Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH:34][NH2:35])=[O:33])[CH2:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C1COCC1>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:35][NH:34][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:33])=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:8]=1
Reactant: CN1CCC(C(=O)NN)CC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C(=O)NNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g, 1.0 eq.) was dissolved in EtOAc:THF (15 mL; 2:1) and cooled to −60° C. where 1-methylpiperidine-4-carbohydrazide (0.123 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (0.85 mL, 2 eq.) was added dropwise followed by DIPEA (0.31 mL, 2.5 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (35° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-1-methylpiperidine-4-carbohydrazide (0.016 g, yield: 4.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].F.F.F.C(N(CC)CC)C.[B-](F)(F)(F)[F:22].CCN([S+](F)F)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:22])[CH3:9]
Reactant: CC(O)c1ccccc1Br
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(F)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromophenyl)ethanol (1 g, 4.97 mmol) in DCM (12 mL) was added triethylamine trihydrofluoride (1.621 mL, 9.95 mmol) and XtalFluor-E® (1.708 g, 7.46 mmol) dropwise over 5 min. After addition the resulting mixture was stirred at room temperature for 1 h and then cooled to 0° C. and quenched by addition of sat. aq. NaHCO3. The layers were separated and the aqueous was extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 1-bromo-2-(1-fluoroethyl)benzene. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.50 (dd, J=7.8, 1.8 Hz, 1H), 7.38 (td, J=7.6, 1.3 Hz, 1H), 7.19 (td, J=7.7, 1.7 Hz, 1H), 5.90 (dq, J=46.6, 6.4 Hz, 1H), 1.60 (dd, J=3-24.2, 6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3C(F)=C[CH:29]=[CH:28][C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[O:56]1C=CC=C1S(Cl)(=O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[O:56][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 48.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and furan-2-sulfonyl chloride (1.81 g, 10.9 mmol) the title compound was obtained (2.0 g, 48.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74-10.87 (br, 1H), 8.53 (d, J=5.3 Hz, 1H), 7.91-7.93 (m, 1H), 7.33-7.38 (m, 1H), 7.21-7.28 (m, 3H), 7.10-7.13 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57-6.60 (m, 1H), 3.23-3.35 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 661 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.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.O.C(O)C>[Cl:25][C:26]1[CH:31]=[C:30]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(Cl)c1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To 20 mL of toluene solution containing 2.0 g of tert-butyl 4-bromo-2-nitrobenzoate, 6.0 mL of ethanol, 3.0 mL of water, 1.2 g of 3-chlorophenylboronic acid, 1.7 g of sodium carbonate and 0.23 g of tetrakis(triphenylphosphine)palladium (0) were added sequentially, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. Water was added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain 0.70 g of tert-butyl 4-(3-chlorophenyl)-2-nitrobenzoate as white solid.
Reaction SMILES: CON(C)[C:4](=[O:15])[CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C(=O)=O.C(#N)C.C([Mg]Cl)(C)C.Br[Mg][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[O:15]=[C:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: Br[Mg]Cc1ccccn1
Reactant: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Temperature: 25 °C

Procedure:
tert-Butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (50.0 g, 215 mmol) in THF (450 mL) was cooled to −40° C. (dry ice/acetonitrile) and slowly charged with isopropylmagnesium chloride (2.0M, 102.2 mL, 0.95 eq). After a clear solution was obtained (became clear at −20° C. and milky again at −40° C.), bromo(pyridin-2-ylmethyl)magnesium solution (see below for preparation) was added drop wise using cannula before warming to rt overnight. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (500 mL×2). The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under high vacuum to give (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate as a tan oil. Small scale reaction was purified by combiflash (EtOAc/hexane, up to 1/3) to give a red oil. Mass Spectrum (ESI) m/e=265 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>C1COCC1>[CH3:16][C:15]([O:14][C:12]([N:3]([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[NH:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[O:13])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
NaH (362 mg, 9.04 mmol) was added to a stirred solution of Di-Tert-Butyl Hydrazodicarboxylate (2 g, 8.61 mmol) in anhydrous THF (50 ml). The reaction was stirred at ambient temperature for 10 minutes then treated with a solution of Methy 4-(Bromomethyl)Benzoate (1.98 g, 8.61 mmol) in anhydrous THF (20 ml). The reaction was stirred at ambient temperature for 4 hours. The reaction was partitioned between ether (˜100 ml) and water (˜100 ml). The layers were separated and the aqueous layer was re-extracted with ether (˜50 ml). The ether layers were combined, washed with brine (˜50 ml), dried (MgSO4), filtered and evaporated to yield the title compound (3.3 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24](O)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=[C:37]([C:46]([N:48]3[CH2:52][C:51](=[O:53])NC3)=O)C=2)C=C(F)C=1.N1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:46][CH2:37][O:53][CH2:51][CH2:52]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Solvent: C1COCCN1
Product: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCOCC1

Procedure:
75 mg (0.20 mmol) of the compound of Example 34A is reacted analogously to the synthesis of the compound of Example 1 with 0.02 ml (0.23 mmol) of morpholine. 80 mg (90% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@H:4]([CH3:25])[O:3]1.[NH:26]1[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]1=[O:34]>C(O)(C)C>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:7][C@@H:2]([CH3:1])[O:3][C@@H:4]([CH3:25])[C@@H:5]1[C:30]1([C:29](=[O:33])[NH:28][C:27](=[O:34])[NH:26][C:31]1=[O:32])[CH2:22]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4ccco4)noc3c2F)C[C@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(-c5ccco5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 90 °C
Yield: 84.1 %

Procedure:
A mixture of 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-3-(furan-2-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 427, 95 mg, 0.28 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (38.9 mg, 0.30 mmol) in isopropanol (10 ml) was heated at 90° C. for 2 days. Solvent removed. Residue was triturated with methanol and the solid was filtered, washed with small amount of methanol, and dried to give title compound (107 mg, 85%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:25][C:26](=[O:37])[CH:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:28])[C:16]1=[O:38])[C:11]([O:13]C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:39][NH2:40]>O1CCCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:25][C:26](=[O:37])[CH:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:28])[C:16]1=[O:38])[C:11]([NH:40][CH3:39])=[O:13])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 70 °C

Procedure:
A mixture of (2R)-methyl 3-(tert-butyldimethylsilyloxy)-2-(5-(2-(3,4-dichlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)propanoate (200 mg, 0.0003 mol), 5 mL of methylamine and tetrahydrofuran (2M) was heated in a sealed tube to 70° C. overnight. The reaction was only partially complete. The solvent was removed and the residue purified by flash chromatography to obtain the product as a light yellow oil. MS m/z=577.4 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH3:37]>CN(C=O)C.Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:36][CH3:37])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCI
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added EtI (81 mg, 0.52 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 55 mg (50%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C([CH2:18][S:19]([CH2:22][S:23]([CH2:26][C:27](O)=O)(=[O:25])=[O:24])(=[O:21])=[O:20])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])/[CH:6]=[CH:18]/[S:19]([CH2:22][S:23](/[CH:26]=[CH:27]/[C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:24])=[O:25])(=[O:20])=[O:21]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CC(=O)O
Product: COc1cc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Yield: 62 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 127-129° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCOCC4)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of methyl 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate (1 g, 2.13 mmol, 1.00 equiv) in 6N hydrochloric acid (40 mL) was refluxed for 8 h. The reaction mixture was cooled to room temperature naturally and then diluted with 100 mL of water/ice. The precipitate was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to give 0.7 g (72%) of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.CC1C=CC(S(NN=[C:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)(=O)=O)=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Li+].C(=O)([O-])O.[Na+]>O1CCOCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[O:37]1[CH2:36][CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH2:39][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)NN=C2CCOCC2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(C3=CCOCC3)ccc2F)C1(F)F
Temperature: 110 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (151 mg, 412 μmol) and 4-methyl-N′-(2H-pyran-4(3H,5H,6H)-ylidene)benzenesulfonohydrazide (CAS1240042-12-9) (122 mg, 454 μmol) in dioxane (5 ml) was treated under argon with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS) (19.7 mg, 41.2 μmol), bis(dibenzylideneacetone) palladium (11.9 mg, 20.6 μmol) and finally lithium tert-butoxide (72.6 mg, 907 μmol). The reaction mixture was stirred in a sealed microwave tube at 110° C. for 16 hours. For the workup, the reaction mixture was poured on a saturated solution of sodium hydrogencarbonate followed by 2 extractions with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and evaporated at reduced pressure to give brown oil. The residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent. The (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (76 mg, 50% yield) was obtained as an off-white foam. MS (ISP): m/z=370.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:14])[CH2:12][CH3:13]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCC(=O)Cl
Product: CCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and propionyl chloride
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([Li])CCC.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:7]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1)=[CH2:12]
Reactant: [Li]CCCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=Cc1cccc([N+](=O)[O-])c1

Procedure:
Treatment of 3-nitrobenzaldehyde (20 g) with methyltriphenylphosphonium bromide (61.5g) and n-butyllithium in hexane (172 mmol), as described in Example 1a, gave 3-ethenylnitrobenzene (10.3 g), δ (360 MHz, CDCl3), 5.44 and 5.59 (2H, 2d, CH2), 6.75 (1H, dd, CH), 7.49 (1H, t, 5-H), 7.70 (1H, dd, 4-H), 8.09 (1H, dd, 6-H) and 8.24 (1H, d, 2-H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:41][C:42]1[C:43]([C:52]([F:54])([F:53])[F:55])=[N:44][N:45]([CH2:48][C:49]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:39])[F:40])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)=[O:50])[C:46]=1[CH3:47]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Trifluromethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.50 (d, 2H), 7.07 (d,2H), 5.38 (s, 2H), 3.60 (m, 4H), 3.41 (m, 2H), 3.31 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=455.1, found=455.0.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]([C:10](=O)[CH2:11][CH3:12])[C:8]#[N:9])=[CH:4][CH:3]=1.O.[NH2:17][NH2:18].C(O)C.C(O)(=O)C>C(OCC)(=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:10]([CH2:11][CH3:12])=[N:18][NH:17][C:8]=2[NH2:9])=[CH:14][CH:15]=1
Reactant: CCC(=O)C(C#N)Cc1ccc(Br)cc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1n[nH]c(N)c1Cc1ccc(Br)cc1
Temperature: 140 °C

Procedure:
A mixture of 2-(4-bromo-benzyl)-3-oxo-pentanenitrile (1, 10.4 g, 39.1 mmol) and hydrazine hydrate (1.9 ml, 39.1 mmol) in 35 ml of a 1:1 mixture of ethanol and acetic acid was heated in a microwave reactor to 140° C. for 15 min. After cooling the reaction mixture was diluted with ethyl acetate and washed several times with sat. sodium bicarbonate, followed by brine. The organic layer was dried over Na2 SO4 and evaporated to give a mixture of 2 and its N-acetamide. For conversion of the latter to 2, the crude product was taken up in 1N sodium hydroxide and heated to 160° C. in a microwave reactor until no N-acetamide could be detected by LC-MS (10-20 min). The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2 SO4 and evaporated to yield 2 as a white powder, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[NH2:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(Cl)cc(F)c1N
Solvent: CCOCC
Product: Nc1c(F)cc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.7 %

Procedure:
To a solution of 2-amino-5-chloro-3-fluoro-N-methoxy-N-methyl-benzamide (250 mg, 1.07 mmol) in diethyl ether (5 ml) was added phenylmagnesium bromide (2.69 ml, 1M in THF, 2.69 mmol) dropwise at 0° C. The resulting mixture was stirred for 2.5 h at 0° C. and the quenched by addition of saturated NH4Cl solution. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-95:5) to afford the title compound (189 mg, 70%) as yellow solid. MS (ESI): 250.2 (M+H)+.