Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH3:50])([CH3:49])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:48])([C@@:18]4([CH3:47])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C([SiH](C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCCl.O1CCOCC1.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH3:50])([CH3:49])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:48])([C@@:18]4([CH3:47])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(3-fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.59 g, 5.27 mmol) in DCE (25 mL) was added TEA (1.176 mL, 8.44 mmol), t-butyldimethylsilane (1.749 mL, 10.54 mmol), and palladium(II) acetate (0.118 g, 0.527 mmol). The mixture was flushed with N2 and heated to 60° C. for 1 h. The mixture was cooled to rt and was filtered through a plug of celite and silica gel (washed with 25% EtOAc in hexanes). The filtrate was concentrated under reduced pressure. The residue was diluted with 25 mL of dioxane and TBAF (75% in water) (2.76 g, 7.91 mmol) was added. The mixture was stirred for 30 minutes at rt then was diluted with 50 mL of 1N HCl. The solids that formed were collected by filtration and were washed with water to give the title compound (2.95 g, 4.99 mmol, 95% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (1H, t, J=7.9 Hz), 6.90-7.00 (2H, m), 5.34 (1H, dd, J=6.1, 1.6 Hz), 4.77 (1H, d, J=2.0 Hz), 4.64 (1H, s), 3.94 (3H, s), 3.04 (1H, td, J=10.7, 4.8 Hz), 2.24-2.34 (2H, m), 2.13 (1H, dd, J=17.3, 6.3 Hz), 1.96-2.06 (2H, m), 1.72 (3H, s), 1.03 (3H, s), 1.02 (3H, s), 0.98 (3H, s), 0.93-0.96 (6H, m), 0.91-1.80 (17H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(NCc3ccccc3)c12
Reactant: BrCC1CC1
Solvent: CI
Product: O=c1c(-c2ccc(Cl)cc2)cn(CC2CC2)c2ccnc(NCc3ccccc3)c12

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-benzylamino-1,6-naphthyridine and iodomethane was replaced with cyclopropylmethyl bromide. MS 426 (M+1)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[N:4]=1)=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C(=O)C(F)(F)F)c2ccccn12
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(C(=O)C(F)(F)F)c2ccccn12

Procedure:
A solution of 15.6 g (0.06 mole) of 3-methylthio-1-trifluoroacetylimidazo[1,5-a]pyridine (J. Bourdais et al. J. Het. Chem. 17, 1351, 1980) in 750 ml of chloroform is cooled to 5° C. 30.6 g (0.132 mole) of m-chloroperbenzoic acid is added in the course of approximately 1 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:22]([N:17]1[CH2:18][CH2:19][C:14]2[NH:13][C:12](=[O:20])[N:11]3[CH:21]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[C:10]3[C:15]=2[CH2:16]1)[CH2:23][CH2:24][CH3:25]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCN1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reaction time: 6 h

Procedure:
To 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (171 mg, 0.6 mmol) in pH4-5 HCL-methanol (6 mL) at room temperature was added n-butyraldehyde (53 uL, 0.6 mmol) and sodium cyanoborohydride (38 mg, 0.6 mmol). After the reaction mixture was stirred for 6 hours, concentrated HCl was added until the mixture became homogenous. The mixture was then diluted with water (5 mL) and extracted twice with ether. The aqueous layer was made alkaline with aqueous ammonium hydroxide, saturated with sodium chloride, and extracted twice with 10% methanol/ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 9-n-Butyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 48). Recrystallization from aqueous ethanol gave a white fluffy solid, m.p. 251°-253° C. (d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19](Cl)=[O:20]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:19](=[O:20])[O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
1-(4-bromophenyl)methanamine (300 mg, 1.612 mmol) was taken up in dichloromethane (8062 μl) and triethylamine (225 μl, 1.612 mmol) was added. The solution was cooled to 0° C. and methyl chloridocarbonate (118 μl, 1.612 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. It was quenched with aqueous sodium bicarbonate and extracted using ethyl acetate (3×). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (50-100% ethyl acetate in hexanes) to yield the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(OO)(=[O:11])C>CC(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([OH:11])[CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)OO
Solvent: CC(C)=O
Product: Cc1ccc(O)c(O)c1

Procedure:
Five-neck flasks having a volume of 500 ml and provided with a stirrer, a reflux condenser, a sampling tube, a test specimen inlet and a thermometer were charged with 108.1g (1.0 mol) of paracresol and a different kind of peracid stabilizer as the catalyst shown in Table 1. Each flask was placed in a constant temperature bath kept at a temperature indicated in Table 1. Into the flask contents, 7.61g (0.1 mol) of peracetic acid in the form of about 35 weight% acetone solution was introduced through a micro-feeder over 20 minutes. Within 75 hours after the start of the addition of the peracetic acid, the contents of the flask were subjected to distillation under reduced pressure to obtain a fraction of 4-methyl-1,2-dihydroxybenzene having a boiling point of 124 - 125°C/6 mmHg. The results of this reaction are shown in the following table.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(N(CC)CC)C>[C:21]1([C:27]2[N:28]=[CH:29][N:30]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.6 mmol of triphenylmethyl chloride in 150 ml of dimethylformamide are added, under an argon atmosphere, to a solution of 6.9 mnmol of 4-phenyl-1H-imidazole in 50 ml of dimethylformamide and 10 ml of triethylamine. The solution is stirred for 4 hours at ambient temperature. After the addition of water, the precipitate obtained is triturated in ethyl ether, filtered and then dried, enabling the product obtained to be isolated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1C#CCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperidine-1-carboxylate (0.0293 g, 0.0570 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-(piperidin-4-yl)prop-1-ynyl]benzofuran-3(2H)-one (0.0123 g, 52%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:37])[NH:9][C:10]([C:12]1[S:13][C:14]([S:35][CH3:36])=[C:15]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][OH:34])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:16]=1)=[NH:11])([CH3:6])([CH3:5])[CH3:4].Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][O:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:15]2[CH:16]=[C:12]([C:10]([NH:9][C:8]([O:7][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:37])=[NH:11])[S:13][C:14]=2[S:35][CH3:36])(=[O:19])=[O:18])[CH:21]=1)[CH3:45]
Reactant: CCOC(=O)CCBr
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCOCc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
To a suspension of NaH (2.7 mg, 68 μmol, 60% oil dispersion) in DMF (0.1 mL) was added a solution of {[4-(2′-hydroxymethyl-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 56.4 μmol) in DMF (0.1 mL), as prepared according to the procedure of step b of Example 213. The mixture was stirred at ambient temperature for 30 min, and then placed in an ice-water bath. After 20 min, a solution of ethyl 3-bromopropionate (8.6 μL, 67.0 μmol) in DMF (0.05 mL) was added once. Ice-water bath was removed, and the mixture was stirred for 16 h. H2O was added, and the mixture was extracted with EtOAc (3×). The extracts were combined, washed with H2O, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (15%) followed by EtOAc/hexane (40%) to give the title compound (9 mg, 25%) yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.[C:10]1(=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11]1.P(CCCC)(CCCC)CCCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[O:20])[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1cc(CO)ncn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Product: Nc1cc(CN2C(=O)c3ccccc3C2=O)ncn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
To a stirred solution of (6-aminopyrimidin-4-yl)methanol (1.0 g, 8.0 mmol), isoindoline-1,3-dione (1.4 g, 9.6 mmol), n-Bu3P (2.42 g, 12.0 mmol) in dry DMF (20 mL) at room temperature was added diisopropyl azodicarboxylate (2.42 g, 12.0 mmol) dropwise. After addition, the resulting mixture was allowed to stir at 80° C. for 48 hours. Solvents were removed under reduced pressure and the residue was purified via chromatography column on silica gel eluting with a 2% gradient of methanol in dichloromethane to give the desired target as a gray solid (0.60 g, 30% yield). 1H-NMR (500 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.95-7.88 (m, 4H), 6.85 (s, 2H), 6.28 (s, 1H), 4.63 (s, 2H). LCMS (ESI) Method B: RT=3.23 min, m/z 233.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][CH3:11].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:9]([CH3:8])[CH2:10][CH3:11])=[N:5][N:6]=1
Reactant: CCC(C)=O
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (5 g) and butan-2-one (5.5 g) in acetic acid was added sodium cyanoborohydride (16 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (4.8 g, 61%).
Reaction SMILES: N[C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.N1CC[C@H]([OH:30])C1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[OH:30][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCN3CC[C@H](O)C3)cc2)cc1
Yield: 61 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (180 mg, 0.65 mmol), (3S)-3-pyrrolidinol (57 mg, 0.65 mmol), potassium carbonate (140 mg) and potassium iodide (180 mg) in 20 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (61 % yield).
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[CH3:1][S:2]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: CS(=O)[O-]
Reactant: CCOC(=O)C(C)Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)S(C)(=O)=O
Temperature: 77 °C
Yield: 31.7 %

Procedure:
Sodium methyl sulfinate (103 g, 937 mmol) was combined with the ethyl 2-chloropropionate (109 g, 892 mmol) in ethanol (350 mL) in a 500 mL one neck round bottom flask. The reaction was warmed to 77° C. for 20 hours, and then allowed to cool to room temperature. Solids were removed by filtration through celite, and the filter pad was washed with ethanol and the combined filtrates were concentrated in vacuo. The crude product was suspended in diethyl ether (250 mL), and solids were removed by filtration. The filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil (51 g, 73%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.05 Hz, 3H) 1.67 (d, J=7.47 Hz, 3H) 3.05 (s, 3H) 3.83-3.92 (m, 1H) 4.18-4.37 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[O:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.O.O.P([O-])(O)(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl.C[Si](C=[N+]=[N-])(C)C.[CH2:44]([O:46]CC)C.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.C(OCC)(=O)C.O.O1CCCC1>[C:17]([C:9]1[C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][C:6]=2[C:12]([F:13])=[C:11]([C:14]([O:46][CH3:44])=[O:15])[C:10]=1[CH3:16])#[N:18]
Reactant: CCOCC
Reactant: Cc1c(C=O)c(F)c2oc(C3CC3)nc2c1C#N
Agent: CC=C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Cyclopropyl-7-fluoro-6-formyl-5-methyl-1,3-benzoxazole-4-carbonitrile (I-182) (280 mg, 1.15 mmol) was dissolved in tert-butanol (8 ml), tetrahydrofuran (6 ml) and water (6 ml), then at 0° C., sodium dihydrogenphosphate dihydrate (268 mg, 1.72 mmol), 2-methyl-2-butene (515 μl, 4.59 mmol), then sodium chlorite (purity 80%, 389 mg, 3.44 mmol) were added. After stirring at room temperature for 6 hours, the solvent was evaporated away under reduced pressure. The residue was fractionated with ethyl acetate and aqueous 1 mol hydrochloric acid solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away under reduced pressure. Benzene (6 ml) and methanol (2 ml) were added to it, then at 0° C., 2 M trimethylsilyldiazomethane/diethyl ether solution (1.15 ml, 2.29 mmol) was added. After stirring at room temperature for 18 hours, an aqueous saturated sodium hydrogencarbonate solution was added at 0° C. The solution was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][C:10]=1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:20].[NH4+].[NH4+].C(O)=O.C(OC(=O)C)(=O)C.P(=O)(O)(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:20])=[CH:11][C:10]=1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P(O)(O)O
Agent: O=S([O-])O
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCc1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a reactor were charged 2.50 g (10 mmol) of 4-benzyloxy-3-ethylbenzaldehyde obtained in Step 3, 3.09 g (14 mmol) of ammonium persulfate, 0.96 g (21 mmol) of formic acid, 0.40 g (4.0 mol) of acetic anhydride, and 15 g of toluene, here was added aqueous solution of phosphoric acid dropwise at 60° C., and the mixture was stirred for 20 hours. After the reaction mixture was cooled to ambient temperature, 0.094 g (0.30 mmol) of p-toluenesulfonic acid dissolved in water was added dropwise, and the mixture was stirred for 9 hours. To the reaction mixture, 20 g of saturated aqueous solution of sodium bisulfite was added, and the mixture was stirred for 30 minutes. The organic layer was washed with water, the solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:hexane=1:10, SiO2) to yield the desired product, 4-benzyloxy-3-ethylphenol, as red liquid (0.92 g, Yield: 39%).
Reaction SMILES: C(N)(C)(C)C.[CH3:6][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].C(=O)=O.C1(/C(=C\C2C=CC=CC=2)/C(O)=O)C=CC=CC=1>CO>[CH3:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: C[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)/C(=C/c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: CO
Solvent: CC(C)(C)N
Product: C[C@H](Cc1ccccc1)C(=O)O

Procedure:
(S)-2-Methyl-3-phenylpropionic acid tert-butylamine salt, reaction time 40 minutes, conversion 100%, ee 96.5% (SFC, 2× Chiralpak AD-H columns, 10% methanol, 3000 psi CO2, 35° C., flow rate 3 ml/minute, retention times R 7.1 minutes, S 7.7 minutes, (E)-phenylcinnamic acid 12 minutes). The free acid was liberated by partitioning between dichloromethane and 2M HCl. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated to give (R)-2-Methyl-3-phenylpropionic acid as a pale yellow solid. [α]D20+98.6, c=2.03, CHCl3. [α]D20+100.6, c=0.54, acetone. [α]D20+103.5 (c=1.00, MeOH). Lit. (M. B. Watson and G. W. Youngson, J. Chem. Soc. C, 1968, 258-261; +140.8, c=2.04, CHCl3). 1H NMR analysis of the (S)-methyl mandelate (E. Tyrell, M. W. H. Tang, G. A. Skinner and J. Fawcett, Tetrahedron, 1996, 52, 9841-9852) confirmed assignment of (S)-configuration.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[C:21]1[CH:22]=[C:23]2[C:29]([NH2:30])=[N:28][NH:27][C:24]2=[N:25][N:26]=1>N1C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[C:21]1[CH:22]=[C:23]2[C:29]([NH:30][C:4](=[O:5])[C:3]3[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])=[N:28][NH:27][C:24]2=[N:25][N:26]=1
Reactant: Nc1n[nH]c2nnc(-c3cccc(F)c3F)cc12
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c(C(=O)Nc2n[nH]c3nnc(-c4cccc(F)c4F)cc23)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,4,6-Trimethylbenzoyl chloride (0.594 g, 3.24 mmol) was added to a solution of 5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (Description 14; 0.400 g, 1.62 mmol) in pyridine (2 mL). The solution was heated at reflux for 72 hours, and the solvent then evaporated in vacuo. Piperidine (50 mL) was added and the solution stirred at room temperature for 16 hours. The mixture was evaporated and the residue azeotroped with ethanol. The crude product was purified firstly by chromatography on silica gel using a gradient elution with 5-20% v/v methanol in dichloromethane, and subsequently by further chromatography on silica gel using diethyl ether as eluent to afford the title compound, a solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.Cl[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>CN(C)C=O.[Mn]>[CH2:11]([S:8]([NH:7][CH2:6][C:5]1[CH:13]=[CH:14][C:2]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][C:4]=1[F:15])(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)NCc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)Cl
Agent: [Mn]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-bromo-2-fluorobenzyl)ethanesulfonamide (305 mg, 1.03 mmol) in dimethylformamide, Manganese (113 mg, 2.06 mmol), (2,2′-Bipyridine)nickel(II)-dibromide (27 mg, 0.07 mmol), ethyl 2-chloropropanoate (0.17 mL, 1.34 mmol) was added. It was followed by addition of trifluoroacetic acid (0.002 mL, 0.028 mmol). The mixture was stirred for 24 h at 65° C. The reaction mixture was quenched by concentrated HCl (7 drops). Then it was extracted with diethyl ether, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to obtain ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate in pure form (65 mg, 20%).