Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]O.[Br:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Yield: 89.4 %

Procedure:
3.1 g (13.6 mmol) of (3R,7R)-3,7,11-trimethyl-1-dodecanol are treated with 4.02 g (15.3 mmol) of N-bromosuccinimide and 2.62 g (14.7 mmol) of triphenylphosphine in 13 ml of methylene chloride according to the method described above in Example 10. After chromatography and distillation, there are obtained 3.54 g (90%) of (3R,7R)-bromo-3,7,11-trimethyldodecane. B.p. 90°/0.05 Torr; [α]D20 =-3.6 (c=1.005, n-octane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: CC(C)=CCBr
Reactant: Oc1cc(Nc2ccccn2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccccn2)ccc1Cl
Yield: 74 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-5-(pyridin-2-ylamino)phenol (34 mg, 0.15 mmol) and Cs2CO3 (51 mg, 0.16 mmol) in acetone (1.5 mL) was treated with 4-bromo-2-methyl-2-butene (0.017 mL, 0.15 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 74% yield (32 mg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[C:17]([O:19]CC3C=CC=CC=3)=[O:18])=[N:8][C:7]=2[CH:27]=1.[OH-].[Li+]>>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[C:17]([OH:19])=[O:18])=[N:8][C:7]=2[CH:27]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1c1nc2cc(C(F)(F)F)ccc2o1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2cc(C(F)(F)F)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from benzyl (2S)-1-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate [see Preparation 30] and 1N aqueous lithium hydroxide solution to afford (2S)-1-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2-piperidinecarboxylic acid as an oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=O)[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:45][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:26])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)CC
Yield: 87.1 %

Procedure:
2.47 g (0.007 mol) of N-[(9-fluorenyl)methoxycarbonyl]-L-isoleucine, 1.89 g (0.007 mol) of octadecylamine, 85.5 mg (0.0007 mol) of 4-(N,N-dimethylamino)pyridine (DMAP), and 1.61 g (0.0084 mol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) was dissolved in 45 ml of dichloromethane, and the resultant solution was stirred for 4 days at room temperature. Then, the obtained reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure, the resultant residue was subjected to re-crystallization treatment using ethyl acetate, and gel-like substance was subjected to a suction filtration, thereby obtaining 3.69 g of N-[(9-fluorenyl)methoxycarbonyl]-L-isoleucylaminooctadecane (hereinafter also referred to as “Intermediate product (1)”) at the yield of 87%.
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:24][CH:23]=[C:22]([C:25]([O:27]C)=[O:26])[CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.[OH-].[Na+]>>[NH2:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1c[nH]c(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)c1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1cc(C(=O)O)c[nH]1)C2

Procedure:
Upon saponification of methyl 5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrole-3-carboxylate (401 mg g, 1.0 mmol) with 1N sodium hydroxide (15 mL) as described in Example 11, there is obtained 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrole-3-carboxylic acid, mp >260° C.: 1H NMR (DMSO-d6) δ 11.49 (s, 1H), 10.12 (br s, 1H), 9.66 (s, 1H), 7.16 (s, 1H), 6.23 (s, 1H), 6.05 (s, 2H), 5.90 (s, 1H), 3.16 (brd, 1H, J=10.9 Hz), 2.78 (m, 1H), 2.63-2.40 (m, 2H), 1.77 (dd, 1H, J=15.2, 8.6 Hz), 1.69-1.43 (m, 3H).
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][C:2]=12.C([NH2:19])(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:19][C:6]1[N:1]=[C:2]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[C:3]2=[CH:4][CH:5]=1
Reactant: COC(=O)C1CCc2c1ccc[n+]2[O-]
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCc2nc(N)ccc21
Temperature: 0 °C

Procedure:
To a solution of methyl 6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate 1-oxide (700 mg, 3.6 mmol) in CF3-toluene (20 mL) and CHCl3 (20 mL) was added tert-butylamine (3.8 mL, 36 mmol). The solution was cooled to 0° C. in an ice bath. To the solution was added p-toluenesulfonic anhydride (3.5 g, 10.9 mmol) in small portions until all SM was consumed according to LC-MS. The volatiles were removed under reduced pressure, and the residue was redissolved in TFA (20 mL). The solution was heated to 70° C. for 2 hours. The reaction was stopped at that point. TFA was removed on a rotavapor, and the residue was taken up in saturated sodium carbonate, and extracted three times with IPA-CHCl3 (1:3, 50 mL each). The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (DCM:MeOH with 10% aq NH4OH). After removal of solvent the title compound was collected: LC-MS (IE, m/z): 193 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[N:42][C:43]([NH:46][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:44][CH:45]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2cc(Cc3ccccc3)c(=O)n(C3CCCC3)c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Cc5ccccc5)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Yield: 19.9 %

Procedure:
6-Benzyl-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.64 g, 1.74 mmol) and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.87 g, 2.96 mmol) in toluene (10 ml) were heated to 95° C. for 28 hours. The reaction mixture was allowed to cool then chromatographed on silica gel using a gradient of 20 to 50% ethyl acetate in hexane. The product-containing fractions were evaporated and the residue was triturated with acetonitrile to give a solid. This solid was collected by filtration and dried in vacuo to provide 4-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.201 g, 19.8%). MS (APCI) M++1: Calc'd, 582.31. Found, 582.3.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12](OCC)=O)=[O:10]>CO>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1cccnc1
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Yield: 38 %

Procedure:
Sodium (1.15 g) was dissolved in methanol (50 ml), and nitroguanidine (4.7 g) was added to the cooled solution. The mixture was heated under reflux for 45 minutes, ethyl 2-formyl-3-(3-pyridyl)propionate (9.3 g) was added portionwise and the mixture was heated under reflux for 45 hours and evaporated to dryness. Water was added to the residue and the mixture was extracted with chloroform. The aqueous phase was adjusted to pH 5 with acetic acid, and the solid which was precipitated was filtered off, washed and dried to give 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 214.5°-216°, in 38% yield.
Reaction SMILES: [OH:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:12]>CN(C=O)C>[CH3:12][O:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A 0° C. solution of methyl 1-hydroxycyclopropane-1-carboxylate (1 g, 8.61 mmol) in DMF (10 mL) was treated with NaH (60% in mineral oil, 0.689 g, 17.22 mmol), stirred at 0° C. for 0.5 h, treated with iodomethane (0.646 mL, 10.33 mmol), allowed to slowly warm to RT and stirred for 2 h. The mixture was quenched with satd. NH4Cl, diluted with water and extracted with Et2O (3×). The combined organics were washed with water, then brine, dried and concentrated to afford methyl 1-methoxycyclopropane-1-carboxylate (1.10 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 3.62 (s, 3H), 3.27 (s, 3H), 1.12-1.11 (m, 4H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH3:22].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCc1cc(-c2ccccc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCc1cc(-c2ccccc2)ccc1OC(C)=O
Yield: 90 %

Procedure:
4.6 g (45 mmol) of acetic anhydride are added dropwise to a solution of 7.3 g (37 mmol) of 4-hydroxy-3-ethyl-biphenyl and 3.2 g (40 mmol) of pyridine in 60 ml of chloroform, and the mixture is boiled under reflux for 3 hours. The solution is allowed to cool and then washed with water and dilute hydrochloric acid and the organic phase is dried and concentrated. 8.0 g (yield: 90% of theory) of 4-acetoxy-3-ethyl-biphenyl are obtained as a very clear oil of log p=3.92 (pH=2.3).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([NH:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][SH:16])(=[O:12])[CH:9]([CH3:11])[CH3:10]>>[CH3:10][CH:9]([CH3:11])[C:8]([NH:13][C@@H:14]([CH2:15][S:16][S:4][CH2:3][C@H:2]([NH2:1])[C:5]([OH:7])=[O:6])[C:17]([OH:19])=[O:18])=[O:12]
Reactant: CC(C)C(=O)N[C@@H](CS)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Product: CC(C)C(=O)N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O

Procedure:
The compound was prepared by the procedure given in Example 17, starting from L-cysteine and N-isobutyryl-L-cysteine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.Cl>CO>[CH2:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH2:1])[CH:3]=2)[CH:7]=[CH:6]1
Reactant: Nc1ccc2c(c1)CCC2O
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CC=C2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-amino-1-hydroxyindane (4.2 g, 0.26 mol) in methanol (100 mL) was added hydrochloric acid (100 mL, 1.0 N). The mixture was stirred at 40° C. for 2 h, and then was concentrated to dryness under vacuum to the product as gray powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].[CH:26]1([CH:33]=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1>[CH:26]1([CH:33]([OH:34])[CH:6]2[C:5](=[O:8])[C:4]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[C:3]([O:2][CH3:1])[CH2:7]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=CC1CCCCCC1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCCCCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a stirred solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (0.46 g, 2.0 mmol) in anhydrous THF (20 ml) at −78 C under an N2 atmosphere was added dropwise a solution of lithium diisopropylamide (1.22 ml of a 1.8M solution in THF/heptanes/ethyl benzene, 2.2 mmol). The reaction was stirred at −78 C for 90 minutes and then a solution of cycloheptanecarbaldehyde (316 mg, 2.5 mmol) in anhydrous THF (3 ml) was added dropwise. The reaction was stirred at −78 C for a further 30 minutes and then allowed to warm to room temperature over 30 minutes. The reaction was quenched by addition of H2O (25 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were washed with brine (15 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give a brown oil (628 mg). The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product as a colourless oil (101 mg).
Reaction SMILES: [CH2:1]1[C:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].[Pt].[Rh]>[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C1=C2CCCC2CCC1
Agent: [Pd]
Agent: [Pt]
Agent: [Rh]
Product: C1CCC2CCCC2C1

Procedure:
Hydrogenating the tetrahydroindane derivative with hydrogen in the presence of a palladium-, platinum-, or rhodium-containing hydrogenation catalyst to produce a perhydroindane derivative;
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][CH3:20])=[CH:6][N:5]=[CH:4][N:3]=1>P(Cl)(Cl)(Cl)=O>[CH2:19]([O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:9]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1)[CH3:20]
Reactant: CCOc1cc(OC)ccc1C(=O)Nc1cncnc1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(OC)ccc1-c1nc2ncncc2[nH]1

Procedure:
An amount of 2.3 g of 4-amino-5-(2-ethoxy-4-methoxybenzoylamino)-pyrimidine was refluxed in 20 ml of phosphorus oxychloride for 2.5 hours. The reaction mixture was poured on ice, and the solid product formed was filtered off. The filtrate was made alkaline by means of sodium bicarbonate and extracted with ethyl acetate. After evaporation of the ethyl acetate phases, the residue was combined with the solid product obtained above and purified by chromatography on silicagel (eluate: methylene chloride/ethanol in volume ratio of from 100:0 to 97:3).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([CH:14]3[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[C:17](=O)[CH2:16][O:15]3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([CH:14]3[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][O:15]3)=[CH:10][CH:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CCCN1CC(c2ccc(-n3c(C)ccc3C)nc2)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN1CCOC(c2ccc(-n3c(C)ccc3C)nc2)C1
Temperature: 25 °C

Procedure:
To a solution of the morpholin-3-one from example 42 (191 mg, 0.61 mmol) in dry THF (5 ml) was added lithium aluminium hydride (1M solution in diethyl ether) (1.25 ml, 0.61 mmol) and the reaction mixture was warmed to reflux for 2.5 hours. The reaction mixture was cooled to room temperature then 1M NaOH (1.25 ml) was added to give a white precipitate. The reaction mixture was filtered and concentrated in vacuo. The white solid was discarded. The concentrated filtrate was purified by column chromatography on silica eluting with dichloromethane:methanol (95:5) to give the title compound as a white film (108 mg, 0.36 mmol, 59%). 1H NMR (CDCl3, 400 MHz) δ: 0.92 (t, 3H), 1.61 (q, 2H), 2.10 (s, 6H), 2.15 (m 1H), 2.29 (dt, 1H), 2.40 (t, 2H), 2.82 (d, 1H), 3.02 (d, 1H), 3.90 (t, 1H), 4.08 (d, 1H), 4.71 (d, 1H), 5.89 (s, 2H), 7.20 (d, 1H), 7.81 (d, 1H), 8.60 (s, 1H). LRMS: m/z 300 (M-H+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:33]>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[C:8]([OH:9])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)Sc1ccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Sc1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Temperature: 110 °C
Yield: 87 %

Procedure:
A solution of (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-2-(4-isopropylsulfanyl-phenyl)-N-methyl-propionamide (830 mg, 1.89 mmol) in dioxane (10 mL) was treated with a 9 N aqueous sulfuric acid solution (6.0 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (100 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL). The organics were concentrated and then the residue dissolved in acetonitrile and silica gel (4 g) was added and it was concentrated in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-3-cyclopentyl-2-(4-isopropylsulfanyl-phenyl)-propionic acid (479 mg, 87%) as a yellow viscous oil: [α]28589=−52.3° (c=0.22, methanol); ES-HRMS m/e calcd for C17H24O2S (M+Na)+ 315.1389, observed 315.1388; 1H NMR JT (300 MHz, DMSO-d6) δ 1.07 (m, 2H, CH2), 1.22 (d, J=6.6 Hz, 6H, 2×CH3), 1.37-1.78 (m, 8H, 4×CH2), 1.94 (m, 1H, CH), 3.45 (m, 1H, SCH), 3.49 (d, J=7.5 Hz, 1H, ArCHCO), 7.25 (d, J=8.4 Hz, 2H, Ar), 7.32 (d, J=8.4 Hz, 2H, Ar), 12.35 (br, 1H, CO2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.Cl.NO.C[N:16](C=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:16]
Reactant: CN(C)C=O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: NO
Solvent: O
Product: COc1cc(C#N)ccc1O
Temperature: 140 °C

Procedure:
To a 3-necked 500 mL round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxy benzoaldehyde (50.2 g, 0.33 mole), hydroxylamine hydrochloride (25.5 g, 0.37 mole), and N,N′-dimethylformamide (40 mL) were successively added at 25° C., followed by heating in an oil bath at 140° C. for 1 hour. The reaction mixture was allowed to cool to 85° C., and water (250 mL) was added to yield 3-methoxy-4-hydroxybenzonitrile. The reaction mixture was further cooled to 10° C. for a complete precipitation, and the resulting solid was then isolated by filtration and dried under reduced pressure to yield a product as an off-white solid with a yield of 95% and a purity of higher than 99% as indicated by HPLC analysis.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.09 g, 0.3 mmol), 4-iodo phenyl acetic acid methyl ester (U.S. Pat. No. 6,252,090, 0.092 g, 0.33 mmol), triethyl amine (3 mL), copper(I)iodide (0.029 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.064 g, 0.09 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained as a yellow oil (0.085 g, 65%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[C@H:3]([OH:19])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[N:9]([CH3:18])[CH2:8][CH2:7]1.[C:29](N1C=CN=C1)(=[O:31])[CH3:30]>ClCCl>[F:27][C:25]1[CH:26]=[C:21]([CH:22]=[C:23]([F:28])[CH:24]=1)[CH2:20][C@H:2]([NH:1][C:29](=[O:31])[CH3:30])[C@H:3]([OH:19])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[N:9]([CH3:18])[CH2:8][CH2:7]1
Reactant: CC(=O)n1ccnc1
Reactant: CCc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCN2C
Solvent: ClCCl
Product: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCN2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]butan-2-ol (0.218 g) in dichloromethane (15 mL) was added 1-acetylimidazole (0.062 g). The mixture was stirred overnight at room temperature. The mixture was partitioned between dichloromethane and brine, and the organic was extracted three times, dried with sodium sulfate, filtered, and concentrated. A silica gel column was run for purification using 3% MeOH in dichloromethane with 0.5% NH4OH as the solvent solution. HPLC still showed small amounts of starting material present, so the mixture was washed one time with 1N HCl, dried with magnesium sulfate, filtered, and concentrated. 0.115 g of the title product were recovered. (48% yield). MS (ESI+) for C24H31F2N3O2 m/z 432.18 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(Cl)cc1C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
(Step 1) To a solution of 4-chloro-2-methylbenzoic acid (5.0 g) in methanol (40 ml) was added concentrated sulfuric acid at room temperature. The mixture was stirred at 70° C. for 3 hr, neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:19→3:7) to give methyl 4-chloro-2-methylbenzoate (5.05 g) as an oil.