Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].[S].O>CN(C=O)C>[NH:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:22]=[C:1]1[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: Nc1ccccc1N
Agent: [S]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Yield: 89.7 %

Procedure:
To 3-formyl-1H-indazole-6-carboxylic acid (2.35 g, 12.42 mmol) in DMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for 6 hours. The reaction was followed by TLC and LC-MS. After cooling, water (50 mL) was added to the reaction and the brown precipitate which formed was filtered and collected to provide 3.1 g (90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, J=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[N:15]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[N:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>C1(C)C=CC=CC=1>[CH:20]([O:19][C:17]([N:16]([C@:3]([C:1]#[N:2])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:15][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[O:18])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C#N)c1ccccc1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@](C#N)(c1ccccc1)N(NC(=O)OC(C)C)C(=O)OC(C)C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
To a solution of ethyl 2-cyano-2-phenylacetate (23.0 mg, 0.11 mmol) and (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (4.1 mg, 0.01 mmol) in toluene (1 mL) was added diisopropyl azodicarboxylate (21.5 μL, 0.10 mmol) at −78° C. After stirring for 15 min, the reaction mixture was concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give the title compound (41.4 mg, yield: 100%, optical purity: 76% ee). Colorless amorphous
Reaction SMILES: C(OC([O:11][C:12]1([CH2:51][CH3:52])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:43][N:42]=[CH:41][CH:40]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:51]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:50])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][CH2:35][O:36][C:37]([C:39]2[O:43][NH:42][CH2:41][CH:40]=2)=[O:38])=[C:23]2[CH:46]=[CH:47][CH:48]=[CH:49][C:22]2=[N:21][C:20]3=1)[CH3:52]
Reactant: [H][H]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccno1
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1=CCNO1

Procedure:
A mixture of Compound 63 (70 mg, 0.1 mmol), 10% palladium on carbon (20 mg, 20%) in 20 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH:12]=[CH:13]Cl)=[O:11].Cl.[NH2:16]O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][N:16]=[CH:13][CH:12]=1
Reactant: O=C(C=CCl)c1cc(F)c(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Product: Fc1cc(-c2ccno2)c(Cl)cc1Cl

Procedure:
A mixture of 57.6 g of 2-chlorovinyl 2,4-dichloro5-fluoro-phenyl ketone, 16.4 g of hydroxylamine hydrochloride and 150 ml of methanol is heated at the boiling point under reflux for 6 hours, a precipitate separating out after about one hour. This is filtered off cold with suction, washed with a little methanol and dried at 50° C. in vacuo. 33.3 g (63.2%) of 5-(2,4-dichloro-5-fluorophenyl)-isoxazole of melting point 112°-113° C., which, according to investigations by NMR spectroscopy, contains about 6 mole % of an isomer, are obtained.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:36][C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=4)[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: Cn1ccnc1C=O
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5nccn5C)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and 1-methyl-1H-imidazole-2-carbaldehyde (33 mg) in tetrahydrofuran (3 ml) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (14 mg, yield 12%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 103° C.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([F:32])[CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].[CH2:33]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O)[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([F:32])[CH:27]=3)=[N:13]2)[CH2:17][CH2:18][N:19]([CH2:40][C:36]2[N:35]([CH2:33][CH3:34])[CH:39]=[CH:38][N:37]=2)[CH2:20][CH2:21]1)#[N:24]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CC[NH2+]CC1
Reactant: CCn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1ccnc1CN1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a reaction vial was added 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-4) (0.020 g, 0.058 mmol), 1-ethyl-1H-imidazole-2-carbaldehyde (0.0072 g, 0.058 mmol), Na(OAc)3BH (0.062 g, 0.29 mmol), TFA (0.030 g, 0.26 mmol) suspended in DMF (0.97 mL). The reaction vessel was sealed and heated to 50° C. with stirring for 12 hours. The completed reaction was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% ACN/water with 0.1% v/v NH4OH modifier) to afford the title compound, Example #22-1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=1O>N1C=CC=CC=1>[CH3:18][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:16]=2[CH:15]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
Benzoyl chloride (79 ml) was slowly added to a stirred suspension of 6-amino-m-cresol (83 gm) in pyridine (600 ml). The temperature was kept below 5° C. The solution was heated under reflux for 2 hr., then was evaporated to dryness to give an oil. This oil was extracted with aqueous 2N sodium hydroxide solution. The aqueous layer was made acid with concentrated hydrochloric acid. The solid, N-(2'-hydroxy-4'-methyl-benzanilide), m.p. 170° C, was filtered off. This product was heated until no more water was evolved. The resulting liquid was allowed to cool and the solid produced was powdered and taken up in petroleum ether. The solution was treated with carbon and the filtrate evaporated to dryness to yield 6-methyl-2-phenyl-benzoxazole, m.p. 93° C.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1I.[CH3:23][N:24](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[C:23]#[N:24]
Reactant: CN(C)C=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(I)c(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(C#N)c(Br)c12
Temperature: 95 °C
Yield: 83 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H -carbazole-1-carboxamide (0.609 g, 1.29 mmol) and zinc cyanide (0.076 g, 0.644 mmol) in DMF (7 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.074 g, 0.064 mmol) and heated overnight at 95° C. The cooled mixture was diluted with EtOAc, washed twice with 10% aqueous LiCl, then with brine. The aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was triturated and sonicated with DCM and the precipitate was collected by filtration to give 4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a pale yellow solid (0.400 g, 83% yield). Mass spectrum m/z 372, 374 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.55 (d, J=8.6 Hz, 1H), 8.38 (s, 1H), 8.31 (br. s., 1H), 8.03 (s, 1H), 7.74 (br. s., 1H), 7.49 (dd, J=8.6, 1.1 Hz, 1H), and 1.52 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[C:31]([CH3:32])=[C:30]([O:12][C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=3[F:1])[N:29]=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2-Fluoro-4-methanesulfonyl-phenol (4) (1.33 g, 7.01 mmol) and 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (3) (2.00 g, 6.39 mmol) were dissolved in DMSO (10 mL). To the resulting solution, potassium iodide (0.21 g, 1.27 mmol) and potassium carbonate (0.97 g, 7.01 mmol) were added. The resulting mixture was heated to 130° C. and stirred overnight. The crude was cooled to room temperature, poured into ice water (150 mL) and stirred for 2 h. The precipitate was filtered, washed twice with water (2×10 mL) and dried at 60° C. in a vacuum oven (2.74 g, 91%). The desired product was recrystallized from isopropanol (10 mL) to afford 2.39 g of the title compound (80%).
Reaction SMILES: O=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[Li+].[O:37]1CCCC1.O>CO>[O:37]=[C:18]1[O:17][C:16]2[CH:21]=[C:22]3[C:10]4([C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]([CH2:23][C:24]5[C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:2]4)[CH2:11][O:12][C:13]3=[CH:14][C:15]=2[O:20][CH2:19]1
Reactant: CCOC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1COc2cc3c(cc2O1)C1(CO3)CN(Cc2ncccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
A 250 mL round-bottom flask was charged with ethyl 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate (2.3 g, 5.0 mmol), lithium hydroxide (0.48 g, 20.0 mmol), tetrahydrofuran (30.mL), water (50.mL) and methanol (30 mL). The reaction mixture was stirred under nitrogen at reflux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in water (100 mL) and acidified to pH 1 by the addition of 10 M hydrochloric acid, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and recrystallized from ethanol (50 mL) to afford 2-[(2-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (1.96 g, 91%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ8.57-8.45 (m, 1H), 8.33-8.26 (m, 1H), 7.42 (dd, J=7.82, 4.77 Hz, 1H), 7.21-6.83 (m, 4H), 6.49-6.44 (m, 2H), 5.39 (ABq, 2H), 4.72 (ABq, 2H), 4.24-4.00 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:23]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:23])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(-c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-[pyridin-3-yl]-benzoic acid (2.2 g, 11 mmol) (reference example 17b) in methanol (33 mL) was added conc. H2SO4 (5 mL). The resulting solution was warmed to 60° C. and stirred at this temperature for 45 min. The reaction mixture was then allowed to cool to room temperature then poured into ice. The pH of the resulting solution was adjusted to 7 using a 10 M solution of NaOH. The product was then extracted into ethyl acetate. This solution was washed with brine, dried over MgSO4 and concentrated to give 1.74 g of the title compound as a tan solid. 1H NMR (CDCl3) d 3.96 (s, 3H), 7.40 (dd, J=8, 5 Hz, 1H), 7.66 (m, 2H), 7.93 (m, 1H), 8.15 (m, 2H), 8.65 (bs, 1H), 8.89 (bs, 1H). MS (EI) m/z 213 (M)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][CH:28]([F:31])[CH2:29][NH2:30].CCOC(C)=O>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][CH:28]([F:31])[F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: NCC(F)F
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCC(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.64 g, 1.63 mmol) in CH3CN, was added neat 2,2-difluoroethylamine (0.23 g, 1.97 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3.5 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1, 2:1, then pure EtOAc, respectively), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2,2-difluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.433 g, 56% yield) 1H NMR (500 MHz, CDCl3) δ 1.99 (s, 3H), 2.00 (s, 3H), 2.03 (s, 3H), 2.06 (s, 3H), 3.83-3.86 (m, 2H), 3.95 (s, 1H), 4.02-4.09 (m, 2H), 4.18-4.23 (m, 1H), 5.05-5.11 (m, 1H), 5.21-5.30 (m, 1H), 5.72 (d, 1H, J=8.6 Hz), 5.94 (t, 1H, J=56.1 Hz), 6.63-6.73 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:24]=[C:23]4[C:18]([C:19](=O)[CH2:20][CH2:21][O:22]4)=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:27][OH:28]>>[CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:24]=[C:23]4[C:18](/[C:19](=[N:27]/[OH:28])/[CH2:20][CH2:21][O:22]4)=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: COC1(c2csc(Sc3ccc4c(c3)OCCC4=O)c2)CCOCC1
Agent: Cl
Product: COC1(c2csc(Sc3ccc4c(c3)OCC/C4=N\O)c2)CCOCC1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 7, 7-[4-(4-methoxytetrahydropyran-4-yl)thien-2-ylthio]chroman-4-one was reacted with hydroxylamine hydrochloride to give (E)-7-[4-(4-methoxytetrahydropyran-4-yl)thien-2-ylthio]chroman-4-one oxime in 82% yield, m.p. 137°-138° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a solution of ethyl 2-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.61 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.088 g, 0.61 mmol) in ethanol (10 mL), piperidine (0.0044 mL, 0.044 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.061 g, y. 23%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.0 g, 5.8 mmol, 1.0 eq.) and ethyldiisopropylamine (17 mL, 3.0 eq.) in methylene chloride (4 mL) at 0° C. was added dropwise MsCl (0.46 mL, 1.0 eq.) and the resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by addition of sat. NaHCO3 and the separated aqueous phase was extracted with 3× methylene chloride and 4×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to give a crude methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-ylmethyl ester.
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[CH:9]=[C:8]([CH2:10][CH:11]2[C:19]3[C:14](=[CH:15][C:16]([O:22]C)=[C:17]([CH:20]=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)[N:7]=[CH:6]1.O.[OH-].[NH4+]>C(Cl)Cl>[OH:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:11]([CH2:10][C:8]3[N:7]=[CH:6][NH:5][CH:9]=3)[CH2:12][CH2:13]2)=[CH:18][C:17]=1[CH:20]=[O:21]
Reactant: COc1cc2c(cc1C=O)C(Cc1c[nH]cn1)CC2
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc2c(cc1O)CCC2Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron tribromide 1.0 M solution in methylene chloride (3.9 ml) is added dropwise to a stirred solution of 3-(1H-imidazol-4-ylmethyl)-6-methoxyindan-5-carbaldehyde (318 mg) in methylene chloride (15 ml) at −70° C. under a nitrogen atmosphere. After the addition the mixture is allowed to warm to room temperature and is stirred for 3 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)([CH2:11]2)[C:9]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH3:24]>CCOCC.C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:13][CH:12]1[CH2:11][C:10]1([C:9](=[O:22])[CH3:24])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a flame-dried, 10 mL round-bottomed flask was added a solution of 1-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 2 mL of ether and 1.0 mL of THF under Ar (g). The solution was cooled in a dry ice/acetone bath with stirring. A solution of MeLi was added drop-wise and the resulting orange colored mixture was stirred at −78° C. for 3 hours. The solution was warmed to ambient temperature and quenched with 15 mL of 1N HCl. The organic layer was extracted with EtOAc (2×20 mL) and the combined layers washed with brine (20 mL). The organic layer was dried over sodium sulfate for 2 hours and filtered, concentrated under reduced pressure, and dried for 1 hour to afford 1.1 g of a brown oil. The oil was purified on a filter pad of silica eluting with 100/1 (v/v) CHCl3/MeOH. The desired fractions were collected, concentrated under reduced pressure, and dried to afford a yellow oil. Yield: 0.659 g 52%; 1H NMR (300 MHz, CDCl3) δ□7.46 (d, 1H, J=2.1 Hz, ArH), 7.39 (d, 1H, J=5.4 Hz, ArH), 7.20 (dd, 1H, J=5.4, 2.1 Hz, ArH), 4.73 (m, 1H, NH), 3.41 (m, 1H, CH2N), 3.15 (m, 1H, CH2N), 2.04 (s, 3H, CH3), 1.80 (m, CHCH2N), 1.45-1.58 (m, 9H, tert-Bu), 1.20 (dd, 2H, J=4.5 Hz, ArCCH2).