Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].C(OC([NH:9][C@H:10]1[C@@H:13](/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]([S:22]([O-:25])(=[O:24])=[O:23])[C:11]1=[O:26])=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.CCOCC.CCCCCC>[NH2:9][C@H:10]1[C@@H:13](/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]([S:22]([OH:25])(=[O:23])=[O:24])[C:11]1=[O:26]
Reactant: CCOC(=O)/C=C(/C)[C@@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)/C=C(/C)[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
1.755 g (4.38 mmol) of rac-cis-3-(1-t-butoxyformamido)-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 7.5 ml of anisole and the solution is treated at -20° C. with 10 ml of trifluoroacetic acid. After stirring at -20° C. for 30 minutes and then at room temperature for a further 3 hours, the solution is diluted with 300 ml of ether/n-hexane (1:1). The crystals obtained are filtered off, dissolved in 10 ml of water and chromatographed on MCI gel. 808 mg (60%) of rac-cis-3-amino-4-[(Z)-2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-1-azetidinesulphonic acid are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[O:24][CH3:23])=[N:3]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1ccc(F)cc1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(NS(=O)(=O)c3ccc(F)cc3)cccc2n1

Procedure:
N-(2-Chloro-quinolin-5-yl)-4-fluoro-benzenesulfonamide (200 mg, 0.593 mmol) and 2-methoxybenzylamine (171 mg, 1.25 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a yellow solid (87 mg, 33%), MS: m/e=438.1 ((M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][CH:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH2:11][CH2:10][N:9]2[CH3:18])=[CH:5][CH:4]=1.[OH-].[K+]>C(O)COCCO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH2:11][CH2:10][N:9]2[CH3:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(CC2C3=C(CCCC3)CCN2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CN1CCC2=C(CCCC2)C1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.7 %

Procedure:
A mixture of 253.9 g (0.935 mol) of (--)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and 1.2 l. of diethylene glycol was warmed to 80°-100° and 260 g of potassium hydroxide (85 % A.C.S. grade) was added. The reaction mixture was heated to 210° and stirred at this temperature under a constant stream of nitrogen for 36 hours. During this period, time to time the stop cock was removed to allow escape of water vapor. If this is not done, the desired inner temperature of 210° cannot be attained. The dark brown solution was cooled to room temperature and diluted with water (600 ml) and extracted with ether (400 ml). The aqueous solution was made acidic with concentrated aqueous hydrochloric acid and then basified with concentrated aqueous ammonium hydroxide. The aqueous suspension was extracted with ethyl acetate (4×250 ml). The ethyl acetate solution was washed with water and dried. Removal of the solvent gave 172.5 g (72%) of crude (--)-1-(p-hydroxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis, a sample of this compound was recrystallized from tetrahydrofuran-heptane, mp 119°-120°, [α]25D-36.01° (c 0.98, MeOH).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([C:19]([O:21][CH3:22])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:4]([C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:6]([C:19]([O:21][CH3:22])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(c1cc(Cc2ccc(F)cc2)cnc1C(=O)OC)C1CC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of methyl 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (234 mg, 0.78 mmol) and ethyl 3-chloro-3-oxopropanoate (0.13 mL, 90%, 1.0 mmol) was heated at 85° C. for 3 hours. Upon cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with dichloromethane and the combined organics dried over sodium sulfate. Filtration and concentration followed by silica gel chromatography provided methyl 3-{cyclopropyl[3-(ethyloxy)-3-oxopropanoyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (285 mg, 88%) as an oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]([NH2:14])=[O:13])[C:9](O)=[O:10].Cl.C(O)(=O)CC(N)=O>CN(C)C=O>[OH:10][C:9]1[S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]=1[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)C(C(=O)O)c1ccccc1S
Agent: Cl
Agent: NC(=O)CC(=O)O
Solvent: CN(C)C=O
Product: NC(=O)c1c(O)sc2ccccc12
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere, a mixture of o-mercaptophenylmalonamic acid (2.1 g, 0.01 m), dimethylformamide (20 ml), and concentrated hydrochloric acid (0.2 ml) are heated in an oil-bath at ca. 100° C. until thin-layer chromatography indicates the absence of starting malonamic acid. The cooled, stirred mixture is diluted with ice-water, aged and filtered to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:19]=3[CH:18]=[C:17]([OH:20])[CH:16]=[CH:15]4)=[N:8][C:4]=2[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>O.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.CCO>[C:23]1([C:2]2[CH:22]=[CH:21][C:5]3[NH:6][C:7]([NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[C:19]=4[CH:18]=[C:17]([OH:20])[CH:16]=[CH:15]5)=[N:8][C:4]=3[CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2cccc(Nc3nc4cc(Br)ccc4[nH]3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Oc1ccc2cccc(Nc3nc4cc(-c5ccccc5)ccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 8-(5-bromo-1H-benzo[d]imidazol-2-ylamino)naphthalen-2-ol (18 mg, 0.05 mmol, Example 14), phenylboronic acid (12 mg, 0.1 mmol, Aldrich), PdCl2(PPh3)2 (3.5 mg, 0.005 mmol, Aldrich), Na2CO3.H2O (12 mg, 0.1 mmol), dimethoxyethane (0.35 mL), H2O (0.15 mL) and EtOH (0.1 1 mL) was subjected to microwave irradiation at 120° C. with stirring for 10 min. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound. MS (ESI, pos. ion) m/z: 352 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2ccc(Br)cc2)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(4-Bromophenyl)piperidin-4-one (765 mg) is dissolved under argon in MeOH (8 mL), cooled to 0° C. and treated with NaBH4 (145 mg). The mixture is stirred for 2 hours at 0° C., treated with saturated aqueous NaHCO3 solution and stirred for 10 minutes. Then the mixture is extracted with ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated to give the title compound. LC (method 2): tR=0.92 min; Mass spectrum (ESI+): m/z=256 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:13]=2)[CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:3]=1
Reactant: CC(=O)Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A mixture of Example 91a (186.0 mg, 0.436 mmol) and HCl (0.20 mL, 6.6 mmol) in ethanol (6 mL) was heated at 95° C. for 3 hours and cooled. Half of the solvent was evaporated; the resulting suspension was filtered and washed with EtOH. The solids were stirred in saturated NaHCO3 for 30 minutes, filtered, washed with water, and oven-dried to give 72.2 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 6.30 (s, 2H), 6.85 (s, 1H), 6.91 (s, 1H), 7.15 (m, 1H), 8.12 (s, 1H), 8.21-8.36 (m, 2H), 12.15 (s, brd, 1H). MS (ESI+) m/z 244.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CCCCC1
Reaction time: 0.62 h
Yield: 91.7 %

Procedure:
Add 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (See Example 34) (0.290 g, 0.830 mmol), Pd(Ph3)4 (0.043 g, 0.037 mmol), 4-methanesulfonylphenylboronic acid (0.249 g, 1.25 mmol), 2N Na2CO3 (2.1 mL), and 1,4-dioxane (1 mL) to a microwave vessel. Microwave at 30 W, 90° C. for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give 1-{2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.323 g, 92%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C@@H:7]12[C:16](=O)[O:15][C:13](=[O:14])[C@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2.O>C(OCC)C>[OH:14][CH2:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[CH2:16][OH:15]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC[C@@H]1CCCC[C@H]1CO
Yield: 70.7 %

Procedure:
To a mixture of lithium aluminum hydride (2.85 g; 75 mmol) and diethyl ether (50 ml), a solution of trans-1,2-cyclohexanedicarboxylic acid anhydride (1) (7.71 g; 50 mmol) in diethyl ether (150 ml) is dropwise added, and the resultant mixture is allowed to react at room temperature for 3 hours and then heated under reflux for 2 hours. After cooling, wet ether is dropwise added to the reaction mixture, followed by addition of water. The organic layer is collected by decantation, followed by concentration to give trans-1,2-bis(hydroxymethyl)cyclohexane (2) (5.1 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([OH:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:16]([O:20][C:21](=[O:24])[CH2:22]Br)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21](=[O:24])[CH2:22][O:15][C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[N:11]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1nc(-c2ccc(F)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
123 mg (2.82 mmol) of sodium hydride (55% in mineral oil) were added to 500 mg (2.56 mmol) of 4-(4-fluoro-phenyl)-thiazol-2-ol in 15 ml of DMF. After stirring at room temperature for 30 min, 549.6 mg (2.82 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated to give 762 mg of a mixture of title compound and N-alkylated product.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23].C(ON=O)(C)(C)C>O1CCCC1>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[CH:2]=[C:3]([C:20]#[C:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[C:4]([CH3:19])=[N:5]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#C[Si](C)(C)C
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#C[Si](C)(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl 4-trimethylsilylethynylpyrazole (1.3 g) in tetrahydrofuran (15 ml) at 65° C. was added dropwise t-butylnitrite (1.65 g) in tetrahydrofuran (5 ml) over a period of 15 minutes and heating continued for 3 hours. The reaction mixture was left at room temperature overnight then evaporated to give the crude product as a gum which was purified by column chromatography on silica gel eluted with dichioromethane:hexane (1:1). Combination and evaporation of appropriate fractions provided the title compound as a pale yellow solid, m.p. 76-78° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
3-(3-Fluoro-4-(4-methylimidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (11.8 g, 40.5 mM) was stirred in a mixture of pyridine (200 ml) and triethylamine (4.86 g, 48.2 mM) under nitrogen in an ice-bath. Methanesulfonyl chloride (5.16 g, 45 mM) was added dropwise, and the mixture stirrd for 2 hours, allowing the temperature to rise to ambient. Solvent was evaporated, and the residue stirred vigorously with a mixture of aqueous sodium bicarbonate (5%, 200 ml) and isohexane (200 ml). The precipitate was filtered, washed with water then isohexane, and dried. The residue was recrystallised from hot acetone (200 ml) by dilution with isohexane (300 ml) to give the title product (11.7 g), mp 151–153°.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Cl:19][Ti:20](Cl)([Cl:31])[C:21]1([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]1[CH3:29]>C1(C)C=CC=CC=1>[Cl:19][Ti:20]([Cl:31])([C:21]1([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]([CH3:27])=[C:25]1[CH3:26])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2ccccc2-c2ccccc2)C(C)=C1C
Reaction time: 12 h
Yield: 85 %

Procedure:
After 0.86 g of 2-phenylphenol (5.07 mmol) (Aldrich, 99%) were dissolved in 40 mL of toluene, 2.4 mL of butyl lithium (2.5 M hexane solution) were slowly dropped thereonto at 0° C. After the reaction was conducted at normal temperature for 12 hours, a solution in which (trichloro)(pentamethylcyclopentadienyl)titanium(IV) (1.32 g, 4.56 mmol) was dissolved in 10 mL of toluene was slowly dropped thereonto at 0° C. After agitation was conducted at normal temperature for 12 hours, filtration was conducted, volatile materials were removed, and recrystallization was conducted using a mixed solution of toluene/hexane at −35° C. to produce 1.64 g of an orange-colored solid component.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8]1.CI>CN(C)C=O>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]([O:20][CH3:1])=[O:19])=[CH:8]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
36.2 g of powdered potassium carbonate was added, with ice-cooling, to a solution of 24.8 g of 3-(indol-3-yl)propionic acid in 500 ml of N,N-dimethylformamide, followed by the addition of a solution of 10.2 ml methyl iodide in 50 ml of N,N-dimethylformamide. The reaction mixture was then warmed to room temperature and stirred for 3 hours. After this time, ice water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic extract was then washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 500 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 25.8 g of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:8][C:6]1[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=1
Reactant: COc1cc(CO)on1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
(3-Methoxy-isoxazol-5-yl)-methanol (822 mg, 6.4 mmol) was dissolved in dichloromethane (10 ml) and triphenyl phosphine (1.84 g, 7.0 mmol) and carbon tetrabromide (2 g, 6.11 mmol) were added at 0° C. The mixture was stirred for 2 hours at 0° C. and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as a colourless oil (1.22 g, 99% yield) which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)=[O:7])C.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].Cl>CCCCCC.O1CCCC1>[CH2:19]([O:18][C:15](=[O:17])[CH2:16][C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:20]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1cc(Cl)ccn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
Under a nitrogen atmosphere, 4 g (approximately 60% dispersion in paraffin oil, about 100 mmol) of sodium hydride are washed twice with 60 ml of n-hexane each time, and then 400 ml of absolute tetrahydrofuran are added. The mixture is heated to 50° C. and, in the course of 2 hours, a solution of 13.36 g (72 mmol) of 4-chloropyridine-2-carboxylic acid ethyl ester and 10.04 g (114 mmol) of ethyl acetate in 60 ml of absolute tetrahydrofuran is added dropwise, during which the mixture begins to boil vigorously. When the exothermic reaction has subsided, stirring is carried out for 12 hours at room temperature to complete the reaction. The yellow suspension is poured into 400 ml of ice-water and rendered neutral with 15% hydrochloric acid, and the solution is concentrated to half its volume. Extraction is then carried out twice with 200 ml of ethyl acetate each time, and the organic extracts are combined, dried (sodium sulfate), filtered and concentrated. 14.5 g of 3-(4-chloropyrid-2-yl)-3-oxopropionic acid ethyl ester are obtained in the form of a light-brown oil, which is used for further syntheses without further purification.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:33][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:33])[NH2:2]
Reactant: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (100 mg, 0.2 mmol, 1.00 equiv) in 10 mL of methanol was added LiOH.H2O (30 mg, 0.7 mmol, 3.26 equiv) and H2O2 (30%, 0.8 mL) and stirred for 4 h at 0° C. The reaction was then quenched with saturated aqueous NaHSO3, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with EtOAc/PE (1:2) to give the desired tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (85 mg) as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].O.O.[F-].[K+].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH2:9].[CH3:8][C:7]1[NH:6][C:5](=[O:9])[NH:4][C:3](=[O:10])[C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccccc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 20.5 g (0.10 mole) of 5-bromo-6-methyl-2,4(1H, 3H)-pyrimidinedione and 10.3 g (0.11 mole) of potassium fluoride dihydrate in 150 ml of 1-phenylpiperazine was heated under reflux at 105° for 72 hours and cooled. The reaction mixture was poured into 200 ml of ice water. The solid was collected, washed with water, and recrystallized from methanol to give 7.12 g of the product as a white solid, mp>300° C.
Reaction SMILES: F[C:2]1C=CC(C2C(C)=C(O)C(=O)N(CC(C)C)N=2)=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[NH:34][N:35]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[F:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[N:34]([CH2:2][CH:3]([CH3:21])[CH3:4])[N:35]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1cc(-c2nn(CC(C)C)c(=O)c(O)c2C)ccc1F
Reactant: COC(=O)c1cc(-c2ccc(F)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(F)c(F)c2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 1 (6), 6-(3,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow oil (yield: quantitative).