Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][NH:27][CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.[CH2:32](N(CC)CC)[CH3:33].C(I)C>CN(C)C=O.Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H]1CCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-N1-[(5-Chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine hydrochloride (500 mg) was dissolved in N,N-dimethylformamide (10 ml), and triethylamine (576 μl) and ethyl iodide (329 μl) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to collect insoluble matter by filtration. This product was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale brown foamy substance. This substance was suspended in 1N hydrochloric acid (2 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (180 mg) as a pale yellow foamy substance.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31]>CC(OC)(C)C>[CH2:35]([N:32]([CH2:33][CH3:34])[C:30](=[O:31])[CH:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[F:6])[CH2:17][CH2:18]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36]
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL, round-bottomed flask under a positive pressure of nitrogen was equipped with a magnetic stirrer and charged with anhydrous DMF (100 mL), 1-(2-fluoro-4-nitro-phenyl)-piperazine (4.0 g, 17.8 mmol), anhydrous K2CO3 (4.9 g, 35.5 mmol) and 2-bromo-N,N-diethyl-2-phenyl-acetamide (6.2 g, 23.0 mmol). The pale yellow reaction mixture was stirred at ambient temperature for 4 h, following which the solvent was removed on the rotary evaporator to yield a yellow colored semi-solid. MTBE (250 mL) was added and the resulting suspension was stirred at ambient temperature for 0.5 h and then filtered. The filtrate was extracted with 1.5N HCl (1×200 mL, then 1×100 mL). The aqueous layers were pooled, cooled to ˜0° C. in an ice bath and then basified with 2N NaOH (to pH ca. 13). The basified reaction mixture was extracted with MTBE (4×125 mL). The organic layers were pooled, dried over anhydrous sodium sulfate, filtered and concentrated to yield a brown colored oil. The oil was purified by silica gel chromatography (solvent: EtOAc/Hexane) to yield the title compound as a reddish-brown oil.
Reaction SMILES: C[C:2]1[O:3][C:4](=O)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.FC(F)(F)[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>CCOC(C)=O.CCCCCC>[C:17]1([N:18]2[CH:4]=[C:5]3[C:6]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[N:7][C:2]2=[O:3])[CH:19]=[CH:20][CH:21]=[CH:15][CH:16]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1nc2ccccc2cn1-c1ccccc1
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of 2-methyl-4H-Benzo[d][1,3]oxazin-4-one (12; 1.0 g, 6.2 mmol) and 3-trifluoromethylaniline (13, R═H, 0.77 mL, 6.2 mmol, 1.0 eq) were heated at 160° C. (oil bath) for 12 hours. The reaction was cooled to room temperature and the resulting solid was subjected to chromatography on silica gel with 20-50% EtOAc/hexane. Product-containing fractions were pooled and evaporated to yield 1.08 g mg (56%) of 14 as a yellow solid: 1H NMR (CDCl3): 8.27 (d, 1H), 7.29-7.28 (m, 7H), 2.25 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 141.7 %

Procedure:
Trifluoroacetic acid (1.7 ml, 2.6 mmol) was added dropwise to a solution of 5-(tert-butoxycarbonylaminomethyl)-3-phenylisoxazole (Method 43; 473 mg, 1.73 mmol) in DCM (8 ml) cooled in an ice bath. The mixture was warmed to ambient temperature and stirred for 18 hours and the volatiles removed by evaporation. The residue was triturated with ether to give the title compound (427 mg, 86%). NMR (DMSO) 4.33 (s, 2H), 7.1 (s, 1H), 7.5 (m, 3H), 7.8 (m, 2H), 8.6 (br s, 3H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=O)[CH:2]=[CH2:3].[CH2:10](O)CCC.O>C(OCCCC)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:10]
Reactant: C=CC(=O)OCCCC
Reactant: CCCCO
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCOCCCC

Procedure:
The organic phase contained from 75 to 85% by weight of butyl acrylate, from 14 to 20% by weight of butanol, from 2 to 3% by weight of water, 1500 ppm of butyl acetate. The excess water corresponding to the conversion in the reaction was removed from the system through line 27. 5% by weight of the bottom product (product II), based on the amount of starting materials fed to the esterification, was discharged via line 28 and fed to a stirred vessel IV. There, the product was evaporated batchwise at ambient pressure and 180° C. until the viscosity rose distinctly. The starting materials butanol and acrylic acid still present therein and the product butyl acrylate were first distilled off. The amount of distillate was up to about 65% by weight, based on the amount fed in. In the subsequent cracking of the high boilers, the bottom discharge was evaporated to about 15% of its original mass, and low-boiling by-products such as butenes and dibutyl ether were formed to a small extent only toward the end. The condensed vapors from the cracking in the stirred vessel IV consisted essentially of acrylic acid, butyl acrylate, butanol and water. This liquid was fed directly to the bottom of the column I for the high-boiler separation. A further rectification was not carried out.
Reaction SMILES: CO.C[C:4](C)([O-:6])C.[K+].[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](F)[C:11]=1[Cl:18]>C1(C)C=CC=CC=1.CN1C(=O)N(C)CCC1.O>[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:6][CH3:4])[C:11]=1[Cl:18]
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(Cl)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Methanol (5 mL) was added to potassium tert-butoxide (3.94 g, 123 mmol) suspended in toluene/DMPU (3:1, 240 mL), and the mixture was placed in an oil bath at 80° C. under N2 with a reflux condenser for 25 minutes to obtain a solution. The solution was then allowed to cool to room temperature under N2, after which 1-bromo-2,5-dichloro-3-fluorobenzene (10 g, 41 mmol) was added dropwise to the solution and the resulting suspension was placed in an oil bath at 80° C. under N2. After 4 hours, the reaction mixture was allowed to cool to room temperature and was then diluted with hexanes (200 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with hexanes (200 mL). The combined organic portions were washed with water (3×300 mL), dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 7.20 (m, 1H), 6.80 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:12]=[C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][C:11]1[CH:12]=[C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2[nH]cc(C(F)(F)F)c2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]cc(C(F)(F)F)c2c1
Yield: 63.4 %

Procedure:
Tin chloride dihydrate (4.0 g) was added to 5-nitro-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.58 g) in ethyl acetate (50 mL). The resulting solution was refluxed for 3 hours. The cooled solution was treated with dilute aqueous sodium bicarbonate. The resulting slurry was filtered through celite, and the filter cake was washed with ethyl acetate. The layers were separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to provide 5-amino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (320 mg, 63%) as a solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1.C(=O)([O-])O.[Na+]>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.C1(C)C=CC=CC=1.O.C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([CH3:23])[CH:25]=[CH:26]4)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(-c3ccc(C(=O)OC(C)(C)C)c(Nc4ccc(F)cc4)c3)ccc21
Temperature: 25 °C

Procedure:
To toluene 2.1 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.1 g were added ethanol 0.60 mL, water 0.30 mL, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole 84 mg, sodium hydrogen carbonate 69 mg and tetrakis(triphenylphosphine)palladium(0) 16 mg at room temperature, and it was heated and refluxed for 4 hours. After the reaction mixture was cooled to room temperature, toluene and saturated sodium hydrogen carbonate aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-(1-methyl-1H-indol-5-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([CH3:38])[NH:33]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH:34]([CH3:38])[CH2:35][CH2:36][CH2:37][CH:32]4[CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1C(C)CCCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 137 μL (1.02 mmol) of cis-2,6-dimethylpiperidine in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure to yield 170.4 mg (64%) tan solid: mp 120-122° C.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCO>[OH-].[OH-].[Pd+2].CN(C=O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[N:10]=[C:9]([OH:8])[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc3ncn(C)c3c(OCc3ccccc3)n2)cc1OC
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2cc3ncn(C)c3c(O)n2)cc1OC
Temperature: 75 °C

Procedure:
To a mixture of 4-(benzyloxy)-6-(3,4-dimethoxyphenyl)-3-methyl-3H-imidazo[4,5-c]pyridine 2.26 (290 mg, 0.772 mmol), Pd(OH)2 (46 mg, 60 mg/mmol), and ammonium formate (975 mg, 15.5 mmol) under N2 was added EtOH (12 mL) and DMF (4 mL) and the mixture was heated to 75° C. for 30 minutes. The reaction was cooled, filtered through celite and washed with EtOH/DCM. The filtrate was concentrated, dry loaded onto a column, and purified by flash chromatography (EtOAc→10% MeOH/EtOAc) to afford 6-(3,4-dimethoxyphenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-ol 2.27.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:9]3[CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:8]=3[CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:18].[N+:19]([O-])([OH:21])=[O:20]>FC(F)(F)C(O)=O>[N+:19]([C:7]1[C:8]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:9]=2[C:10]2[NH:11][C:2](=[O:1])[C:3](=[O:18])[NH:4][C:5]=2[CH:6]=1)([O-:21])=[O:20]
Reactant: O=C(O)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 2,3-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxaline-8-carboxylic acid (4 g, 16 mmol) in trifluoroacetic acid (75 mL) was cooled to 0° C. and then treated with fuming nitric acid (5 mL). After stirring in an ice bath for 3 h, the mixture was warmed to room temperature for 1 h, the solvent evaporated, and the residue was suspended in water. A solid precipitate was collected by filtration, washed with ether and dried in vacuo (4 g). Calc'd for C12H9N3 O6.0.5 H2O: C, 48.00; H, 3.36; N, 14.00; found: C, 48.64; H, 3.13; N, 13.86. MS M+1 (292).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:64][CH2:65][O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.O>CN(C)C(=O)C>[CH2:67]([O:66][CH2:65][CH2:64][N:19]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[CH3:60])[C:17]([O:24][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:48])[CH3:47])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: BrCCOCc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCOCc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2 g) in N,N-dimethylacetoamide (36 mL) were added sodium hydride (55%, 0.26 g) and benzyl 2-bromoethyl ether (0.76 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.89 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:28])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]([CH3:27])[CH3:26])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:28])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]([CH3:27])[CH3:26])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(C)C)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(C)C)c1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a suspension of anhydrous zinc chloride (9.12 g, 67.0 mmol) in diethyl ether (100 ml) was added sodium borohydride (5.07 g, 134 mmol) by small portions, and the mixture was stirred for 2 hrs. Insoluble material was filtered off, and washed with diethyl ether. The filtrate was ice-cooled, and to the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[3-(isopropyloxy)benzyl]propanoate (12.0 g, 33.5 mmol) in diethyl ether (20 ml). The mixture was stirred at room temperature for 2 hrs. and ice-cooled again. 1N Hydrochloric acid was added to stop the reaction. The mixture was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=10:1) to give the objective substance (10 g, 83%) as a colorless oil
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:9]/[C:10](/[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11]\[OH:12])[CH:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Product: CS(=O)(=O)c1cccc(-c2cccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)c2)c1

Procedure:
In analogy to example 22, from (E)-3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 12) and (3-methylsulfonylphenyl)boronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: [F:1][CH:2]([F:26])[CH:3]([C:5]1[CH:6]=[C:7]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4].FC(F)(F)C(O)=O>ClCCl>[F:26][CH:2]([F:1])[CH:3]([C:5]1[CH:6]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)cc(C(O)C(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(C(O)C(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 5-(2,2-difluoro-1-hydroxyethyl)-2′,4′-difluorobiphenyl-3-carboxylate (1.03 g, 2.79 mmol) in dichloromethane (5.6 mL) was added trifluoroacetic acid (5.4 mL). The mixture was stirred at ambient temperature. After 48 h, the mixture was concentrated to dryness to give the title compound (0.85 g). MS 315.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29]>C1COCC1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].O>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Sodium hydride (48 mg, 60% dispersion in mineral oil, 12.0 mmol) was added to a cooled (0° C.) mixture of 1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.56 g, 1.16 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (0.25 g, 1.20 mmol) in dry THF (3.5 mL). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then diluted with DCM (40 mL), saturated aqueous sodium carbonate solution (20 mL) and water (20 mL). The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash column chromatography (silica, 5 g cartridge, Si-SPE, DCM) to afford the title compound as a beige solid (0.59 g, 80%). LCMS (Method B): RT=4.28 min, M+H+=617/619.
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:7]=[C:8]([O:28][C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([C@H:18]4[CH2:22][O:21]C5(CCCCC5)[O:19]4)[N:14]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([CH2:4][S:5][C:6]2[CH:7]=[C:8]([O:28][C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([C@H:18]([OH:19])[CH2:22][OH:21])[N:14]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a solution of (S)—N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.30 g, 0.586 mmol) in ethanol (20 mL) was added 1 M HCl (0.87 mL) and the reaction heated to 80° C. for 2 hours. The reaction was cooled and concentrated in vacuo and the solid triturated with ethanol. The solid was dried in vacuo to afford (S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.146 g, 0.338 mmol, 57.7% yield) as the mono HCl salt. Mass Spectrum (apci) m/z=432.0 (M+H−HCl).