Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[C:8](=[N:9][CH:10]=[C:11]([C:23]#[N:24])[C:12]=3[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[C:6]=2[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:37](O)(=[O:40])[CH:38]=[CH2:39].C(N(C(C)C)CC)(C)C>CN(C)C=O.O1CCCC1>[Br:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:12]1[C:11]([C:23]#[N:24])=[CH:10][N:9]=[C:8]2[C:6]3[CH:7]=[C:2]([NH:1][C:37](=[O:40])[CH:38]=[CH2:39])[CH:3]=[CH:4][C:5]=3[S:14][C:13]=12
Reactant: C=CC(=O)O
Reactant: N#Cc1cnc2c(sc3ccc(N)cc32)c1Nc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc2sc3c(Nc4cccc(Br)c4)c(C#N)cnc3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
To a 0° C. solution of 164 mg (0.417 mmol) of 8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile and 120 mg (0.626 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 2 mL of dimethylformamide and 2 mL of tetrahydrofuran is added 0.045 mL (0.656 mmol) of acrylic acid followed by 0.110 mL (0.633 mmol) of diisopropylethylamine. The reaction mixture is stirred at room temperature for 4 hours then partitioned between methylene choride and water. The aqueous layer is extracted with additional methylene chloride and the organic layers are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography, eluting with a gradient of 95:5 methylene chloride/methanol to 9:1 methylene chloride/methanol, to provide 69 mg of N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-8-yl]acrylamide as a light tan solid, mp>300° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:17](N)(N)(=[O:19])=[O:18]>COCCOCCOC>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:16][S:17]2(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1Nc1ccc(F)c(F)c1
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
Dry diglyme (10 mL) was added to a flask equipped with a dropping funnel under a nitrogen atmosphere and brought to a vigorous reflux. N-(3,4-difluorophenyl)benzene-1,2-diamine (1.03 g, 4.7 mmol) and sulfamide (0.54 g, 5.6 mmol) were dissolved in 5 mL of diglyme and placed in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes and then refluxing was continued for an additional 15 minutes. The mixture was cooled to ambient temperature and the reaction mixture was evaporated using high temperature. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/hexane) to provide 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.62 g, 47%) as a pink solid:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:45][C:41]([OH:40])([CH3:46])[C:42]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:43]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)C(C)(C)O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrochloride (1 g, 4.34 mmol) in DMF (50 mL) was added HATU (9.89 g, 26.0 mmol), 2-hydroxy-2-methylpropanoic acid (0.677 g, 6.50 mmol), and DIPEA (2.272 mL, 13.01 mmol). After stirring overnight at rt, the solvent was removed, the residue was redissolved in DCM (100 mL), washed with 1M HCl (100 mL), adsorbed to silica gel, and purified by column chromatography (10% to 40% ethyl acetate/hexanes) to afford 2-methyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanol (0.84 g, 69%). ESIMS (M+H)+=281.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[NH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccc2ccccc2c1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc3ccccc3c2)c1C(=O)OC
Yield: 75 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-aminonaphthalene (0.44 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.78 g of the product at 85:15 hexanes-ethyl acetate, in 75% yield: 1H NMR (CDCl3) δ 3.89 (s, 3H), 3.90 (s, 3H), 7.14 (dd, J=7.3 Hz, J=1.0 Hz, 1H), 7.27-7.50 (m, 5H), 7.55 (d, J=1.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.77-7.82 (m, 2H), 8.20 (br, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4]N1CC(C)(C)C(O)=O.Cl.[NH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23]>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:19]1[C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)CC(C)(C)N
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Agent: Cl
Product: CC(C)(CC(=O)O)N1C[C@@H]2CNCCN2C1=O

Procedure:
The title compound was prepared in analogy to Compound Q in Example 19 by using methyl 3-amino-3-methyl-butanoate hydrochloride salt (Compound AP-1) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([Br:15])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23][N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)C.CC([O-])(C)C.[K+]>C1COCC1>[CH2:29]([O:28][C:26]([CH:25]1[N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:7]2[N:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:9]([Br:15])=[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:6]=2[C:4]1=[O:3])=[O:27])[CH3:30]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)c(C(C)(C)C)c(Br)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2c(C(C)(C)C)c(Br)n(-c3ccc(F)cc3)c2CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 5-bromo-2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-4-tert-butyl-1-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (4.0 g, ˜6.28 mmol) in THF (15 mL) at −78° C. was added a solution of KOtBu in THF (9.42 mL, 9.42 mmol, 1 M); the reaction was stirred for 30 min at −78° C. and for 30 at room temperature. The reaction was subsequently quenched with saturated ammonium chloride aqueous solution, extracted with EtOAc, washed with water, and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, to give an oil, the title product (3.24 g, crude), which was not further purified. The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.4-7.0 (m, 4H), 4.5-4.1 (m, 5H), 1.6-1.2 (m, 21H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[O:7]1CC[CH2:9][CH2:8]1.CC(C)([O-])C.[K+].O1CCOS1(=O)=O.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:9][CH2:8][OH:7])[N:3]=1
Reactant: Brc1cc[nH]n1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCn1ccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-1H-pyrazole obtained in Step C (1.20 g) in N,N-dimethylformamide (82 mL) was added potassium tert-butoxide tetrahydrofuran solution (1 M, 12.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 min, 1,3,2-dioxathiolane 2,2-dioxide (1.52 g) was added thereto at room temperature, and the mixture was stirred for 1 hr. conc. Hydrochloric acid (7.5 mL) was added thereto at room temperature, and the reaction mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (880 mg).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15](=[O:23])[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH3:25]>C1COCC1.O>[CH3:25][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[C:10]([C:15](=[O:23])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11]1
Reactant: CI
Reactant: O=C(C(=O)N1CCCC1)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(=O)C(=O)N2CCCC2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Add NaH (0.83 g, 20.8 mmol) to a solution of 1-(6-nitro-1H-indol-3-yl)-2-pyrrolidin-1-yl-ethane-1,2-dione (5.0 g, 17.42 mmol) in THF (60 mL). Stir at room temperature for 10 min, add iodomethane (1.18 mL, 19.2 mmol), and continue stirring for 18 h. Dilute with water and extract with EtOAc (2×). Filter the solid that formed between the layers during the extraction. Dry organic portion, concentrate, and combine the solids. Triturate the solid with ether, filter, and dry to obtain the title compound (5.20 g, 99%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (m, 2H), 8.30 (d, 1H, J=8.8 Hz), 8.17 (dd, 1H, J=8.8, 2.2 Hz), 4.01 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.41 (t, 2H, J=6.4 Hz), 1.85 (m, 4H).
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][OH:49])=[CH:44][CH:43]=1>>[Cl:27][C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:28][C:29]1[CH:30]=[C:31]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][OH:49])=[CH:44][CH:43]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:5])[CH3:6])[CH2:14][CH2:13]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: OCc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(CO)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (210 mg, 0.36 mmol) is coupled to (4-bromophenyl)-methanol (80 mg, 0.43 mmol) using Method B to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[N:11]([CH3:17])[C:12](=[O:16])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Nc1c(Cl)ccnc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)N(C)c1c(Cl)ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.5 %

Procedure:
Ethyl 4-chloro-2-nitropyridin-3-yl-carbamate (350 mg, 1.4 mmol) was dissolved in acetone and potassium carbonate (280 mg, 2 mmol) was added followed by dimethyl sulfate (161 μL, 1.7 mmol). The reaction mixture was heated to reflux for 5 hours, cooled at room temperature, diluted with water and extracted with DCM. The organic layer was dried and evaporated to afford the title compound (340 mg, 93%). 1H-NMR (δ, ppm, DMSO-d6): 1.02+1.25 (t+t, rotamers, 3H, CH3,Et), 3.14+3.19 (s+s, rotamers, 3H, NCH3), 4.05+4.14 (q+q, rotamers, 2H, CH2,Et), 8.21 (d, 1H, HPy,5, J=5.70 Hz), 8.60 (d, 1H, HPy,6, J=5.20 Hz). LC-MS (m/z): 259 (M+H, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:17][CH2:18][CH3:19].C([Li])(C)(C)C.[B:25](OC)([O:28]C)[O:26]C>COCCOC>[CH2:17]([O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:7][C:2]=1[B:25]([OH:28])[OH:26])[CH2:18][CH3:19]
Reactant: COB(OC)OC
Reactant: CCCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: COCCOC
Product: CCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 108.3 %

Procedure:
1-Bromo-3,5-di-tert-butyl-2-propoxy-benzene (6.55 g, 20 mmol) was dissolved in anhydrous 1,2-dimethoxy-ethane (125 mL under a nitrogen atmosphere. The solution was cooled to −75° C. and t-butyl lithium (30 mL, 50 mmol, 1.7M in pentane) was added dropwise over 20 min at −73° C. to −68° C. The reaction was stirred at −74° C. for 1 h and then treated with trimethyl borate (11.4 mL, 100 mmol). The reaction was kept cold for 1 h and then the bath was removed and the reaction allowed to warm to room temperature over 24 h. It was treated with 1N hydrochloric acid (70 mL) and stirred for 30 min. The reaction was then diluted with water (150 mL) and extracted with ethyl acetate (300 mL, 2×150 mL). The combined organic portions were washed with bicarbonate solution (150 mL), water (150 mL), brine (2×150 mL), dried (Na2SO4), filtered and evaporated in vacuo to provide 6.33 g of a yellow semi-solid. The material was purified by flash chromotography (eluet:(9:1)hexane:ethyl acetate and (3:1) hexane:ethyl acetate) to provide 3.34 g (57%) of a white solid. 1H NMR (250 MHz, CDCl3): δ 7.67 (d, 1H, J=2.6), 7.49 (d, 1H, J=2.6), 5.91 (m, 1H), 3.82 (t, 2H, J=7.1), 1.89 (m, 2H), 1.42 (s, 9H), 1.33 (s, 9H), 2.63 (t, 3H, J=7.4). MS [EI+] 293 (M+H)+ [EI−] 291 (M−H)+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+].O>CC(O)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:10]=[CH:9]2
Reactant: O=N[O-]
Reactant: Cc1cc(I)ccc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
To a solution of 4-iodo-2-methylaniline (1.09 g, 4.68 mmol) in CH3CO2H (40 mL), were added NaNO2 (0.39 g, 5.65 mmol) and water (1 mL) at 10° C. The resulting mixture was stirred at room temperature for 6 hours. Upon completion, the reaction mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜40% EtOAc in petroleum ether) affording the title compound (0.90 g). 1H NMR (DMSO-d6, 400 MHz): δ 13.23 (br, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.57 (d, 1H), 7.41 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][CH:15]=[O:16].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][CH2:15][OH:16]
Reactant: COc1cc(Br)c(CC=O)cc1OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Br)c(CCO)cc1OC(C)C
Reaction time: 2 h

Procedure:
2-Bromo-5-(1-methylethoxy)-4-methoxybenzene acetaldehyde (2.60 g, 9.05 mmol) is added at 15° C. within 30 minutes to a suspension of sodium borohydride (0.341 g, 9.05 mmol) in absolute ethanol (40 ml), and it is stirred for two hours at this temperature.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:6][CH:7]1[CH:10]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH:8]1[N:30]=[N+]=[N-])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:4][C:2]([Si:5]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:6][CH:7]1[CH:10]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH:8]1[NH2:30])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](OCC1CC(N=[N+]=[N-])C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](OCC1CC(N)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 92.3 %

Procedure:
2-(((1,1-dimethylethyl)diphenylsilyl)oxy)-3-(((1,1-dimethylethyl)diphenyl-silyl)oxymethyl)-1-azidocyclobutane (800 mg, 1.29 mmol), the product of Step M, was dissolved in 20 mL of methanol. To this solution was added 200 mg of 5% palladium on carbon, followed by 420 mg of ammonium formate. The flask was stoppered and the reaction mixture was stirred at ambient temperature for 23 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 200 mL of diethyl ether and the ether solution was washed with 100 mL of 5% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 707 mg (92% yield) of the title compound; MS DCI-NH3M/Z: 594 (M+H)+ ; 1H NMR (CDCl3) δ 0.88-1.08 (m, 18H), 1.95-2.15 (m, 3H), 3.01 (q, 1H), 3.5 (m, 2H), 3.68 (t, 1H).
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(C(C)C)=CC=1.C(N(CC)CC)C.C(O)=O>ClC1C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][CH:2]([C@H:8]([OH:16])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Product: CCOC(=O)C(Cl)[C@H](O)Cc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 107.1 %

Procedure:
Ethyl 2-chloro-3-oxo-4-phenylbutyrate (180 mg, 0.7 mmol) and RuCl[(S,S)-TsDPEN])p-cymene) complex (10 mg, 2 mol %) were mixed, and the mixture was dissolved in chlorobenzene (1 ml). A chlorobenzene solution (1 ml) of triethylamine (374 mg, 5 equivalents) was added, and then a chlorobenzene solution (1 ml) of formic acid (102 mg, 3 equivalents) was gradually added dropwise. After the mixture was stirred at 40° C. for 3 hours, water (4 ml) was added. Ethyl acetate (10 ml) was added for extraction, and the organic layer was concentrated under reduced pressure to obtain the title compound as a brown oil (182 mg, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: N#Cc1ncc(N)cc1Cl
Yield: 48 %

Procedure:
3-Chloro-2-cyano-5-nitropyridine (0.35g, 1.9 mmol), iron powder (0.56g, 10 mmol, 325 Mesh) and calcium chloride (0.06g, 0.55 mmol) were combined in 10 mL of 90% ethanol and as described in example 772B. Purification of the crude product via silica gel chomatography using 10% ether/CH2Cl2 as the eluent gives compound 775D (0.14g, 43%) as a light brown solid. HPLC: 95.5% at 1.69 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 154.03 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[CH3:25][S-:26].[Na+].C(OCC)C>C(#N)C.C(Cl)Cl.O>[CH3:23][N:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:17](=[O:18])[N:12]([C:9]2[CH:10]=[CH:11][C:6]3[S:5][N:4]=[C:3]([CH2:2][S:26][CH3:25])[C:7]=3[CH:8]=2)[C:13]1=[O:24]
Reactant: C[S-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CSCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.66 g, 3.95 mmol) in acetonitrile is treated with sodium thiomethoxide (0.332 g, 4.74 mmol), stirred overnight at room temperature, treated with additional sodium thiomethoxide (about 15 mg), stirred for one hour, and concentrated in vacuo to obtain a residue. The residue is diluted with methylene chloride and water. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel and a 2% diethyl ether in methylene chloride solution gives the title product as a white solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[CH:22][S:23][C:17]=2[CH:16]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:14])(C)(C)C.C(N(CC)CC)C.ClC(O[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=O>C(Cl)Cl>[CH2:49]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[CH:22][S:23][C:17]=2[CH:16]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(F)cc1C1c2scnc2CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)COc1ccc(F)cc1C1c2scnc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (8.2 mL) was added to a solution of (±)-4-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (237 mg, 0.52 mmol, 1.0 eq.) in DCM (12 mL). The resulting mixture was stirred at r.t. for 5 hours. The solvent was removed in vacuo. To an-ice cooled suspension of the residue and triethylamine (0.11 mL, 0.79 mmol, 1.5 eq.) in DCM (5 mL), benzyl chloroformate (79 μL, 0.52 mmol, 1.0 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 18 hours. Triethylamine (0.11 mL, 0.79 mmol, 1.5 eq.) and benzyl chloroformate (39 μL, 0.26 mmol, 0.5 eq.) were added again. The mixture was stirred at r.t. for 18 hours. The reaction was quenched with 1M aq. citric acid soln. (12 mL). The layers were separated. The aq. phase was extracted with DCM (3×6 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. To a solution of the crude ester in THF (2.3 mL), 1M aq. NaOH soln. (0.7 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was diluted with water (2 mL), 1M aq. HCl soln. (0.7 mL), and DCM. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The residue was dissolved in DMF (1.2 mL), purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions), and concentrated in vacuo to give the title compound as a pale yellow foam.