Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]([F:20])([F:19])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:20])([F:19])[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
2-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (2.77 g, 8.8 mmol), 4-amino-3-methoxy benzoic acid (1.61 g, 9.6 mmol), i-PrOH (30 mL) and conc. HCl (30 drops) were heated to 95° C. for 18 hours. A this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid (2.74 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=12.13 Hz, 1H) 1.23-1.42 (m, 2H) 1.53-1.78 (m, 5H) 1.82 (d, J=12.63 Hz, 2H) 3.32 (s, 3H) 3.94 (s, 3H) 4.26 (t, J=12.38 Hz, 2H) 4.52 (t, J=11.62 Hz, 1H) 7.47-7.65 (m, 2H) 8.13 (d, J=8.08 Hz, 1H) 8.28-8.45 (m, 1H) 9.43 (br. s., 1H). [M+H] calc'd for C22H25F2N5O4, 462. found 462.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44][C@H:45]([CH3:53])[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([NH:44][C@@H:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH3:53])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Prepared using General Procedure 7. To a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (1000 mg, 1.762 mmol) and (R)-tert-butyl 2-aminopropanoate HCl (352 mg, 1.938 mmol) in DMF (8 mL). The solution was cooled to 0° C. and TEA (737 μl, 5.28 mmol) was added. To this mixture was slowly added HATU (804 mg, 2.114 mmol) over 5 mins then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with EA (150 mL) and washed with 1M HCl (100 mL) then brine (100 mL). The organic layer was isolated and dried over MgSO4. The solvents were removed to give a white solid and ACN (50 mL) was added and the suspension was sonicated. The fine suspension was stirred for 30 mins then filtered and washed with iso-hexanes to afford 881 mg (70.5%) of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-23 as a white powder. LCMS-ESI (m/z) calculated for C41H50N4O6: 694.4; no m/z observed, tR=3.39 min (Method 11). The chiral purity was calculated at >99% e.e. (Chiral Method).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:18](=[O:20])[CH3:19])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1C(C)=O
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A solution of 2′-aminoacetophenone (5.0 g, 37 mmol) in dichloromethane (150 mL) at room temperature was treated with triethylamine (5.3 mL, 40 mmol) and acetyl chloride (3.2 mL, 45 mmol), stirred for 3 hours, then washed with water. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined extracts were concentrated to provide the desired product (6.5 g, 100%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=2)O1.Br[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[Cl:35].[OH-].[Na+].Cl>C1(C)C(CCO)=CC=CC=1.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.C(O)C>[Cl:35][C:29]1[CH:30]=[C:31]([OH:34])[CH:32]=[CH:33][C:28]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=1
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: Cl
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2ccc(O)cc2Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
After a 2N aqueous sodium carbonate solution (12 ml) and tetrakis(triphenylphosphine)palladium (0) (504 mg, 0.436 mmol) were added to a solution of methyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (2.41 g, 8.73 mmol) obtained in Example (12-1) and 4-bromo-3-chlorophenol (2.17 g, 10.5 mmol) in a mixture of toluene-ethanol (5:1, 36 ml), the mixture was stirred at 110° C. for 8 hours. After the temperature of the reaction mixture was returned to room temperature and ethanol (12 ml) and a 1N aqueous sodium hydroxide solution (15 ml, 15 mmol) were added thereto, the mixture was stirred at 60° C. for 3 hours. The reaction mixture was poured into 0.5N hydrochloric acid and the mixture was extracted with ethyl acetate (three times). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=85/15-50/50) to give (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetic acid as a pale yellow powder (1.95 g, yield: 85%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([C:3](=[CH:17][N:18]([CH3:20])[CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1cc(F)ccc1F
Product: CN(C)C=C(C#N)C(=O)Nc1cc(F)ccc1F

Procedure:
As for Example 1, 2-cyano-2',5'-difluoroacetanilide, colorless crystals, m.p. 165°-167° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2-cyano-3-dimethylamino-2',5'-difluoroacrylanilide as colorless needles, m.p. 175°-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C(Cl)Cl>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([NH:6][C:24](=[NH:25])[C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=2)=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Reactant: COc1cccc(C#N)c1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(C(=N)Nc2c(C(C)C)cc(Br)cc2C(C)C)c1
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
One 2 L 3-neck flask was charged with 4-bromo-2,6-diisopropylaniline (19 g, 74.2 mmol) and toluene (200 ml). Trimethylaluminum (2M solution in toluene, 25 ml) was added dropwise into the reaction mixture at 0° C. After the addition was over, the ice bath was removed and reaction mixture was allowed to stir at room temperature (20-25° C.) for 3 hours. 3-methoxybenzonitrile (9.88 g, 74.2 mmol) in toluene (300 ml) was then added into reaction mixture. The reaction mixture was allowed to heated to 80° C. for 17 hours. The reaction mixture was poured slowly into a slurry of 200 gm of celite in 900 ml of a 2:1 mixture of DCM in methanol. The reaction mixture was then filtered and filtrate was evaporated to dryness, the residue was re-suspend with heptane and filtered to yield N-(4-bromo-2,6-diisopropylphenyl)-3-methoxybenzimidamide (19.73 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15](I)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[F:20][C:21]1([F:36])[CH2:26][CH2:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.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>[F:20][C:21]1([F:36])[CH2:26][CH2:25][C:24]([C:15]2[NH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][CH3:19])[C:9]=3[CH:16]=2)=[CH:23][CH2:22]1
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(F)(F)CC3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of Example 61A (129 mg, 0.528 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (129 mg, 0.528 mmol), and bis(triphenylphosphine)palladium(II) dichloride (28.5 mg, 0.041 mmol) in 10 mL dimethoxyethane/ethanol/water (7/2/3) was added sodium carbonate (129 mg, 1.219 mmol). The reaction was stirred at 100° C. for 2 hours, cooled and then extracted with ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate, water and brine, then dried over magnesium sulfate and concentrated. The crude material was triturated with ethyl acetate, and the solid was collected by filtration. The solid was purified via flash chromatography: Analogix Intelliflash™ 280, 24 g silica column, 20% to 60% ethyl acetate/hexanes gradient over 30 minutes to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H) 8.65-8.90 (m, 1H) 7.09-7.48 (m, 3H) 6.45 (s, 1H) 6.37 (s, 1H) 3.73-3.82 (m, 3H) 2.80 (t, J=14.19 Hz, 2H) 2.69 (t, J=5.95 Hz, 2H) 2.08-2.27 (m, 2H). MS (ESI+) m/z 360.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:26][CH:27]=1)[CH2:34][C:30]1[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=1
Reactant: CN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 112 %

Procedure:
The compound (116.3 mg) obtained in Example 44-6 was dissolved in methanol (5.81 ml) and added with 1-methyl-2-imidazole carboxaldehyde (52.0 mg) and sodium cyanoborohydride (39.6 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 6 days. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution, and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (163.4 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1ccsc1C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccsc1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 151.4 mg of the 3-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 157.8 mg (65%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]2[N+]([O-])=O)=[CH:6][C:5]=1[O:19][CH2:20][CH3:21])[CH3:2].[O-:22]CC.[Na+].Cl.NC(N)=O>C(O)C.O>[CH2:20]([O:19][C:5]1[CH:6]=[C:7]([CH:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C:11]2=[O:22])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:21]
Reactant: CC[O-]
Reactant: CCOc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OCC
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C2CC=CCC2=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
15.0 g of (+/−)-trans-1,2-diethoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissolved in 375 ml of ethanol and added dropwise to 42 ml of 20% strength sodium ethoxide solution. The mixture is stirred at RT for 20 min. and then added dropwise to an ice-cooled solution of 67.5 ml of conc. hydrochloric acid and 1.35 g of urea in 225 ml of water and 170 ml of ethanol. The solution is extracted with water/dichloromethane and the organic phase is dried with sodium sulfate and concentrated under reduced pressure. The residue is chromatographed over silica gel using petroleum ether/ethyl acetate in a ratio of 2/1. Concentration of the appropriate eluate fractions gives 10.33 g (77.1% of Th.) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[N:3]1[C:12]2[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1.[CH2:19]([OH:22])[C:20]#[CH:21].O.C(OC(C)C)(C)C>CC#N.[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>[CH3:1][N:2]([CH3:18])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:21]#[C:20][CH2:19][OH:22])=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: O
Solvent: CC(C)OC(C)C
Product: CN(C)n1cc(C(=O)O)c(=O)c2cc(C#CCO)ccc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 181.9 %

Procedure:
To a solution of 1-dimethylamino-6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2.77 g, 7.73 mol) in MeCN (70 ml), CuI (0.15 g, 0.773 mol) and TEA (37.5 ml, 270 mol) were added and stirred for 20 minutes and then warmed up to 50° C. To the reaction mixture propargyl alcohol (1.08 ml, 2.4 mmol) and Pd(PPh3)2Cl2 (0.27 g, 0.39 mol) were added and stirred at 50° C. for 3 hours. Then water (130 ml) and diisopropyl-ether (100 ml) were added, the pH was adjusted to 12, the layers were separated and H2O layer extracted with diisopropyl-ether (2×50 ml). To the water layer EtOH (14 ml) and charcoal were added, heated to the reflux temperature, and filtered through celite. Then the pH of H2O solution was adjusted to 6, extracted with DCM (200 ml), combined organic layers were evaporated to obtain the crude product. Precipitation from DCM-hexane afforded the title product (1.25 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[CH2:43]=O>>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:43][N:32]1[C@@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]
Reactant: CC[C@@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Reactant: C=O
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((R)-1-phenyl-propylamino)-propionic acid methyl ester (0.165 g) was treated with formaldehyde according to General Procedure V to give (3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (0.13 g). This was treated with LiOH in THF:MeOH (1:3) according to General Procedure B to give (3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (75 mg). LCMS (m/z): 604
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[N:8]([CH2:13][C:14]#[CH:15])[Si](C)(C)C.[CH3:18][N:19]1[C:27]2[N:26]=[CH:25][N:24]([CH2:28][CH2:29][CH3:30])[C:23]=2[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:38])[CH3:37])[C:20]1=[O:39]>CCCCCC.O1CCCC1>[NH2:8][CH2:13][C:14]#[C:15][C:36]([OH:38])([CH3:37])[CH2:35][CH2:34][CH2:33][CH2:32][N:21]1[C:22](=[O:31])[C:23]2[N:24]([CH2:28][CH2:29][CH3:30])[CH:25]=[N:26][C:27]=2[N:19]([CH3:18])[C:20]1=[O:39]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C#CCN([Si](C)(C)C)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
29 ml (46.5 mmol) of a 15% strength butyllithium solution in n-hexane were slowly added dropwise to a stirred solution of 9.26 g (46.5 mmol) of N,N-bis(trimethylsilyl)-2-propynylamine from stage C1 in 50 ml of tetrahydrofuran at -40° C. under argon. The mixture was then warmed to room temperature and again cooled to -40° C., and a solution of 14.25 g (46.5 mmol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 40 ml of tetrahydrofuran was slowly added. After removal of the cooling bath, the mixture was stirred at room temperature for 6 hours. The reaction mixture was then added to saturated ammonium chloride solution at 0° C., the aqueous phase was extracted with ether, the organic phase was dried over sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure. The crude product was subjected to flash chromatography first with the mobile phase mixture dichloromethane/methanol/saturated ammonia solution=19/1.5/2.5 and then with 9/1/2.5. Yield: 9.79 g (58% of theory); yellowish oil
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([OH:24])([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[ClH:1].[C:31]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([O:24][C:37](=[O:39])[CH3:38])([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OC1(Cc2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC1(Cc2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 24 h

Procedure:
A mixture of 1.0 part of 1-(3,3,3-triphenylpropyl)-4-hydroxy-4-benzyl piperidine hydrochloride, 10 parts by volume of pyridine and 3.0 parts by volume of acetic anhydride is allowed to stand for 24 hours. Volatile material is removed under reduced pressure and the resulting residue is partitioned between dilute sodium hydroxide and ether. The ether layer is separated, washed with water, dried over sodium sulfate and then treated with an excess of a solution of hydrogen chloride in 2-propanol. The solid which forms is separated by filtration and then washed successively with ether, water, and ether, and then air-dried to give 1-(3,3,3-triphenylpropyl)-4-acetoxy-4-benzylpiperidine hydrochloride and having the following structural formula ##STR19## Replacement of acetic anhydride with 3.0 parts of propionic acid anhydride provides 1-(3,3,3-triphenylpropyl)-4-propionyloxy-4-benzylpiperidine hydrochloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:28][CH:29]=[CH2:30])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C=CCN
Solvent: CC#N
Product: C=CCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), prop-2-en-1-amine (0.5 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. MS m/z (rel. intensity, 70 eV) 317 (M+, 2), 113 (3), 71 (5), 70 (bp), 68 (3) 63 (3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22].[NH2:24][CH2:25][CH2:26][SH:27]>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[S:27][CH2:26][CH2:25][N:24]=1
Reactant: NCCS
Reactant: COc1cc(SC)ccc1/C=C/C(=O)c1c(O)cc(C)oc1=O
Solvent: CCO
Product: COc1cc(SC)ccc1C1CC(c2c(O)cc(C)oc2=O)=NCCS1
Temperature: 80 °C
Yield: 41.6 %

Procedure:
4-Hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one (41.8 mg, 0.126 mmol), prepared as in Reference 5, Step 5.1, was dissolved in absolute ethanol (5 mL) and then 2-aminoethanethiol (9.8 mg, 0.126 mmol) was added to the solution. The mixture was stirred at 80° C. The progress of the reaction was followed by analytical HPLC and when complete (approximately 12 hours) the solvent was removed in vacuo. Product was purified by silica flash column chromatography to provide 4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one (20.5 mg) as a pale, yellow solid. LCMS: MH+ 392.6.