenesulfonyl}piperazine-1-carboxylate: m/z (ES+)=599.5 [M+H]+. A solution of this compound (189 mg, 316 μmol) in CH2Cl2-TFA (1:1, 7 mL) was stirred for 1 h. The solvents were evaporated off under reduced pressure, then the residue was triturated with Et2O. The product was collected, washed with Et2O, and air-dried to furnish the trifluoroacetate salt of the title compound: RTA=2.64 min; m/z (ES+)=499.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].C(OCC)(=O)C>C1COCC1>[CH:10]1([C:8](=[O:9])[CH2:7][C:2](=[O:4])[CH3:1])[CH2:12][CH2:11]1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)C1CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)C1CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a a stirring solution of THF (100 mL) was suspended potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35° C., via addition funnel over a 25 min period. The contents were heated and stirred at 60° C. After 3 h, the contents were removed from heating, and allowed to stir with cooling to room temperature. The reaction mixture was carefully diluted with 30 mL 2N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3×50 mL), and the combined organic layers washed with brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was chromatographed on silica gel (eluent: 0 to 15% EtOAc in hexanes) with good separation to afford the desired product as a light yellow colored oil, 3.9 g in ˜75% purity (residual solvent), for an overall yield of 70%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89-0.96 (m, 2H), 1.09-1.15 (m, 2H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1H), 15.5-16.0 (br s, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[C:23]([C:25]1[CH:26]=[C:27](Br)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[F:31][C:30]1[CH:29]=[CH:28][C:27]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:26][C:25]=1[C:23]#[N:24]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(F)c(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 80 °C

Procedure:
Prepared according to the method described in Example 12 from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.4 g, Example 33), 3-cyano-4-flurobromobenzene (0.399 g), ethanol (10 ml), 2M aqueous sodium carbonate (1.66 ml) and tetrakis(triphenylphosphine)palladium (0) (0.3 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid. (0.24 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[F:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[CH:4][C:5]([B:19]([OH:22])[OH:20])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(C(C)C)cc1I
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene (Example 77, 2.61 g, 8.88 mmol) in THF at −78° C., n-BuLi (4.26 ml, 10.65 mmol, 2.5 M) was added dropwise. The solution was stirred at −78° C. for 30 min. Trimethyl borate (2.98 ml, 26.6 mmol) was added. The solution was then stirred at −78° C. for 3 h. The reaction was quenched at −78° C. with saturated ammonium chloride and the mixture was warmed to room temperature. The organic was extracted with ethyl acetate (3×50 ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. The title compound was obtained as a solid pure enough for next step. Further purification with silica gel caused decomposition of product. 1H NMR (CDCl3, 500 MHz) δ 7.74 (d, J=10.0 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 5.65 (br s, 2H), 3.92 (s, 3H), 3.20 (m, 1H), 1.22 (m, 6H).