Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCCCC(=O)O)CCc2ccc(C#N)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 798 mg (1.48 mmol) of ethyl 7E-8-[2-(4-tert-butylbenzyloxy)phenyl]-6-[2-(4-cyanophenyl)ethyl]oct-7-enoate in 20 ml of THF and 20 ml of water is mixed with 71 mg (2.97 mmol) of lithium hydroxide and stirred at 50° C. for 12 hours. Cooling is followed by dilution with water and diethyl ether and separation of the phases. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 700 mg (1.4 mmol, 93% of theory) of the title compound are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:11]([NH2:12])=[C:10]([F:13])[C:9]([CH3:14])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:11]([NH:12][C:1](=[O:3])[CH3:2])=[C:10]([F:13])[C:9]([CH3:14])=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cl)c(N)c1F
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(Cl)ccc(C)c1F

Procedure:
Acetylchloride (2.56 mL, 36.0 mmol) was added to a mixture of 6-chloro-2-fluoro-3-methyl-aniline (5.00 g, 31.3 mmol) and toluene (200 mL), additional toluene (50 mL) was added and the mixture was heated to reflux for 3 h. The reaction mixture was cooled with an ice bath and the formed precipitate was filtered off, washed with cold toluene and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][S:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(O)C.O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: N#CSCC(=O)c1ccc(Cl)cc1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(-c3ccc(Cl)cc3)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of 51 mg (0.25 mmol) 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and of 53 mg (0.25 mmol) 1-(4-chloro-phenyl)-2-thiocyanato-ethanone in ethanol (1.25 ml) and dioxane (1.25 ml) was refluxed over night. After cooling to room temperature the solvent was evaporated under vacuo and the residue was purified on silica gel with methylene chloride/methanol 19/1 yielding 35 mg (35%) [4-(4-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 397.1/399.1 (100/50) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.54 (s, 1H), 7.96 (d, 2H), 7.86 (s, 1H), 7.68 (s, 1H), 7.50 (d, 2H), 7.48 (s, 1H), 7.31 (d, 1H), 7.22 (d, 1H), 7.06 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 717.3 [(M+H)+]
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][CH2:12][NH:13][C:14](OC2C=CC=CC=2)=[O:15])=[CH:6][CH:5]=1.C([N:33](CC)CC)C>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][CH2:12][NH:13][C:14]([NH2:33])=[O:15])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(CCNC(=O)Oc1ccccc1)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCNC(N)=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 100.5 %

Procedure:
Ammonium chloride (113 mg, 2.11 mmol) was added in one portion to tert-butyl N-[1-(4-chlorophenyl)-3-(phenoxycarbonylamino)propyl]carbamate (Intermediate 109) (427 mg, 1.05 mmol) and triethylamine (0.882 mL, 6.33 mmol) in DMF (3 mL). The resulting solution was stirred at 0.352 molar for 24 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 1-(4-chlorophenyl)-3-ureidopropylcarbamate (346 mg, 100%),
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[C:12]=1[OH:22])=[O:10].[Na].[CH2:24](COC)[O:25]C>CO>[CH3:19][O:18][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]2[C:9](=[O:10])[C:3]3[C:4]([O:22][C:12]=2[C:13]=1[O:20][CH3:21])=[CH:5][CH:6]=[CH:7][C:2]=3[O:25][CH3:24]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1OC
Reactant: COCCOC
Agent: [Na]
Solvent: CO
Product: COc1cc(C)c2c(=O)c3c(OC)cccc3oc2c1OC
Temperature: 80 °C
Reaction time: 72 h

Procedure:
At about 0-5° C. under a protective atmosphere, 37.5 g (0.11 mol) of the benzophenone derivative from Example 1a in 100 ml of dimethoxyethane were added to a solution of 2.6 g (110 mol) of sodium in 50 ml of methanol. After about 72 hours of stirring at 80° C., the title compound was precipitated by adding a 1:1 mixture of water and ethyl acetate. 33.4 g (100% of theory) of product of m.p. 158° C. were isolated by filtration.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37]O)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCCl.ClCCCl.ClCCCl.C(Cl)Cl>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][Cl:20])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of triphenylphosphine (4.55 g, 17.4 mmol) and hexachloroethane (3.9 g, 16.5 mmol) in 1,2-dichloroethane (18 mL) prepared at 0° C. was added via cannula into a flask containing a solution of methyl N-(tert-butoxycarbonyl)-L-serinate (3.2 g, 14.6 mmol) in 1,2-dichloroethane DCE (40 mL), kept at 0° C. under N2 atmosphere. After the addition was completed, the reaction mixture was further stirred at room temperature for 2 h, diluted with DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated. Purification made through chromatographic column of silicagel eluted with 10% to 50% EtOAc in hexane for 30 min, to afford 2.13 g (61% yield) of title compound as white crystals. MS: m/z=260.0 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:4]=1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride 1H-NMR (400 MHz, CDCl3): δ 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m, 4H), 7.65 (m, 2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z454.0 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1.[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29](F)[CH:28]=[CH:27][N:26]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[C:29]([O:1][CH2:2][CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:6][CH:5]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)c2ccccc12
Reactant: Fc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a degassed solution of tert-butyl 4-(2-hydroxyethyl)naphthalen-1-ylcarbamate (32) (0.64 g, 2.23 mmol) in DMF (10 mL) was added sodium hydride (0.267 g, 60% dispersion in mineral oil, 6.68 mmol) under nitrogen at 0° C. The solution was warmed to RT and was stirred for 30 min and then cooled to 0° C. To this mixture was added a solution of 2-chloro-4-fluoro-pyridine (0.381 g, 2.90 mmol) in DMF (5.0 mL) and the reaction mixture was warmed to RT and stirred for 16 hr. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine (3×), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 0-40% ethyl acetate in isohexane, gradient elution) to afford the title compound (33) (0.67 g, 75%); m/z 399 (M+H)+, (ES+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[N:14][C:13]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH2:18][C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: NCc1ncccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ncccn1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a flask was charged with 4-bromo-2-fluorobenzoic acid (180 mg, 0.821 mmol), pyrimidin-2-ylmethanamine (89.6 mg, 0.821 mmol), DIEA (0.358 mL, 2.05 mmol) in DMF (3 mL), and to the resulting solution was added PyBOP (513 mg, 0.915 mmol) and the resulting mixture was stirred at room temperature overnight, then was concentrated under reduced pressure and the residue was diluted with EtOAc (20 mL), washed with water (3×10 mL), brine (10 mL) and dried (Na2SO4), concentrated and the residue was purified by flash chromatography on silica gel eluted with gradient EtOAc/heptane (0-100%) and 4-bromo-2-fluoro-N-(pyrimidin-2-ylmethyl)benzamide (74.5 mg, 29.3%) was obtained as light color solid. LCMS (m/z): 310.0/312.0 (MH+), 0.64 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:20]([OH:21])=[N:14][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)Nc1nc(Cl)ccc1N
Solvent: C1CCOC1
Product: CCC(CC)n1c(O)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 6-chloro-N2-(pentan-3-yl)pyridine-2,3-diamine (936 mg, 4.37 mmol) in THF (10 mL) and CDI (1.1 g, 12.9 mmol) was added as a solid. After heating for 3 h, the reaction was cooled to room temperature. The excess CDI was quenched by the careful addition of water. The mixture was diluted with EtOAc and washed three times with water and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5%-40% EtOAc/hexanes) provided the title compound as a light purple solid (682 mg, 65%). m/z=240.0 (M+H)+
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])#[N:2].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21].[H-].[Na+]>C1COCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([CH:3]([C:1]#[N:2])[C:4]2[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=2)[C:9]#[N:10])=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21]
Reactant: N#CCc1ccc(F)c(C#N)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C#N)c2ccc(F)c(C#N)c2)nnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold solution of 5-(cyanomethyl)-2-fluorobenzonitrile (1 eq) and 3,6-dichloro-4-isopropylpyridazine (1.3 eq) (Reference: Org. Prep.+Proc. Int. 1988, 20, 117 and U.S. Pat. No. 4,628,088, 1986) in THF (38 mL, 0.1 M) was added portionwise NaH (1 eq). The reaction was stirred at 0° C. for 15 min and then warmed to RT and stirred for 2 hrs. The reaction was quenched with a sat. aq. NaHCO3 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by silica gel chromatography, eluting with petroleum ether:EtOAc (8:2) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ: 7.80-7.79 (2H, m), 7.49 (1H, s), 7.31-7.29 (1H, m), 5.63 (1H, s), 3.34-3.28 (1H, m), 1.36-1.29 (6H, m). MS (ES) C16H12ClFN4 required: 314/316. found: 315/317 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[C:10]1([C@@H:9]2[N:7]3[C:6](=[O:8])[CH2:5][CH2:4][C@H:3]3[CH2:2][O:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CC[C@@H](CO)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12

Procedure:
A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891 mL of toluene is treated with 172.1 mL of benzaldehyde at room temperature. p-Toluenesulphonic acid (2.94 g) is added and the reaction mixture stirred at reflux for 20 hours with azeotropic removal of water. The reaction mixture is treated with 500 mL of a 5% solution of sodium hydrogen carbonate in water. The organic layer is separated and washed once with 500 mL of a 40% solution of sodium bisulphite solution followed by 2×250 mL of water. The organic layer is dried with sodium sulphate, filtered and the solvent removed to give an oil. Fractional distillation in vacuum produces pure (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[N:32]=[C:31](Cl)[C:30]([Cl:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of tert-butyl (3-{[(3-aminophenyl)acetyl]amino}phenyl)carbamate (0.31 g, 0.91 mmol) and 2,4,5-trichloropyrimidine (0.15 g, 0.82 mmol) in DMF (3 mL) was added potassium carbonate (0.14 g, 0.99 mmol). The resulting mixture was stirred overnight at rt. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc and the combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude mixture was purified by column chromatography to give the desired product (0.25 g, 62%). LCMS for C23H23Cl2N5O3 (M-tBu+H)+: m/z=432.0, 434.0. 1H NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.54 (s, 1H), 9.32 (s, 1H), 8.35 (s, 1H), 7.93 (s, 1H), 7.78 (t, J=2.1 Hz, 1H), 7.47 (s, 1H), 7.46 (m, 1H), 7.33 (dd, J=8.7, 7.5 Hz, 1H), 7.31 (m, 1H), 7.15 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 6.98 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.C1(C=CC(O)=CC=1)O.[CH3:19][O:20][CH:21]=[CH:22][C:23]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH2:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:24][C:23]([O:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[CH:22][CH:21]2[O:20][CH3:19]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: COC1=CC(=O)C=CC1=O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COC1=CC(=O)C2CC(O[Si](C)(C)C)=CC(OC)C2C1=O
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
In a 50 mL round bottom flask, 2-methoxy-1,4-benzoquinone (2.3 g, 16.7 mmol) was suspended in toluene (30 mL). Hydroquinone (95 mg) was added and the resulting suspension was stirred magnetically for 5 min. 1-Methoxy-3-trimethylsilyloxy-1,3-butadiene (Aldrich, used as received, 5.0 g, 4.5 mL, 29.1 mmol) was added in one portion and the reaction was heated under N2 at 60° C. using an oil bath for 18 h. The reaction was removed from the oil bath, allowed to cool to rt and the solvent was removed by evaporation. Crystallization occurred after cooling the mixture to -30° C. for 1 hour. The colorless solid was collected by filtration and washed with hexane (30 mL) giving 4a,5,8,8a-tetrahydro-2,8-dimethoxy-6-trimethylsilyloxynapthalene-1,4-dione ##STR137## as a colorless powder (3.6 g, 11.6 mmol, 70%, >95% pure by 1H NMR, mp 108°-110° C.; 1H NMR (CDCl3) δ0.52 (s, 9H), 2.2-2.4 (m, 2H), 3.18 (s, 3H), 3.47 (t, 1H), 3.80 (s, 3H), 3.92 (m, 2H), 5.20 (d, 1H), 6.12 (s, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)#[CH:2].[SH:11][CH2:12][CH:13]([CH:16]([CH3:18])[CH3:17])[CH2:14]O>>[C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[S:11][CH2:12][CH:13]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:10]2)[CH2:5][CH2:4]1)#[CH:2]
Reactant: C#CC1CCC(C=O)CC1
Reactant: CC(C)C(CO)CS
Product: C#CC1CCC(C2OCC(C(C)C)CS2)CC1

Procedure:
Using the method described in Example 1(v) and starting from 4-ethynyl cyclohexanecarboxaldehyde (European Patent Application No. 88305107) and 2-mercaptomethyl-3-methylbutan-1-ol, 2-(4-ethynylcyclohexyl)-5-isopropyl-1,3-oxathiane was obtained as a mixture of isomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(Sc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)cc1

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 4-methylbenzenethiol under conditions analogous to Example D-110; MS (−) m/z 367.09 (M−1)
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][CH2:42][OH:43].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]12[O:43][CH2:42][CH2:41][CH2:40][O:27]1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Yield: 61.7 %

Procedure:
To a rapidly and efficiently stirred suspension of 5-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (16.13 g, 41.7 mmol) in benzene (785 mL) was added p-toluenesulfonic acid mono-hydrate (1.58 g, 8.34 mmol, 0.2 mole % ) and 1,3 propanediol (12.2 mL, 167 mmol, 4 eq) and the mixture was heated to reflux under a Dean Stark Trap for 5 hr. Additional p-toluenesulfonic acid (1.50 g, 0.2 mole % ) was added and the mixture was heated for another 1.5 hr. After cooling in an ice bath, the black reaction mixture was washed with sat. aq. NaHCO3 (3×350 mL), water (2×500 mL), brine (3×500 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified on silica gel eluting with CH2Cl2 followed by 50/50 Pet ether/EtOAc to give the title compound as an orange solid (11.44 g, 61.7% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 443 [M−H]. MS: (ES+) m/z 445 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:25])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32.94 g (100 mmol) of N-benzyloxycarbonyl-tyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 15.6 g (110 mmol) of iodomethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, dispersed between ethyl acetate and water, and the organic phase is mixed with hexane after drying (Na2SO4). The title compound crystallizes out.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].O.OS(O)(=O)=O>C(Cl)Cl>[C:10](=[O:11])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Benzyl alcohol (10.8 g, 100.0 mol) was dissolved in 100 mL of CH2Cl2. The solution was cooled down to 0° C. and phenyl chloroformate (15.7 g, 100 mol) was slowly added dropwise. The solution was stirred at RT overnight. Addition of 100 mL of H2O was followed by 2× washes with 100 mL of 2M H2SO4 each time. The organic phase was separated off and dried over Na2SO4. The solvent was removed in vacuo to obtain a colorless liquid (22.5 g, 99%).