Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23].O.Cl>N1CCCCC1.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)c(F)cc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(C#CCCCO)c(F)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 455.2 %

Procedure:
A mixture of 3.04 g (9.67 mmol) 5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester, 670 mg (0.58 mmol) Pd(PPh3)4, and 111 mg (0.58 mmol) CuI in 25 ml of piperidine was heated to 60° C., treated with 1.61 ml (1.80 mmol) 4-pentyne-1-ol and stirred at 80° C. for 2 hrs. After cooling to room temperature the mixture was poured into water, acidified with 2M aqueous HCl and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2 gave 2.6 g (85%) of 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butyl ester as a viscous orange oil, MS: 318 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[C:35]([O:34][C:32]([NH:31][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:39])=[O:2])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)C(Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoic acid methyl ester (125 mg, 0.24 mmol) in THF (2 mL) and methanol (2 mL) was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring at room temperature for 1 h the solution was acidified with 10% HCl to pH 2 and diluted with ethyl acetate (25 mL). After being seperated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoic acid (80 mg, 67%) as white solid. 1H NMR (CDCl3), 7.98 (d, J=9 Hz, 2 H), 7.93 (d, J=8 Hz, 2 H), 7.74 (d, J=9, 2 H), 7.59 (m, 4 H), 7.41 (m, 5 H), 5.01 (d, J=8 Hz, 1 H), 4.66 (m, 1H), 3.30 (m, 2 H), 1.47 (s, 9 H). LCMS 408 (M+−100).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]=[CH:8][C:7](=[O:13])[C:6]=2[NH:5][C:4](=[O:14])[CH:3]=1.CN(C)[N:17]=[CH:18][C:19]([CH2:21][CH3:22])=[CH2:20]>C(Cl)(Cl)Cl>[CH2:21]([C:19]1[CH:20]=[C:9]2[C:8](=[N:17][CH:18]=1)[C:7](=[O:13])[C:6]1[NH:5][C:4](=[O:14])[CH:3]=[C:2]([CH3:1])[C:11]=1[C:10]2=[O:12])[CH3:22]
Reactant: Cc1cc(=O)[nH]c2c1C(=O)C=CC2=O
Reactant: C=C(C=NN(C)C)CC
Solvent: ClC(Cl)Cl
Product: CCc1cnc2c(c1)C(=O)c1c(C)cc(=O)[nH]c1C2=O
Yield: 30.2 %

Procedure:
A solution of 150 mg (0.9 mmol) of 4-methyl-1H-quinoline-2,5,8-trione and 150 mg (0.79 mmol) of 2-ethylacrolein dimethylhydrazone in dry chloroform (130 ml) was stirred at room temperature for five minutes. After evaporation of the solvent, the residue was purified by silica gel chromatography using ethyl acetate as eluent to yield 29 mg of the starting hydrazone, 64 mg (30%) of 5 and 60 mg of 6-dimethylamino-4-methyl-1H-quinoline-2,5,8-trone.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH2:17][CH2:18][C:19](=[O:25])[NH:20]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=C(C)C=C(C)C=1>[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2c(cccc2OCCCCS(=O)(=O)c2ccccc2)N1
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Product: O=c1ccc2c(OCCCCS(=O)(=O)c3ccccc3)cccc2[nH]1
Reaction time: 3.5 h

Procedure:
100 mgm of 5-(4-phenylsulfonyl-butoxy)-3,4-dihydro-carbostyril were refluxed with 30 mgm of palladium-on-charcoal and 1 ml of mesitylene. After 3.5 hours, another 30 mgm of palladium-on-charcoal were added, and the mixture was heated for 9 hours more. Subsequently, the reaction mixture was filtered while still hot, the filtrate was evaporated, and the residue was chromatographed on a silica gel column with a mixture of benzene/ethanol/conc. ammonia=75/25/3. Besides unreacted starting material, 9 mgm of 5-(4-phenylsulfonyl-butoxy)-carbostyril were obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)O1.Br[C:21]1[N:22]=[C:23]([C:28]2[O:29][C:30]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:31]=3[N:32]=2)[C:24]([NH2:27])=[N:25][CH:26]=1>C1(C)C=CC=CC=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[N:22][C:23]=1[C:28]1[O:29][C:30]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:31]=2[N:32]=1
Reactant: CC1(C)OB(c2cccc(CC(=O)O)c2)OC1(C)C
Reactant: Nc1ncc(Br)nc1-c1nc2ccc(F)cc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2cccc(CC(=O)O)c2)nc1-c1nc2ccc(F)cc2o1
Temperature: 85 °C
Yield: 12.7 %

Procedure:
A mixture of 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (85 mg), 5-bromo-3-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine (100 mg) in toluene-dioxane (1 ml-1.5 ml) and 2M aqueous sodium carbonate (5 ml) was degassed. Pd(dppf)Cl2 (24 mg) was added. The resulting mixture was heated to 85° C. for 6 hours. 1-Butanol (5 ml) was added to the mixture and the mixture was washed with brine (3×5 ml). The resulting organic layer was concentrated and purified by chromatography on silica gel eluting with a gradient of methanol in ethyl acetate to give the title compound (15 mg) as a solid. NMR Spectrum: (DMSOd6, 400 MHz) 7.25 (m, 2H), 7.30 (m, 1H), 7.40 (m, 1H), 7.90 (m, 6H), 8.80 (s, 1H); Mass spectrum: M+H+ 365.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>ClCCl.CO.C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:25][CH3:26])=[CH:37][CH:36]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(C)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 2.2 %

Procedure:
A mixture of 160 mg (0.45 mmol) of 3-(2-chloro-6-methylphenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution each time, dried over magnesium sulfate, filtered and evaporated. The residue was purified further by HPLC. The mobile phase was water/0.1% trifluoroacetic acid (A) and acetonitrile/0.07% trifluoroacetic acid (B); the gradient was 5%-95% B over 20 minutes; and the product was detected using an ultraviolet detector at a wavelength of 215 nm. Product-containing fractions were lyophilized and the lyophilisate was dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution each time, dried over magnesium sulfate, filtered and evaporated to give 5 mg (2%) of 3-(2-chloro-6-methylphenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow gum. [Mass spectrum (ESI) MH+ =495].
Reaction SMILES: [CH2:1]([N:3]([CH2:55][CH3:56])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:54])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[C:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][OH:53])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2]>[Pd].CO>[CH2:55]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:54])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][OH:53])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:56]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C#CCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 841.5 %

Procedure:
A mixture of 2-(5-(diethylamino)-2-(3-(1-hydroxy-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzamido)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (107 mg, 0.014 mmol) and 10% palladium on carbon (water content 50%, 40 mg) in methanol (3 mL) was stirred under one atmosphere of H2 for 1 hour. The mixture was filtered and concentrated under vacuum to give the title compound (92 mg). 1H NMR (400 MHz, CDCl3, ppm) δ□ 12.13 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 8.39 J=9.0 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.69 (dd, JAB=5.1 Hz, JAC=1.4 Hz, 1H), 7.64 (s, 1H), 7.63-7.54 (m, 3H), 7.47 (t, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H), 7.67 (dd, JAB=9.0 Hz, JAC=2.3 Hz, 1H), 4.74 (d, j=6.1 Hz, 2H), 3.66-3.56 (m, 14H), 3.53-3.51 (m, 2H), 3.48 (t, J=6.5 Hz, 2H), 3.32 (quar, J=7.0 Hz, 4H), 2.96 (br s, 1H), 2.77 (t, J=7.2 Hz, 2H), 1.98-1.91 (m, 2H), 1.13 (t, J=6.9 Hz, 6H). MS (ES, m/z): 781.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cccc(Br)c1C

Procedure:
A solution of 3-bromo-2-methylbenzoic acid (9.95 g) and conc. sulfuric acid (0.2 ml) in methanol (50 ml) was stirred at room temperature for 69 h and heated under reflux for 96 h. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution and concentrated. The residue was diluted with ethyl acetate, washed 3 times with 1N aqueous sodium hydroxide solution and with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10.2 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[CH:44]=[C:43]([CH3:45])[O:42][N:41]=1>CC(C)=O.C(OCC)(=O)C>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([O:1][CH2:39][C:40]2[CH:44]=[C:43]([CH3:45])[O:42][N:41]=2)[CH:20]=1)[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3C)c2)nc1
Reactant: Cc1cc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cc(OCc3cc(C)on3)cc(OCc3ccccc3C)c2)nc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 135.2 %

Procedure:
Methyl 6-{[3-hydroxy-5-(2-methylbenzyloxy)benzoyl]amino}-3-pyridinecarboxylate (150 mg, 0.38 mM), potassium iodide (13 mg, 0.08 mM) and potassium carbonate (56 mg, 0.41 mM) in acetone (3 ml) were heated to 55° C. and a solution of 3-chloromethyl-5-methyl isoxazole (55 mg, 0.421 mM) in acetone (2 ml) was added. The reaction was stirred for 1 hour at 55° C. and a further addition of 3-chloromethyl-5-methyl isoxazole (33 mg, 0.25 mM) in acetone (1 ml) was made. The reaction was stirred for 24 hours at 55° C. before being allowed to cool to ambient temperature. Ethyl acetate (15 ml) was added and the resulting mixture was washed with 1N aqueous HCl (10 ml), saturated aqueous sodium bicarbonate solution (10 ml) and water (10 ml). The solvent was removed under reduced pressure to give methyl 6{[3-(2-methylbenzyloxy)-5-(5-methylisoxazol-3-ylmethoxy)benzoyl]amino}-3-pyridinecarboxylate as a white solid (252 mg); H1 NMR δ (d6-DMSO) 2.24 (3H s) 2.26 (3H s) 3.85 (3H s) 5.08 (2H s) 5.15 (s 2H) 6.28–6.35 (1H m) 6.88 (1H s) 7.17–7.43 (7H, m), 8.29 (1H s), 8.9 (11H d). MS [MH]+488
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[C:9](=[O:17])[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[OH:20]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([C:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]=2[OH:17])=[O:20])=[CH:18][CH:19]=1
Reactant: CC1(C)CC(=O)C(SCc2ccc(F)cc2)=C(O)C1
Reactant: OO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)Cc2ccc(F)cc2)=C(O)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(p-fluorobenzylthio)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (12.4 g., 0.0443 mole) 30 percent hydrogen peroxide (5.0 g., 0.044 mole) and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 24 hours. The solution was poured into ice water and the precipitated pink crystals were filtered and dried (12.3 g., m.p. 122°-125°C.).
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH3:30])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:29][CH3:30])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC[C@H](NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CC[C@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 188 h

Procedure:
To a solution of tert-butyl {(3S)-1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]pyrrolidin-3-yl}carbamate (the product from step ii), 0.75 g) in DCM (10 ml) was added TFA slowly. The reaction then stirred at room temperature for 188 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield: 70 mg
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:32]([NH2:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:32]([NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[CH:17]=2)[CH2:19]1)=[O:26])[CH3:33]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 8.3 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), ethylamine (11 mg, 0.236 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 25-35% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (8.8 mg, 8%). Melting point (227.8-228.7° C.). 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.05 (t, J=5.4 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.56-7.65 (m, 2H), 7.41 (s, 1H), 6.36 (d, J=2.3 Hz, 1H), 4.31 (br. s., 2H), 3.29 (dd, J=12.0, 10.5 Hz, 2H), 2.93-3.17 (m, 4H), 1.92 (br. s., 1H), 1.77-1.87 (m, 1H), 1.73 (br. s., 2H), 1.45 (s, 6H), 1.02 (t, J=7.3 Hz, 3H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Temperature: 2.5 °C

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (6.5 g, 0.049 mol) in concentrated sulfuric acid (118 ml) cooled to 0° C. was added a solution of concentrated nitric acid (4.9 ml) in concentrated sulfuric acid (12 ml) dropwise over 0.3 h so as to maintain the temperature at 0-5° C. On completion of addition, the reaction mixture was poured onto crushed ice then neutralised with solid potassium carbonate. EtOAc (500 ml) was added and the mixture was filtered to remove undissolved solids then extracted with further EtOAc (4×500 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 5% EtOAc/60-80° C. petroleum ether gave the title compound as an orange solid (5.46 g). 1H NMR (250 MHz, CDCl3) δ(ppm): 7.40 (dd, 1H), 7.26 (d, 1H), 7.02 (d, 1H), 4.16 (br, 1H), 3.35 (m, 2H), 2.81 (t, 2H), 1.95 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].S(=O)(=O)(O)[OH:12].[K].S(=O)(O)[O-].[Na+]>CCOCC.O>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:12])=[O:4]
Reactant: CCCCCCC(C)CO
Reactant: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(C)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To 21.2 g (147 mmol) of (-)-2-methyloctanol were added an aqueous solution of 330 ml of water and 46.4 g of concentrated sulfuric acid, which was stirred to form an emulsion. To this emulsion was added dropwise 63.4 g (401 mmol) of potassium permaganate over 7 hours. Then, the reaction mixture was added with 51.5 g of sodium bisulfite and poured into 270 ml of ice water together with 70 ml of ice water and 200 ml of ether. After the separation into two layers, the reaction product was extracted from the aqueous layer with ether, which was further extracted with a 10% aqueous solution of sodium hydroxide, added with ice and further with a concentrated hydrochloric acid to adjust the pH to not more than 1. Thereafter, the extraction with chloroform on the aqueous layer was performed, which was washed with water, dried on magnesium sulfate and filtered. The filtrate was concentrated and distilled under a reduced pressure to obtain 16.5 g (yield: 71%) of a colorless and transparent liquid of (+)-2-methyl octanoic acid.
Reaction SMILES: C(=O)=O.C([Sn](CCCC)(OCCCC)[O:9][Sn:10]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])CCC.[CH2:33](O)[CH2:34][CH2:35][CH3:36]>>[CH2:20]([Sn:10]([CH2:16][CH2:17][CH2:18][CH3:19])([O:9][CH2:33][CH2:34][CH2:35][CH3:36])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCO
Reactant: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Agent: O=C=O
Product: CCCCO[Sn](CCCC)(CCCC)OCCCC
Reaction time: 0.22 h
Yield: 37.5 %

Procedure:
From the gas supply line 29, 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) was fed at 566 g/Hr and carbon dioxide was fed at 3 NL/Hr. All of the 1-butanol was vaporized by the heat exchanger 30 and fed to the reactor lower portion 33. A feed pump was used to start supplying the starting material 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane prepared in the same manner as in Example 12 from supply line 26 at 280 g/Hr and the reaction solution 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) from supply line 27 at 1,330 g/Hr. The holding time in the reactor was 13 minutes. The liquid temperature inside the reactor was 140° C., and the pressure of the back pressure valve 37 was adjusted to 0.096 MPa-G. Continuous supply was continued in this state for 10 hours, after which the system reached a steady state. Low boiling point components flowed from the reactor upper portion 32 and through the low boiling point component recovery line for liquefaction at the condenser 35, and were thereby recovered from the liquid-phase recovery line 39 at 1,006 g/Hr. Furthermore, from the reactor lower portion 33 a dibutyltin alkoxide-containing component was recovered at 1,170 g/Hr from the extraction line 40. Analysis of the liquid recovered from the generated product extraction line 40 showed that, using dibutyltin oxide as a reference, the liquid contained a dibutyltin alkoxide consisting of a yield of about 37.5% dibutyl-di(butyloxy)tin and 62.4% of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane. Tributyltin butoxide had a yield of 0.022%. Meanwhile, the liquid recovered from the liquid-phase recovery line 39 was transparent and contained 2,200 ppm of moisture. The dehydration rate in the column reactor was 0.39 mol/Hr, which was greater than the value 0.0015 mol/Hr calculated from expression (16).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.[OH-].[Na+]>Cl>[CH3:6][C:7]1[C:12]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Cc1ncccc1Oc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: Cc1ncccc1Oc1ccc(N)cn1

Procedure:
A solution of 14.35 g of tin chloride in 30 ml of concentrated hydrochloric acid is added to a mixture of 5 g of 2-(2-methylpyrid-3-yloxy)-5-nitropyridine and the whole is heated at reflux for 1 hour. The reaction mixture is cooled and adjusted to basic pH by the addition of concentrated sodium hydroxide solution. After the removal of a precipitate by filtration, the aqueous phase is extracted with ethyl acetate. After conventional working up, the expected product is isolated in the form of a violet powder.