Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>N.CO>[F:42][C:30]([F:29])([F:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:38])=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1C(F)(F)F)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-(Trifluoromethyl)benzenesulfonyl chloride (24 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (3.3 mg). MS m/z 397 [M+H]+.
Reaction SMILES: CC1C=CC=CC=1O[CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1.N(C(OCC)=O)=N[C:45](OCC)=O>O1CCCC1.C(Cl)(Cl)Cl>[N:38]1([CH:5]2[CH2:6][CH:7]([C:9]([O:11][CH3:45])=[O:10])[NH:8][C:12]2=[O:14])[CH:42]=[N:41][CH:40]=[N:39]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: c1nc[nH]n1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CC(n2cncn2)C(=O)N1
Temperature: 5 °C
Reaction time: 17 h

Procedure:
A mixture of the compound prepared as described in Example 4 (318 mg), triphenylphosphine (577 mg), and 1,2,4-triazole (152 mg) in dry tetrahydrofuran (4.5 ml) was cooled to about 5° C., and treated with diethyl azodicarboxylate (383 mg) over a ten minute period. After the addition was complete, the reaction was allowed to warm to room temperature. After about 17 hours, the reaction solution was concentrated in vacuo and allowed to stand at room temperature under reduced pressure to give a crystalline solid. This solid was diluted with chloroform and purified by centrifugal thin-layer chromatography, eluting with ethyl acetate/hexane (1:1) followed by ethyl acetate/hexane (3:1), ethyl acetate, ethyl acetate/methanol (19:1), and ethyl acetate/methanol (9:1). The fractions containing the title compound were combined and concentrated in vacuo to give 280 mg.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>CCO>[OH:16][CH2:17][C@H:18]1[N:23]([CH2:14][CH:12]([OH:13])[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:15])[O:3][C@H:2]([CH3:1])[CH2:11]3)[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO)ccc2C(=O)O1
Temperature: 155 °C

Procedure:
A solution of (3R)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (325 mg, 1.59 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (345 mg, 1.59 mmol dissolved in EtOH (7 mL) was heated in a sealed tube to 155° C. for 3 hours in the microwave. The reaction was cooled and concentrated to give crude product which was purified via MPLC (40-100% EtOAc/Hexane) to give the title compound as a mixture of diastereomers.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][C@H:12]([NH:26]C(OC(C)(C)C)=O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[NH:35]1[C:39]([C:40]([OH:42])=[O:41])=[CH:38][C:37]([C:43]([OH:45])=O)=[N:36]1.CCN=C=NCCCN(C)C.[CH:57]1[CH:58]=CC2N(O)N=N[C:61]=2[CH:62]=1>O1CCOCC1.CN(C=O)C.C(O)CCC>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:43]([C:37]2[NH:36][N:35]=[C:39]([C:40]([OH:42])=[O:41])[CH:38]=2)=[O:45])[CH2:11][C:8]2([C:6]([O:5][CH2:58][CH2:57][CH2:62][CH3:61])=[O:7])[CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)OC(C)(C)C)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCCCO
Product: CCCCOC(=O)C1(C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC(=O)c2cc(C(=O)O)n[nH]2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
1-((R)-3-Biphenyl-4-yl-2-t-butoxycarbonylaminopropyl)cyclopropanecarboxylic acid t-butyl ester (1.0 g, 2.2 mmol, 1.0 eq.), 1-butanol (5 mL) and 4 M of HCl in 1,4-dioxane (2 mL) were combined and stirred at 65° C. overnight. To this was added a mixture of 3,5-pyrazoledicarboxylic acid (34.6 μg, 221 μmol, 1.0 eq.), EDCI (39.2 μL, 221 μmol, 1.0 eq.) and HOBt (29.9 mg, 221 μmol, 1.0 eq.) that had been combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. The resulting mixture was stirred for 30 minutes. The reaction was then quenched with ACOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (29 mg, 95% purity). MS m/z [M+H]+ calc'd for C28H31N3O5, 490.23; found 490.6.
Reaction SMILES: O[C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C:8](=[O:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1.O.O=P(Cl)(Cl)[Cl:27]>CN(C)C=O>[Cl:27][C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C:8](=[O:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1
Reactant: CC1(C)CC(=O)c2c(nc(O)c3c2C2(CCOCC2)OC3=O)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2c(nc(Cl)c3c2C2(CCOCC2)OC3=O)C1

Procedure:
6.2 g 4-Hydroxy-7,7-dimethyl-2′,3′,5′,6′,7,8-hexahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3,9(6H)-dione are suspended in 25 ml phosphoroxychloride, 1 drop of N,N-dimethylformamide is added and the mixture is heated for 18 hours to 65° C. Under vigorous stirring the mixture is added dropwise to 300 ml water while keeping the temperature below 35° C. After completion of the addition the mixture is stirred for 1 hour, the product is isolated by filtration, washed with water and dried in vacuo.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=[CH:18][C:13]=2[CH:12]=[O:11])=[CH:26][CH:25]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCOc1ccc(-c2cc(CO)ccc2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCOc1ccc(-c2cc(C=O)ccc2C=O)cc1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
70 ml of dichloromethane were placed in a reaction vessel, admixed with oxalyl chloride (8.4 g, 5.7 ml, 66 mmol) and cooled to −60° C. A solution of DMSO (10.2 g, 9.3 ml, 131 mmol) in 30 ml of dichloromethane was added dropwise to this mixture over a period of 10 minutes. The mixture was stirred for another 5 minutes. A solution of 2,5-bis(hydroxymethyl)-4′-hexyloxybiphenyl (10 g, 32 mmol) (cf. D1) in 70 ml of dichloromethane was then added dropwise over a period of 15 minutes (the reaction solution became turbid). It was stirred for another 10 minutes and triethylamine (15.9 g, 21.8 ml, 157 mmol) was subsequently added dropwise. The reaction solution became yellow during this procedure and a precipitate was formed. The acetone/dry ice bath was removed and the mixture was stirred for 2 hours at RT. A light-colored solid was then floating on the yellow liquid phase. The mixture was admixed with 150 ml of water, stirred for another 10 minutes (solid entered solution), the organic phase was separated off, the aqueous phase was extracted twice with dichloromethane, the combined organic phases were subsequently washed three times with water, dried over Na2SO4, filtered and subsequently evaporated to dryness on a rotary evaporator. The yellow oil crystallized after some time at RT and was subsequently recrystallized from hexane. It took a relatively long time for the product to become solid: pale beige, microcrystalline powder, 5.67 g (57%), purity about 98%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[O:24])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:35][S-:36].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[O:24])=[C:4]([S:36][CH3:35])[N:3]=1
Reactant: C[S-]
Reactant: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a round bottom flask is added 2-(2-amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (80.0 mg, 0.21 mmol, 1.0 eq.), THF (5.0 mL), and DIEA (0.036 mL, 0.21 mmol, 1.0 eq.). The flask was then cooled to 0° C. before adding sodium thiomethoxide (16.0 mg, 0.23 mmol, 1.1 eq.). The reaction was warmed to RT and stirred for 3 hrs before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give pure 2-(2-amino-5-formyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (75.0 mg, 92%). LC/MSD (HP Series 1100 MSD): Expected MW: 385, Observed M+H, 386.1, Retention time: 1.58 min. ANALYTICAL HPLC: >95%, Retention time: 4.30 min (8 minute run). 1H-NMR (d6-DMSO): 10.48 (s, 1H), 9.98 (s, 1H), 9.35 (t, 1H), 8.10 (s, 1H), 7.80 (d, 1H), 7.59 (t, 1H), 7.41 (m, 2H), 7.25 (br s, 1H), 4.25 (d, 2H), (3 thiomethyl protons are buried under DMSO peak) ppm. 1H-NMR (d-MeOH): 10.0 (s, 1H), 8.00 (s, 1H), 7.78 (d, 1H), 7.50 (t, 1H), 7.39 (d, 1H), 4.33 (s, 2H), 2.51 (s, 3H) ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]1([S:15]([NH:18][CH:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(Cl)CCl>[CH3:6][C:5]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[CH2:27][CH:19]([NH:18][S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:16])=[O:17])[CH2:20]2)=[O:7]
Reactant: O=S(=O)(NC1Cc2ccccc2C1)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
29.6 g (0.22 mol) of anhydrous aluminium chloride are suspended in 250 ml of ethylene chloride and 10.5 g (0.133 mol) of acetyl chloride and 24.2 g (0.0885 mol) of 2-(benzenesulphonamido)-indane are added successively. After the mixture has been stirred for approx 3 hours at room temperature, it is decomposed with ice and concentrated hydrochloric acid. The reaction product is obtained by concentrating the organic phase and subsequently crystallising the product from cyclohexane/ethyl acetate.
Reaction SMILES: [CH2:1]([O:3]C(=O)CC(CC1C=CC=CC=1)=O)C.[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:17].[C:31]1([O:38][CH3:39])[CH:36]=[CH:35][C:34](Cl)=[CH:33][CH:32]=1>>[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH:21]([NH:29][C:1](=[O:3])[C:34]1[CH:35]=[CH:36][C:31]([O:38][CH3:39])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:17]
Reactant: CCOC(=O)CC(N)Cc1ccccc1
Reactant: COc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Product: CCOC(=O)CC(Cc1ccccc1)NC(=O)c1ccc(OC)cc1

Procedure:
γ-Phenylacetoacetic acid ethyl ester was converted into 3-amino-4-phenylbutyric acid ethyl ester (M.P. of hydrogen oxalate 151°-153°). Further reaction with p-anisolyl chloride gave 3-p-methoxybenzamido-4-phenylbutyric acid ethyl ester (M.P. 102°-104°). A Bischler-Napieralski reaction (boiling with phosphorus oxychloride) gave 3,4-dihydro-1-p-methoxyphenyl-3-isoquinolinylacetic acid ethyl ester. Hydrogenation using a palladium/charcoal (10% w /w) gave cis-1-p-methoxyphenyl-1,2,3,4-tetrahydro-3-isoquinolinylacetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=2)[C:10](=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CN(C=O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:20])[CH3:21])[CH:13]=3)[C:10](=[O:22])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:34])=[CH:28][CH:27]=1
Reactant: CC(C)Oc1cccc(-n2c(N)nc3ccccc3c2=O)c1
Reactant: O=C=Nc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-n2c(NC(=O)Nc3ccc(Br)cc3)nc3ccccc3c2=O)c1
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
To a solution of 2-amino-3-(3-isopropoxy-phenyl)-3H-quinazolin-4-one (295 mg, 1.0 mmol) in anhydrous DMF (10 mL) was added 50% NaH (48 mg, 1 mmol) at room temperature and stirred for 30 minutes. To this mixture was added, 4-bromo phenyl isocyanate and stirred for 2 hours at room temperature. The reaction mixture was quenched with water and concentrated. It was then diluted with ethyl acetate and filtered. The filtrate was concentrated and chromatographed using 100% CH3Cl to isolate pure product as a white solid (70 mg, 14.2%), mp 230°-233° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1Cl
Temperature: 0 °C
Yield: 84.6 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and then the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 60/40 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (210 mg, 85%) as a colorless oil: EI-HRMS m/e calcd for C20H23N2O3SCI (M+) 406.1118, found 406.1120.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].O>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)Nc1nc(Cl)ncc1C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)Nc1nc(N[C@H]2CC[C@H](O)CC2)ncc1C(N)=O
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide (0.5 g), trans-4-aminocyclohexanol hydrochloride (0.40 g), Na2CO3 (0.28 g) in NMP (3.5 mL) was heated at 85° C. and held for 6 h. The mixture was cooled to 35° C., and water (10 mL) was added. After 30 minutes, the batch was cooled to 25° C. and held for 1 h. The suspension was filtered, washed with water (2.5 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 24 h to give 4-(tert-butylamino)-2-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide as a white solid (0.6 g, 89%). 1H NMR (DMSO-d6) δ 9.17 (broads, 1H), 8.32 (s, 1H), 7.01 (broads, 1H), 4.52 (d, J=4.5 Hz, 1H), 3.70-3.25 (m, 2H), 1.84 (m, 4H), 1.41 (s, 9H), 1.33-1.16 (m, 4H).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2].N.[H][H]>CO.O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Reaction time: 22 h
Yield: 97.9 %

Procedure:
A solution of 1.19 g of (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate in 30 mL of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaker at 50 pounds per square inch gage (psig) and 40° C. After 22 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1; ethyl acetate:methanol:ammonium hydroxide) to give 1.18 g of (±)-cis-1,1-dimethylethyl 4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate as a clear oil which solidifies upon standing.
Reaction SMILES: O.C([O:4][C:5]([CH:7]1[CH2:19][CH2:18][C:10]2[N:11]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[S:13][C:9]=2[CH2:8]1)=[O:6])C.[OH-].[Na+]>C(O)(=O)C>[C:15]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:19][CH2:18][C:10]=2[N:11]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)C1CCc2nc(NC(C)=O)sc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CC(C(=O)O)CC2
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 200 ml of water, 30 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(II), R1=ethyl, R=—NH—CO—CH3] and 52.2 g of 30% sodium hydroxide, keeping the temperature below 30° C.; during the addition the solid gradually solubilized until complete dissolution. After 2 hours, glacial acetic acid was dropwise added to pH=4.5-5.5; after approx. 1 hour the precipitated white solid was filtered, washed with 70 ml of water and dried to obtain 24.8 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1([C:30](OC)=[O:31])[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[C:18]([NH:19][CH2:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[OH:22])[C:8]=2[O:7]1)[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:5].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>C(O)C>[ClH:29].[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH2:4][CH2:6][O:7][CH3:8])[C:30]([C:6]1([C:4]([OH:3])=[O:5])[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[C:18]([NH:19][CH2:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[OH:22])[C:8]=2[O:7]1)[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:31]
Reactant: COC(=O)C1(C(=O)OC)Oc2cc3c(c(NCC(O)c4cccc(Cl)c4)c2O1)CCCC3
Reactant: COCCN
Agent: Cl
Solvent: CCO
Product: COCCN(CCOC)C(=O)C1(C(=O)O)Oc2cc3c(c(NCC(O)c4cccc(Cl)c4)c2O1)CCCC3

Procedure:
A solution of product from Example 20 in ethyl alcohol is stirred at room temperature for 20 hours with an excess of methoxyethylamine. The reaction mixture is evaporated in vacuo and combined with a sodium carbonate solution and diethyl ether. The layers are separated and the diethyl ether layer is dried over sodium sulfate and filtered. Gaseous hydrogen chloride is bubbled into the filtered diethyl ether solution and the desired product is collected.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:24]([C@@H:26]2[C@H:29](OC(=O)C)[N:28]([NH2:34])[C:27]2=[O:35])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:24]([C@@H:26]2[CH:29]([O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:28]([NH2:34])[C:27]2=[O:35])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)CCc2ccccc2)C(=O)N1N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NN1C(=O)[C@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)CCc2ccccc2)C1OCc1ccccc1
Yield: 23 %

Procedure:
A mixture of (3S,4S)-3{N-(3-phenylpropionoyl)-β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one (236 mg, 0.5 mmol), benzyl alcohol (54 mg, 0.5 mmol), and zinc acetate dihydrate (110 mg, 0.5 mmol) in benzene (20 ml) and toluene (20 ml) was refluxed for 5 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate, containing a small volume of acetone, and water. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1) as eluent and the title compound was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]2[O:11][CH:6]12)([CH3:4])([CH3:3])[CH3:2].C(OC1(O)CCC(C(C)(C)C)CC1)(=O)C(C)=C.C(C1CCCCC1)(C)(C)C.ClC1C=C(C=CC=1)C(OO)=O>C(OC(=O)C)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]=[C:7]2[O:11][CH:6]12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCCC2OC21
Agent: C=C(C)C(=O)OC1(O)CCC(C(C)(C)C)CC1
Agent: CC(C)(C)C1CCCCC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)C1CCC=C2OC21
Reaction time: 2 h

Procedure:
4-t-butyl-2-epoxycyclohexane, an intermediate in the synthesis of 4-t-butylhydroxycyclohexyl methacrylate, is prepared by reacting a 4-t-butylcyclohexane with m-chloroperoxybenzoic acid in ethylacetate below 5° C. until mixing is complete, and then at room temperature for two hours. The reaction mixture is washed with aqueous NA2CO3, dried over MgSO4, and filtered. The theoretical reaction is: ##STR20##