Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([O-])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C([O-])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The chelating agent, which is sometimes referred to as gluconate and/or as sodium gluconate, can be purchased from Jungbunzlauer AG, St. Alben—Vorstadt 90, CH-4002, Basel, Switzerland. It can be purchased as a powdered concentrate in 25 kg bags and 1000 kg bags. Sodium gluconate is the sodium salt of gluconic acid, which can be produced by fermentation of glucose. It can be white to tan in color, granular to fine in particle size, very soluble in water, non-corrosive, non-toxic, and/or readily biodegradable (98% after 2 days).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:13]2[CH:22]=[CH:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:14]=2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1.[CH:33]1([OH:37])[CH2:36][CH2:35][CH2:34]1.[H-].[Na+]>O1CCCC1>[CH:33]1([O:37][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:4][C:3]=2[C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(S(C)(=O)=O)ccc4F)cn(C)c(=O)c32)cc1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OC2CCC2)c2cc[nH]c2c1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 4 mL vial was charged with a stir bar, a solution of Example 138a (30 mg, 0.063 mmol) in tetrahydrofuran (1 mL), a solution of cyclobutanol (32 mg, 7 equivalents, 0.46 mmol) in tetrahydrofuran (1 mL) and neat sodium hydride (19 mg, 7 equivalents, 0.46 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The crude material was filtered, concentrated, and purified by reverse phase HPLC (C18, 10-100% CH3CN/water (0.1% TFA)) to afford the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 7.98-7.75 (m, 2H), 7.33 (d, J=1.4 Hz, 2H), 7.16 (d, J=8.7 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.82 (p, J=7.2 Hz, 1H), 3.59 (s, 3H), 3.19 (d, J=8.5 Hz, 3H), 2.47-2.38 (m, 2H), 1.96 (p, J=9.6 Hz, 2H), 1.81-1.72 (m, 1H), 1.72-1.57 (m, 1H). MS (ESI+) m/z 373 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@H:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1>>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:15][CH2:14]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(C)(=O)=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using methanesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 458.6 (M+H)+.
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].C([SiH:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])CCC>C1COCC1>[CH:15]([SiH:14]([CH:18]([CH3:20])[CH3:19])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:17])[CH3:16]
Reactant: CCCC[SiH](C(C)C)C(C)C
Reactant: CC(C)(C)CBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)[SiH](CC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Magnesium (2.43 g, 100 mmol) and iodine (catalytic amount) were added to THF (100 mL), and 1-bromo-2,2-dimethylpropane (10.7 mL, 100 mmol) was added dropwise thereto for 20 minutes, followed by stirring at room temperature for 1 hour. After termination of exothermic reaction, the resultant mixture was further stirred at 50° C. for 5 hours, whereby 2,2-dimethylpropylmagnesium bromide THF solution was prepared. The procedure of synthesizing Compound 47a was repeated, except that the thus-prepared mixture was employed, whereby the Compound 51a was obtained as a colorless liquid (boiling point; 40 mmHg, 120.0 to 122.5° C. fraction, 7.65 g, 45%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25](O)(=O)[CH3:26].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCNC3)cc2)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.3 g of 4-Isopropyl-N—((S)-4-pyrrolidin-3-yl-phenyl)-benzenesulfonamide (0.87 mmol) were dissolved in 20 ml dichloromethane. After addition of 0.07 ml of acetic acid, 0.073 ml of acetaldehyde (1.31 mmol) and 0.277 g of sodium triacetoxyborohydride (1.31 mmol), the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, the residue dissolved in water and the pH adjusted to pH 8-9 with aqueous sodium hydroxide solution. The aqueous phase was extracted three times with diethyl ether, the combined organic phases dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography (chromabond column) with dichloromethane, dichloromethane/methanol 4% as eluent to yield 64 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].CO>O>[CH:21]([N:18]1[CH2:19][CH2:20][CH:16]([O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:17]1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)C1
Temperature: 100 °C

Procedure:
A mixture of 2.05 g (6 mmol) 5-(1-Isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester and 0.299 g (7 mmol) lithiumhydroxide monohydrate 30 ml THF, 30 ml methanol and 15 ml water was heated to 100° C. for 2 h. The organic solvents were removed and aq. 1N HCl was added to adjust the pH of the solution to 2-3. Subsequently, the mixture was evaporated to dryness and the mixture was used without further purification in the next step. MS (m/e): 289.1 (MH+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:17][C:16]([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:15]1[CH3:36])=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH:29]1([NH:28][C:27]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[F:26])[N:14]([CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[C:15]=2[CH3:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Cc1c(C(=O)NC2CCCCC2)cc(-c2cc(Cl)ccc2F)n1CC1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)NC2CCCCC2)cc(-c2cc(Cl)ccc2F)n1CC1CCCN1
Yield: 95 %

Procedure:
To a solution of 2-[5-(5-chloro-2-fluoro-phenyl)-3-cyclohexylcarbamoyl-2-methyl-pyrrol-1-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (51 mg) in methylene chloride (1 mL) was added at 0° C. TFA (0.5 mL). After 3 hours the volatiles were evacuated in vacuo and the residue was azeotroped with ethyl acetate (3×) and dried on high vacuum overnight to afford the desired title compound (50 mg, 95%) as a pale yellow solid, MS (ISP) 418.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)[C:10]([CH3:24])=[CH:9][N:8]=1)(=O)=O.[SH:25][C:26]1[NH:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(CC)CC)C>O1CCCC1>[CH3:23][C:19]1([CH3:22])[O:18][CH2:17][CH:16]([CH2:15][O:14][C:11]2[C:10]([CH3:24])=[CH:9][N:8]=[C:7]([CH2:6][S:25][C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)[C:12]=2[CH3:13])[CH2:21][O:20]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1cnc(COS(C)(=O)=O)c(C)c1OCC1COC(C)(C)OC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 95.5 %

Procedure:
To a mixture of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl methanesulfonate (500 mg, 1.39 mmol), 2-mercaptobenzimidazole (209 mg, 1.39 mmol) and tetrahydrofuran (5 ml), triethylamine (0.387 ml, 2.78 mmol) was added and the mixture was stirred at room temperature for 14 hours and 25 minutes. The reaction mixture was concentrated under reduced pressure, and toluene and a 0.1N aqueous sodium hydroxide solution were added to the residue and insoluble substance was removed by filtration. The organic layer was taken out and the aqueous layer was extracted again with toluene. The organic layers were combined, washed with a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (1/1) and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (549 mg, 95.5%) as a colorless viscous oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[C:5]2[O:6][CH:7]([CH3:9])[CH2:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+]>[Pd].CO>[CH3:9][CH:7]1[O:6][C:5]2[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][CH:2]=[CH:3][C:4]=2[CH2:8]1
Reactant: CC1Cc2cc(Br)cc(S(N)(=O)=O)c2O1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC1Cc2cccc(S(N)(=O)=O)c2O1
Yield: 79.3 %

Procedure:
72.5 g (0.25 mole) of 5-bromo-2,3-dihydro-2-methyl-7-sulfamoylbenzo[b]furan are hydrogenated in the presence of 22.4 g (0.25 mole) of sodium acetate and 7.5 g of 5% palladium on carbon catalyst in 750 ml of methanol. The catalyst is removed, the solvent evaporated, and the residue crystallised from a mixture of water/ethanol, affording 42.3 g (79% of theory) of 2,3-dihydro-2-methyl-7-sulfamoylbenzo[b]furan with a melting point of 174°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][NH:36][CH2:37]2>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH:38]6[N:33]([CH3:32])[CH:34]([CH2:40][CH2:39]6)[CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN1C2CCC1CNC2
Product: CN1C2CCC1CN(C1=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S1)C2

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>CS(C)=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:24][CH:21]2[CH2:23][CH2:22]2)=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(CCO)ccc1OCc1ccccc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(CCOCC2CC2)ccc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
To a flask charged with redistilled dimethylsulphoxide (100 ml) and sodium hydride (50% dispersion, 4.28 g), at 60°-65° C. was added 2-(4-benzyloxy-3-methylphenyl)ethanol (18.0 g) followed by the dropwise addition of cyclopropylmethyl bromide (12.04 g). The reaction mixture was stirred at about 75° C. for 48 hours, poured on to ice-water (1000 ml) and extracted with vigorous stirring into diethyl ether (1000 ml). The ether layer was dried (MgSO4) and evaporated under reduced pressure to afford an oily residue. This residue was chromatographed on preparative high pressure liquid chromatography using petroleum ether (40°-60°) and petroleum ether/diethyl ether (5:1) as eluants. The desired fractions were collected and evaporated under reduced pressure to give 1-benzyloxy-2-methyl-4-[2-(cyclopropylmethoxy)ethyl]-benzene (13.0 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45]CC2C=CC=CC=2)=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:53])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCO)cc1
Reaction time: 4 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 145 mg) in methanol (4 ml), a solution of Compound 25 (655 mg, 0.868 mmol) in methanol (6 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for 4 hours. After a nitrogen atmosphere was restored, ethyl acetate (about 10 ml) was added, and this was followed by filtration on silica gel and washing with an ethyl acetate solution containing 10% methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 26.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]1([C:12]2[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([CH:27]=[CH2:26])=[CH:29][CH:30]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: Brc1cccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2cccc(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c2)cc1

Procedure:
1.16 g (0.003 mol) of 2-(3-bromophenyl)-4,6-diphenyl-1,3,5-triazine, 0.74 g (0.005 mol) of 4-styreneboronic acid and 0.023 g (0.02 mmol) of tetrakispalladium phosphate are stirred under reflux for 24 h in 45 ml of THF and 30 ml of 1M sodium carbonate solution.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 94.4 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (154 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (96 mg) according to an analogous synthetic method to Example 404,the title compound (150 mg) was obtained.
Reaction SMILES: CN(C)C=O.CS(O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[C:19]([CH3:34])[N:20]([CH2:24][C:25]3[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:21](=[O:23])[N:22]=2)[CH2:13][CH2:12]1)(=O)=O.[Br:35][C:36]1[CH:37]=[N:38][NH:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:35][C:36]1[CH:37]=[N:38][N:39]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[C:19]([CH3:34])[N:20]([CH2:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:21](=[O:23])[N:22]=3)[CH2:13][CH2:12]2)[CH:40]=1
Reactant: Cc1nc(N2CCC(OS(C)(=O)=O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCC(n3cc(Br)cn3)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 48.5 %

Procedure:
To an N,N-dimethylformamide solution (1.0 mL) of 1-(6-methyl-4-oxo-5-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-4,5-dihydro-1,3,5-triazin-2-yl)piperidin-4-yl methanesulfonate (45.2 mg, 0.100 mmol) synthesized in Reference Synthesis Example 349, 4-bromo-1H-pyrazole (29.4 mg, 0.200 mmol) and potassium carbonate (27.6 mg, 0.200 mmol) were added and the resultant mixture was stirred at 100° C. for 1 hour. After the completion of the reaction, to the reaction solution, water was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (24.4 mg, yield: 48%).
Reaction SMILES: [CH2:1]([O:4]C(=O)NC1CC(=O)OC1OC1CCCC1)[CH:2]=C.[O:20]=[C:21]1[O:25][CH:24]([O:26][CH2:27][CH2:28][C:29]2C=CC=[CH:31][CH:30]=2)[CH:23]([NH:35][C:36]([CH:38]2[CH2:42][CH2:41][CH2:40][N:39]2[C:43](=[O:57])[CH:44]([NH:46][C:47](=[O:56])[C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]([Cl:55])[CH:49]=2)[CH3:45])=[O:37])[CH2:22]1>>[CH:27]1([O:26][CH:24]2[CH:23]([NH:35][C:36]([CH:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43](=[O:57])[CH:44]([NH:46][C:47](=[O:56])[C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:1](=[O:4])[CH3:2])=[C:50]([Cl:55])[CH:49]=3)[CH3:45])=[O:37])[CH2:22][C:21](=[O:20])[O:25]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OC2CCCC2)cc1Cl
Yield: 69 %

Procedure:
Prepared from 97b and (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 215 mg of title compound (69% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.35-1.90 (m, 11H), 1.90-2.35 (m, 4H), 2.24 (s, 3H), 2.40-3.10 (m, 2H), 3.50-3.95 (m, 3H), 4.15-4.90 (m, 3H), 5.44 (s, 0.55H), 5.56 (s, 0.15H), 5.64 (d, 0.22H), 5.71 (d, 0.08H), 7.70-8.25 (m, 3H). Analytical HPLC: 12.13 min. LC-MS (ES+): m/e=549.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]1[CH2:20][CH3:21].Cl.ClC1C([F:31])=C(F)C=CC=1CN>>[Cl:1][C:2]1[C:7]([F:31])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]1[CH2:20][CH3:21]
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Reactant: NCc1ccc(F)c(F)c1Cl
Agent: Cl
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)c(F)c1Cl

Procedure:
N-[(2-chloro-3,4-difluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (E130) but using [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (prepared as described above for Example 36) in the place of [(2-chloro-4-fluorophenyl)methyl]amine.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[NH:33][C:34]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21])=[O:35]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Product: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 62 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound (26 mg, 62%) was obtained as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7]O.[CH2:9]([N:11](CC)[CH2:12]C)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:9][N:11]([CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccsc1CO
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccsc1CN(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In 200 ml of methylene chloride were dissolved 20.8 g of 3-methyl-2-thenyl alcohol and 27.1 ml of triethylamine, and 12.9 ml of thionyl chloride was added thereto dropwise at -15° C. to -10° C. over a period of 30 minutes, after which the resulting solution was further subjected to reaction at the same temperature for 30 minutes. The reaction mixture was poured into ice water, and the organic layer was separated and then dried over anhydrous magnesium sulfate. Subsequently, the dried organic layer was added dropwise with ice-cooling to a solution of 95 g of dimethylamine in 550 ml of ethanol, and the resulting mixture was allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure, after which 100 ml of water was added to the residue, and the resulting mixture was adjusted to pH 10 with potassium carbonate, and then extracted with 200 ml of ethyl acetate. The extract was washed with 50 ml of a saturated aqueous sodium chloride solution and dried over anhydrous potassium carbonate, after which the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was distilled under reduced pressure to obtain 19.0 g (yield 75%) of 2-(dimethylamino)methyl-3-methylthiophene having a boiling point of 85°-86° C./14 mmHg.