Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22](Cl)[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH3:35]>CN1CCN(C)C1=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:35])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A suspension of Intermediate 26 (0.20 g), and potassium carbonate (0.31 g) in 1,3-dimethyl-2-imidazolidinone (3 ml, Tokyo Kasei Kogyo) is added with 25% aqueous ammonia (2 ml), and the mixture is stirred at 80° C. for 24 hours in a sealed tube. The reaction mixture is added with saturated brine (30 ml), and extracted 3 times with chloroform (30 ml for each time). The combined organic layer is washed twice with saturated brine (50 ml for each time), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (chloroform:methanol=9:1) to obtain the title compound (64.4 mg (predictive yield)).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([N:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][N:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([N:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][N:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3ccc4ccncc4c3=O)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc2nc(-n3ccc4ccncc4c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-oxo-2,7-naphthyridin-2(1H)-yl)benzo[d]thiazol-6-yl)acetate (18.8 mg, 0.034 mmol)) in pyridine (0.8 mL) was added LiI (100 mg, excess). The reaction mixture was heating in a microwave at 170° C. for 90 min. The mixture was concentrated in vacuo and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H25ClN3O4S: 534.1; found: 534.2. 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.27 (d, J=7.6 Hz, 1H), 8.93 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.58-7.50 (m, 3H), 6.93 (d, J=7.6 Hz, 1H), 5.36 (s, 1H), 2.59 (s, 3H), 1.01 (s, 9H).
Reaction SMILES: [N+](C1C=CC(N)=C(N)C=1)([O-])=O.[F:12][C:13]([F:27])([F:26])[C:14]1[NH:15][C:16]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:17]=2[N:18]=1.[N+](C1NC2C=CC=CC=2N=1)([O-])=O>FC(F)(F)C(O)=O.CCOC(C)=O.CO.[Pd]>[F:27][C:13]([F:12])([F:26])[C:14]1[NH:15][C:16]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1ccc2nc(C(F)(F)F)[nH]c2c1
Agent: [Pd]
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=[N+]([O-])c1nc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Reaction time: 12 h
Yield: 80 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (3.0 g, 20 mmol) in 15 ml of trifluoroacetic acid was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield a oily residue, which was dissolved in 100 ml of EtOAc and washed with aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to provide an oil which was characterized as 2-trifluoromethyl-5-nitrobenzimidazole and subjected to the following reaction without further purification. The nitrobenzimidazole and 500 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo, yielding 3.2 g (16 mmol, 80%) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:30])[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1)C.[OH-].[K+].Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[CH3:30][N:20]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:23])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:31])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of ethyl(2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (470 mg) in tetrahydrofuran (6 ml) and methanol (6 mL) was added a solution of potassium hydroxide (85% purity, 170 mg) in water (2.5 mL), and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and neutralized with 1M hydrochloric acid. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (400 mg, yield 91%) as white crystals. MS:431(MH+). melting point 231-233° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:23](/[C:20]1[CH:21]=[CH:22][C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(/C=C/c3ccccc3)cc2)OC1(C)C
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: COCCOC
Product: Nc1ncccc1-c1ccc(/C=C/c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (0.141 g) was added to a mixture of (E)-1-bromo-4-styrylbenzene (1.00 g), potassium acetate (1.14 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.03 g) in DMF (dry) (10 ml). The mixture was stirred at 90° C. under nitrogen for 12 hr. The insoluble solid was removed by filtration through Celite pad (eluted with EtOAc). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate. Activated-carbon powder and silica-gel were added and the mixture was shaken, sonicated and filtered through silica-gel/Celite pad (eluted with EtOAc). The filtrate was concentrated in vacuo to give the crude (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (0.186 g) was added to a suspension of 3-bromopyridin-2-amine (0.557 g), the prepared (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane and sodium carbonate (1.02 g) in DME (20 mL) and water (4 mL) and the mixture was stirred at 80° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (532 mg) as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9][CH:10]1[N:13]([CH2:14][C:15]([OH:17])=O)[C:12](=[O:18])[CH2:11]1.ClC(OCC)=O.[CH2:25]([O:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][NH:33][C:15](=[O:17])[CH2:14][N:13]1[CH:10]([S:9][CH3:8])[CH2:11][C:12]1=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSC1CC(=O)N1CC(=O)O
Reactant: NOCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSC1CC(=O)N1CC(=O)NOCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Triethylamine (2 ml) was added to a solution of (4-methylthio-2-oxo-azetidin-1-yl)acetic acid (1.67 g) in dry chloroform (15 ml) cooled to -10° C. After 5 mins ethyl chloroformate (1.6 ml) was added, then after a further 5 mins a solution of O-benzylhydroxylamine free base (1.67 g) in chloroform was added. The solution was allowed to warm to room temperature and stirred for 16 hours then washed with brine, dried (MgSO4) and evaporated. Chromatography of the residue on silica gel (petroleun ether/ethyl acetate) gave N-benzyloxy-(4-methylthio-2-oxo-azetidin-1-yl)acetamide as a clear gum (22% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11])#[N:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10]([Cl:26])=[O:11])#[N:2]
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Temperature: 98 °C

Procedure:
A stirred slurry of 1.1 grams (0.003 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid and 1.0 mL of thionyl chloride in 20 mL of toluene was heated at about 72° C. for 25 minutes. The slurry was warmed to 98° C. over a 45 minute period, during which time the reaction mixture became homogeneous. The reaction mixture was heated at 98° C. for 35 minutes. After this time, the reaction mixture was cooled and concentrated under reduced pressure, yielding 1.1 grams of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride. The acid chloride was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.C(O)(=[O:37])C.O.B(O[O-])=O.[Na+]>CCO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:37])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CC(=O)O
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: O=BO[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Temperature: 0 °C

Procedure:
4.41 g (8.72 mmol) {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester is dissolved in 10 ml EtOH and 2.20 ml glacial acetic acid and 2.20 ml water are added. The funnel is rinsed with 7.50 ml EtOH. Then, 2.28 g (14.8 mmol) sodium perborate is added in portions at r.t. and the mixture is stirred. After complete addition, 1.40 ml water and 1.6 ml toluene is added. The organic phase is separated and 1.60 ml water is added. After cooling to 0° C., the 2-phasic mixture is seeded and stirring is continued. The precipitated product is filtered off, washed with cold toluene and dried. Yield: 2.86 g; Rf=0.22 (silica gel, PE/EtOAc=7/3); Mass spectrum (ESI): m/z=359 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1.S(Cl)([Cl:20])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:20][C:10]1[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=1
Reactant: O=c1[nH]c(-c2ccccc2F)nc2sccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1-c1nc(Cl)c2ccsc2n1
Yield: 45.3 %

Procedure:
2-(2-Fluoro-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one (900 mg, 3.65 mmole) was dissolved in chloroform and thionyl chloride (0.532 ml, 7.30 mmole) was added to the mixture followed by 1 ml dimethylformamide. Heated the reaction mixture to reflux for 2.5 hours, the cooled mixture was washed with 10% sodium carbonate, dried the chloroform solution over sodium sulfate (anh) and removed solvent. The crude product was chromatographed on silica gel, eluting with chloroform. Upon removal of solvent obtained 438 mg product (yield: 45%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Oc1ccc2cccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2cccnc2n1

Procedure:
1,8-Naphthyridin-2-ol (2.80 g, 19.16 mmol) was suspended in phosphorus oxychloride (100 ml, 1092 mmol) and heated at gentle reflux. The chlorination was followed by LC/MS and once the conversion was complete the reaction was evaporated to dryness and the residue partitioned between water (400 mL) and ethyl acetate (2×400 mL). The aqueous was extracted with additional ethyl acetate (2×400 mL). The combined organic layers were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude compound was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]2[O:10][C:9]([CH3:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][C:7](=[O:18])[C:6]=2[CH:19]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C=O)C>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]2[O:10][C:9]([CH3:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][C:7](=[O:18])[C:6]=2[CH:19]=1)([CH3:28])[CH3:27]
Reactant: CC(C)=CCCC1(C)CC(=O)c2cc(O)c(C)c(C)c2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCC1(C)CC(=O)c2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A mixture of 2,3-dihydro-6-hydroxy-2,7,8-trimethyl-2-(4-methylpent-3-enyl )-4H-1-benzopyran-4-one (9.4 q, 34.3 mmole), tert-butyldimethylsilyl chloride (7.75 g, 51.5 mmole), and imidazole (6.99 g, 0.1 mole) were dissolved in 50 mL of dry DMF. The solution was stirred under nitrogen for about 18 hours, poured into water and extracted with ether. The organic layers were dried (brine, MgSO4) and concentrated in vacuo. The crude material was purified by flash chromatography (gradient 20:1 to 10:1 hexanes:ether) to give the title compound as a colorless oil (9.9 g, 24.6 mmole, 72%): 1H NMR (CDCl3) δ 0.20 (s, 6H), 1.0 (s, 9H), 1.37 (s, 3H), 1.55 (s, 3H), 1.55-1.60 (m, 1H), 1.65 (s, 3H), 1.74-1.84 (m, 1H), 2.0-2.1 (m, 2H), 2.14 (s, 3H), 2.16 (s, 3H), 2.63 (ABq, J=16.5 Hz, 2H), 5.07 (t, J=7.0 Hz, 1H), 7.09 (s, 1H); MS m/e 403 (MH+).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:25])[CH:16]=1.[C:26](#[N:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[K+]>C(O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:25][C:17]1[C:16]2[N:15]([N:14]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:33]=2)[CH:20]=[CH:19][C:18]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: N#Cc1ccccc1
Reactant: COC(=O)c1cc[n+](N)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccn2nc(-c3ccccc3)nc2c1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
To a suspension of 1-amino-4-(methoxycarbonyl)-3-methylpyridinium2,4,6-trimethylbenzenesulfonate (2.409 g, 6.57 mmol) in ethanol (40 ml) are added benzonitrile (675 μl, 6.57 mmol), copper(II) acetate monohydrate (1.31 g, 6.57 mmol) and finally potassium hydroxide (2M in ethanol, 3.62 ml, 7.23 mmol). The resulting mixture is heated to 90° C. and stirred for 18 hours under air atmosphere while air was slightly bubbled through the reaction mixture. The dark green mixture is poured on sat. aqueous sodium bicarbonate solution (100 ml) and stirred for 5 minutes, then extracted twice with ethyl acetate (filtration over dicalite is required because of emulsion). The combined organic layers are washed twice with water and brine, dried with magnesium sulfate and the solvent is evaporated. The crude material is loaded on silica and separated by flash chromatography on a 70 g silica column using heptane/ethyl acetate 10-30% as eluent affording methyl 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (634 mg, 36%) as a white solid (MS: m/z=268.1 (M+H+) and methyl 6-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (112 mg, 6.37%) as a white solid. MS: m/z=268.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8]C(=O)[O:10][C:11](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1(C)C(C)=CC=CC=1>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[C:16]=1[CH3:22])=[O:10]
Reactant: Cc1c(N)cccc1Br
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Solvent: Cc1ccccc1C
Product: Cc1c(Br)cccc1NC(=O)c1cccc(Cl)c1N
Yield: 91.1 %

Procedure:
A suspension of 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (4.00 g, 20.3 mmol) and 3-bromo-2-methylaniline (5.65 g, 30.4 mmol) in xylene (20 mL) was heated at reflux for 2.5 h. The cooled mixture formed a yellow precipitate. The mixture was diluted with hexanes, and the precipitate was collected by filtration, washed with hexanes and dried to give 2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide as a yellow solid (6.28 g, 91% yield). Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.68 (d, J=8.1 Hz, 1H), 7.61 (br. s., 1H), 7.52-7.43 (m, 3H), 7.15 (t, J=8.0 Hz, 1H), 6.70 (t, J=7.8 Hz, 1H), 6.12 (br. s., 2H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[N+:11]([C:14]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)([O-:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[N+:11]([C:14]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:3][C@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:19][CH:18]=1)([O-:13])=[O:12]
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.4 %

Procedure:
To a stirred solution of known tert-butyl L-(+)-lactate (1.00 g), 4-(2',4'-dinitrophenoxy)phenol (2.08 g) and triphenylphosphine (1.98 g) in dry tetrahydrofuran (58 ml) on an ice bath, diethylazodicarboxylate (1.18 ml) was added dropwise. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 19 hours. The reaction mixture was evaporated with a rotary evaporator. The residue thus obtained was purified by silica gel chromatography [silica gel 344 g, eluant:ethyl acetate-hexane (1:5)] to give tert-butyl (2R)-(+)-2-(4'-(2",4"-dinitrophenoxy)phenoxy]propionate (1.45 g). Since the product was decomosed even by high vacuum distillation, the viscous oily substance of the product thus obtained was left to stand at room temperature under high vacuum (0.25 Torr) for 2 hours, and then its physical data thereon were measured.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:5][CH:6]=1.[CH3:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1O.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C@@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:15]2[CH3:14])[CH:6]=1
Reactant: C[C@@H]1CCC[C@H]1O
Reactant: CCOC(=O)/C=C/c1cc(Br)c[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(Br)cn1[C@@H]1CCC[C@@H]1C
Yield: 35 %

Procedure:
A solution of ethyl (2E)-3-(4-bromo-1H-pyrrol-2-yl)acrylate (1.3 g), trans-2-methylcyclopentanol (0.64 g) and 2-(tributylphosphoranylidene)acetonitrile (1.928 g) in toluene (12.6 mL) was stirred with heating under reflux for 22 hr under argon atmosphere. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (608 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(=S)=S>[F:18][C:8]1[CH:7]=[C:6]([Br:5])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:14][CH:13]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 0 °C
Yield: 33.9 %

Procedure:
40 g of aluminum chloride and 280 ml of carbon disulfide were taken into a flask, cooled with an ice-salt bath to 0° C. or lower and stirred. A solution of 70 g of 4-bromo-2-fluorobiphenyl as dissolved in 180 ml of carbon disulfide was dropwise added thereto. A solution of 26 g of propionic acid chloride as dissolved in 100 ml of carbon disulfide was dropwise added thereto at 0° C. or lower. After addition, the whole was stirred for 2 hours at 0° C. or lower and then at room temperature overnight. After reaction, the reaction solution was poured into 30 ml of concentrated hydrochloric acid and 300 g of ice and extracted with chloroform. The organic layer was washed three times with water, two times with an aqueous 2% sodium hydroxide solution and then three times with water, and chloroform and carbon disulfide were removed by distillation. The residue was recrystallized from a mixed solvent comprising acetone and methanol to obtain 29 g of 2-fluoro-4-bromo-4'-propionylbiphenyl.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([OH:34])[CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:34][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccc(F)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
5-Fluoro-N-methylpyridine-2-carboxamide (122 mg, 0.79 mmol) synthesized in Example (123a) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (275 mg, 0.83 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (219 mg, 1.58 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (283 mg, yield 77%) as a white solid.