Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20]2[CH:21]=[C:22]([NH:25]C(=O)OC(C)(C)C)[S:23][CH:24]=2)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:7]1([CH3:8])[CH:6]=[CH:5][C:4]([S:1]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]3[CH:21]=[C:22]([NH2:25])[S:23][CH:24]=3)=[CH:12]2)(=[O:3])=[O:2])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3csc(NC(=O)OC(C)(C)C)c3)c3cccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3csc(N)c3)c3cccnc32)cc1

Procedure:
tert-Butyl 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-ylcarbamate (120 mg, 0.26 mmol) was dissolved in 2 mL CH2Cl2, 2 mL TFA. After 15 minutes the reaction mixture was concentrated to an oil, dissolved in EtOAc, and washed with 0.1 NaOH. The organic layer was dried to a brown oil which was used as obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:17])[C:7]=1[C:8]([NH:10][C:11]1[S:12][C:13](Br)=[CH:14][N:15]=1)=[O:9].[F:18][C:19]1([F:38])[O:23][C:22]2[CH:24]=[C:25]([CH3:37])[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:21]=2[O:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:17])[C:7]=1[C:8]([NH:10][C:11]1[S:12][C:13]([C:26]2[C:25]([CH3:37])=[CH:24][C:22]3[O:23][C:19]([F:18])([F:38])[O:20][C:21]=3[CH:27]=2)=[CH:14][N:15]=1)=[O:9]
Reactant: O=C(Nc1ncc(Br)s1)c1c(F)cncc1F
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cncc3F)s1)OC(F)(F)O2
Temperature: 85 °C
Yield: 40.8 %

Procedure:
Argon was bubbled through a mixture of (3,5-difluoro(4-pyridyl))-N-(5-bromo(1,3-thiazol-2-yl))carboxamide (148) (32 mg, 0.1 mmol), 2-(2,2-difluoro-6-methylbenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45 mg, 0.15 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (11 mg, 10% mol) and K3PO4 (32 mg) in 1 mL ACN, 1 mL dioxane, 0.5 ml H2O. The reaction mixture was heated at 85° C. for 4 h. After cooling to room temperature, the reaction mixture was taken up in ethyl acetate, washed with aqueous NaHCO3 and brine. The organic phase was dried (Na2SO4), concentrated and then subjected to prep HPLC chromatography to give (3,5-difluoro(4-pyridyl))-N-[5-(2,2-difluoro-6-methylbenzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl)]carboxamide (149) (16.8 mg, yield: 40.8%, purity>95%). LC-MS: calcd. for C17H9F4N3O3S: 412 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#[N:2].C(N)(=[S:32])C.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([C:1](=[S:32])[NH2:2])[CH:4]=2
Reactant: CC(N)=S
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1

Procedure:
Heat N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 51) (1.00 g, 2.57 mmol) with thioacetamide (0.386 g, 5.14 mmol) at reflux temperature in 4N HCl in dioxane (30 mL) for 4 h. Allow to cool, pour onto water and neutralize with NaHCO3. Collect 0.98 g (90%) of a precipitate. Purify a portion of the material by silica gel chromatography (25-80% EtOAc/hexanes gradient) to give a yellow solid. MS (ES): m/z 424 (M+1); HPLC: Rt=1.90 min, (95%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13](OC)=[O:14])[CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2ccn(C(C)C)c2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ccc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a 0° C. solution of methyl 1-isopropyl-1H-indole-6-carboxylate (0.50 g, 2.30 mmol) in THF (5 mL) was added 1M lithium borohydride in THF (6.90 mL, 6.90 mmol). After stirring at rt for 96 h, quenched with MeOH and let stir for 1 h. The reaction mixture was concentrated, partitioned between saturated sodium bicarbonate and EtOAc, washed with H2O and brine, dried with Na2SO4, and concentrated. The crude compound was chromatographed to give the desired product.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][N:18]([C:21]([F:28])([F:27])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:29][C:30]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[C:31]=1[O:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>C(O)CC>[F:27][C:21]([F:28])([N:18]1[CH:19]=[CH:20][C:16]([S:13](=[O:15])(=[O:14])[NH:12][C:3]2[C:2]([NH:29][C:30]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[C:31]=3[O:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[N:17]1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: CN(C)C(=O)C(F)(F)n1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)n1
Reactant: COc1cc(N)c(OCCC(C)O)c(OC)c1
Solvent: CCCO
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccn(C(F)(F)C(=O)N(C)C)n2)c(OCCC(C)O)c(OC)c1
Yield: 72.3 %

Procedure:
300 mg of 2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamide and 258 mg of 4-(2-amino-4,6-dimethoxyphenoxy)butan-2-ol in 4 ml of 1-propanol are heated at 140° C. in a microwave-suitable glass vessel with high absorption in the microwave until starting material 1 has reacted virtually completely (about 45 minutes). The cooled reaction mixture is filtered off with suction, rinsed with 1-propanol and dried, giving 320 mg of 2,2-difluoro-2-(3-{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide as slightly yellowish solid (yield 74%). MS-FAB (M+H+)=636.2. Rf (polar method): 2.41 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[CH:19]=[N:18][NH:17][C:14]3=[CH:15][N:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[CH3:22]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[CH:19]=[N:18][N:17]([CH3:22])[C:14]3=[CH:15][N:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1Oc1cc2cn[nH]c2cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ncc21
Temperature: 0 °C
Yield: 51.1 %

Procedure:
The intermediate (2u) (0.23 g) was dissolved in DMF (9 mL) and cooled to 0° C. Sodium hydride (60% in oil, 0.054 g, 1.36 mmol) and methyl iodide (0.28 mL, 642 mg, 4.52 mmol) were added to the solution at 0° C. and then the reaction mixture was stirred for an hour at 0° C. The mixture was quenched with 10 mL of water and extracted three times with 30 mL of ether. The combined organic layer was washed with 5 mL of water twice and brine once, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil residue was purified on silica gel with EtOAc/hexane (1:1) to afford colorless oil (3u) (0.124 g, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.02 (s, 1H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 2H), 7.11-7.05 (m, 1H, 4.17 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)cc1
Reaction time: 10 h

Procedure:
A mixture of 0.1 mol 4-fluorobenzaldehyde, 0.15 mol malonic acid, and 0.1 ml piperidine in 30 ml pyridine is boiled for 10 hours, cooled, and treated with 150 ml HCl having a 10% concentration. The precipitate is filtered and crystallized with ethanol. The yield of 4-fluorocinnamic acid is 68% and the melting point is 211° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(CO)CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CC1(c2ccc3ccccc3c2)CCCC1
Agent: OCC1(c2cc(Cl)ccc2Cl)CCCC1
Product: OCC1(c2ccc3ccccc3c2)CCCC1
Yield: 99 %

Procedure:
(1-Naphthalen-2-yl-cyclopentyl)-methanol (213) (22.0 g, crude) was synthesized as a colourless liquid from 1-naphthalen-2-yl-cyclopentanecarbaldehyde (212) (22.0 g, 98.21 mmol) following the procedure described for 1-(2,5-dichlorophenyl)-cyclopentane-methanol (200).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][C:12]2([C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29].O>O1CCCC1>[C:32]([O:31][C:27](=[O:30])[CH2:28][CH2:29][N:17]1[C:18]2[C:23](=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:12]2([CH2:13][C:14](=[O:15])[N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:11]2=[O:26])[C:16]1=[O:25])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of sodium hydride (60% dispersion in oil, 7 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2 ml) was treated with 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 14 (50 mg, 0.15 mmol). After stirring at ambient temperature for 30 minutes, tert-butyl acrylate (0.03 ml, 0.19 mmol) was added and the resultant mixture stirred for 2 hours and left to stand at ambient temperature for 18 hours. Water (15 ml) was added and the mixture extracted with ethyl acetate (3×15 ml). The combined extracts were washed with brine (15 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude 3-(1′-Benzyl-5-chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)-propionic acid tert-butyl ester. This was purified by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 50%) of ethyl acetate to give a white solid (37 mg 54%). This was sufficiently pure by 1H NMR to take on to the final hydrolysis step.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>CC1C=CC(C(C)C)=CC=1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: ClCCl
Product: CCCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in p-cymene (11 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine hydrochloride SLA 28178 (323 mg, 1.07 mmol) at RT followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1 h before addition of a new portion of SLA 28178 (323 mg, 1.07 mmol, done 3 times). After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 14.8 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.26 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum, to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 42 as a yellow solid (6 mg, 10% yield).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>O>[CH2:4]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:1]([CH:14]([OH:15])[C:13]1[CH:16]=[CH:17][C:18]([F:19])=[C:11]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:12]=1)#[N:2]
Reactant: [C-]#N
Agent: O=Cc1ccc(F)c(Cc2ccccc2)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(O)c1ccc(F)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium cyanide (0.26 g) in water (2 cm3) was added portionwise to a suspension of 3-benzyl-4-fluorobenzaldehyde (0.5 g) in glacial acid (10 cm3) whilst the temperature was maintained at 0° C. After 30 minutes, the reaction mixture was allowed to warm to the ambient temperature (ca. 25° C.), and allowed to stand for a period of 16 hours. A further portion of glacial acetic acid (5 cm3) was added and stirring continued for 8 hours at the ambient temperature. After standing for sixteen hours, a further portion of potassium cyanide (0.26 g) in water (1 cm3) was added, and after the reaction mixture had been allowed to stand for a period of 7 days, it was diluted with water, and extracted with diethyl ether. The ethereal layer was washed sequentially with aqueous sodium bicarbonate, and brine, dried, and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexane containing diethyl ether (40% by volume) as eluent to give firstly recovered 3-benzyl-4-fluorobenzaldehyde (0.2 g), and secondly α-cyano-3-benzyl-4-fluorobenzyl alcohol (0.24 g) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([S:27]([NH2:29])=[O:28])([CH3:26])[CH3:25]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:29][S:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-benzyl-2-(2,5-difluorophenyl)oxazole-4-carbaldehyde (898 mg, 3.0 mmol) in THF (30.0 mL) was added (±)-2-methylpropane-2-sulfinamide (364 mg, 3.0 mmol), and Ti(OEt)4 (1.37 mL, 6.6 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with brine (30 mL) and EtOAc (60 mL) followed by addition of Celite®. Then, the mixture was vigorously stirred for 1 h, and filtered. The filtrate was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (770 mg, 64%) was purified by automatic column chromatography to yield (±)—N-((5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide as pale yellow solid. LC/MS (uplc): MH+ 403.0, 1.21 min.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C[O-].[Na+].CO>C(OCC)(=O)C>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 178.2 %

Procedure:
10.0 g of p-acetoxystyrene was dissolved in 40.0 g of ethyl acetate, and the resulting solution was cooled to 0° C. Subsequently, 4.76 g of sodium methoxide (a 28 mass % methanol solution) was added dropwise over 30 minutes, and the resulting solution was stirred at room temperature for 5 hours. The organic layer was washed with distilled water three times and dried over anhydrous sodium sulfate, and the solvent was removed by distillation to obtain 13.2 g of p-hydroxystyrene (the compound represented by the following formula (1), a 54 mass % ethyl acetate solution). Thereafter, 11.0 g of a 54 mass % ethyl acetate solution of the obtained p-hydroxystyrene (1) (containing 5.9 g of p-hydroxystyrene (1)), 9.4 g of the compound represented by the following formula (2) (produced by KNC Laboratories Co., Ltd.), 2.2 g of the compound represented by the following formula (3) (produced by Daicel Corporation) and 2.3 g of polymerization initiator V-601 (produced by Wako Pure Chemical Industries, Ltd.) were dissolved in 14.2 g of propylene glycol monomethyl ether (PGME). After charging 3.6 g of PGME into a reaction vessel, the solution prepared above was added dropwise at 85° C. over 4 hours in a nitrogen gas atmosphere, and the reaction solution was heated with stirring for 2 hours and then allowed to cool to room temperature. The obtained reaction solution was added dropwise and reprecipitated in 889 g of a mixed solution of hexane/ethyl acetate (8/2 (by mass)), and the precipitate was filtered to obtain 15.5 g of (P-2).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38])#[N:31].C(=O)([O-])[O-].[Na+].[Na+].O>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>[Cl:13][C:11]1[CH:12]=[C:7]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([C:30]#[N:31])[CH:33]=2)[CH:8]=[C:9]([Cl:27])[C:10]=1[CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:16]1=[O:26]
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: N#Cc1cc(B(O)O)ccc1F
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: C1CCOC1
Product: N#Cc1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)ccc1F
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a solution of 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.34 g, 2.83 mmol) in THF (30 mL) in a round bottom flask was added 3-cyano-4-fluorophenylboronic acid (560 mg, 3.39 mmol), sodium carbonate (900 mg, 8.48 mmol) and water (10 mL). The mixture was stirred at 60° C. for 5 minutes, palladium tetrakis (163 mg, 0.14 mmol) was added. Reaction mixture was brought to 80° C. and stirred for 3 hours. Cooled and partitioned between ethyl acetate and HCL(1 N). Organic was separated, wash with water, brine; dry over sodium sulfate, filter, and concentrate. Purify by silica gel (25-50% ethyl acetate in hexane) to afford 1.10 g (88%) of the title compound: Mass spectrum (LCMS) m/z=445.0 (M+H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:6]([O:25][CH3:26])=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:24][NH:23][CH2:22][CH2:21][N:11]3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[C:6]([O:25][CH3:26])=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:24][N:23]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:22][CH2:21][N:11]3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:14]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCN(Cc3ccccc3)CC1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline dihydrochloride (the compound obtained in Example 1-(6)) (2 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added potassium carbonate (2.8 g) and benzyl bromide (0.7 ml), and the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitates (1.2 g) are dissolved in chloroform, and thereto is added a 4M hydrochloric acid in ethyl acetate, and the solvent is removed by evaporation under reduced pressure. The resultant is recrystallized from ethanol to give 8,9-dimethoxy-2-benzyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline dihydrochloride (1.2 g).