Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC1C=CC=CC=1>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCc2cc(N)ccc2O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C1CCc2cc(NS(C)(=O)=O)ccc2O1
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 40 parts of ethyl 6-amino-3,4-dihydro-2H-1-benzopyran-2-carboxylate, 86 parts of pyridine and 234 parts of methylbenzene was added dropwise a solution of 20.6 parts of methanesulfonyl chloride in 135 parts of methylbenzene. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the oily residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 210 parts of 2,2'-oxybispropane and 12 parts of acetonitrile, yielding 10.2 parts (18.9%) of ethyl 3,4-dihydro-6-[(methylsulfonyl)amino]-2H-1-benzopyran-2-carboxylate; mp. 111.1° C. (intermediate 25).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:28])[CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[H][H]>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:28])[CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: COC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Yield: 87.4 %

Procedure:
22.6 g (58.8 mmol) of methyl 7-(N-benzyloxycarbonylamino)-3-oxo-2-phenylheptanoate, 435 mg (0.39 mmol) of [RuI(p-cymene)(S)-BINAP]I, 72 mg (0.39 mmol) of tin chloride and 364 mg (1.56 mol) of camphor-10-sulfonic acid (hereinafter referred to as "CSA") were placed in a 500 ml autoclave. After air in the autoclave was replaced with nitrogen, 160 ml of methanol was added to the mixture. The nitrogen in the autoclave was replaced with hydrogen and then the mixed solution was reacted at 80° C. under a hydrogen pressure of 80 kg/cm2 for 40 hours. After the completion of the reaction was confirmed by means of HPLC, the reaction solution was concentrated under reduced pressure. The residue was then purified by means of SGIC (eluent: hexane/ethylacetate=2/1 by volume) to prepare the target compound as a colorless oil in an amount of 37.4 g at a yield of 87.4%. The products were analyzed using HPLC. As a result, the rate of the syn-form to the anti-form was 76.3:23.7 and the optical purity of each of the forms was 95.6% ee and 97.8% ee respectively. The analytical results on the target compound are given below.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:20]1CCOCC1.ClC(OCC)=O>C(Cl)Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:18])[NH2:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: NC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (30.0 g, 121 mmol) was dissolved in DCM (180 mL). The solution was cooled to 0° C. and N-methyl-morpholine (12.8 g, 127 mmol) was added over a period of 10 mins. The solution was then cooled to −15° C. and the ethyl chloroformate (13.7 g, 126 mmol) in DCM (30 mL) was added dropwise. The solution was then stirred for 2 hours at −25° C. Next, the solution was placed under NH3 (g) while maintaining the temperature below −20° C. The reaction mixture was then stirred for 1 hour while allowing the temperature to return to 0° C. The solution was poured in H2O (120 mL) and the organic layer was partitioned from the aqueous layer. The organic layer was then washed with 1N HCl (2×50 mL), 1N NaHCO3 (2×50 mL), dried over MgSO4 and concentrated under vacuo to afford 27.8 g (88%) of 2-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester, as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.Cl.O1CCOCC1>CC(O)C.O1CCOCC1>[N:5]1[C:4]2[S:8][C:9]3[CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[C:3]=2[C:2]([NH:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)=[N:7][CH:6]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Temperature: 80 °C
Yield: 132.1 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (1.00 g, 3.07 mmol) was dissolved in 2-propanol (10 mL). 3-Aminophenol (352 mg, 3.22 mmol) and a 4 M solution of gaseous hydrogen chloride in dioxane (38 μL, 0.15 mmol) were added, and the mixture was heated to 80° C. for 20 h. Subsequently, further 4 M hydrogen chloride in dioxane (1.54 mL, 6.14 mmol) was added, and the mixture was heated for additional 3 h. The precipitate was collected by suction filtration to yield 1.21 g of the title compound as hydrochloride salt. An analytical amount was dissolved in 1 M aqueous sodium hydroxide solution which was then concentrated in vacuo. The precipitate was collected by suction filtration and dried to yield the product as free base.
Reaction SMILES: C([Zn]CC)C.F[C:7](F)(F)[C:8]([OH:10])=O.[C:13]1(CO)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>ClCCl>[C:7]12([CH2:8][OH:10])[CH2:16][CH:15]1[CH2:14][CH2:13][CH2:18][CH2:17]2
Reactant: O=C(O)C(F)(F)F
Reactant: OCC1=CCCCC1
Agent: CC[Zn]CC
Solvent: ClCCl
Product: OCC12CCCCC1C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 125.8 %

Procedure:
To a solution of diethyl zinc (1.0 M in hexanes, 15.70 mL, 15.70 mmol) in anhydrous dichloromethane (15.7 mL) was added dropwise trifluoroacetic acid (1.79 g in 15.7 mL anhydrous dichloromethane, 15.7 mmol) at 0° C. over 20 minutes. The reaction mixture was stirred at the same temperature for 20 minutes, and then added dropwise a solution of diidomethane (4.20 g, 15.70 mmol) in anhydrous dichloromethane (15.7 mL) at 0° C. over 10 minutes. The reaction mixture was further stirred at the same temperature for another 20 minutes. To this reaction mixture was added a solution of cyclohexenylmethanol (1.07 g, 6.30 mmol) in anhydrous dichloromethane (17 mL) at 0° C. The resulting mixture was warmed to ambient temperature and further stirred for 1 hour. The mixture was quenched with a saturated solution of ammonium chloride (50 mL) and separated the organic layer. The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with diethyl ether in hexanes (30%) to afford the title compound as colorless oil (1.00 g, 86%): 1H NMR (300 MHz, CDCl3) δ 3.32 (dd, J=10.9, 10.9 Hz, 2H), 1.90-1.80 (m, 2H), 1.75-1.55 (m, 2H), 1.34 (br, s, 1H), 1.26-1.14 (m, 2H), 0.45 (dd, J=9.3, 4.5 Hz, 1H), 0.24 (t, J=4.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:17])[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc2c(O)c(C)c(C)nc12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(Cl)c(C)c(C)nc12
Temperature: 25 °C
Yield: 185.7 %

Procedure:
2.09 g of 2,3-dimethyl-4-hydroxy-8-methoxy-quinoline, 10 ml of phosphorus oxychloride and 0.43 g of phosphorus pentachloride are introduced into a 25 ml two-necked flask fitted with a condenser. The mixture is refluxed for 1 h. The reaction medium, cooled to room temperature, is poured onto 100 g of ice and extracted with ethyl acetate (2×100 ml). The organic phases are combined, washed with saturated sodium bicarbonate solution (200 ml), dried over magnesium sulphate and concentrated. The residue is purified by column chromatography on silica (elution solvent: dichloromethane). 0.85 g (yield: 37%) of 2,3-dimethyl-4-chloro-8-methoxyquinoline is obtained—m.p.: 130° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[Br:12][C:13]1[CH:14]=C2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17]C2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:12][C:13]1[CH:14]=[C:6]2[C:20]([C:19]([CH3:23])([CH3:24])[CH2:18][CH2:17][C:5]2=[O:7])=[CH:21][CH:22]=1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F1) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cn1
Yield: 82 %

Procedure:
Compound 3a (950 mg, 2.17 mmol) was subjected to Suzuki coupling conditions with compound 1f (prepared in Example 1, Step F) as described in Example 1, Step G to obtain compound 3b as a white solid (820 mg, 82% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H23N7O: 462.2 (M+H). found: 462.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:19]([CH3:20])=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:10]2=[O:18]
Reactant: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2oc(C)c(-c3ccccc3)c(=O)c2c1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Intermediate 20 (4 g, 16.51 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (9.48 g, 115.57 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as yellow solid (3 g, 68% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.60(d, J=3.0 Hz, 1H), 7.45(t, J=7.1 Hz, 2H), 7.37(m, 2H), 7.29(m, 3H), 3.89(s, 3H).2.31(s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][CH:28]([CH3:44])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]2[O:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36](=[O:42])[C:35]=2[CH:43]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH3:41][C:38]1([CH3:40])[NH:37][C:36](=[O:42])[C:35]2[CH:43]=[C:31]([O:30][CH2:29][CH:28]([N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:17]([OH:19])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)[CH3:44])[CH:32]=[CH:33][C:34]=2[O:39]1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)NCc1ccccc1
Solvent: CC(C)O
Product: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)N(Cc1ccccc1)CC(O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 15.4 g of benzyl [4-(2,3-epoxypropoxy)-phenyl]ether and 17.0 g of 6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one in 100 ml of isopropanol is refluxed for 24 hours, filtered and concentrated by evaporation. Trituration of the residue with approximately 200 ml of ether results in crystallisation of 1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethyl]benzylamino]-3-(4-benzyloxyphenoxy)propan-2-ol having a melting point of 149°-160° (in which the enantiomer pair A is present in greater amount).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.088 mmol), 4-aminobutyric acid (726 mg, 7.0 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 15.5 mg of the title compound as a light yellow solid. MS: (+) m/z 526.26 (M+1).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([OH:11])=[O:10].[C:12](=O)([O-])[O-].[Na+].[Na+].CI>CN(C)C=O>[CH3:12][O:7][C:6]([C:5]1[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)O)s1
Yield: 26.3 %

Procedure:
Thiophene-2,5-dicarboxylic acid (1.72 g, 10 mmol) and sodium carbonate (3.18 g, 30 mmol) suspended in dimethylformamide (25 mL) were stirred with methyl iodide (623 μL) at room temperature overnight. The sodium salt of the desired product was extracted with water, and 12 M hydrochloric acid was added to the combined aqueous layer. The desired product was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and purified by silica gel column chromatography to give 0.49 g of the desired product as a colorless solid (yield 28%).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:1]([NH:8][C:9]1[S:10][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:12][C:13]=1[N+:17]([O-:19])=[O:18])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(C(C)C)s1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1sc(C(C)C)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
2-Ethoxalylamino-5-isopropylthiophene (6.9 g, 28.5 mol) was dissolved in 50 ml of acetic anhydride, cooled to -10° C., and treated with a solution of fuming nitric acid (1.8 g, 28.5 mmol) in 15 ml of acetic acid. After 20 minutes, the mixture was evaporated in vacuo to yield 8.4 g of crude product which was purified by chromatography on silica gel (toluene:acetone 95:5), to yield 4.8 g (57%) of 2-ethoxalylamino-5-isopropyl-3-nitrothiophene. 1H-NMR (CDCl3, δ): 1.3 (d, 6H), 1.5 (t, 3H), 3.1 (m, 1H), 4.5 (q, 2H), 12.0 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2.[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(C#N)ccc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2cc(CBr)ccc2c1
Yield: 78.6 %

Procedure:
6.11 g of 6-methyl-2-naphthalenecarbonitrile was dissolved in 100 ml of carbon tetrachloride, and the solution was mixed with 6.63 g of N-bromosuccinimide and 30 mg of 2,2-azobis-iso-butylonitrile. After refluxing under heating for 4 hours, the resulting reaction solution was mixed with chloroform, washed with water, and then dried. By distilling off the solvent, 7.07 g of colorless 6-bromomethyl-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH3:3].[CH3:12][O:13][N:14]=[CH:15][CH3:16].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:12][O:13][N:14]1[CH:15]([CH3:16])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11]
Reactant: C=C(C)C1CCCCCC1=O
Reactant: CC=NOC
Agent: CON1C(=O)CCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cycloheptanone (0.97 g, 6.38 mmol), acetaldehyde O-methyl oxime (0.56 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.29 g, 90% yield).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: O=C1OC(CCl)CN1c1ccc(Cl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 66.4 %

Procedure:
A mixture of 5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (204 mg, INTERMEDIATE 1) and sodium azide (107 mg) was heated to 100° C. in 10 ml of dimethylformamide for 15 h. The sample was then diluted with 100 ml of water and extracted with 100 ml of ethyl acetate (3×). The combined organic layers were washed with water (100 ml) and brine (100 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 139 mg (67%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:9](=[C:10]([CH3:16])[C:11]([CH3:15])=[CH:12][CH:13]=2)[N:8]=[C:4]([C:5](O)=[O:6])[CH:3]=1.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:9](=[C:10]([CH3:16])[C:11]([CH3:15])=[CH:12][CH:13]=2)[N:8]=[C:4]([C:5]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:6])[CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(Cl)cc(C(=O)O)nc2c1C
Solvent: CN(C)C=O
Product: Cc1ccc2c(Cl)cc(C(=O)Nc3nnn[nH]3)nc2c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Chloro-7,8-dimethylquinaldic acid (1.72 g) and N,N'-carbonyldiimidazole (1.18 g) in dimethylformamide (15 ml) were stirred for 4 hours at room temperature. 5-Aminotetrazole (1.24 g) was added and the mixture was stirred for 2 days at room temperature. The solid was filtered off and dissolved in a mixture of dimethylformamide and dimethylaminoethanol and the solution was acidified with dilute hydrochloric acid. 4-Chloro-7,8-dimethyl-N(1H-tetrazol-5-yl)quinaldamide was collected, m.p. 262° (d).
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH:19]([C:21]1[CH:22]=[C:23]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[CH:24]=[CH:25][CH:26]=1)=[CH2:20].I[C:37]1[C:45]2[C:40](=[CH:41][C:42]([CH:46]=[O:47])=[CH:43][CH:44]=2)[N:39]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:38]=1>>[CH3:35][N:32]1[CH2:31][CH2:30][N:29]([C:27]([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)/[CH:19]=[CH:20]/[C:37]2[C:45]3[C:40](=[CH:41][C:42]([CH:46]=[O:47])=[CH:43][CH:44]=3)[N:39]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[N:38]=2)=[O:28])[CH2:34][CH2:33]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1cccc(C(=O)N2CCN(C)CC2)c1
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: CN1CCN(C(=O)c2cccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)c2)CC1

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing 1-[(3-ethenylphenyl)carbonyl]-4-methylpiperazine (76 mg, 0.33 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a colorless material (30.1 mg, 24%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1H), 8.27 (s, 1H), 7.80 (m, 1H), 7.71 (s, 1H), 7.65 (d, J=16.6 Hz, 1H), 7.56-7.60 (m, 1H), 7.57 (s, 1H), 7.48-7.55 (m, 2H), 7.35 (d, J=7.28 Hz, 1H), 5.86 (s, 2H), 3.69-3.90 (m, 2H), 3.63 (t, J=7.91 Hz, 2H), 3.43-3.56 (m, 2H), 2.40-2.64 (m, 4H), 2.35 (s, 3H), 0.88 (t, J=7.91 Hz, 2H), −0.09 (m, 9H); MS ESI 505.4 [M+H]+, calcd for [C28H36N4O3Si+H]+ 505.7.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10]>C1C=CC=CC=1>[CH3:8][C:9]1[CH2:10][CH:3]2[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]2[CH2:12][C:11]=1[CH3:13]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CC1=C(C)CC2C(=O)OC(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of maleic anhydride (5.4 g, 55 mmol) in benzene (50 ml) was added dropwise 2,3-dimethyl-1,3-butadiene (6.3 ml, 55 mmol), and stirred overnight at 25° C. After separating the insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give 9.5 g of 5,6-dimethyl-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:22][NH2:23]>CC(O)C.O>[Br:1][C:2]1[CH:9]=[C:6]2[CH:7]=[N:23][NH:22][C:5]2=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: Brc1cnc2[nH]ncc2c1
Temperature: 145 °C

Procedure:
A mixture of 5-bromo-2-fluoronicotinaldehyde (0.580 g, 2.8 mmol), 4-methylbenzenesulfonic acid (0.060 g, 0.35 mmol) and anhydrous hydrazine (0.450 ml, 14 mmol) in 5 mL of i-PrOH was heated at 145° C. for 15 min in the microwave (Initiator by Biotage). The reaction was diluted with H2O and the solid was filtered washed with H2O and air-dried to give a white amorphous solid. MS (M+H)+ 198, 200.