Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]([CH3:13])=[CH:11][C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.FC1(F)OC2C=C(C)C(C3N=C[C:27]([NH:30][C:31](=O)[C:32]4[CH:37]=[CH:36]C=CC=4F)=[N:28]C=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O>[CH3:9][C:8]1([CH3:10])[CH2:7][O:6][C:5]2[CH:11]=[C:12]([CH3:13])[C:2]([C:32]3[CH:37]=[CH:36][C:27]([NH2:28])=[N:30][CH:31]=3)=[CH:3][C:4]1=2
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Reactant: Cc1cc2c(cc1Br)C(C)(C)CO2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Cc1cc2c(cc1-c1ccc(N)nc1)C(C)(C)CO2
Temperature: 85 °C
Yield: 90.8 %

Procedure:
A mixture of 5-bromo-3,3,6-trimethyl-2,3-dihydrobenzo[b]furan (171) (241 mg, 1 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (330 mg, 1.5 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (106 mg), and K3PO4 (636 mg) in 3 ml ACN, 3 ml dioxane, 1.5 ml H2O was bubbled with argon before heated at 85° C. for 2.5 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected silica gel column purification to give 231 mg 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (172) (yield: 90.8%, purity>95%) as thick yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[NH:28][CH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][O:12][CH3:11])=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CCc1nccc(Cl)c1Cl
Reactant: COCCOc1ccc(C2CCC(N)CC2)cc1
Product: CCc1nccc(NC2CCC(c3ccc(OCCOC)cc3)CC2)c1Cl
Yield: 11 %

Procedure:
Preparation took place analogously to Example 59 from 3,4-dichloro-2-ethylpyridine and 4-(4-(2-methoxyethoxy)phenyl)cyclohexylamine. Yield: 11% (cis/trans mixture)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:31][C:32]([F:35])([F:34])[F:33])=[C:12]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][CH2:20][C:19]5[C:25]([C:28]([NH2:30])=[O:29])=[N:26][NH:27][C:18]=5[C:17]=4[N:16]=3)[CH:13]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:43][CH2:44][Cl:45].O>CN(C=O)C>[Cl:45][CH2:44][CH2:43][N:27]1[C:18]2[C:17]3[N:16]=[C:15]([NH:14][C:12]4[CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=[CH:10][C:11]=4[O:31][C:32]([F:33])([F:35])[F:34])[N:24]=[CH:23][C:22]=3[CH2:21][CH2:20][C:19]=2[C:25]([C:28]([NH2:30])=[O:29])=[N:26]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3[nH]nc(C(N)=O)c3CC4)c2)CC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3CCCl)CC4)c2)CC1
Yield: 96 %

Procedure:
A suspension of 8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (488 mg, 1.0 mmol) and Cs2CO3 (490 mg, 1.5 mmol) was suspended in DMF (1 mL) and treated with 1-bromo-2-chloro-ethane (0.1 mL, 1.2 mmol) at room temperature. After 2 h the reaction mixture was poured into water and filtered, washed with water and dried to give the title compound (529 mg, 96% yield) as a white solid.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][CH:12]=[O:13])[O:8][C:7](=[O:14])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([Mg]Br)[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>C1COCC1.CC(C)=O>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[O:8][C:7](=[O:14])[NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC[Mg]Br
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCC=O
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC(=O)CC[C@@H]1OC(=O)N[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A 2 g (0.01 mole) portion of the compound from Example 26 was dissolved in THF (50 mL) and treated at 0°-5° C. with 37.5 mL of an 0.8 M solution of isopentyl magnesium bromide in THF. The reaction was stirred for 2 hours at room temperature and then poured into ice water which contained 6.5 mL of 6 N HCl. The mixture was extracted with methylene chloride. Evaporation of the dried methylene chloride solution gave a quantitative yield of the Grignard adduct. This material was dissolved in 300 mL of acetone and treated by dropwise addition with Jones solution until the orange color persisted. The chromium salts were filtered and the filtrate was evaporated. The residue was diluted with ether and the resulting solution was washed successively with aqueous NaHCO3 and brine solution. After drying over MgSO4, the solvent was evaporated to give 1.7 g (66%) of product as an oil. NMR (300 MHz, CDCl3, ppm): 0.86-0.96 (m, 12H), 2.41 (M, 2H), 2.67 (m, 2H), 3.5 (m, 1H), 4.15 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[CH:9]=2)=[CH:15][CH:14]=1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)cn1
Reactant: c1ccncc1
Product: Fc1ccc(-c2cnn(CCC#Cc3ccccn3)c2)cc1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 50 mg (0.23 mmol) of 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole. Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) and SCX column (DCM, DCM/MeOH 95:5, DCM/MeOH/NH4OH 94:5:1) to yield 2 mg (7 mmol, 3%) of 244-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[C:18]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[C:18]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15]
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OCCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OCCN)cc1
Yield: 89 %

Procedure:
N1-[2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-methoxybenzoyl]-N2-(4-methoxybenzoyl)-1,2-benzenediamine (124 mg, 231 μmol) was dissolved in 3 ml of neat trifluoroacetic acid (TFA) in a capped vial for 90 min at room temperature. The volatiles were removed in vacuo and the residue was resuspended in a few ml of toluene and re-evaporated. This step was repeated twice more with toluene and once with dichloromethane. The resulting white solid was dried under high vacuum to give 113 mg (89%) of N1-[2-(2-aminoethoxy)-4-methoxybenzoyl]-N2-(4-methoxybenzoyl)-1,2-benzenediamine trifluoroacetate as a solid white film.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[N:13]=2)[C:10]=1[CH3:11])=[O:5])C.C(O[C:23]([C:25]1[CH:26]=NN(C2C=CC(Br)=CC=2)C=1C)=O)C>>[CH:26]1([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)=[N:13][C:14]=2[CH3:19])[CH2:25][CH2:23]1
Reactant: CCOC(=O)c1cnn(-c2ccc(I)c(C)n2)c1C
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C
Product: Cc1nc(-n2ncc(C(=O)O)c2C)ccc1C1CC1

Procedure:
1-(5-Iodo-6-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester described in Reference Example 31 was used in place of 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester in Reference Example 26(2), and reacted and treated in a similar manner to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([CH:10](O)[CH3:11])[CH:9]=[C:4]2[CH:3]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([CH:10]([N:19]3[C:15](=[O:25])[C:16]4[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:18]3=[O:20])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: CC(O)c1cc2cc(Br)sc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2cc(Br)sc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round-bottomed flask containing 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanol (2.0 g, 6.8 mmol), pthalimide (1.2 g, 8.2 mmol, 1.2 eq), and triphenylphosphine (2.15 g, 8.2 mmol) was added THF (45 mL). The solution was cooled to 0° C. and diisopropylazodicarboxylate (DIAD, 1.6 mL, 8.2 mmol, 1.2 eq) was added dropwise. The reaction was allowed to warm to room temperature. After 1 h, the reaction was judged to be complete by LC/MS. The solvent was removed in vacuo and the residue was redissolved in ether and washed with water. The water layer was back extracted with ether. The combined ether layers were washed with brine and dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography using 15% EA in hexanes to afford 2-(1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. LC/MS (M+1, found=422.8). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.82 (m, 2H), 7.72 (m, 2H), 5.92 (q, J=7.0 Hz, 1H), 1.92 (d, J=7.0 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[C:6]2[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]cc(-n3cccn3)c2c1
Product: COc1ccc2c(Cl)ncc(-n3cccn3)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
6-methoxy-4-(1H-pyrazol-1-yl) isoquinolin-1(2H)-one (0.25 g, 1.036 mmol) was taken in phosphorous oxychloride (5 mL) and stirred for 1 h at 100° C. The volatiles were evaporated and the crude was poured into ice. The pH was adjusted to 9.0, extracted with ethyl acetate and washed with brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The crude product was purified by silica gel chromatrography using 10% Ethyl acetate in Pet-ether to get 1-chloro-6-methoxy-4-(1H-pyrazol-1-yl)isoquinoline (0.019 g, 0.062 mmol, 6.00% yield) as solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77-8.84 (m, 2H) 8.74-8.84 (m, 1H) 8.52-8.58 (m, 2H) 8.52-8.57 (m, 1H) 8.28-8.34 (m, 1H) 8.27-8.34 (m, 2H) 7.90-7.96 (m, 1H) 7.77-7.83 (m, 1H) 7.46-7.52 (m, 1H) 7.32-7.38 (m, 1H) 6.58-6.66 (m, 1H) 3.96 (s, 3H). MS: MS m/z 260.10 (M++1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]2[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:12])[F:14])[N:8]=[C:7]([C:15]2[N:20]=[CH:19][C:18]([NH:21][C:31](=[O:32])[CH2:30][Cl:29])=[CH:17][CH:16]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOc1cc(C(F)(F)F)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 57 (0.100 g, 0.337 mmol) in THF (5 mL), at 0° C. was added triethylamine (0.051 g, 0.506 mmol) and chloroacetylchloride (0.057 g, 0.506 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([I:13])=[CH:11][C:10]([N:14]3C(C)=CC=C3C)=[N:9]2)=[CH:4][CH:3]=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccc(Cl)cc2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cc(I)n(-c2ccc(Cl)cc2)n1
Temperature: 95 °C
Reaction time: 86 h
Yield: 55.5 %

Procedure:
To a suspension of 1-(4-chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1H-pyrazole (4.19 g) in ethanol/water (2/1, 72 ml) were sequentially added hydroxylammonium chloride (14.64 g) and triethylamine (2.9 ml) at room temperature, and the mixture was stirred at 95° C. for 86 hours. This reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added an 8M aqueous solution of sodium hydroxide, and then the mixture was extracted with ethyl acetate. This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=[C:15](O)[N:10]2[N:9]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:28].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:28][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(-c3ccccc3Cl)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)cc2n1
Temperature: 95 °C
Yield: 85.6 %

Procedure:
To a slurry of 2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (I-1A-3f; 700 mg, 2.70 mmol) and triethylamine (0.57 ml, 4.0 mmol) in toluene (30 ml) at room temperature was added POCl3 (1.3 ml, 14 mmol), dropwise. The mixture was heated at 95° C. for 21 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product (0.79 g). Purification on a Biotage™ Flash 40S column using 0–20% ethyl acetate in hexanes as eluant afforded I-1A-3g as an off-white solid (643 mg, 86%): +ESI MS (M+1) 278.12; 1H NMR (400 MHz, CD2Cl2) δ 7.96–7.93 (m, 1H), 7.54–7.51 (m, 1H), 7.50–7.35 (m, 2H), 7.15 (s, 1H), 6.90 (s, 1H), 2.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].[SH:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([S:40][C:41]1[CH:42]=[CH:43][C:44]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][CH:46]=1)=[O:12]
Reactant: CS(=O)(=O)Nc1ccc(S)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(SC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.5 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared with an analogous procedure to that described in Scheme 3, Step 1), (200 mg, 0.342 mmol) in DCM (10 ml), DMAP (41.7 mg, 0.342 mmol), and N-(4-mercaptophenyl)methanesulfonamide (83 mg, 0.410 mmol) were sequentially added. The mixture was stirred at RT for 4 hours, then the solvent was removed and the crude purified by flash chromatography on silica gel (DCM:MeOH 10:0.2). The resulting product was further purified by flash chromatography on silica gel (EtOAc:DCM 8:2) and the desired product was obtained (81 mg, 0.125 mmol, 36.5% yield, MS/ESI+ 649.28 [MH]+, [αD]=−59.64, c=0.44 in DCM).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2[nH]c3ccccc3n12
Reactant: CCCCCCBr
Product: CCCCCCn1c2ccccc2n2c(=O)c3ccc(Br)cc3nc12

Procedure:
3-Bromo-6-(n-hexyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-bromobenzimidazo[2,1-b]quinazolin-12(6H)one and n-hexyl bromide.
Reaction SMILES: C(OC([N:11]([CH2:32][CH2:33][O:34][CH3:35])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH3:35][O:34][CH2:33][CH2:32][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N(CCOC)C(=O)OCc3ccccc3)cn2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Oc2ccc(NCCOC)cn2)cc1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of ethyl 3-(4-{5[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl}propionate (1.82 g, 3.8 mmol) in ethanol-ethyl acetate (10 mL-10 mL) was added under a nitrogen atmosphere 10% palladium-carbon (0.2 g), and the resulting solution was stirred for 3 hours under a hydrogen atmosphere at atmospheric pressure. The palladium-carbon was filtered off through Celite, and the filtrate was evaporated to yield 1.23 g of the title compound.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:30])[CH:26]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[CH:32]=1>O1CCCC1>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[CH2:26][C:25]([CH:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[OH:38])([Br:30])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC2=C(C=CC(Br)(C(O)c3cccnc3)C2)C1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
8.8 ml of a solution of n-butyl lithium in hexane (2.5 mol) was dropped to a solution of 3.25 g of 2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydro-naphthaline in 50 ml of absolute tetrahydrofurane cooled to -70° C. and stirring was continued for 1.5 hours at -50° C. Subsequently, 1.1 g of pyridine-3-aldehyde were dropped into the mixture at -70° C. After stirring for one hour, the reaction mixture was poured on ice and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated. The obtained residue was recrystallised from cyclohexane/ethyl acetate.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:11]=2[CH:10]=[CH:9][C:8]1=[O:21].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[O:21]=[C:8]1[CH:9]=[CH:10][C:11]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=[CH:15][C:16]=2[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2c1ccc(=O)n2CC=O
Temperature: 25 °C
Reaction time: 11.5 h

Procedure:
22 mg of methyl 1-(1,3-dioxolan-2-ylmethyl)-1,2-dihydro-2-oxoquinoline-5-carboxylate was dissolved in 2 mL of 50% aqueous trifluoroacetic acid solution, and stirred at room temperature for 11.5 hours. After the reaction mixture was alkalized by adding aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate as a colorless oil.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH:10]=[N:11][NH:12][C:5]=12.Br[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>CN(C=O)C>[I:3][C:4]1[C:5]2[C:6](=[CH:10][N:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:12]=2)[N:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: Ic1ccnc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc3nccc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.5 %

Procedure:
Sodium hydride (55.2 mg, 1.379 mmol) was added to a solution of 7-iodo-1H-pyrazolo[4,3-b]pyridine (260 mg, 1.061 mmol) in DMF (1.5 mL) at 0° C., and the reaction was stirred for 5 minutes. tert-Butyl 4-bromopiperidine-1-carboxylate (364 mg, 1.379 mmol) was added and the reaction was warmed to room temperature and then heated at 65° C. for 2 hours. The reaction was cooled, quenched with water, and concentrated in vacuo. The residue was partitioned between saturated NH4Cl solution and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to afford a residue. The residue was purified with silica column chromatography eluted with hexanes/ethyl acetate step gradient (0-100% EtOAc over 45 minutes), to afford tert-butyl 4-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)piperidine-1-carboxylate (57 mg, 13%). The fractions containing tert-butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate were chromatographed again under the same conditions to give tert-butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate (60 mg, 13%). MS [M+H] found 429.2
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:29])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:27][OH:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:29])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[CH:27]=[O:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1CO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
A solution of oxalyl chloride (2.6 mL, 29.4 mmol) in dichloromethane (80 mL) at −78° C. was treated with a solution of dimethyl sulfoxide (4.3 mL, 60.8 mmol) in dichloromethane (10 mL) over 5 minutes. The mixture was stirred for 40 min, then treated with a solution of benzyl[(1R,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (5.0 g, 19 mmol) in dichloromethane (20 mL) over 5 minutes. The mixture was stirred for 45 minutes, then was treated with triethylamine (8.6 mL, 61.7 mmol) and allowed to warm to room temperature. After 60 minutes, the mixture was washed with water, then with brine, and dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography using 30% ethyl acetate in hexane to provide a white solid (4.8 g, 97%).