Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4]C)(C)=O.O(CC)[K].C1(O)C=CC=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C@H:29]([S:4][CH3:1])[C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:31])=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(=C[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CSC(C)=O
Agent: CCO[K]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CS[C@H]([C@@H](C)C(=O)OCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AcSMe (24.4 g, 0.27 mol) in THF (580 ml) cooled in an ice-bath was added KOEt (22.8 g, 0.27 mol). After stirring for 3.5 h at room temperature, phenol (11.9 ml, 0.14 mol) and a solution of (2S)-2-(2-benzyloxycarbonyl-propenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (15.6 g, 0.045 mol) in THF (50 ml) were successively added to the mixture. After 45 min, the mixture was quenched with saturated NH4Cl aqueous solution and concentrated in vacuo. The residue was diluted with EtOAc (600 ml), and washed with 1N NaOH aqueous solution (300 ml×3) and saturated brine (200 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc=9/1) to give (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester which was contaminated with PhOH. The collected fraction which included (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was washed with 5N NaOH aqueous solution (300 ml) and H2O (300 ml) to remove phenol, and dried over anhydrous MgSO4. The organic layer was concentrated in vacuo to obtain (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (12.5 g, 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:3]=1.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH:9]([O:8][C:6]1[N:7]=[C:2]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Reactant: CCCCNCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCN(CCCC)c1nc(OC(C)C)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 16 h

Procedure:
12.5 g of 2-chloro-4-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine and 5.5 g of dibutylamine are dissolved in 100 ml of xylene. After addition of a solution of 1.8 g of sodium hydroxide in 10 ml of water, the water is slowly removed by distillation in a water separator under a weak flow of nitrogen. The contents of the flask are subsequently stirred at 135° for about 16 hours. The mixture is allowed to cool somewhat, 50 ml of water are added to the contents of the flask and the mixture is stirred vigorously for 10 minutes. The aqueous phase is separated off and the organic layer is washed four times, each with 50 ml of water, dried over sodium sulfate and completely evaporated in vacuo. The 2-isopropyloxy-4-dibutylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine obtained is a weakly yellowish resin.
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](=[NH:37])[NH:35]O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[N:37]=[C:3]([CH2:2][OH:1])[O:5][N:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)CO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2noc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of hydroxy-acetic acid (1.67 g, 22 mmol), NEt3 (4.4 g, 44 mmol) in toluene (150 mL) was added isobutylchloroformate (6 g, 44 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (5.35 g, 22 mmol) was added to the mixture. The mixture was heated under reflux overnight, and then cooled to room temperature; the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was dissolved in THF (20 mL), and aqueous NaOH (10 mL, 10 mmol) was added. The mixture was stirred at room temperature for 2 hours and diluted with EtOAc (50 mL). The organic layer was washed with brine, after drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([I:16])C(=O)C1>>[I:16][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1I
Product: Cc1cc(N)ncc1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 2.0 g (18 mmol) 4-methyl-pyridin-2-ylamine and 4.2 g (18 mmol) NIS. Yield after precipitation from the reaction mixture: 3.6 g (83%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([OH:24])[CH:17]=2)=[CH:11][CH:10]=1)=[O:8].Br[CH:34]([CH2:40][CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C>[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([CH:17]=2)[O:24][CH2:41][CH2:40][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:11][CH:10]=1)=[O:8]
Reactant: CCOC(=O)C(Br)CC
Reactant: O=Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C=O)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(N(c2ccc(C=O)cc2)c2ccc(C=O)cc2)ccc1C=O
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
K2CO3 (1.1 g, 8.0 mmol, 10 eq.) is added to a solution of compound 10 (280 mg, 810 μmol) in dry DMF (12 mL). The reaction is stirred for 15 minutes and ethyl bromobutanoate (175 μL, 1.22 mmol, 1.5 eq.) is slowly added. The mixture is stirred for 24 hours at room temperature and then concentrated. The residue is taken up in dichloromethane and water. The two-phase mixture is allowed to separate by settling, and the organic phase is washed several times with water. After drying and concentrating, a solid is obtained which is purified by chromatography (elution with a methanol gradient from 0 to 1% in dichloromethane) to give 275 mg (530 μmol) of compound 11 in the form of an orange powder (yield: 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccc(C#N)cc2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of the product from Example G (1.0 g, 2.18 mmol) was dissolved in DMF and cooled to 0° C. The resulting solution treated with NaH (2.18 mmol) and was stirred for 1 hour at 0° C. and treated with α-bromo-p-tolunitrile (0.45 g, 2.30 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into a separatory funnel containing ethyl acetate (50 mL) and water (50 mL) and shaken. The organic phase was separated and washed with brine, dried, and concentrated to give the title compound (0.76 g, 61%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:39])[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][CH2:34]Br)[C:23]=1[CH2:36][CH2:37][CH3:38])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:39])[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][CH2:34][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:23]=1[CH2:36][CH2:37][CH3:38])[CH3:16]
Reactant: CCCc1c(OCCC(=O)OCC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 68.7 %

Procedure:
A mixture of 3.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.4 g of racemic-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]methylacetic acid ethyl ester and 4.3 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a red oil which was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to give 5.6 g (69%) of racemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylacetic acid ethyl ester as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15]C(C)(C)C)=[O:14])[C:8]2=[O:24])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C@@H:12]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:13]([OH:15])=[O:14])[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccc(O)cc2)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccc(O)cc2)C1=O
Yield: 100.9 %

Procedure:
A solution of Example 144B (0.04 g, 0.11 mmol) in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was twice azeotroped with ethyl acetate to give the crude title compound (0.034 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([N:36]([CH3:37])[C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(N(C)C(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11 mmol, 1.0 eq) is added at room temperature to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine (40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16 μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide as a yellow solid (22 mg, 35% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=O)=[N:6][C:7]=1[CH3:8].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[N:6][C:7]=1[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(C=O)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A 250 mL round-bottom flask was charged with 5-bromo-6-methylpyridine-2-carbaldehyde (4.90 g, 24.6 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (4.60 g, 24.7 mmol, 1.01 equiv), 1,2-dichloroethane (150 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (15.6 g, 73.6 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with water (50 mL), extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (30/70) to provide 7.80 g (82% yield) of tert-butyl 4[(5-bromo-6-methylpyridin-2-yl)methyl]piperazine-1-carboxylate as a light yellow solid. LCMS (ESI, m/z): 370 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:27][C:7]2[N:8]=[CH:9][N:10]=[C:11]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]3)[C:6]=2[CH:5]=1)[CH3:3]>ClCCl>[CH3:3][CH:2]([C:4]1[S:27][C:7]2[N:8]=[CH:9][N:10]=[C:11]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(OC3CCC(NC(=O)OC(C)(C)C)CC3)ncnc2s1
Solvent: ClCCl
Product: CC(C)c1cc2c(OC3CCC(N)CC3)ncnc2s1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
To a 100-mL round-bottom flask was added a solution of tert-butyl N-(4-[[6-(propan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexyl)carbamate (4.8 g, 12.26 mmol, 1.00 equiv) in dichloromethane (100 mL). Hydrogen chloride was bubbled through the solution. The resulting solution was stirred for 5 h at 0-10° C. The resulting mixture was concentrated under vacuum. This resulted in 3.6 g (90%) of 4-[[6-(propan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexan-1-amine hydrochloride as a yellow solid. MS: m/z 292 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CN1CCOCC1.[C:16]1(=[O:35])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28]O)[C:22](O)=[O:23])[C:19](=[O:30])[C:18]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:17]12.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[C:19]1(=[O:30])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH3:28])[C:22]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])[C:16](=[O:35])[C:17]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:18]12
Reactant: CCOC(=O)CN
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCC[C@@H](C(=O)NCC(=O)OCC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A slurry of glycine, ethyl ester, hydrochloride salt (2.718 g, 19.5 mmol.) in dimethylformamide (36 ml.) was treated with 4-methyl morpholine (2.60 ml., 2.39 g., 23.6 mmol.) and stirred at room temperature for 5 minutes. The mixture was then treated with (S)-2-phthalimido-6-hydroxyhexanoic acid (4.50 g., 16.2 mmol.) and hydroxybenzotriazole (2.225 g., 16.5 mmol.), cooled to 0° C., and then treated with ethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (3.438 g., 17.9 mmol.). After stirring at 0° C. for 1 hour and at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid and subsequently extracted three times with ethyl acetate. The pooled ethyl acetate extracts were washed in succession with water, saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 5.77 g. of title product as a colorless oil. TLC (ethyl acetate) Rf =0.34.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)[N:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-(5-Chloro-1H-indol-3-yl)ethanamine hydrochloride (0.044 g; 0.187 mmol), 6-(3-fluorobenzyl)picolinic acid (0.045 g; 0.196 mmol), HATU (0.073 g; 0.192 mmol) and N,N-diisopropylethylamine (0.082 mL; 0.466 mmol) in DMF (3 mL) was stirred overnight at room temperature and was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed three times with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% of ethyl acetate in dichloromethane) to give 0.053 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(3-fluorobenzyl)picolinamide as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccsc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccsc3)CC12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(3-thienyl)acetic acid (0.99 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.24 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 16 hours at 20° C., then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-thienyl)acetyl]-4-perhydroisoindolone (2.2 g) melting at 224° C. is obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
The title compound was prepared (0.029 g, 14%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dichlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.26 g, 0.56 mmol) and methylamine (0.174 g, 5.6 mmol). mp 169-171° C.
Reaction SMILES: C12(C3C=C[C:14]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=CC=3)CC3CC(CC(C3)C1)C2.N1C=CC=CC=1.[CH3:29][O:30]CC1COC(=O)O1>>[CH3:29][O:30][CH2:21][CH:20]1[O:19][C:18](=[O:22])[NH:17][CH2:14]1
Reactant: CCOC(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COCC1COC(=O)O1
Solvent: c1ccncc1
Product: COCC1CNC(=O)O1
Reaction time: 20 h

Procedure:
5.42 g (18.1 mmol) of ethyl 4-adamantan-1-yl-phenylcarbamate were treated with 1.43 g (18.1 mmol) of pyridine and 18.0 g (0.136 mol) of (RS)-4-methoxymethyl-1,3-dioxolan-2-one and stirred at 160° bath temperature for 20 hours. After cooling the reaction mixture was chromatographed on 500 g of silica gel 60 with ether. 1.4 g of (RS)-3-(4-adamantan-1-yl)phenyl]-5-methoxymethyl-oxazolidin-2-one were obtained as a white crystallizate after recrystallization from methylene chloride/ether. M.p.: 145°-147°.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B.C1C[O:21]CC1.B#B.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH:2]1([CH2:1][OH:21])[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]1
Reactant: C1CCOC1
Reactant: C=C1CCCCCCCCCCCCCC1
Agent: B
Agent: B#B
Agent: O=C([O-])[O-]
Solvent: O
Product: OCC1CCCCCCCCCCCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of the starting alkene 51 (1.5 g, 6.7 mmol) in THF (8 mL) was added dropwise to a cooled 1 M solution of BH3-THF (20.2 mL, 20.2 mmol). The reaction was stirred at 0° C. for 1 h and then allowed to stir for 2 h at room temperature. Excess diborane was decomposed by dropwise addition of water (10 mL). A 3 M solution of NaOH (10 mL) was then added, followed by dropwise addition of 30% H2O2 (10 mL). The reaction was stirred for 1 h at room temperature and K2CO3 (100 mg) was then added. The layers were then separated and the aqueous layer was extracted three times with CH2Cl2, the organic layers were pooled, dried over Na2SO4, then filtered and concentrated. After column chromatography (Rf=0.31, 50% hexanes/50% CH2Cl2) 52 was isolated as a yellow oil (1.2 g, 74%). 1H NMR (CDCl3) δ 3.49 (t, 2H), 1.53 (m, 1H), 1.41-1.22 (m, 28H); 13C NMR (CDCl3) δ 67.0, 39.5, 29.6, 27.5, 27.0, 26.7, 26.6, 26.5, 25.0.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:47]=[C:45]1[C:44]2[C:43](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:42](=[O:52])[N:46]1[CH2:2][C@@H:3]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1C(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 1,1-dimethylethyl ((1S)-2-hydroxy-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate (4.2 g, 13.2 mmol), triphenylphosphine (4.5 g, 17.1 mmol) and phthalimide (1.9 g, 13.2 mmol) in THF (66 mL) at 25° C. was added diethyl azodicarboxylate (2.7 mL, 17.1 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue purified on silica gel (1% MeOH in DCM) affording the title compound (3.2 g, 54%) as a white solid: LCMS (ES) m/z 449 (M+H)+.