Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([Cl:10])=[C:8](Cl)[S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>[Pd].CO>[C:1]([NH:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(Cl)c(Cl)c1NC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1scc(Cl)c1NC(C)=O

Procedure:
A mixture of 25 g of methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate, about 10 g of triethylamine, 300 ml of methanol and 1 g of palladium on carbon is, at room temperature and under atmospheric pressure, hydrogenated until the uptake of hydrogen has stopped. The catalyst is filtered off and the mixture is then concentrated by distillation under reduced pressure until crystallization begins, water is then added and the solid is filtered off. Colorless crystals from isopropanol. M.p. 142-147° C.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(C)C=CC=C[CH:12]=1.CC1OC(C)OC(C)O1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:11][CH:12]1[O:10][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][O:9]1
Reactant: Cc1ccccc1
Reactant: OCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC1OC(C)OC(C)O1
Product: CC1OCC(c2ccccc2)O1
Temperature: 20 °C
Yield: 85.3 %

Procedure:
100 g (0.63 mol) of (±)-1-phenyl-1,2-ethanediol (3) (87% pure according to GC) according to Example 1, 200 ml of toluene, 32 g (0.24 mol) of paraldehyde and 1 g of para-toluenesulfonic acid were charged to a 1 l stirrer, heated to boiling (110° C.) and stirred under reflux for a period of 4 h. A total of 10 ml of water were eliminated. After this time, the mixture was cooled to 20° C. and washed until neutral with sodium carbonate solution and water, and the solvent was distilled off under reduced pressure, leaving 103 g of crude product (85.3% pure according to GC). GC conditions see Example 2.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].[ClH:28].O1CCOCC1>C(OCC)(=O)C>[ClH:28].[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([NH2:17])[CH:19]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Reactant: Cc1ccc(B(O)O)cc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1N

Procedure:
The product of Example 1A (330 mg, 1 mmol) was treated with 3-amino-4-methyl-phenylboronic acid (Lancaster, 302 mg, 2 mmol) according to the procedure of Example 1B. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.10) as oil (230 mg, yield, 75%). The free base of the title compound (230 mg, 0.75 mmol) in ethyl acetate (5 mL) was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The title compound was obtained as solid (180 mg, yield, 74%): 1H NMR (MeOH-d4, 300 MHz) δ 1.85-2.19 (m, 3H), 2.28-2.38 (m, 1H), 2.43 (s, 3H), 2.51-2.57 (m, 1H), 3.31-3.45 (m, 5H), 3.82-3.89 (m, 1H), 4.93-4.99 (m, 1H), 7.13 (dt, J=8.8, 3.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.56-7.66 (m, 4H) ppm. MS (DCl/NH3) m/z 309 (M+H)+. Anal. Calculated for C19H22N2O.2.0HCl.0.1H2O: C, 62.70; H, 6.89; N, 7.31. Found: C, 62.52; H, 6.59; N, 7.35.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:14]=[N:15][N:16]([CH3:18])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O1CCOCC1>[CH3:18][N:16]1[CH:17]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[N:14]=[N:15]1
Reactant: Cn1cc(Br)nn1
Reactant: OCc1ccc(B(O)O)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(CO)cc2)nn1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of [4-(hydroxymethyl)phenyl]boronic acid (7.10 g), 4-bromo-1-methyl-1H-1,2-3-triazole (5.00 g), sodium carbonate (6.59 g) and tetrakis(triphenylphosphine)palladium(0) (3.59 g) in a mixed solvent of water (30.0 mL)-1,4-dioxane (100 mL) was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was allowed to be cooled to room temperature, the organic layer was concentrated under reduced pressure, and the residue was extracted with dichloromethane (×3). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.40 g).
Reaction SMILES: C1(S(N2CCNC(=O)[C@H]2CC#C)(=O)=O)C=CC=CC=1.[O:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C@H:32]2[CH2:38][C:39]#[CH:40])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH3:21]>>[O:20]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[C@H:32]2[CH2:38][C:39]#[CH:40])(=[O:30])=[O:29])=[CH:26][CH:27]=1)[CH3:21]
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(OC)cc1
Agent: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccccc1
Product: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
Using the procedure described for compound 51, (R)-4-(4-methoxylbenzenesulfonyl)-3-(prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one afforded the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6): δ 2.65 (m, 1H), 2.86 (m, 2H), 2.90 (s, 1H), 3.05 (m, 1H), 3.61 (m, 2H), 3.87 (s, 3H), 4.25 (t, 5.4 Hz, 1H), 7.08 (d, 8.3 Hz, 2H), 7.81 (d, 8.3 Hz, 2H), 8.06 (s, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]2([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:9][O:10][C:11]1[C:20]([C:5](=[O:7])[CH3:6])=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a suspension of AlCl3 (6.6 g, 49.6 mmol) in CH2Cl2 (225 mL) at 0° C. was added acetyl chloride (3.5 mL, 49.6 mmol) dropwise via syringe. To the resulting homogeneous light brown solution was added 6-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 2, 9.0 g, 41.3 mmol) in CH2Cl2 (25 mL) via cannula. The mixture was then stirred at ambient temperature for 1 h, poured onto ice and extracted with Et2O (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a white solid (10.7 g, 100%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].O1CCCC1.CON(C)[C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C.CCCCCC>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][C:13](=[O:31])[CH2:1][CH3:2])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CON(C)C(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Ethyl magnesium bromide (1.15 mmol, 3.0M in ethyl ether) is added drop-wise to a tetrahydro-furan (3 mL) solution of N-methoxy-N-methyl-2-(4′-trifluoromethyl-biphenyl-4-yl)-acetamide (0.248 g, 0.77 mmol) at −45° C. and stirred for one hour. Gradually raise temperature to −20° C. and stirred for one hour. The reaction is quenched by saturated ammonium chloride solution (1 mL) at 0° C., extracted with ethyl acetate and washed with water and brine. Organics are dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel with 0-30% ethyl acetate/hexane gradient gives 0.095 g (0.33 mmol, 42%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC>[C:13]1([C:23]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(c1cccc2ccccc12)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a cooled solution of indole (5.85 g, 50 mmol) in ether (50 ml) under nitrogen was added slowly a solution of methylmagnesium bromide (3M) in ether (17.5 ml). After addition, the reaction mixture was warmed up to room temperature and stirred for 2 h at room temperature. Then the mixture was cooled down again to 0° C., and to it was added slowly with stirring a solution of 1-naphthoylchloride (9.5 g, 50 mmol) in ether (50 ml). The resulting mixture was warmed up to room temperature and stirred for 2 h at room temperature followed by slow addition of saturated ammonium chloride solution (375 ml). The mixture was then stirred overnight at room temperature. A white solid was formed, filtered, washed by ether and dried under high vacuum to give 3-(1-naphthoyl)-1H-Indole 1 (12.3 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.C([Sn](CCCC)(CCCC)[C:20]([F:22])=[CH2:21])CCC>ClC(Cl)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[C:20]([F:22])=[CH2:21]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: C=C(F)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=C(F)c1c(C(=O)OC)nc(Cl)c(F)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (0.4 g, 1.210 mmol), tributyl(1-fluorovinyl)stannane (0.608 g, 1.816 mmol), and bis(triphenyl-phosphine)palladium(II) chloride (0.127 g, 0.182 mmol) were combined in dichloroethane (2.4 mL) and stirred at 70° C. overnight. The reaction mixture was concentrated onto celite and purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (211 mg, 0.849 mmol, 70.1% yield) as a yellow solid: mp 98-100° C.; 1H NMR (400 MHz, CDCl3) δ 5.28 (dd, J=15.0, 3.6 Hz, 1H), 4.94 (s, 2H), 4.81 (dd, J=47.3, 3.6 Hz, 1H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −89.04, −138.74; ESIMS m/z 249 [(M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NCc2ccc(O)cc2)cc1
Yield: 49.6 %

Procedure:
The procedure of Example 40 was repeated, except that 3.58 g of 4-aminobenzonitrile was used in place of aniline, and 4.62 g of 4-hydroxybenzaldehyde was used in place of 4-formylphenyl sulfamate. The resulting crude product was purified by silica gel column chromatography (using a 39:1 mixture of chloroform and acetone as the eluent) to obtain 3.37 g of 4-[N-(4-hydroxybenzyl)amino]-benzonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([O:27][CH:28]([F:30])[F:29])[C:23]([F:26])([F:25])[F:24])[C:16]=4[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([CH3:31])[CH:3]=1.[CH3:32][S:33]([O-:35])=[O:34].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+].[Cl-].[NH4+]>CS(C)=O.[Cu]I>[Cl:21][C:20]1[C:15]2[N:14]=[C:13]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:3][C:4]=4[CH3:31])[CH2:9][CH2:10][CH2:11][N:12]3[C:16]=2[C:17]([CH:22]([O:27][CH:28]([F:29])[F:30])[C:23]([F:24])([F:25])[F:26])=[CH:18][CH:19]=1
Reactant: CS(=O)[O-]
Reactant: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Solvent: CS(C)=O
Product: Cc1cc(S(C)(=O)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reaction time: 96 h
Yield: 10.5 %

Procedure:
A mixture of 1-(4-bromo-2-methylphenyl)-9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (200 mg, 0.381 mmol), sodium methanesulfinate (311 mg, 3.04 mmol), L-proline (44.0 mg, 0.382 mmol), sodium hydroxide (30.6 mg, 0.765 mmol) and copper (I) iodide (72.6 mg, 0.381 mmol) in dimethylsulfoxide (2.0 mL) was attired at 110° C. for 4 days. Aqueous ammonium chloride was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (21.2 mg, 0.040 mmol, 11%) as white amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8](=O)[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1.[CH3:23][C:24]([S:27]([NH2:30])(=O)=[O:28])([CH3:26])[CH3:25]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8](=[N:30][S:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28])[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCC(F)(F)C(=O)c1cc(Br)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-one (16.0 g, 40.4 mmol) in dry THF (350 mL) was added Ti(OEt)4 (16.7 mL, 80.4 mmol) and 2-Methyl-2-propane sulfonamide (5.8 g, 48.4 mmol) and refluxed for 16 h. Reaction mixture was concentrated under reduced pressure and the crude residue was directly purified by column chromatography on silica gel with 3% ethyl acetate in Hexane to furnish title compound as a colorless liquid. Yield=13.1 g (65.5%). TLC (10% ethyl acetate in Hexane): Rf=0.2),
Reaction SMILES: C(OC([C:7]1([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([N+:30]([O-:32])=[O:31])=[C:25]([F:33])[CH:24]=2)[C:12](=[O:13])[CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][S:9][CH2:8]1)=O)C=C>C1COCC1.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:18]([O:17][C:15](=[O:16])[NH:14][C@@H:11]1[C:12](=[O:13])[C@H:7]([CH2:22][C:23]2[CH:24]=[C:25]([F:33])[C:26]([N+:30]([O-:32])=[O:31])=[C:27]([F:29])[CH:28]=2)[CH2:8][S:9][CH2:10]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C=CCOC(=O)C1(Cc2cc(F)c([N+](=O)[O-])c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)C1=O
Reaction time: 16 h

Procedure:
To a degassed solution of 5-tert-butoxycarbonylamino-3-(3,5-difluoro-4-nitro-benzyl)-4-oxo-tetrahydro-thiopyran-3-carboxylic acid allyl ester (30.4 g, 62.4 mmol) in THF (300 mL) was added under argon 5,5-dimethyl-cyclohexane-1,3-dione (11.6 g, 81.2 mmol) and Pd(PPh3)4 (0.76 g, 0.62 mmol) and the reaction mixture was stirred for 3 h at 25° C. The reaction mixture was poured into aq. NaH2PO4 solution, concentrated and extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The crystallized product containing the (3R*,5S*)-diastereoisomer was filtered off and dried. The mother liquor containing a larger amount of the (3S*,5S*)-diastereoisomer was dissolved in THF and equilibrated with a catalytic amount of DBU to the (3R*,5S*)-diastereoisomer for 16 h at 25° C. After removal of the THF the (3R*,5S*)-diastereoisomer was crystallized from Et2O-hexane to provide more of the title compound as white crystals: TLC (hexane-EtOAc 3:1) Rf=0.23; HPLC RtA=2.23 min; ESIMS [M+NH4]+=420; 1H NMR (400 MHz, CDCl3): δ 6.96 (d, 2H), 5.65 (d, 1H), 4.55 (m, 1H), 3.40 (m, 1H), 3.25 (dd, 1H), 3.14 (m, 1H), 2.86 (m, 1H), 2.6-2.75 (m, 3H), 1.44 (s, 9H).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)/[C:7]([O:9]CC)=[O:8])[CH3:4].C(O)(=O)C.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:36])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)/[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
1.2 mL (1.2 mmol) of aqueous 1 M lithium hydroxide solution are added to a solution of 0.4 g (0.8 mmol) of ethyl (Z)-2-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 8 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 18 hours. After cooling, the reaction is worked up by addition of 1.2 mL (1.2 mmol) of aqueous 1 M acetic acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 98/2 dichloromethane/methanol mixture to give 240 mg (68%) of (Z)-2-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid in the form of a colorless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:15])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:15])[CH:9]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(Br)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Ethyl chloroformate (15.91 g) was added dropwise to a solution of 4-bromo-2-fluoroaniline (25.33 g) and pyridine (21.06 g) in methylene chloride (260 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, it was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting crude crystals were crystallized from ethyl acetate-n-hexane (1:5 v/v) to obtain the objective ethyl N-(4-bromo-2-fluorophenyl)carbamate (34.45 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@@H:4]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13](CCNC1C=CC=CN=1)[C:12]2=O)=[O:8].[OH-].[Na+]>CO>[CH2:14]1[C:15]2[C:11](=[CH:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:28][S:29]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)(=[O:30])=[O:31])[C:3]([OH:38])=[O:2])=[O:8])=[CH:17][CH:16]=2)[CH2:12][NH:13]1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2)NS(=O)(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC[C@H](NS(=O)(=O)c1cccnc1)C(=O)O)c1ccc2c(c1)CNC2

Procedure:
A methanol solution (3 mL) of 8-2 (184 mg, 0.34 mmol) and 1 N NaOH (3.4 mL, 3.4 mmol) was stirred under ambient conditions for 3 h. The reaction was concentrated to dryness and the residue dissolved in H2O and neutralized with 1 N HCl to provide 8-3 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N+:12]([CH3:15])([O-:14])=[O:13].Cl.CN.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:15]/[N+:12]([O-:14])=[O:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: COc1cc(Cl)ccc1/C=C/[N+](=O)[O-]
Reaction time: 12 h
Yield: 78.2 %

Procedure:
4-Chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol) was diluted with nitromethane (556 μL, 10.3 mmol) followed by the addition of methylamine hydrochloride (59.4 mg, 0.879 mmol) and sodium acetate (72.1 mg, 0.879 mmol). After stirring for 12 hours, the reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to yield (E)-4-chloro-2-methoxy-1-(2-nitrovinyl)benzene (245 mg, 1.15 mmol, 78.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=O)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: FC1(F)CNC1
Reactant: O=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCC(N2CC(F)(F)C2)c2ccccc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension of 1-[2-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-2,3-dihydro-1H-quinolin-4-one (50 mg, 0.12 mmol, 1.0 equiv; Example 128) in ethanol (1.2 mL) was added 3,3-difluoroazetidine hydrochloride (31 mg, 0.24 mmol, 2.0 equiv; [CAS RN 288315-03-7]), acetic acid (27 mg, 26 μL, 0.48 mmol, 4.0 equiv; [CAS RN 64-19-7]) and N-ethyldiisopropylamine (31 mg, 42 μL, 0.24 mmol, 2.0 equiv; [CAS RN 7087-68-5]). The reaction mixture was heated by microwave irradiation to 100° C. for 10 min. Sodium triacetoxyborohydride (33 mg, 0.16 mmol, 1.3 equiv; [CAS RN 56553-60-7]) was added and heating at 100° C. continued for 15 min. The reaction mixture was extraction from a sat. solution of NaHCO3 (50 mL) with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate afforded 0.04 g (7%) of the title compound as a light yellow solid. MS (ISP): 490.0 [M+H]+.