Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][Cl:15].CCCCCCC>CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=[CH:2]1
Reactant: ClCCBr
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: ClCCn1cnc2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
6.5 g (54.56 mmol) 3H-imidazo[4,5-b]pyridine were dissolved under argon in 100 ml DMF and cooled to 0° C. in an ice bath. 4.6 g (109.1 mmol) sodium hydride were added and the mixture was stirred for 1 hour at room temperature. Then a solution of 9 ml (109.1 mmol) 1-bromo-2-chloroethane in 30 ml DMF was added over the period of an hour and the solution was stirred at room temperature during 20 hours. The brownish solution was poured onto ice water and extracted 3 times with ethyl acetate. The organic layers were combined, washed once with brine, dried over Na2SO4 and evaporated in vacuo to give a yellow oil. The oil was stirred with three times 50 ml warm heptane. Heptane was decanted, the tree fractions pooled and evaporated to give 2.08 g of light yellow crystals. MS(ISP): 182.2 [MH]+; 1H-NMR (CDCl3): 3.99 (t, 2H), 4.66 (t, 2H), 7.28-7.32 (m, 1H), 8.11-8.17 (m, 2H), 8.40-8.42 (m, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl.O>[CH3:9][S:10]([O:1][CH:2]1[CH:3]([C:7]#[N:8])[CH2:4][S:5][CH2:6]1)(=[O:12])=[O:11]
Reactant: N#CC1CSCC1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CSCC1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxytetrahydrothiophene-3-carbonitrile (1.0 g, 7.7 mmol) in DCM (15 mL) was stirred at 0° C. TEA (4.3 mL, 31 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (1.77 g, 15.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes then warmed to ambient temperature and stirred for an additional 30 minutes. The mixture was carefully diluted with water and extracted with DCM (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH/DCM) to afford the title compound, which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:18]([O:37][CH3:38])=[C:19]([NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[C:25]([F:35])[CH:24]=3)[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[Pd+2].[OH-]>[C:39]([C:17]1[C:18]([O:37][CH3:38])=[C:19]([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[C:25]([F:35])[CH:24]=2)[CH:20]=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: COc1c(NC(=O)c2ccc(NCC(F)(F)F)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)c(F)c2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Reaction time: 1.5 h

Procedure:
step 4—To a solution of 320 (86 mg, 0.148 mmol) in a mixture of MeOH/EtOAc (2 mL and 1 mL, respectively) at RT was added 20% palladium (II) hydroxide on carbon (moist) (9 mg, 10 wt. %). The reaction mixture was stirred under 1 atm of H2 for 1.5 h. The reaction mixture was filtered through a plug of CELITE and the pad washed with EtOAc. The filtrate was concentrated to afford 72 mg (99%) of I-251 as a light pink solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:10](=[O:20])[CH2:9][CH2:8]2.CN(C=O)C.[CH3:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=O.C(N(C(C)C)CC)(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:34][C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH3:37])[CH2:18][CH2:19]1)[C:10](=[O:20])[CH2:9][CH2:8]2
Reactant: Cc1ccccc1C=O
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCNCC1)C(=O)CC2
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC1CCN(Cc3ccccc3C)CC1)C(=O)CC2
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To 5-(8-methoxy-1-piperidin-4-ylmethyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione (20 μmol, 1.0 eq.) was added a DMF (200 μl) solution of 2-methylbenzaldehyde (24 μmol, 1.2 eq) and acetic acid (10 μl). Si-sodium cyanoborohydride was added further thereto. The solution was shaken for several minutes, diisopropylethylamine (30 μl) was added, and a reaction was carried out at room temperature overnight. The resin was removed by filtration and washed with dichloromethane. The solvent was distilled off from the filtrate in a nitrogen gas stream, and the residue was purified by HPLC (UV-trigger, column: CAPCELL PAK C18, UG 120 S-5, 20 mm×50 mm, 0.05% trifluoroacetic acid-H2O, 0.05% trifluoroacetic acid-CH3CN). The structure was confirmed by LC-MS, and freeze-drying was conducted, giving 5-{8-methoxy-1-[1-(2-methylbenzyl)piperidin-4-yl]methyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione in 50.5% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[NH2:34][C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:34][C:35]([CH3:44])([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:43])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Yield: 60.8 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (320 mg, 950 μmol, prepared according to Example 1 A-C) was dissolved in 1,4-dioxane (950 μL) and N-ethyl-N-isopropylpropan-2-amine (507 μL, 2851 μmol) before tert-butyl 2-amino-2-methylpropanoate hydrochloride (279 mg, 1425 μmol) was added. The resulting mixture was heated at 80° C. for 24 hours and then diluted with 150 mL of EtOAc. The resulting mixture was added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed with saturated aqueous NaHCO3 (2×75 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (260 mg) after chromatography as an amorphous solid. MS (m/z)=394 (M+H-tert-butyl)+.
Reaction SMILES: C([N:3]1[C:11]2[C:6](=[C:7]3[CH:14]=[CH:13][NH:12][C:8]3=[N:9][CH:10]=2)[N:5]([C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[O:21]C)[C:4]1=[O:23])C.I[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[OH:21][C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]1[N:5]1[C:6]2=[C:7]3[CH:14]=[CH:13][NH:12][C:8]3=[N:9][CH:10]=[C:11]2[NH:3][C:4]1=[O:23]
Reactant: CCn1c(=O)n([C@H]2CCCC[C@H]2OC)c2c3cc[nH]c3ncc21
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 162.8 %

Procedure:
To a solution of ethyl 1-[(1S,2R)-2-methoxycyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (10 mg) in acetonitrile (0.38 mL) was added iodo(trimethyl)silane (0.025 mL) at 5° C. and the mixture was stirred at ambient temperature for 2 hours and further stirred at 60° C. for 2 hours. The mixture was cooled to 4° C. To the mixture were added saturated disodium thiosulfate aqueous solution and saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative Thin layer chromatography (chloroform:methanol=10:1) to give 1-[(1S,2R)-2-hydroxycyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (14.1 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:23]1.C([O-])(=O)C.[K+].C(O)(=O)C.OO.O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([OH:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: OO
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
To a stirred solution of 4-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (12.4 g, 34.8 mmol, 1.0 equiv) in dioxane (100 mL) was added bis(pinacolato)diboron (13.25 g, 52.2 mmol, 1.5 equiv) and potassium acetate (10.4 g, 105 mmol, 3.0 equiv). After 15 min, bis(triphenylphosphine) palladium(II) chloride (1.47 g, 2.1 mmol, 0.06 equiv) was added and the reaction mixture was warmed up to 90° C. After 3 h, the reaction mixture was cooled down to 0° C. and glacial acetic acid (3.02 mL, 3.17 g, 52.2 mmol, 1.5 equiv) was added, followed by a solution of 30% hydrogen peroxide in water (6.58 mL, 7.44 g, 76.5 mmol, 1.5 equiv) and then warmed up to rt. After 16 h, the reaction mixture was poured into ice water and extracted twice with dichloromethane. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 6.81 g (66%) of the title compound as yellow foam. MS (ISP): 295.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[S:13][N:12]=3)[CH:9]=2)[N:4]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]cc(I)c3c2)ns1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
To a solution of tert-butyl (3-(3-iodo-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (80 mg, 0.18 mmol) in DMF (2.5 mL) at 0° C. was added 60% NaH (80 mg, 0.199 mmol) at 0° C. and the reaction was stirred at RT. After 5 min, the mixture was again cooled to 0° C. and 4-methylbenzene sulfonyl chloride (38 mg, 0.199 mmol) in DMF (2.5 mL) was added dropwise. The reaction was stirred at RT for 1 h, then treated with ice cold water (5 mL) and extracted with EtOAc (10 mL). The aqueous layer was back extracted with EtOAc (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica-gel column Chromatography (eluent: 15% EtOAc in petroleum ether) to give tert-butyl (3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 46.7%) as an off white solid. MS (ESI, pos. ion) m/z: 540.9 (M+1) (carbamic acid mass). 1H NMR (400 MHz, DMSO-d6) δ 12.45 (brs, 1H), 8.22-8.19 (m, 1H), 8.15 (s, 1H), 8.11-8.07 (m, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 2.31 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][NH:25][CH3:26]>[OH-].[Na+]>[CH3:24][N:25]([CH3:26])[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1-c1nc2nc(N(C)C)nnc2c(=O)[nH]1

Procedure:
3-Methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.6 g) was treated with a solution of dimethylamine in industrial methylated spirit (33%, 20 ml) at 100° C. in a pressure vessel for 24 hours. The cooled reaction mixture was evaporated under reduced pressure to afford a yellow solid residue which was dissolved in dilute aqueous sodium hydroxide and filtered. The filtrate was acidified with a few drops of concentrated hydrochloric acid to afford a yellow precipitate which was collected, washed with water and recrystallised from methanol to afford the title compound, 0.44 g, m.p. 257.5°-259° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6](Cl)[N:7]=1.[SH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)[nH]c1=O
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a stirred suspension of 500 mg (2.93 mmol) 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml DME were added 0.61 g (4.40 mmol) 2-mercapto-ethylpyridine and 1.10 ml (7.33 mmol) DBU and the mixture stirred at room temperature for 1 hour. The reaction mixture was then partitioned between water and ethyl acetate and the organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (dichloromethane then methanol/dichloromethane 5/95) followed by trituration in ether/methanol afforded 310 mg (39%) 2-amino-6-oxo-4-(2-pyridin-2-yl-ethylsulfanyl)-1,6-dihydro-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 274 (M+H+, 100).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:9]=1[C:10](OC(C)C)=[O:11].O.[OH-].[Na+]>CCOCC>[Cl:7][C:8]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:9]=1[CH2:10][OH:11]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1ccc(CO)c(Cl)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Lithium aluminum hydride (100 mg) was added to a solution of isopropyl 2-chloro-4-isopropoxybenzoate (675 mg) in ether (6.8 ml) and the mixture was stirred for 2 hr. To the reaction mixture were dropwise added successively water (0.8 ml), a 1N aqueous sodium hydroxide solution (0.8 ml) and water (2.4 ml) under ice-cooing, and the mixture was stirred for 30 min at room temperature. Then ether and water were added and the organic layer was separated. The resulting product was extracted with ether from the aqueous layer. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the objective compound (513 mg) as a brown oil.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][C:8]#[C:9][CH2:10]O)([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=[N:18]CCC2)CC1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])(O)=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-]=[N+]=[N-]>C1COCC1>[Si:5]([O:6][CH2:7][C:8]#[C:9][CH2:10][NH2:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCO
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold, stirred solution of the known 4-(tert-Butyl-dimethyl-silanyloxy)-but-2-yn-1-ol (3.14 g, 15.7 mmol) in THF (50 ml) was added DBU (2.6 ml, 17.4 mmol) and DPPA (3.8 ml, 17.6 mmol). The solution was warmed to room temperature and stirred under an inert atmosphere overnight. The reaction was poured into sat. NaHCO3 and the layers separated. The aqueous layer was re-extracted with EtOAc (2×) and the combined organic layers were dried (Na2SO4), and concentrated under vacuum. Triphenylphosphine (4.61 g, 17.6 mmol) was added to this crude azide dissolved in THF (50 ml), followed by addition of H20 (0.44 ml). The resultant solution was stirred overnight at room temperature, concentrated under reduced pressure and the residue was slurried in a 1:1 mixture of Et2O/pet ether. The solids were removed and the filtrate was concentrated and purified by flash chromatography on silica gel eluting CH2Cl2/MeOH (19:1) to give an amber oil. 1H NMR (CDCl3) δ 4.19 (2H, t, J=1.9 Hz), 3.33 (2H, t, J=1.9 Hz), 0.79 (9H, s), 0.00 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Br:26]Br>C(Cl)Cl.C(OCC)C>[Br:26][C:9]1[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (1 g, 2.4 mmol) in methylene chloride (30 ml) at room temperature was added bromine (4.9 ml, prepared 1.0 M solution in methylenechlordie, 4.9 mmol) dropwisely. The reaction mixture was stirred at room temperature for 1 hour and the resulting solution was diluted with ethyl ether (50 ml). The reaction mixture was quenched with saturated sodium bicarbonate solution (30 ml) and extracted with ethyl ether (50 ml twice). The organic solution was evaporated under reduced pressure, and crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (401 mg, 40%) and produce the title compound (520 mg, 45% yield) as white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:25]([F:28])([F:27])[F:26])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:23][OH:24])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:29])[C:8]1=[O:30])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:25]([F:28])([F:26])[F:27])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:23][OH:24])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:29])[C:8]1=[O:30])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.6 g (3.8 mmol) of the compound of Example 74 were dissolved in 100 ml of tetrahydrofuran, and 0.4 g (15.1 mmol) of lithium hydroxide dissolved in 25 ml of water was added. The mixture was stirred at room temperature for 2 h and then the tetrahydrofuran was removed under reduced pressure and the aqueous phase was acidified. The precipitate was filtered off with suction.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.53 mL, 6.80 mmol) was added to a −20° C. solution of tert-butyl 4-hydroxycyclohexanecarboxylate (1.05 g, 5.25 mmol) and triethylamine (1.46 mL, 10.5 mmol) in dichloromethane (21 mL). The reaction was stirred for 2 hours, then saturated aqueous sodium bicarbonate was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 4.96-4.55 (m, 1H), 3.00 (s, 3H), 2.23-2.12 (m, 2H), 2.03-1.98 (m, 2H), 1.93-1.81 (m, 1H), 1.79-1.66 (m, 1H), 1.66-1.48 (m, 3H), 1.42 (s, 9H).
Reaction SMILES: CC(C1CC(C2C3C(=C(C(N)=O)C=C(C4SC=CC=4)C=3)NC=2)CCN1C([O-])=O)(C)C.Br[C:32]1[CH:33]=[C:34]2[C:38](=[C:39]([C:41]([NH2:43])=[O:42])[CH:40]=1)[NH:37][CH:36]=[C:35]2[CH:44]1[CH2:49][CH2:48][N:47]([S:50]([CH2:53][CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)(=[O:52])=[O:51])[CH2:46][CH2:45]1.[OH:62][CH2:63][C:64]1[S:68][C:67](B(O)O)=[CH:66][CH:65]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:62][CH2:63][C:64]1[S:68][C:67]([C:32]2[CH:33]=[C:34]3[C:38](=[C:39]([C:41]([NH2:43])=[O:42])[CH:40]=2)[NH:37][CH:36]=[C:35]3[CH:44]2[CH2:45][CH2:46][N:47]([S:50]([CH2:53][CH2:54][CH2:55][N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)(=[O:52])=[O:51])[CH2:48][CH2:49]2)=[CH:66][CH:65]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Reactant: OCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)C1CC(c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CCN1C(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc(CO)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12

Procedure:
The title compound was prepared according to the general procedure for intermediate 16. Thus, 5-bromo-3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (400 mg, 0.78 mmol) in dioxane (3 mL) and water (1 mL), [5-(hydroxymethyl)-2-thienyl]boronic acid (493 mg, 3.12 mmol), Pd(PPh3)4 (90 mg, 10%) and potassium carbonate (861 mg, 6.24 mmol) were reacted to form the desired product which was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (83 mg, 20%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12](=[O:14])[CH3:13])[C:5]([O:7]C(C)(C)C)=[O:6].[Br:15]Br.[Cl-].[Na+].ClCCCl>O1CCOCC1>[Br:15][CH2:13][C:12](=[O:14])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: CON=C(C(C)=O)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CON=C(C(=O)O)C(=O)CBr
Temperature: 20 °C
Reaction time: 20 h
Yield: 41.1 %

Procedure:
In 50 ml of 1,4-dioxane was dissolved 20.1 g (0.1 mole) of tert-butyl 2-methoxyimino-3-oxobutyrate, and 32.0 g (0.2 mole) of bromine was added dropwise at 0° to 5° C. over a period of 1 hour and 30 minutes and stirred at 20° C. for 20 hours. After completion of the reaction, 25 ml of a saturated aqueous sodium chloride solution and 50 ml of 1,2-dichloroethane were added and then stirred, and the resulting mixture was allowed to stand and then separated and the aqueous layer was removed. The organic layer was further washed with 25 ml of water and dried over anhydrous magnesium sulfate, after which the 1,2-dichloroethane was distilled off under reduced pressure, and the residue was crystallized from 50 ml of xylene to obtain 9.2 g (yield 41.1%) of 4-bromo-2-methoxyimino-3-oxobutyric acid as white crystals.