Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:60]([C:59]2[O:55][N:56]=[CH:57][CH:58]=2)=[O:61])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(Cl)c1ccno1
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(C(=O)c2ccno2)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 60% yield. LCMS for C27H26ClN8O4 (M+H)+: m/z=561.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([O:33]CC)=[O:32])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([OH:33])=[O:32])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 64.4 %

Procedure:
To a solution of ethyl 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetate (0.09 g, 0.2 mmol, obtained in example 32) in EtOH (4.2 mL), a solution of KOH (0.09 g, 2.5 mmol) in water (0.5 mL) was added. This was heated to reflux for 1 h. It was allowed to cool and concentrated. The residue was dissolved in a mixture of EtOAc and water. The phases were separated. The aqueous phase was acidified and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness, to afford 57 mg of title compound (yield: 66%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=1)([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)[CH3:6].[OH-].[Na+].Cl>C(O)C>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=2)([CH3:6])[CH2:4][C:3]([OH:29])=[O:2])=[CH:8][C:9]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)CC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(C(C)(CC(=O)O)c2ccc(O)c(C(C)(C)C)c2)ccc1O
Temperature: 25 °C

Procedure:
200 g of 3,3-bis(4'-hydroxy-3'-tert.-butylphenyl)butanoic acid methyl ester (m.p. 82° C) were added to a solution of 40 g of sodium hydroxide in 600 ml of ethanol and the mixture was refluxed. After cooling to room temperature, the mixture was acidified with hydrochloric acid. The alcohol was removed by distillation and the solid residue was dissolved in hot toluene. The hot solution was filtered. Upon cooling, the 3,3-bis(4'-hydroxy-3'-tert.butyl-phenyl)butanoic acid precipitated from the toluene solution, m.p. 156° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[OH:11])[CH:6]=[O:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH3:29].C(Cl)Cl>CN(C=O)C.O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[O:11][CH2:27][CH2:28][CH3:29])[CH:6]=[O:7]
Reactant: CCCBr
Reactant: CSc1cc(C=O)cc(OCc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OCc2ccccc2)cc(C=O)cc1SC
Reaction time: 8 h

Procedure:
64.5 g of 3-Methylthio-4-hydroxy-5benzyloxybenzaldehyde dissolved in a 75 mL of DMF was treated with 50 g of K2CO3 and 32 g of 1-bromopropane and stirred overnight at 70°. The next day about 1.5 liters of methylene chloride and an equal amount of water was added to the reaction mixture. The organic layer was removed, washed three times with distilled water, dried over MgSO4 and evaporated to a viscous liquid that solidified slowly: NMR(200 MHz, CDCl3) δ 1.02 (t, CH2CH2CH3), 1.82(m, CH2CH2CH3), 2.48(s, SCH3), 4.12(t, OCH2CH2CH3), 5.18(s, OCH2Ar), 7.26-7.52(m, ArH), 9.86(s, ArCHO).
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>ClCCl>[N:10]1([CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1ccnc1
Yield: 54.9 %

Procedure:
To 1.95 g (0.013 mole) of pivaloyloxymethyl chloride, dissolved in 20 ml of dichloromethane, were added 1.76 g (0.026 mole) of imidazole. The reaction mixture was refluxed for 32 hours, then was cooled and filtered. The filtrate was concentrated in vacuo to give an oil which was triturated with 100 mL of ether. The ether was decanted and concentrated in vacuo to give 1.30 g (55% yield) of the desired ester: IR (neat) 1720 cm-1 (s) (C=O); NMR (CDCl3) δ 7.7 (s, 1, N=CH--N), 7.07 (s, 2, N--CH=CH--N), 5.9 (s, 2, N--CH2 --O2C), and 1.17 (s, 9, (CH3)3C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[CH:11]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:12].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>O1CCOCC1.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>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[CH:11]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(c1cc2ccsc2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(c1cc2ccsc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 2-(1-(6-chlorothieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (300 mg, 0.875 mmol), 2-(tributylstannyl)pyridine (340 μL, 1.05 mmol, 1.2 eq) and tetrakis(triphenylphosphine)palladium(0) (101 mg, 0.0875 mmol, 0.1 eq) was dissolved in 10 mL of dioxane under nitrogen. The reaction was heated to 100° C. for 2 days, cooled to rt and concentrated in vacuo. Purification by column chromatography using ethyl acetate/hexanes afforded 2-(1-(6-(pyridin-2-yl)-thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. LC/MS (M+1, found=386.0). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.66 (ddd, J=4.9, 1.6, 0.8 Hz, 1H), 7.76 (td, J=7.8, 1.8 Hz, 1H), 7.73-7.62, series of m, 5H), 7.57 (d, J=5.9 Hz, 1H), 7.36 (d, J=5.9 Hz, 1H), 7.31 (ddd, J=7.2, 4.7, 1.4 Hz, 1H), 6.33 (q, J=7.2 Hz, 1H), 1.99 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N1CCCC1
Temperature: 85 °C
Yield: 61.2 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41.3 mg, 0.098 mmol) and pyrrolidine (0.024 mL, 0.293 mmol) in DMSO (0.8 mL), heating at 85° C. for 40 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-(pyrrolidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21.0 mg, 0.060 mmol, 62% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (1H, br. s.), 7.90 (1H, dd, J=7.4, 1.2 Hz), 7.58 (1H, dd, J=7.9, 1.1 Hz), 7.34 (1H, t, J=7.8 Hz), 7.11 (1H, d, J=2.2 Hz), 6.96 (1H, s), 3.71-3.85 (4H, m), 3.42 (2H, td, J=6.8, 2.3 Hz), 2.86 (2H, t, J=6.8 Hz), 2.79 (3H, s), 1.94-2.05 (4H, m). m/z (ESI, +ve) 348.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:19]2[CH2:20][CH2:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Clc1nccc(I)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1nccc(N2CCC(c3ccccc3)CC2)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (4 g, 14.605 mmol), 4-phenylpiperidine (3.532 g, 21.907 mmol) and DIPEA (5.088 ml, 29.209 mmol) in CH3CN (150 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution). The resulting mixture was extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH/EtOAc gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D14 (2.32 g, 52%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>C(O)C.O>[CH:1]1([CH2:6][CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NCCC2CCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCC2CCCC2)cc1

Procedure:
A solution of 2 g. of ethyl p-[2-(cyclopentyl)ethylamino]benzoate in 50 ml. of ethanol:water (9:1) containing 2 g. of potassium hydroxide is stirred at the reflux temperature under argon atmosphere for 3 hours. The chilled solution is acidified with concentrated hydrochloric acid, diluted with 45 ml. of water, and filtered to furnish 1.52 g. of white crystals. Recrystallization from ethanol/hexane provided product as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]4=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]4[N:25]=[C:24]3[CH3:34])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:34][C:24]1[N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:17][CH:18]=2)[C:27]2=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 4-[4-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-ylmethyl)phenylamino]methylpiperidine-1-carboxylic acid tert-butyl ester (1.53 g, 3.31 mmol) obtained in Step 1 in chloroform (15 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (7.0 mL) followed by stirring at room temperature for 2 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 157 (1.20 g, 3.3 mmol, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(F)c(F)c2[nH]1
Product: CCOC(=O)c1cc2ccc(F)c(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=383.3 (M+H+), was prepared in accordance with the general method of example 12b) from 6,7-difluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
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]O>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][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: CO
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)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 0.083 mL (2.1 mmol) of methanol. MS (m/z, ES+): 339.34 (M+1, 100%).
Reaction SMILES: Cl.[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[CH3:13]>>[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH2:10])=[CH:5][C:4]=1[CH3:13]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Br
Agent: Cl
Product: Cc1cc(N)cc(C)c1Br
Temperature: 50 °C

Procedure:
153 g of tin dichloro dihydrate (678 mmol) are added to 1.7 l of conc. HCl and heated to about 50° C. 26 g (113 mmol) of 2-bromo-1,3-dimethyl-5-nitrobenzene (Example II) are added. The suspension is heated at about 70° C. for 20 min. It is then allowed to cool slowly to room temperature. The precipitated white solid is filtered off and washed with cold acetone. The resulting hydrochloride is taken up in 1 N NaOH, briefly stirred and extracted 5 times with ethyl acetate. The organic phases are combined and dried over sodium sulphate, and the solvent is removed in vacuo.
Reaction SMILES: C(OC(N[C@H](C(O)=O)C(C)C)=O)(C)(C)C.C(OC(N[C@@H](C(C)C)C(=O)C=[N+]=[N-])=O)(C)(C)C.[C:33]([O:37][C:38]([NH:40][C@@H:41]([CH:47]([CH3:49])[CH3:48])[CH2:42][C:43](OC)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([NH:40][C@@H:41]([CH:47]([CH3:49])[CH3:48])[CH2:42][CH2:43][OH:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)[C@@H](CCO)NC(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)-(L)-valine was converted to (S)-3-(tert-butoxycarbonylamino)-1-diazo-4-methylpentan-2-one according to Method B6a, Step 1. The diazo compound was converted to methyl (R)-3-(tert-butoxycarbonylamino)-4-methylpentanoate according to Method B6a, Step 2. The ester was reduced according to Method B6a, Step 3 to give (R)-3-(tert- butoxycarbonylamino)-4-methylpentan-1-ol. The carbamate was deprotected and converted to (R)-3-amino-1-chloro-4-methylpentane according to Method B7e. The 3-chloropropylamine was treated with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazine. The thiazine was alkylated with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazine HCl salt.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[N:9]([Si](C(C)(C)C)(C)C)[CH:10]=[CH:11][C:3]=12.C([Li])(C)(C)C.[C:24](=[O:26])=[O:25]>O1CCCC1>[Cl:8][C:5]1[C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]([C:24]([OH:26])=[O:25])=[CH:7][N:6]=1
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(Br)cnc(Cl)c21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-1-(tert-butyl-dimethyl-silanyl)-7-chloro-1H-pyrrolo[2,3-c]pyridine (500 mg) in dry tetrahydrofuran (25 ml) at −78° C. under an atmosphere of nitrogen was added tert-butyllithium (1.7M in pentane, 1.88 ml). After addition, the reaction mixture was stirred for 15 minutes at −78° C. then poured onto crushed pellets of carbon dioxide. The mixture was allowed to warm to room temperature and then evaporated. The residue was dissolved in water and the aqueous washed twice with diethyl ether. The aqueous was then acidified with 2M hydrochloric acid and extracted twice with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give the title compound as a yellow solid (120 mg).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[CH3:19][C:20]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:21]=1[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[CH3:15][C:11]([NH:10][C:9]1[C:8](=[O:16])[C:7](=[O:17])[C:6]=1[NH:23][CH2:22][C:21]1[C:20]([CH3:19])=[CH:27][C:26]([CH3:28])=[CH:25][C:24]=1[CH3:29])([CH3:14])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1cc(C)c(CN)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2c(C)cc(C)cc2C)c(=O)c1=O
Yield: 42.2 %

Procedure:
Tetrahydrofuran (15 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol), 2,4,6-trimethylbenzylamine hydrochloride (0.928 g, 5 mmol, Example 9, Step 2) and triethylamine (0.506 g, 5 mmol) were stirred together at room temperature for 3 days. The mixture was then prepared as in Example 9, Step 3. Three recrystallization of the crude product from acetonitrile provided 0.664 g of the title compound as a white solid: mp 284°-5° C. (dec) (softens 282° C.). MS (m/z) 314 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([OH:16])[C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:19])=[N-]>CCOCC>[OH:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([OH:16])[C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: CCCCCc1cc(O)c(C(=O)O)c(O)c1
Solvent: CCOCC
Product: CCCCCc1cc(O)c(C(=O)OC)c(O)c1
Reaction time: 0.17 h

Procedure:
A solution of 2,6-dihydroxy-4-pentylbenzoic acid (2.0 g, 8.9 mM) in ether was treated with a 0.3 M solution of diazomethane in ether (30 mL) and stirred for 10 minutes. Nitrogen was bubbled through the solution for 10 minutes and then glacial acetic acid (4 drops). The reaction was concentrated under reduced pressure and purified by chromatography (5% ethyl acetate in hexanes) to give the desired product. MS ESI(−)) m/e 237 (M−H)+; 1H NMR (300 MHz, CDCl3) δ 9.62 (bs, 2H), 6.33 (s, 2H), 4.06 (s, 3H), 2.50 (t, 2H), 1.64-1.55 (m, 2H), 1.34-1.27 (m, 4H), 0.92-0.87 (m, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH3:23])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C([O-])([O-])=O.[K+].[K+]>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH3:31][S:32]([O:1][C@H:2]([CH3:23])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H](Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C)OS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (R)-6-(2-hydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (925 mg, 2.95 mmol) in DCE (16 ml) was added triethylamine (2.05 ml, 14.8 mmol), DMAP (36 mg, 0.29 mmol) and methanesulfonyl chloride (1.15 ml, 14.8 mmol) at 0° C. and reaction stirred for 30 min. Solid K2CO3 was added to the reaction mixture and the resulting mixture was diluted with water and extracted with DCM (3×20 ml) The organics were passed through a hydrophobic frit and concentrated in vacuo to yield a yellow oil. The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11].O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)c1coc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(C(=O)O)co3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 2-[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]-4-oxazolecarboxylate (i.e. the product of Example 9, Step E) (665 mg, 1.87 mmol) was dissolved in 5 mL tetrahydrofuran, and 3.3 mL of water was added. The reaction mixture was cooled to 0° C. with vigorous stirring. A 1 N aqueous sodium hydroxide solution (3.7 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated sodium chloride solution (4 mL), washed with diethyl ether, and the aqueous phase was acidified to pH 3-4 by dropwise addition of 20% citric acid solution. The precipitated solid was filtered and dried to give 490 mg of the title compound. 1H NMR (DMSO-d6) δ 1.55 (m, 2H), 2.0 m, 2H), 2.14 (s, 3H), 2.23 (s, 3H), 2.85 (m, 1H), 3.1-3.3 (m, 2H), 3.65 (m, 2H), 3.9 (m, 1H), 4.35 (m, 1H), 6.8-7.1 (m, 3H), 8.66 (s, 1H), 13.0 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([N:9]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[N:8]2)=[CH:23][CH:22]=1)(=[O:25])=[O:26]
Reactant: CCOC(=O)CCc1cc(-c2ccccc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(CCCO)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
To a solution of ester 17 (1.27 g, 4 mmol) in 40 mL of THF was added LiAlH4 (0.24 mg, 6.4 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAC (5 mL) and water (10 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes=7:3) to give the titled compound (0.97 g, 85%) as a white solid mp 119.5-123.4° C. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H), 7.43-7.37 (m, 3H), 7.31-7.25 (m, 2H), 6.56 (s, 1H), 4.52 (t, J=5 Hz, 1H), 3.54-3.46 (m, 2H), 3.24 (s, 3H), 2.79-2.60 (m, 2H), 1.88-1.77 (m, 2H).