Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:6]=2[CH:18]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[CH2:11][O:10][C:7]1[C:6]2[CH:18]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=3)[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2onc(OCc3ncccn3)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3onc(OCc4ncccn4)c3c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
5-Bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (120 mg, 0.39 mmol), 4-(trifluoromethoxy)phenylboronic acid (120 mg, 0.58 mmol), potassium carbonate (500 mg), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.034 mmol) were combined in 6 mL DMF. 3 mL water was added and the mixture was stirred at 80° C. for two hours. The reaction mixture was diluted with 60 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-60% ethyl acetate in hexane gave 3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole (94 mg, 0.24 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O>N1CCCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1ccc(C=O)cn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Yield: 79.2 %

Procedure:
A mixture of 6-methoxypyridine-3-carboxaldehyde (2.34 g), monoethyl malonate (4.51 g), pyridine (12 ml) and piperidine (6 drops) was heated under reflux for 5 hours and was evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The separated ether layer was washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate (2.8 g, 79%), m.p. 49°-52°.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+].CO>>[OH:22][C:7]1[C:8]2[S:14][C:13]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(Oc3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(Oc3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A mixture of 7-hydroxy-2-phenoxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.26 mmol) and glycine (386 mg, 5.14 mmol) in 0.5 M sodium methoxide/methanol (9.8 mL, 4.88 mmol) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and extracted with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (7.3 mL). The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified on a C18 reverse column with a gradient of 0.1% TFA in water and 0.1% TFA in acetonitrile to give the title compound as a brown solid (49 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.16 (s, 1H), 9.39 (br s, 1H), 8.60 (s, 1H), 7.55 (m, 4H), 7.42 (m, 1H), 4.01 (d, J=6.4 Hz, 2H); MS: (+) m/z 346.00 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([C:13]([F:16])([F:15])[F:14])=[N:7]2.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:19])[C:8]([C:13]([F:16])([F:15])[F:14])=[N:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(Br)cccc2nc1C(F)(F)F
Product: FC(F)(F)c1nc2cccc(Br)c2nc1Cl
Reaction time: 60 h
Yield: 52 %

Procedure:
A solution of 8-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one (432.0 mg, 1.474 mmol) in POCl3 (5.0 mL) was heated at reflux for 10 h then at 100° C. for 2.5 d, then at 140° C. for 10 h. Excess POCl3 was removed in vacuo, and the residue was taken up in DCM (60 mL) and transferred to an Erlenmeyer flask before saturated aq. NaHCO3 (40 mL) was added cautiously (over 5 min) with rapid stirring. The resulting biphasic mixture was stirred rapidly for 5 min (some gas evolution), and the organic layer was separated. The aq. layer was extracted with DCM (3×20 mL), and all organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to provide 5-bromo-3-chloro-2-(trifluoromethyl)quinoxaline (224c, 52%). MS (ESI, pos. ion) m/z: 310.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[N:20]=[CH:19][N:18]([CH2:21][CH2:22][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[N:17]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([S:23]([CH2:22][CH2:21][N:18]3[CH:19]=[N:20][C:16]([CH3:15])=[N:17]3)(=[O:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1ncn(CCS(=O)(=O)c2ccc(C(=O)O)cc2)n1
Product: Cc1ncn(CCS(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)n1

Procedure:
60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)ethylsulfonyl)benzamide. MS (Q1) 482.1 (M)+.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH3:18])[CH3:17])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:18][N:16]([CH3:17])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:41]([C:40]4[CH:44]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[N:45]4[N:49]=[CH:48][CH:47]=[N:46]4)=[O:42])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(N(C)C)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-methyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 8) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H25FN8O, 436.49; m/z found 437.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.14-6.61 (m, 5H), 5.82-5.45 (m, 1H), 4.75-3.27 (m, 6H), 3.22-2.55 (m, 8H), 2.37-1.78 m (m, 5H).
Reaction SMILES: C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].Cl.[OH-].[Na+].N[C@H](CO)[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32](S(C)(=O)=O)=[CH:31][CH:30]=1)O>CO.O>[CH3:17][S:14]([C:11]1[CH:10]=[CH:9][C:8]([C@H:6]2[O:7][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C@@H:5]2[CH2:4][OH:19])=[CH:13][CH:12]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Temperature: 25 °C

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) in methanol (about 100 mL) is reacted in a reaction vessel with potassium borohydride (about 1.1 g, 0.0207 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl and water (about 25 ml) are added, followed by neutralization with sodium hydroxide (about 25%) to generate (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) in situ. Next, the methanol is evaporated, followed by the addition of 1,2-dichloroethane (about 200 mL). Next, 2,2-dichloro-ethanimidic acid ethyl ester (Compound IV wherein R2 is dichloromethyl and R4 is ethyl) is added (about 10.9 g, 0.0696 moles) with heating up to about 85° C. for about 6 hours. The reaction is then cooled to below about 25° C. After cooling, glycerin is added (about 50 mL). Next, the 1,2-dichloroethane is distilled by heating to about 85° C., followed by continued heating to about 105° C. to about 110° C. for about 10 hours, then followed by cooling to below about 25° C. Thereafter, water is added (about 100 mL). The resulting solids are filtered and washed with water (about 10 mL) and isopropanol (about 10 mL) to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:20]>C1COCC1>[CH3:20][C:5]1([CH:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH2:4]1
Reactant: COc1cccc(C2CCCCC(=O)N2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=CC=CC(C)(C2CCCCC(=O)N2)C1
Reaction time: 0.25 h

Procedure:
7-(3-Methoxyphenyl)-azepan-2-one, as described above in Step C, (0.13 g, 0.6 mmol) and NaH (60% dispersion in mineral oil) (0.03 g, 0.75 mmol) were dissolved in THF (5 mL) under Ar at ambient temperature. After 0.25 hours, iodomethane (0.064 mL, 1.0 mmol) was added and stirring was continued for 20 h. The reaction mixture was partitioned between EtOAc (100 mL)—H2O (100 mL), the organic layer separated, washed with H2O, dried (MgSO4), filtered and concentrated to give the title compound after SiO2 chromatography (CHCl3:MeOH, 100:1 to 50:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[CH2:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.B1C2CCCC1CCC2.[OH2:25].[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH:13]([CH2:15][OH:25])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(c2ncc3c(Cl)nccn23)C1
Reactant: O
Agent: B1C2CCCC1CCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC1CC(c2ncc3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (4.48 g, 20.4 mmol) in anh THF (255 mL) at −78° C. under Ar, 9-BBN (61.2 mL, 0.5 M in THF, 30.6 mmol) was added dropwise over 8 min (a suspension). The cooling bath was replaced with ice-H2O and the reaction was allowed to warm slowly to rt. After being stirred for 17 h, H2O (100 mL,) was added followed by, after ˜5 min, NaBO3.H2O (12.2 g, 122.3 mmol) added in one lot. The reaction was stirred at rt for 5 h and then filtered through Celite. The Celite and residual solids were washed with DCM and EtOAc. The filtrate was concentrated under reduced pressure to yield an aq solution, which was saturated with NaCl and extracted with EtOAc (3×). The extracts were dried (Na2SO4) and concentrated under reduced pressure to yield a light yellow oil which was purified by flash chromatography on SiO2 (9:1 DCM:MeOH) to afford the title compound as a light yellow oil; HPLC: tR (mass-directed HPLC, polar7 min) 2.52 min; MS (ES+): 238.0. The addition may be carried out at 0° C. Suspension quickly clears up after the exchange of cooling baths. The final product contained 1,5-cis-octanediol derived from 9-BBN. Based on 1H NMR estimated roughly to be 66% target material and 33% of the byproduct. The crude product was taken onto next step crude, stereoselectivity of the product was 4-5:1 as judged by 1H NMR.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=O)[CH3:27]>C(O)C.C(OCC)(=O)C>[CH2:26]([O:23][C:22](=[O:24])[CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([F:25])=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1)[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The compound (80 mg, 0.22 mmol) prepared in Example 37 was dissolved in ethanol (2 ml). Acetyl chloride (0.1 ml) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (50 mg, Yield 58%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:9](O)=[O:10]>>[CH:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=CO
Product: CC(C)[C@H](NC=O)C(=O)O
Reaction time: 17 h

Procedure:
To valine (11.7 g, 0.10 mole) in 88% formic acid (40 ml) is added acetic formylanhydride (26.3 g, 0.30 mole) over 0.5 hr at 5°. The reaction mixture is warmed to 24° and stirred for 17 hours. The reaction is worked up by distilling off (bath temp. 45°-50°) the solvent, excess anhydride and acetic acid, to give, as a white solid, N-formylvaline, recrystallized from hot ethanol, m.p. 143°-145°.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)C(O)=[O:33]>>[CH:3]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
14.65 g (0.05 mol) of 2-aminomethyl-4-(1,1-dimethylethyl)-6-methylsulfonylphenol hydrochloride are dissolved in 100 ml of trifluoroacetic acid, 9 g (0.065 mol) of urotropine (hexamethylenetetraamine) are added, and the mixture is boiled under reflux for 2.5 h. Then 50 ml of 4 N hydrochloric acid are added, the mixture is again boiled under reflux for 10 minutes, and the reaction mixture is poured onto ice-water and filtered with suction. Pale yellow crystals of melting point: 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][N:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1.[N+](=[CH2:33])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[C:14]([CH:15]2[CH2:33][CH2:16]2)=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:20][N:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:29])[CH:11]=2)[CH:6]=1
Reactant: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1Oc1ccc(S(=O)(=O)CC)cn1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc(Oc2c(C3CC3)c(CC(=O)OC)cc3ccc(F)cc23)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled solution of [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-3-vinyl-naphthalen-2-yl]-acetic acid methyl ester (6.0 mg, 0.014 mmol, methyl ester of example 17-1) in tetrahydrofuran, was added a solution of diazomethane (0.1 M, 5 mL) in diethyl ether at 0° C. under an argon atmosphere, followed by palladium acetate (1 mg) in two portions. After being stirred at 0° C. for 2 hours, the reaction mixture was treated with acetic acid (0.2 mL) to quench the reaction, and then filtered. The filtrate was concentrated in vacuo to afford the crude product of [3-cyclopropyl-4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](C=O)=[CH:7][CH:8]=1.CO[CH:13]([O:16][CH3:17])[O:14][CH3:15].Cl.[OH-].[K+]>CO>[CH3:17][O:16][CH:13]([O:14][CH3:15])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(OC)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(OC)OC)cc1
Temperature: 12.5 °C
Reaction time: 17 h
Yield: 95.2 %

Procedure:
Anisaldehyde (40 g) and trimethylorthoformate (48.25 ml) were added to MeOH (60 ml) at 20-25° C. and the mixture was cooled to 10-15° C. Conc. HCl (0.26 ml) was then added to the mixture at 10-15° C. and was warmed to 20-25° C. followed by stirring at the same temperature for 16-18 hours. 5% aqueous KOH (40 ml) was added to the reaction mixture at 20-25° C. in 10 min and further stirred for 10 minutes. The reaction mixture was extracted with hexane (2×200 ml) and the combined organic layer was washed with DM water (200 ml). The organic layer was concentrated below 40° C. to obtain title compound (51.0 g, 95.2%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]#[N:9])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)[OH:18].[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH2:9])=[O:18])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(-c2ccccc2)c(C)c1CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(-c2ccccc2)c(C)c1CC(N)=O
Temperature: 25 °C
Yield: 63 %

Procedure:
10 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetonitrile were added to 40 milliliters concentrated sulfuric acid and the mixture was stirred over night at room temperature. The reaction mixture was poured into a mixture of ice and water and the pH was adjusted to 8 by the addition of aqueous sodium hydroxide. 6.8 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetamide, melting at 169°-170° C., were obtained, representing a yield of 63%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:3][C:2]=1[F:1]
Reactant: Fc1ccc(S)cc1F
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(SCCC(F)(F)F)cc1F
Temperature: 140 °C

Procedure:
To 3.4 mmol 3,4-difluoro-thiophenol and 5.1 mmol 1-iodo-3,3,3-trifluoropropane in 5 ml acetone was added 3.7 mmol potassium carbonate, and the mixture heated at 140° C. for 3 h under microwave irradiation. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound. MS (m/e): 243.1 (M+H+, 100%)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[CH:11]=[O:12])O1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](Br)[CH:31]=1>>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:10]=2[CH:11]=[O:12])[CH:31]=1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Reactant: COC(=O)Cc1cncc(Br)c1
Product: COC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde and (5-bromo-pyridin-3-yl)-acetic acid methyl ester were reacted as described in Example 8, Step 4 to provide [5-(2-formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCCC(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using 5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 118.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.88 min, m/z=473.1-474.1 [M+H]+, m/z=471.1-472.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.38 (m, 2H) 1.53-1.61 (m, 1H) 1.79-1.86 (m, 1H) 2.53 (s, 3H) 2.57 (dd, J=12.10, 9.17 Hz, 1H) 2.72 (t, J=10.51 Hz, 1H) 3.35-3.41 (m, 1H) 3.42-3.51 (m, 1H) 3.56-3.63 (m, 1H) 4.73 (d, J=4.40 Hz, 1H) 7.34-7.39 (m, 3H) 7.86 (d, J=8.80 Hz, 2H) 7.90 (dd, J=8.07, 2.20 Hz, 1H) 8.06 (d, J=2.20 Hz, 1H) 8.67 (d, J=1.96 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:23][N:24](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN.C(=O)([O-])O.[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([NH:24][CH3:23])=[O:22])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOc1ccc(C#Cc2ccc(CCC(=O)O)cc2)cc1
Agent: CN
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C#Cc2ccc(CCC(=O)NC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 100 mg (0.34 mmol) 3-[4-(4-ethoxy-phenylethynyl)-phenyl]-propionic acid (XIV.1) in 5 mL DMF are added 0.12 mL (0.85 mmol) TEA and 0.12 g (0.37 mmol) TBTU and the mixture is stirred for 5 min at rt. After that time, 21 mg (0.68 mmol) methylamine are added and the mixture is stirred at rt for 2 h. Subsequently saturated potassium hydrogencarbonate solution and water are added. The precipitate is filtered, washed with water and dried at 45° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:18][C:19]([F:27])(S(F)(=O)=O)C(O)=O>C(#N)C>[F:18][CH:19]([F:27])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC(F)F)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 mL) was added sodium sulfate (1.5 g, 10.6 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the acetonitrile was removed in vacuo. The remaining aqueous component was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The pale brown oily solid was triturated with ether/hexanes, filtered and the filtrate concentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol, 49% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (d, J=2.76 Hz, 1 H), 8.68 (dd, J=9.03, 2.76 Hz, 1 H), 7.98 (s, 0.5 H), 7.62 (s, 0.5 H), 7.34 (d, J=9.03 Hz, 1 H).