Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:42])=[CH:4][C:5]([O:40][CH3:41])=[C:6]([CH:39]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][N:13]([CH:16]([CH3:36])[CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][C@H:11]1[O:37][CH3:38])=[O:8].ClCCl.[C:46](Cl)(=[O:50])[CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[Cl:42][C:3]1[C:2]([NH:1][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[CH:39][C:6]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:36])[CH2:17][C:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:12][C@H:11]2[O:37][CH3:38])=[O:8])=[C:5]([O:40][CH3:41])[CH:4]=1
Reactant: CCCC(=O)Cl
Reactant: COc1cc(Cl)c(N)cc1C(=O)N[C@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C(=O)N[C@H]2CCN(C(C)CC(C(=O)N(C)C)(c3ccccc3)c3ccccc3)C[C@H]2OC)c(OC)cc1Cl
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a stirred solution of 6.52 parts of cis-4-[(5-amino-4-chloro-2-methoxybenzoyI)amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1piperidinebutanamide in 195 parts of dichloromethane were added 2.6 parts of butanoyl chloride. After stirring for 15 minutes, 2.94 parts of N,N-diethylethanamine were added. The whole was stirred overnight at room temperature. The reaction mixture was washed successively with a sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.39 parts (46.5%) of cis-4-[[4-chloro-2-methoxy-5-[(1-oxobutyl)amino]benzoyl]amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 130.7° C. (compound 65).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=2)[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=2)[CH:18]=1)[CH2:30][CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1CCNCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC=O
Product: CCN(CCC1CCCN1C(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 106 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 445.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.C[O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:3]([CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:13][CH2:14][CH2:15][O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([OH:30])=[O:21])([OH:2])=[O:19]
Reactant: COC(=O)c1cccc(O)c1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2cccc(C(=O)O)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 3-hydroxybenzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H22O7 [M+Na]+: 397.4.
Reaction SMILES: [C:1]([Si:5]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[O:6][CH:7]1[C:11]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:12][O:13][N:14]=[CH2:15])[O:10][CH:9]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[CH:8]1[OH:43])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>N1C=CC=CC=1>[C:1]([Si:5]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[O:6][CH:7]1[C:11]([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:12][O:13][N:14]=[CH2:15])[O:10][CH:9]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[CH:8]1[O:43][S:60]([CH3:59])(=[O:62])=[O:61])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(OS(C)(=O)=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
The mesylation of hydroxyl groups proceeds readily under these conditions (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 150-160 and references cited therein). Briefly, to a solution of Compound 17 in a 1:1 mixture of anhydrous dichloromethane and anhydrous pyridine is added methanesulfonyl chloride (1.2 eq.). After stirring at room temperature for several hours, this mixture is quenched with methanol, concentrated, diluted with dichloromethane, washed with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography will yield Compound 18.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[Cl-].[CH2:33]([O:35][C:36](=[O:48])[CH:37]([OH:47])[CH:38]([NH3+:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:34].[N:49]1[N:50]([C:58]2[N:66]=[CH:65][CH:64]=[CH:63][C:59]=2[C:60](O)=[O:61])[CH:51]=[C:52]2[C:57]=1[CH:56]=[CH:55][CH:54]=[CH:53]2>ClCCl>[N:49]1[N:50]([C:58]2[N:66]=[CH:65][CH:64]=[CH:63][C:59]=2[C:60]([NH:46][CH:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]([OH:47])[C:36]([O:35][CH2:33][CH3:34])=[O:48])=[O:61])[CH:51]=[C:52]2[C:57]=1[CH:56]=[CH:55][CH:54]=[CH:53]2
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)c1cccnc1-n1cc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h
Yield: 56.5 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.748 g, 4.60 mmol) and Et3N (1 ml, 7.17 mmol) were successively added to a suspension of 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride (1.303 g, 5.02 mmol) and 2-(2H-indazol-2-yl)nicotinic acid (1 g, 4.18 mmol) in dichloromethane (75 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (750 μl, 5.41 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and poured into 100 ml of water. The precipitate formed was filtered off with suction and dried in vacuo to give 1.05 g of the title compound as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]#[CH:19]>C1COCC1>[CH3:13][C:12]([O:14][CH2:19][C:18]#[CH:17])([CH3:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(O)COCc1ccccc1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOC(C)(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a mixture of NaH (5.0 g) in THF (50 mL) at 0° C. was added 1-(benzyloxy)-2-methylpropan-2-ol (9.36 g, 51.9 mmol) dropwise. After being stirred at room temperature for 0.5 h, 3-bromoprop-1-yne (12.4 g, 104 mmol) was added slowly at 0° C. The mixture was then stirred at reflux overnight. The reaction was quenched by addition of sat. NH4Cl. The resulting mixture was extracted with ethyl acetate (30 mL×3). The organic layer was combined, dried over with Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (20/1) to afford the title compound (9.72 g, 86%) as pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.34-7.35 (m, 5H), 4.56 (s, 2H), 4.18 (d, J=2.0 Hz, 2H), 3.38 (s, 2H), 2.34 (t, J=2.0 Hz, 1H), 1.25 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH2:12])=[C:7]([CH3:13])[CH:6]=1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH:12][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])=[C:7]([CH3:13])[CH:6]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: CNC(=O)Oc1cc(C)c(N)c(C)c1
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1c(C)cc(OC(=O)NC)cc1C

Procedure:
Following the procedure of Example 22, 3,5-dimethyl-4-aminophenyl N-methylcarbamate (0.8g., 0.004 mole) was reacted with n-propanesulfonyl chloride (0.60g., 0.0042 mole) in pyridine. The product (0.8g.) melted at 173°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])=[C:8](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])[CH:7]=1>[Pd].O1CCCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])=[C:8]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(OCCCCCOC(C)=O)c(/C=C/C(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCCCCCOC(C)=O)c(CCC(=O)OC)c1

Procedure:
Catalytic hydrogenation of 10.17 g (26.04 mmol) of (E,E)-3,3'-[4-[[5-(acetyloxy)pentyl]oxy]-1,3-phenylene]bis-2-propenoic acid dimethyl ester from the preceding example was carried out using 2.03 g of 10% palladium on carbon, in 125 mL of dry tetrahydrofuran, at room temperature and 1 atmosphere. After filtration of the catalyst and concentration of the filtrate, the title compound was obtained in quantitative yield, as a pale-yellow oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: CC(C)O
Reactant: C[C@H]1O[C@@H](C(Cl)(Cl)Cl)OC(=O)[C@@H]1C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2R, 5R, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by procedures similar to (1)-(4) of Example 1 were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol and stirred at room temperature for one hour, and 20 ml of water was added to effect ether extraction. After drying the ether phase over anhydrous sodium sulfate, the ether was distilled off and the residue was subjected to distillation to give 0.4 g of isopropyl (2R, 3R)-2-methyl-3-hydroxybutanoate. The NMR chart is shown in FIG. 6. ##STR44##
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][CH2:5][C:4](=O)[N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CC(C[AlH]CC(C)C)C.[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:38](=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.OC1N(C(OC(C)(C)C)=O)C(C)(C)CC1>CCOCC.C1(C)C=CC=CC=1.ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:25]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:38](=[O:47])[C@H:39]([C@H:4]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([CH3:15])([CH3:1])[CH2:6][CH2:5]1)[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1(C)C
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)OC(=O)N1C(O)CCC1(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Cl)cc2)CCC1(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
tert-Butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (1.17 g, 5.49 mmol) was dissolved in Et2O (15 mL) and cooled to −78° C. The solution was treated with DIBAL-H (3.73 mL, 5.60 mmol). The mixture was stirred at −78° C. for 2 hours and then warmed to ambient temperature overnight. The reaction was quenched by addition of an aliquot (7 mL) of a solution of p-toluenesulfonic acid hydrate (0.012 g) in MeOH (12 mL). The mixture was stirred at ambient temperature for 60 hours. The suspension was concentrated in vacuo and re-suspended in a mixture of Rochelle's salt (0.5N) and ethyl acetate. After separation, the aqueous portion was washed with ethyl acetate (2×). The combined organics were then washed with saturated NaCl, dried over Na3SO4 and concentrated in vacuo to an oil (92%). A solution of titanium(IV) chloride (3.71 mL, 3.71 mmol) in toluene was cooled to 0° C. and treated with a solution of (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (1.11 g, 3.38 mmol) dissolved in dichloromethane (7 mL). After 5 minutes, diisopropylethylamine (0.647 mL, 3.71 mmol) was added. The resultant solution was stirred for 1 hour at 0° C. and then cooled to −20° C. A solution of tert-butyl 5-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (1.09 g, 5.06 mmol) in dichloromethane (7 mL) was added, and the mixture was stirred at −20° C. for 75 minutes. The reaction was quenched with saturated NH4Cl (about 4 mL) and diluted with water to dissolve the solids. After separation, the aqueous portion was washed with methylene chloride (3×). The combined organics were washed with water (2×), dried over Na3SO4 and concentrated in vacuo. The crude product was subjected to chromatography on SiO2 and eluted with 9:1 hexanes/ethyl acetate to produce (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.62 g, 61%). MS (ESI+) [M+H] 526.7/528.8.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[NH2:23])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.CCOC(C)=O>C1COCC1>[O:11]=[C:10]1[NH:23][C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[NH:14][CH2:13][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Cc1cc(C)c(N)c(NC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c2c(c1)NC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A 0° C. solution of (2S)-2-tert-butoxycarbonylamino-3-(2-amino-3,5-dimethylphenyl-amino)-propionic acid (763 mg, 2.36 mmol) and N-methylmorpholine (483 mg, 4.78 mmol) in 60 ml of anhydrous THF was treated dropwise with isobutylchloroformate (352 mg, 2.5 mmol). The reaction was stirred for 2 h at 0° C., at RT for 1 h and poured over EtOAc. The mixture was washed with aq. 5% NaHSO4, sat. aq. NaHCO3, and sat. aq. NaCl, dried over NaSO4, and concentrated in vacuo. Chromatography (flash, SiO2, 10% to 25% to 50% EtOAc/CH2Cl2) gave 490 mg (68%) of the desired product.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+]>>[CH2:1]([O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 104 gms. (0.348 moles) of arachidyl alcohol, 46 gms. (0.362 moles) of benzoic acid and 225 mgms. stannous oxalate was heated under nitrogen to 230° C. The reaction was held at 230° C. for two hours under nitrogen. The acidity was 10 mgms. KOH/gms. The mixture was then cooled to 100° C. During the reaction distillate was collected. The ester formed was solid at room temperature and showed solidication at 80° C. The ester was given a treatment at 85° C. with 50 gms. deionized water containing 2 gms. sodium carbonate, 2 gms. sodium chloride and 1 gm. hydrogen peroxide. The mixture was allowed to stand and separate. The top layer was washed with 50 gms. deionized water at 80°-85° C., separated and cooled. The top layer solidified and bottom layer was completely drained off. The ester was then vacuum stripped at 100°-105° C. The ester so formed was a white solid benzoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=2)[CH3:13])=[C:4]([CH3:28])[N:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=3)=[CH:18][CH:19]=2)[CH3:13])=[C:4]([CH3:28])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 115 °C
Yield: 26.1 %

Procedure:
A solution of 2.0 grams (0.005 mole) of 2,4-diamino-5-[4-(4-trifluoromethylsulfonyloxyphenyl)pentyl]-6-methylpyrimidine (prepared in Step K of this Example), 2.4 grams (0.015 mole) of 3,5-difluorophenylboronic acid, and 0.3 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 90 mL of N,N-dimethylformamide was stirred, and 3.5 grams (0.025 mole) of potassium carbonate was added in one portion. Upon completion of addition, the reaction mixture was warmed slowly to 115° C. where it was maintained for about 40 hours. The reaction mixture was cooled and poured into 250 mL of water. The mixture was then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with three 150 mL portions of an aqueous 10% lithium chloride solution and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on neutral alumina (deactivated with 6% wt/wt water), using 2-10% methanol in methylene chloride as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.5 gram of 2,4-diamino-5-[4-[4-(3,5-difluorophenyl)phenyl]pentyl]-6-methylpyrimidine, mp 129°-134° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C[O-].[Na+].Br.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1.P(=O)(O)(O)O>C(O)C>[OH:4][CH2:3][CH2:2][S:1][CH2:15][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: OCCS
Reactant: BrCc1ccncc1
Agent: Br
Agent: C[O-]
Agent: O=P(O)(O)O
Solvent: CCO
Product: OCCSCc1ccncc1
Reaction time: 1 h

Procedure:
In an alternative procedure, 2-mercaptoethanol (11.9 g., 0.152 mole) was dissolved in 138.5 ml. of absolute ethanol and cooled to 18° C. Sodium methoxide (15.7 g., 0.291 mole) was added; the temperature rose to 38° C. and a clear solution resulted. The reaction mixture was cooled somewhat and, while maintaining the temperature below 30° C., 4-picolyl bromide hydrobromide (35 g., 0.138 moles) was added portionwise over 10 minutes. The reaction mixture was then heated to reflux and refluxed for 80 minutes. The reaction was concentrated to a thick mass, which was dissolved in 140 ml. of water and extracted twice with 140 ml. of ethyl acetate. Salt was dissolved in the aqueous phase during the second extraction. The combined ethyl acetate extracts were back washed twice with 150 ml. of 1 N NaOH, dried over anhydrous magnesium sulfate, filtered, and concentrated to about half-volume. While maintaining the temperature between 30° and 35° C., phosphoric acid (12.0 g., 0.122 moles) was added very slowly to directly precipitate crude product as the dihydrogen phosphate salt, recovered by filtration after stirring for 1 hour. The crude was recrystallized from absolute ethanol, yielding purified 4-(2-hydroxyethylthiomethyl)pyridinium dihydrogen phosphate (14.0 g.).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[NH:16][S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])=[O:5])C.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([NH:16][S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:19])=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a mixed solution of ethyl-4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.88 g) in tetrahydrofuran (20 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.56 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (777 mg, yield 96%) as colorless crystals. melting point>280° C. (decomposition).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[C:45]3[C:44]4[C:39](=[CH:40][C:41]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:43]=4)[NH:38][C:37]=3[N:36]=[C:35]([CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]([OH:62])[C:58]([F:61])([F:60])[F:59])[CH:52]=3)[N:34]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[C:45]3[C:44]4[C:39](=[CH:40][C:41]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:43]=4)[NH:38][C:37]=3[N:36]=[C:35]([CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57](=[O:62])[C:58]([F:59])([F:61])[F:60])[CH:52]=3)[N:34]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(O)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (56.5 mg, 0.133 mmol) was added to methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (20 mg, 0.036 mmol) in DCM (753 μL) to give a white suspension. After stirring at 20° C. for 1 hour the mixture was purified by flash chromatography to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate as Example 33 (18.4 mg, 92% yield) as a yellow solid: 1H NMR in DMSO-d6 was consistent with the desired product but complicated because of the presence of hydrate forms; HRMS m/z 554.2384 (M+H)+; HPLC >95%, RT=1.76 and 1.87 minutes (ketone+hydrate).