Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4](=[S:13])[NH:3]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=2)=[CH:17][C:16]=1[C:30]([F:33])([F:32])[F:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][S:13][C:4]3[NH:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2](=[O:1])[N:3]=3)=[CH:26][CH:27]=2)=[CH:17][C:16]=1[C:30]([F:31])([F:32])[F:33]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: CCOC(=O)c1c[nH]c(=S)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of ethyl 4-oxo-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (1.016 g, 5.07 mmol), 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (1.793 g, 5.58 mmol) and K2CO3 (0.771 g, 5.58 mmol) in DMF (15 mL) was heated with a microwave reactor at 80° C. for 0.5 h. The mixture was poured into 100 mL water and extracted with EA. The organic phase was dried over sodium sulfate, filtered, and concentrated to afford the title compound (2.461 g, 5.07 mmol, 100% yield). LCMS: rt=3.64 min, [M+H]=485
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[CH3:13][N:14]([CH3:42])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:18]1[C:39](O)=[O:40].C(N)CC.O>C(Cl)Cl>[CH2:4]([NH:3][C:39]([C:18]1[N:17]([CH2:16][CH2:15][N:14]([CH3:13])[CH3:42])[C:25]2[C:20]([C:19]=1[CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:40])[CH2:5][CH3:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)CCn1c(C(=O)O)c(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCCN
Product: CCCNC(=O)c1c(C(c2ccccc2)c2ccccc2)c2ccccc2n1CCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 59.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.45 g, 7.53 mmol) was added to a solution of Compound 93 (1.5 g, 3.76 mmol) obtained in Example 93 and propylamine (0.47 ml, 5.65 mmol) in 50 ml of methylene chloride, followed by stirring at room temperature for 4.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was purified with silica gel column chromatography (chloroform/methanol=40/1) followed by recrystallization from diisopropyl ether to give 0.98 g (yield: 59%) of the title compound.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)C.[O:17]=[C:18]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([CH:36]=O)[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1.O>O1CCCC1>[O:17]=[C:18]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32](/[CH:36]=[CH:7]/[C:6]([OH:5])=[O:16])[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1
Reactant: O=C[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in oil) (7 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (53 μl). After stirring at ambient temperature for 5 minutes, trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (250 μl), and 1M NaOH solution (176 μl) was added, then stirred at 110° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (176 μl) and pH 4 buffer (5 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylic acid (11.0 mg) as a brown powder.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N:18]1([S:22]([NH:25][C:26](=[O:36])[C:27]2[CH:32]=[C:31]([Cl:33])[C:30](F)=[CH:29][C:28]=2[F:35])(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19]1>CS(C)=O>[N:18]1([S:22]([NH:25][C:26](=[O:36])[C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([O:11][CH2:10][CH:7]3[CH2:6][CH2:5][C:4]4([CH2:1][CH2:2][CH2:3]4)[CH2:9][CH2:8]3)=[CH:29][C:28]=2[F:35])(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCC2(CCC2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CCC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
To a solution of spiro[3.5]nonan-7-ylmethanol (0.58 g, 3.76 mmol) in anhydrous dimethyl sulfoxide (20 mL) was added potassium t-butoxide (1.05 g, 9.35 mmol) at ambient temperature. After stirring at ambient temperature for 30 minutes, N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide (1.17 g, 3.76 mmol) was added to the reaction mixture; stirring was continued at ambient temperature for 2 hours. The mixture was cooled to 0° C. and quenched with 5% aqueous hydrochloride acid (10 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (2×40 mL) and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-40% ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as a colorless solid (0.60 g, 36%): 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=15.6 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 6.66 (d, J=13.8 Hz, 1H), 4.23 (t, J=7.8 Hz, 4H), 3.82 (d, J=6.3 Hz, 2H), 2.32-2.20 (m, 2H), 1.88-1.66 (m, 11H), 1.35-1.24 (m, 2H), 1.18-1.05 (m, 2H); MS (ES+) m/z 445.1, 447.1 (M+1), MS (ES−) m/z 443.2, 445.2 (M−1).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24][CH:25](O)[CH3:26]>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH:25]([CH3:26])[CH3:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CC(C)O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC(C)C)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.161 mL (2.1 mmol) of 2-propanol. MS (m/z, ES+): 366.30 (M+, 100%); 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.0 (p, 1H), 4.1 (t, 2H), 1.7 (p, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:14][C:15](=O)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:12])[O:11][CH2:14][C:15]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CCl
Reactant: COc1cccc(CC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(C2=C(C)COC2=O)c1
Yield: 78.3 %

Procedure:
A mixture of 3-methoxyphenylacetic acid (3.32 g, 20 mmol), chloroacetone (2.02 g, 22 mmol) and potassium carbonate (6.07 g, 44 mmol) in acetonitrile (30 mL) was heated at reflux for 5 hours. The resultant mixture was cooled to room temperature, diluted with ethyl acetate (60 ml), filtered through a silica gel pad, and washed with ethyl acetate (2×50 mL). The filtrate was concentrated in vacuo and the residue was treated with ether and hexanes to give a yellowish solid (3.2 g, 78% yield). 1H NMR (CDCl3):2.22 (s, 3H), 3.84 (s, 3H), 4.79 (s, 2H), 6.92 (m, 1H), 7.05 (m, 2H), 7.36 (m, 1H).
Reaction SMILES: N1C=CN=C1.C([O:9][C:10]1[CH:31]=[CH:30][C:13]([CH:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][C:19]([O:26]C(=O)C)=[CH:20][C:21]=3[CH3:25])[O:16][CH2:15]2)=[CH:12][CH:11]=1)(=O)C>C(O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][C:19]([OH:26])=[CH:20][C:21]=3[CH3:25])[O:16][CH2:15]2)=[CH:30][CH:31]=1
Reactant: CC(=O)Oc1ccc(C2COc3cc(OC(C)=O)cc(C)c3C2=O)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: Cc1cc(O)cc2c1C(=O)C(c1ccc(O)cc1)CO2
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Imidazole (0.63 g) was added to a suspension of 4′,7-diacetoxy-5-methylisoflavan-4-one (0.50 g, 1.4 mmol) in absolute ethanol (20.0 ml) and the mixture was refluxed for 45 min under argon. The solution was concentrated under reduced pressure and distilled water (10 ml) was added to the residue. The mixture was left overnight in the fridge and the resulting precipitate was filtered, washed with water and dried to yield 4′,7-dihydroxy-5-methylisoflavan-4-one (0.25 g, 66%) as a white powder. 1H NMR (d6-acetone): δ 2.51 (s, 3H, Me), 3.76 (t, 1H, J 5.7 Hz, H3), 4.57 (d, 2H, J 7.1 Hz, H2), 6.26 (d, 1H, J 2.2 Hz, H8), 6.35 (d, 1H, J 2.2 Hz, H5), 6.78 (d, 2H, J 8.7 Hz, ArH), 7.11 (d, 2H, J 8.7 Hz, ArH).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([NH2:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CCO.[OH-].[OH-].[Pd+2]>[N:11]1([N:14]=[CH:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][C:18]([F:29])([F:28])[F:17])=[CH:21][CH:22]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(C=NN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 4-benzylpiperazin-1-yl-amine (43.18 g, 225 mmol) in etanol (400 ml), a suspension of 20% palladium hydroxide/carbon (6.50 g) in etanol (30 ml) was added, and the mixture was stirred at room temperature under an atmospheric pressure of hydrogen for 3 hours and then at 50° C. for 2 hours. The reaction mixture was filtered through Celite, 4-(trifluoromethoxy)benzaldehyde (42.92 g, 225 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford piperazin-1-yl-(4-trifluoromethoxybenzylidene)amine (56.88 g, yield 93%) as a pale yellow crystalline powder.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH-].[Na+]>O1CCCC1>[CH3:24][S:25]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12][CH2:13]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Nc2ccc3[nH]ncc3c2)CC1
Yield: 21.5 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of the N-(4-piperidinyl)-1H-indazol-5-amine (0.300 g, 1.39 mmol) obtained in Example 15, (a) in tetrahydrofuran (5 ml) at room temperature, followed by adding thereto a solution of methanesulfonyl chloride (0.175 g, 1.53 mmol) in tetrahydrofuran (2 ml) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain N-[1-(methylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine (0.088 g, 22%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH2:26][C:27](O)=[O:28])[CH2:22][C:23](O)=[O:24]>C1(C)C=CC=CC=1.CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([B:15]3[O:17][C:27](=[O:28])[CH2:26][N:21]([CH3:20])[CH2:22][C:23](=[O:24])[O:16]3)=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Yield: 75.5 %

Procedure:
A slurry of (4-(4-fluorophenethoxy)phenyl)boronic acid (122 g, 469 mmol) and 2,2′-(methylazanediyl)diacetic acid (76 g, 516 mmol) in anhydrous toluene (500 mL) and DMSO (200 mL) was refluxed for 4 h. Then, cooled, diluted with EtOAc (500 mL), washed with water (5×200 mL), brine (2×100 mL), dried (MgSO4), filtered and concentrated to give light orange foam which was purified by flash chromatography using 5-40% acetone/CH2Cl2 (5% increment per 2-lit) to afford 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (131.38 g, 354 mmol, 75% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J=8.4 Hz, 2H), 7.28-7.24 (m, 2H), 7.04-6.99 (m, 2H), 6.92 (d, J=8.5 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.00 (d, J=16.6 Hz, 2H), 3.76 (d, J=16.6 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H), 2.54 (s, 3H). LCMS (M+H)=372.3.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3[CH2:35][CH2:34][O:33]C3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O1CCC[C@@H]1C(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([C@H:30]3[CH2:31][CH2:35][CH2:34][O:33]3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Agent: NNC(=O)[C@H]1CCCO1
Product: Cc1cc(C)c(-c2nnc([C@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using (R)-tetrahydrofuran-2-carbohydrazide (compound 133.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 446 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:7][C:8]=1[S:22]([Cl:21])(=[O:24])=[O:23]
Reactant: COc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(C)C)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of crude 1-methoxy-4-(propane-2-sulfonyl)benzene (8 mmol) in dry dichloromethane (20 mL), chlorosulfonic acid (1 mL) was added dropwise at 0° C. The reaction mixture was warmed to room temperature followed by the addition of PCl5 (0.5 g). The resulting reaction mixture was refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into ice water (50 mL) with vigorous stirring. The aqueous layer was then extracted with EtOAc (2×75 mL). The combined organic extracts was washed with saturated sodium chloride aqueous solution (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1) to give 1.25 g of 2-methoxy-5-(propane-2-sulfonyl)benzenesulfonyl chloride. 1H NMR (CDCl3, 400 MHz): δ 1.31 (d, 1H), 3.23 (m, 1H), 4.18 (s, 3H), 7.30 (d, 1H), 8.18 (dd, 1H). 8.46 (d, H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:15])[CH:7]=1.[CH:17](OC)=[O:18].CC(C)([O-])C.[K+]>C1COCC1>[OH:18]/[CH:17]=[C:4](/[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:15])[CH:7]=1)\[C:3]([O:2][CH3:1])=[O:16]
Reactant: COC(=O)CCc1cn(C)c2ccccc12
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C\O)Cc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1-methylindole-3-propionic acid methyl ester (700 mg, 3.22 mmol) and methyl formate (0.397 mL, 6.44 mmol) in THF (20 mL) was added potassium tert-butoxide (723 mg, 6.44 mmol). The mixture was stirred at room temperature for 1 h. concentration in vacuo then afforded the title compound. LCMS: rt=2.81 min, [M+H+]=246
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][N:40]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:9]=3)[N:7]=2)[CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Yield: 67 %

Procedure:
Following the procedures of Example 144, and starting with 3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate were reacted and purified via silica gel chromatography using a gradient of EtOAc in heptane to afford 241 mg (67%) of Methyl 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylate. ESI MS m/z 614.2 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:18])[CH3:17]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-5-(isopropyl-methyl-amino)-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M9;) (0.37 g, 0.70 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (219 mg, 76%).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[C:4](=[O:7])([O-])O.[Na+].CS(C)=O.[Si]([O:20][C:21]([C@H:24]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[C:42](=[O:43])[C:41]([CH2:44][C:45]4[CH:50]=[CH:49][C:48]([C:51]5[C:52]([C:57]#[N:58])=[CH:53][CH:54]=[CH:55][CH:56]=5)=[CH:47][CH:46]=4)=[C:40]([CH2:59][CH2:60][CH3:61])[N:39]=[C:38]3[CH2:62][CH3:63])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)([CH3:23])[CH3:22])(C(C)(C)C)(C)C>O>[CH2:62]([C:38]1[N:37]([C:34]2[CH:33]=[CH:32][C:31]([O:30][C@H:27]3[CH2:26][CH2:25][C@H:24]([C:21]([OH:20])([CH3:23])[CH3:22])[CH2:29][CH2:28]3)=[CH:36][CH:35]=2)[C:42](=[O:43])[C:41]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[C:57]3[NH:58][C:4](=[O:7])[O:2][N:3]=3)=[CH:49][CH:50]=2)=[C:40]([CH2:59][CH2:60][CH3:61])[N:39]=1)[CH3:63]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(O[C@H]3CC[C@H](C(C)(C)O[Si](C)(C)C(C)(C)C)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc(O[C@H]3CC[C@H](C(C)(C)O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.82 g), sodium hydrogen carbonate (1.2 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-{[trans-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexyl]oxy}phenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.48 g) was added, and the mixture was stirred at 90° C. for 8 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (5 mL), tetrabutylammonium fluoride (2.1 mL, 1.0 M tetrahydrofuran solution) was added and the mixture was heated under reflux for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.094 g, 21%).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([NH:15][CH3:16])=O)=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.O>C1(C)C=CC=CC=1>[F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([NH:15][CH3:16])=[S:35])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A mixture of 3 g (0.009 mol) of product of Example 201 and 7.28 g (0.018 mol) of Lawesson's reagent in 100 ml of toluene was refluxed for 16 days. The reaction mixture was cooled to 25° C., poured into H2O, and extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to 1.4 g of a brown oil. Chromatography using 10% ethyl acetate/cyclohexane as an eluting solvent afforded 0.35 g (11%) of product as a beige solid: mp 129°-131° C.