Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]cc(CCNC(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 63.9 %

Procedure:
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.100 g, 0.515 mmol), biphenyl-4-carbonyl chloride (0.120 g; 0.541 mmol), and triethylamine (0.087 mL; 0.616 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent with 10% ethyl acetate in dichloromethane) furnished 0.122 g (64%) of N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [Na+].[I-].[Cl:3][C:4]1[N:9]=[CH:8][C:7]2[C:10]([C:32]([CH3:34])=[CH2:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=1.[F:35][C:36]([Si](C)(C)C)([F:38])F>C1COCC1>[Cl:3][C:4]1[N:9]=[CH:8][C:7]2[C:10]([C:32]3([CH3:34])[CH2:33][C:36]3([F:38])[F:35])=[N:11][N:12]([C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]=2[CH:5]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=C(C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)CC1(F)F
Temperature: 65 °C
Yield: 107 %

Procedure:
Reference: Angew. Chemie Int. Ed., 2011, 50(31), 7153. To a 2 dram pressure vial charged with a magnetic stir bar was added anhydrous NaI (3.4 mg, 0.023 mmol), THF (1 ml), and 6-chloro-3-(prop-1-en-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (50 mg, 0.115 mmol) under nitrogen. To this was added (trifluoromethyl)trimethylsilane (0.042 ml, 0.287 mmol). The reaction vessel was sealed and heated to 65° C. in an oil bath for a period of 2.5 hours. LCMS and TLC indicated product and remaining starting material. Additional sodium iodide (3.4 mg, 0.023 mmol) and (trifluoromethyl)-trimethylsilane (0.042 ml, 0.287 mmol) were added and the reaction was heated overnight at 65° C. The reaction mixture was concentrated and taken up in ether (15 ml). The organic layer was washed with water (15 ml), saturated sodium thiosulfate solution (15 ml), saturated sodium bicarbonate solution (15 ml), and water (15 ml), in that order. The ethereal layer dried over anhydrous magnesium sulfate, concentrated, and purified (12 g silica gel, eluting with 0-10% tOAc/hexanes) to give 6-chloro-3-(2,2-difluoro-1-methylcyclopropyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (60 mg, 0.123 mmol) as a beige foam. MS ESI calc'd. for C29H22ClF2N3[M+1]+ 486, found 486.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O.C(O)C>[CH:25]1[CH:24]=[C:21]2[C:22]([N:2]([CH2:3][C:4]([NH2:6])=[O:5])[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=1)=[O:23]
Reactant: NCC(N)=O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a stirred solution of glycinamide hydrochloride (2.20 g, 20.0 mmoL) and sodium carbonate (2.54 g, 24 mmoL) in 25 mL of water is added N-carbethoxyphthalimide (4.38 g, 20.0 mmoL). The resulting suspension is stirred for 1.5 hour and then filtered to afford 3.22 g (79%) of the crude product as a white powder. The crude product is slurried in 200 mL of refluxing ethanol. The resulting suspension after cooling to room temperature is filtered and the solid dried in vacuo (60° C., <1 mm) to afford 2.65 g (65%) of N-phthaloylglycinamide as a white powder: mp 199°-201° C.; 1H NMR (DMSO-d6) δ 8.00-7.8 (m, 4 H, Ar), 7.70 (br s, 1 H, CONH2), 7.26 (br s, 1 H, CONH2), 4.16 (s, 2 H, CH2); 13C NMR (DMSO-d6) δ 167.8, 167.5, 134.4, 131.7, 123.1, 39.9. Anal. Calcd for C11H10N2O3. Theoretical: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.49; H, 4.59; N, 12.82.
Reaction SMILES: [Cs].[CH3:2][CH:3]([CH3:15])[CH2:4][CH2:5][CH:6]1[N:10]([CH3:11])[S:9](=[O:13])(=[O:12])[NH:8][C:7]1=[O:14].CC(C)CCC1N(C)S(=O)(=O)NC1=O.[C:30]1([S:36][CH2:37]Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO.CN(C=O)C>[C:30]1([S:36][CH2:37][N:8]2[C:7](=[O:14])[CH:6]([CH2:5][CH2:4][CH:3]([CH3:15])[CH3:2])[N:10]([CH3:11])[S:9]2(=[O:13])=[O:12])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCSc1ccccc1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Agent: [Cs]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 85 °C
Yield: 70.6 %

Procedure:
A mixture of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 7.7 g (34.95 mmol) of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide in methanol with 5.13 g of CS2CO3 followed by removal of the solvent and drying under high vacuum) and phenylthiomethyl chloride (6.65 g, 41.94 mmol) suspended in DMF was heated at 85° C. for 17 hours. The mixture was cooled, and poured into 300 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3×) and the organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 8.15 g (70.6%) of 2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VII: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>O1CCCC1>[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[O:20][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: COCCl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c([N+](=O)[O-])cc(C(C)=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (65 ml, 373 mmol) was added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (58.6 g, 247 mmol) in tetrahydrofuran (350 ml) under a nitrogen atmosphere while cooling on ice, and then chloromethyl methyl ether (24.5 ml, 322 mmol) was added dropwise. After stirring at the same temperature for 30 minutes, ice water (250 ml) was added and extraction was performed twice with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid water, water, saturated aqueous sodium hydrogencarbonate and brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to yield the title compound (69.4 g, 99.9% yield) as a light brown oil. This was used without purification for the following reaction.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[OH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:39]5[CH2:40][CH2:41][C@@H:37]([OH:36])[CH2:38]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: O[C@@H]1CCNC1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CC[C@@H](O)C1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(((R)-3-hydroxypyrrolidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and (R)-3-hydroxypyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxo-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:34][C@@H:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.CO>C(Cl)Cl>[N:37]12[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38]1)[C@@H:35]([NH:34][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=1)[CH2:36]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of 4-phenoxybenzoic acid (75 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1M in DMF, 0.2 mL, 0.2 mmol) is added and the resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (49 mg, 76%). MS for C20H22N2O2 (ESI) (M+H)+ m/z 323.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:31]([Si:28]([CH3:30])([CH3:29])[O:35][C:36]1[CH:41]=[CH:40][C:39]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:10]([CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:27])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:21][CH:22]=2)=[CH:38][CH:37]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (710 mg), 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (457 mg), triethylamine (1.26 ml) and powdered 4 Å molecular sieves (700 mg) in dichloromethane (18 ml) was added copper(II) acetate (330 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [2-[4-[4-[[tert-butyl(dimethyl)-silyl]oxy]phenoxy]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (600 mg).
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][N+:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1>O.CO>[CH3:4][N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[CH:15]=2)[CH2:9][CH2:10]1
Reactant: C[n+]1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC=C(c2cc3cc(Cl)ccc3o2)CC1

Procedure:
A solution of 70 g of sodium borohydride in 150 ml of water is added dropwise, with stirring and external cooling, to a solution of 70 g of 1-methyl-4-(5-chloro-2-benzofuranyl)-pyridinium-iodide in 500 ml of methanol, the manner of addition being such that the reaction temperature does not exceed 35°. The solution is subsequently stirred for 20 hours at room temperature. The methanol is thereupon evaporated off in vacuo; the aqueous phase remaining behind is extracted twice with 500 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The 1-methyl-4-(5-chloro-2-benzofuranyl)-1,2,3,6-tetrahydropyridine obtained is recrystallised from hexane, and then melts at 108°-118°. The hydrochloride prepared therefrom with a solution of hydrogen chloride in ethyl acetate melts, after recrystallisation from ethyl acetate, at 266°.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.N([O-])=[O:35].[Na+]>CC(O)=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([OH:35])[N:7]=4)=[CH:13][CH:12]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: C[C@@H](c1ccc(-c2ccnc(N)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccnc(O)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (40 mg, 0.089 mmol) in CH3COOH (0.3 mL) and H2O (0.13 mL) was added an aqueous solution of NaNO2 (2 mol/L, 0.5 mL) dropwise at 0° C. The reaction was stirred for 10 min at this temperature before heating at 60° C. for 3 h. After the mixture was evaporated to dryness, the mixture was adjusted pH 9 with aqueous NaHCO3 solution. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (3.18 mg, 8%). LC-MS Method 2 tR=0.87 min, m/z=452. 1H NMR (CD3OD): 1.19-1.23 (m, 2H), 1.48 (d, 3H), 1.82-1.86 (m, 2H), 2.05-2.41 (m, 3H), 3.01-3.10 (m, 1H), 3.37 (t, 2H), 5.50 (q, 1H), 6.90 (d, 1H), 6.95-7.02 (m, 4H), 7.18-7.22 (m, 2H), 7.00-7.05 (m, 3H), 7.21-7.24 (m, 2H), 7.80 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])/[CH:35]=[CH:34]/[C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: O=C(O)/C=C/c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(/C=C/c1ccncc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
To a solution of the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (41 mg, 0.10 mmol) obtained in Example 351, (E)-3-(pyridin-4-yl)acrylic acid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol), and N-methylmorpholine (0.011 ml, 0.10 mmol) in dichloromethane (1 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.10 mmol) at 0° C. The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer thus obtained was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with ethyl acetate was concentrated under reduced pressure. The solid thus obtained was washed with diethyl ether and then collected by filtration, whereby the title compound (35 mg, 0.065 mmol, 65%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[C:9]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)[CH:7]=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[CH3:40]>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([F:30])=[C:32]([CH3:40])[CH:33]=4)[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH:19]=[CH:18][C:17]1=[O:20]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Product: CSc1nc(-c2cc(NC(=O)c3ccc(F)c(C)c3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound was prepared as described in Example 7b from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one and 4-fluoro-3-methylbenzoyl chloride: LC-MS m/z 547(M+H)+, 2.70 min (ret time).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]([CH3:8])[C:6]([CH2:9]Cl)=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1>CC(C)=O>[Cl:2][C:3]1[N:7]([CH3:8])[C:6]([CH2:9][S:24][C:22]2[N:21]=[C:20]([OH:25])[CH:19]=[C:18]([CH3:17])[N:23]=2)=[N:5][CH:4]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1c(Cl)cnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2ncc(Cl)n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (1.0 g, 5.0 mmol), potassium carbonate (1.65 g, 12 mmol), and 6-methyl-2-sulfanylpyrimidin-4-ol (560 mg, 4.0 mmol) were mixed in acetone (20 mL). The mixture was stirred at room temperature overnight. Acetone was then removed under reduced pressure. The crude solid was purified by column chromatography to provide the title compound as a white solid (850 mg, 79% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.60 (s, 3H), 4.51 (s, 2H), 6.04 (br, 1H), 6.93 (s, 1H); M+ 271.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:33][C:34]#[N:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1OC
Yield: 76 %

Procedure:
(3,4-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (3.3 g, 10 mmol), cyanomethylphosphonic acid diethyl ester (2.4 ml, 15 mmol) in anhydrous THF (50 ml), and potassium bis(trimethylsilyl)amide (3.0 g, 15 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified by flash column chromatography to give 3-(3,4-dimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as a solid (2.7 g, 77%): mp, 119-121° C.; 1H NMR (DMSO-d6) 7.14-7.07 (m, 1H), 7.00-6.77 (m, 2H), 6.66 (d, J=3 Hz, 2H), 6.25 (s, 0.5H), 6.19 (s, 0.5H), 3.84-3.71 (m, 15H); 13C NMR (DMSO-d6) □ 161.38, 161.31, 152.65, 150.99, 150.14, 148.64, 148.18, 139.44, 138.44, 133.69, 132.47, 130.01, 128.88, 122.66, 122.43, 118.66, 118.62, 112.75, 111.31, 111.22, 110.94, 106.88, 106.27, 94.23, 93.53, 60.08, 56.02, 55.98, 55.60, 55.55, 55.48; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.66; H, 5.98; N, 3.88.
Reaction SMILES: C([NH:18][C@H:19]([C:24]([S:26][NH:27][C@H:28]([CH2:36][OH:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53]([NH:55][C@@H:56]([C:61]([OH:63])=O)[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:53]([NH:55][C@@H:56]([C:61]([NH:18][C@H:19]([C:24]([S:26][NH:27][C@H:28]([CH2:36][OH:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:63])[CH2:57][CH:58]([CH3:59])[CH3:60])([O:52][CH2:51][CH:49]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:50]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:54]
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)SN[C@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)SN[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
Dipeptide Fmoc-NH-L-Ile-S-Phe-CH2OH (1b) (2.0 g, 4.11 mmol) was taken in 20% piperidine in DMF (20 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-S-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×20 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (5 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-D-leucine (1.59 g, 4.52 mmol), DCC (931 mg, 4.52 mmol) and HOBt (610.0 mg, 4.52 mmol) in dry DMF (150 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (5% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2b with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 4% MeOH: CH2Cl2 to give 450 mg of the tripeptide Fmoc-NH-D-Leu-L-Ile-S-Phe-CH2OH (2b) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:12](OC)=[O:13])[C:7]=1[C:8](OC)=[O:9].O.[NH2:20][NH2:21]>CO>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:21][NH:20][C:12](=[O:13])[C:6]=2[C:5]([O:16][CH3:17])=[N:4][C:3]=1[CH3:18]
Reactant: NN
Reactant: COC(=O)c1c(OC)nc(C)c(N)c1C(=O)OC
Solvent: O
Solvent: CO
Product: COc1nc(C)c(N)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 8 ml of methanol was dissolved 280 mg of 3-amino-4,5-dimethoxycarbonyl-6-methoxy-2-methylpyridine, and then 0.54 ml (10 eq.) of hydrazine monohydrate was added to the solution. The mixture was refluxed. The resulting crystals were collected by filtration and washed with methanol. The crystals were suspended in water, and the suspension was acidified with hydrochloric acid. The crystals were collected by filtration and washed with water.