Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1N
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8, 7.0 g) in dichloromethane (100 ml) was added trifluoroacetic acid (36.3 ml) and stirring was continued at 22° C. for 4 h. The mixture was evaporated and the residue partitioned between saturated aqueous NaHCO3 and dichloromethane, the organic layer was dried and evaporated and the residue triturated with n-pentane to give the intermediate (S)-2-amino-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (5.4 g) as a white solid. To a solution of the intermediate (0.88 g) in dichloromethane (13 ml) was added 4,4′-dimethoxytrityl chloride (0.96 g) and triethylamine (0.52 g) and stirring was continued at 22° C. for 2 h. The solution was washed with water, the organic layer was dried, evaporated and the residue was purified by chromatography over silica using AcOEt/n-heptane, gradient from 0 to 20% AcOEt) to give (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one as (1.61 g) as a pale blue solid. MS (ESI): m/z=642.3 and 644.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]([CH2:22]Cl)[N:19]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][C@H:17]1[CH3:31])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]([CH2:22][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[N:19]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][C@H:17]1[CH3:31])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: O=C1CCCN1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 187.7 %

Procedure:
Three separate reaction flasks were each charged with sodium hydride (60% in mineral oil, 0.486 g, 12.16 mmol) and anhydrous DMF (40.5 mL). To these, pyrrolidinone (0.924 mL, 12.16 mmol) was added dropwise. After stirring at this temperature for 30 minutes, (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.74 g, 8.11 mmol) was added to each at room temperature. The reactions were stirred at 80° C. for 4 h. The reactions were combined and saturated aqueous sodium bicarbonate was added and the mixture extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (5.9 g), MS: [M+H]+=388.
Reaction SMILES: C(O)(=O)CC.[Si:6]([O:13][C:14]1[C:22]([CH2:23][CH:24](O)[C:25]([CH3:27])=[CH2:26])=[C:21]([O:29][CH3:30])[C:20]([CH3:31])=[C:19]2[C:15]=1[C:16](=[O:32])[O:17][CH2:18]2)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:33][O:34][C:35](OC)([O:40]C)[CH2:36][CH2:37][CH2:38][Br:39]>>[Br:39][CH2:38][CH2:37][CH:36]([CH2:26][C:25]([CH3:27])=[CH:24][CH2:23][C:22]1[C:14]([O:13][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8])=[C:15]2[C:19](=[C:20]([CH3:31])[C:21]=1[O:29][CH3:30])[CH2:18][O:17][C:16]2=[O:32])[C:35]([O:34][CH3:33])=[O:40]
Reactant: COC(CCCBr)(OC)OC
Reactant: C=C(C)C(O)Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: CCC(=O)O
Product: COC(=O)C(CCBr)CC(C)=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2

Procedure:
A solution of trimethyl 4-bromoorthobutyrate (20 ml), propionic acid (0.22 ml) and 4-(4-tert -butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-2-methylbut-1-ene (3.18 g) was heated at 110° C. in a three-necked flash with a slow nitrogen stream passing over the reaction mixture. After 1 hr 40 min the excess orthoester was removed in vacuo at 55° C. Flash chromatography of the residue on silica gel eluting with 20-30% ethyl acetate/hexane gave methyl 2-(2-bromoethyl)-6-(4-t -butyldimethylsiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl -hex-4-enoate (2.66 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=O)[CH2:28][CH2:27]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:21])[CH2:27][CH2:28]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=C1CCc2cccc(Cl)c21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCc4cccc(Cl)c43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 7-chloro-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=429.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:16])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:16])[C:5]2[CH:11]=[C:10]([Br:17])[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1ccc(=O)n2C(C)C
Reactant: BrBr
Solvent: ClCCl
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2C(C)C
Yield: 56.1 %

Procedure:
To a solution of 2-amino-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.88 g, 13.19 mmol) dissolved in 80 mL of DCM at 0° C., (4.21 g, 26.39 mmol) bromine was added. Reaction vessel was removed from ice bath and allowed to react at room temperature over night. LCMS indicated complete conversion of starting material to product. Sample was evaporated to remove DCM and excess bromine. Orange solid was diluted in ethyl acetate and extracted with 10% NaHSO3, H2O, and brine. Organic layer was dried over Na2SO4, filtered, and reduced to dryness yielding 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light yellow powder (2.2 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.83 (m, 1H), 5.69 (br s, 2H), 2.60 (s, 3H), 1.58 (d, J=6.8, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][O:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11].CCN(C(C)C)C(C)C.[Br:26][CH2:27][C:28](Br)=[O:29]>C(#N)C>[CH2:8]([N:12]([O:13][CH2:14][CH2:15][CH3:16])[C:28](=[O:29])[CH2:27][Br:26])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNOCCC
Reactant: O=C(Br)CBr
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(OCCC)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The salt of Example 538B (0.60 g) was dissolved in acetonitrile (5 mL) and cooled to −20° C. Hünig's base (5.5 mL) was added slowly. Bromoacetyl bromide (0.5 mL) was added dropwise over five minutes. The solution was stirred at −20° C. for 30 minutes. The bath was removed and the solution was stirred for six hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×25 mL), 1N phosphoric acid (3×25 mL), and brine (1×25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.65 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCCCBr
Product: CCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
Using ethyl p-hydroxybenzoate (33.3 g, 0.20 mol) and n-heptyl bromide (39.4 g, 0.22 mol), the reaction was carried out in the same manner as described in Example 21, (1), and then recrystallized from ethanol to give the title compound as a white microneedles; yield: 19.0 g (40.2%); mp 86.2°-90.3° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:43])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]5[N:38]([CH3:40])[CH3:39])[N:23]=[C:22](Cl)[N:21]=3)[CH:17]=2)[N:12]=[C:11]([CH3:42])[CH:10]=1.[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH2:49]>CN(C=O)C>[CH3:7][N:8]([CH3:43])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]5[N:38]([CH3:40])[CH3:39])[N:23]=[C:22]([NH:49][CH2:48][CH2:47][CH2:46][N:45]([CH3:50])[CH3:44])[N:21]=3)[CH:17]=2)[N:12]=[C:11]([CH3:42])[CH:10]=1
Reactant: Cc1cc(N(C)C)c2cc(Nc3nc(Cl)nc(Nc4ccc5nc(C)cc(N(C)C)c5c4)n3)ccc2n1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C)c2cc(Nc3nc(NCCCN(C)C)nc(Nc4ccc5nc(C)cc(N(C)C)c5c4)n3)ccc2n1
Temperature: 100 °C

Procedure:
0.5 g (0.0036 mol) of potassium carbonate, 1 g (0.00189 mol) of 2,4-bis(4-dimethylamino-2-methylquinolin-6-yl)amino-6-chloro-[1,3,5]triazine prepared according to patent WO001561 and 1 ml (0.0078 mol) of N,N-dimethyl-1,3-propanediamine are successively loaded into a 250 ml round-bottomed flask containing 50 ml of DMF, with stirring, and then the mixture is heated for 15 hours at 100° C. The reaction medium is concentrated and taken up in 100 ml of water. The precipitate formed is filtered, washed with 2×50 ml of 0.1N NaOH and then dried. There are thus obtained 1.2 g of N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-N″-(3-dimethylaminopropyl)-[1,3,5]triazine, which is purified by flash chromatography on 30 g of silica (35-70 μm), eluting with a mixture (85/10/5) of dichloromethane, methanol and triethylamine. There is thus obtained, after drying under vacuum at 40° C., 0.45 g (41%) of 2,4-bis(4-dimethylamino-2-methylquinolin-6-yl)amino-6-(3-dimethylaminopropyl)-amino-[1,3,5]triazine, in the form of a yellow powder whose characteristics are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29]([NH:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH2:44][C:45](O)=[O:46])[C:37]2=[O:48])(=[O:31])=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:45](=[O:46])[CH2:44][N:38]1[C:37](=[O:48])[C:36]2[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH:35]=2)[C:39]1=[O:43]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.229 g, 0.544 mmol), 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetic acid (0.170 g, 0.544 mmol), EDC (0.313 g, 1.633 mmol) and DMAP (0.133 g, 1.089 mmol) were dissolved in DCM (20 ml), and the solution was stirred at room temperature for 20 hours. The mixture was diluted with DCM and washed with 0.5N HCl, aqueous 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, and the solvent removed under vacuum. The crude was purified by preparative HPLC (Method 1) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(methylsulfonamido methyl)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (0.120 g, 0.168 mmol, 30.9% yield, MS/ESI+ 714.06 [MH]+, [aD]=−27.89, c=0.9, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.88-7.94 (m, 2H), 7.85 (dd, 1H), 7.77 (t, 1H), 7.19 (d, 1H), 7.08 (s, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.42 (s, 2H), 4.23-4.56 (m, 2H), 3.83-4.00 (m, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 2.95 (s, 3H), 1.10-1.34 (m, 1H), 0.49-0.67 (m, 2H), 0.30-0.46 (m, 2H)
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[C:7]([CH3:18])[CH:6]=1)([O-])=O>CO>[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[C:7]([CH3:18])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCCC1=O
Solvent: O
Solvent: CO
Product: Cc1cc(N)ccc1N1CCCCC1=O
Reaction time: 22 h

Procedure:
800 mg of water-moist palladium on activated carbon are added to a solution of 4.00 g (17.1 mmol) of 1-(4-nitro-2-methylphenyl)piperidin-2-one in 150 ml of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure for 22 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving 1-(4-amino-2-methylphenyl)piperidin-2-one as a colourless solid; ESI 205.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=2)=[CH:9][CH:8]=1)[CH3:2].C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1.ClC(Cl)(Cl)C(O)=O>C(OCC)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(C2=CC(=O)CC2)cc1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)CSc1ccc([C@@H]2CCC(=O)C2)cc1
Temperature: 0 °C
Yield: 49 %

Procedure:
{[4-(3-Oxo-1-cyclopenten-1-yl)phenyl]thio}acetic acid ethyl ester 378 mg (1.37 mmol) and (2S,5S)-5-benzyl-3-methyl-2-(5-methyl-2-furyl)-4-imidazolidinone 54 mg (0.20 mmol) were dissolved in 10 mL of diethylether, followed by stirring at 0° C. Trichloroacetic acid 33 mg (0.20 mmol) and 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid t-butyl diester 340 mg (1.10 mmol) were added thereto, and the mixture was stirred for 12 days at room temperature. The solvent was concentrated, and purified by silica gel column chromatography (Biotage, solvent for elution; hexane/ethyl acetate) to give the title compound 187 mg (yield 67%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 77.5 %

Procedure:
L-Citrulline (35.2 g., 0.2 mole) was dissolved in 200 mL of 2 N sodium hydroxide. Cyclohexanoyl chloride (29 mL, 0.2 mole) was added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 1 hour. The mixture was then acidified to pH 2.6 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide to pH 6.5 and dried by lyophilization to furnish 44.2 g of N-cyclohexanoyl-(L)-citrulline. The product was a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-cyclopropylmethoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A23) (5.18 g, 13.8 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light brown solid (3.80 g, 80%).
Reaction SMILES: NC1N=CC(C2N=C(N3CCOCC3)C3=CC(C(O)=O)=CN3N=2)=C(C(F)(F)F)C=1.C[O:31][C:32]([C:34]1[CH:35]=[C:36]2[N:41]([CH:42]=1)[N:40]=[C:39]([C:43]1[CH:44]=[N:45][C:46]([NH:53]C(=O)C(C)(C)C)=[CH:47][C:48]=1[C:49]([F:52])([F:51])[F:50])[N:38]=[C:37]2[N:60]1[CH2:66][CH:65]2[O:67][CH:62]([CH2:63][CH2:64]2)[CH2:61]1)=[O:33]>>[NH2:53][C:46]1[N:45]=[CH:44][C:43]([C:39]2[N:38]=[C:37]([N:60]3[CH2:66][CH:65]4[O:67][CH:62]([CH2:63][CH2:64]4)[CH2:61]3)[C:36]3=[CH:35][C:34]([C:32]([OH:33])=[O:31])=[CH:42][N:41]3[N:40]=2)=[C:48]([C:49]([F:52])([F:51])[F:50])[CH:47]=1
Reactant: COC(=O)c1cc2c(N3CC4CCC(C3)O4)nc(-c3cnc(NC(=O)C(C)(C)C)cc3C(F)(F)F)nn2c1
Agent: Nc1cc(C(F)(F)F)c(-c2nc(N3CCOCC3)c3cc(C(=O)O)cn3n2)cn1
Product: Nc1cc(C(F)(F)F)c(-c2nc(N3CC4CCC(C3)O4)c3cc(C(=O)O)cn3n2)cn1

Procedure:
Compound 23b was prepared by the method which was identical with that for preparing compound 23a, wherein compound 22b (250 mg, 0.45 mmol) was used as the starting material. White solid (102 mg, 51.9%). m.p. 284-285° C. 1H NMR (300 MHz, DMSO-d6): δ 12.44 (br s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.30 (s, 1H), 6.82 (s, 3H), 4.47 (br s, 2H), 4.42 (br s, 2H), 3.32 (br s, 2H), 1.87-1.84 (m, 2H), 1.75-1.68 (m, 2H). LC-MS: 435 (M+1).
Reaction SMILES: C[CH:2]([N+:7]#[C-:8])[C:3]([O:5][CH3:6])=[O:4].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:6][O:5][C:3]([C@H:2]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:16][CH:8]=[N:7]1)=[O:4]
Reactant: [C-]#[N+]C(C)C(=O)OC
Reactant: O=Cc1ccccc1
Product: COC(=O)[C@@H]1N=CO[C@H]1c1ccccc1
Yield: 90 %

Procedure:
Methyl α-methylisocyano-acetate was reacted with benzaldehyde in the presence of the same catalyst and under the same reaction conditions of those of Example 2. After the solvent was concentrated, the reaction mixture was subjected to silica-gel column chromatography to obtain trans-4-methoxycarbonyl-5- phenyl-2-oxazoline and the corresponding cis-form in a ratio of 87/13). Total yield: 90%. The optical purity of the trans-(4S,5R) form was measured in the same manner as in Example 1, which was 93% ee.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][N:4]1[C:13]([CH3:15])([CH3:14])[CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][C:5]1([CH3:17])[CH3:16].[C:19]([OH:28])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:3][N:4]1[C:5]([CH3:16])([CH3:17])[CH2:6][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:12][C:13]1([CH3:14])[CH3:15])[CH2:18][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:28][CH2:18][CH:2]([OH:1])[CH2:3][N:4]1[C:5]([CH3:17])([CH3:16])[CH2:6][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:12][C:13]1([CH3:15])[CH3:14])=[O:27]
Reactant: CC1(C)CC2(CC(C)(C)N1CC1CO1)OCCO2
Reactant: O=C(O)CCCCC(=O)O
Solvent: Cc1ccccc1C
Product: CC1(C)CC2(CC(C)(C)N1CC(O)COC(=O)CCCCC(=O)OCC(O)CN1C(C)(C)CC3(CC1(C)C)OCCO3)OCCO2

Procedure:
To 60 ml of xylene were added 10.0 g of 8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane and 2.4 g of adipic acid and the mixture was refluxed for 16 hours, under stirring. After completion of the reaction, the residue obtained by removing xylene from the reaction mixture under a reduced pressure was purified by column chromatography on silica gel (eluent: benzene:ethyl acetate=1:1), giving the desired compound as pale yellow, viscous product. The compound showed Rf value of 0.53 on a thin-layer chromatography on silica gel when developed with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:25][C:24]([F:26])([F:27])[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]2[NH:28][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CSC(=N)Nc1ccc(OC(F)(F)F)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
4-hydroxybenzoic acid hydrazide (0.643 g, 4.23 mmol) and S-methyl N-[4-(trifluoromethoxy)phenyl]isothiourea hydroiodide (1.6 g, 4.23 mmol) were suspended in 10 mL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mL of ice-water. The formed white solid was collected, washed thoroughly with water and dried in air. The resulting residue was purified by silica gel chromatography using Isco column with 10% to 100% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a pinkish solid (575.2 mg). Yield 40.4%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][NH:10][CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:10]([CH3:11])[CH3:9])[S:5][CH:6]=1
Reactant: CNC
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)Cc1cc(Br)cs1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a mixture of 4-bromothiophene-2-carbaldehyde (1.91 g, 10 mmol) and dimethylamine (2 M in THF, 7.5 mL, 15 mmol) in DCE (30 mL) was added NaBH(OAc)3 (2.65 g, 12.5 mmol), followed by AcOH (0.2 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction was quenched with sat. NaHCO3 (20 mL) and brine, and was then extracted with EtOAc (100 mL+30 mL). The solvents were removed in vacuo to afford the crude title compound as a light yellow liquid (1.70 g, 77%). 1H NMR (400 MHz, CDC3) δ 7.15 (s, 1H), 6.84 (s, 1H), 3.60 (s, 2H), 2.29 (s, 6H); MS ESI 219.7 [M+H]+, calcd for [C7H10BrNS+H]+ 220.0.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=O)[CH3:9])=[O:6])[CH3:3].Cl.[CH3:15][C:16](=[CH2:19])[CH2:17][NH2:18].CN1CCOCC1>>[CH3:9][C@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:3])[CH3:13])[C:10]([NH:18][CH2:17][C:16]([CH3:19])=[CH2:15])=[O:12]
Reactant: C=C(C)CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Product: C=C(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a cooled (0° C.) mixture of 18.9 parts of (S)-N-[(1,1,-dimethylethoxy)carbonyl]-alanine, 10.8 parts of 2-methyl-2-propen-1-amine monohydrochloride, 27.0 parts of 1-hydroxy-1H-benzotriazle hydrate and tetaahydrofuran, there were added 10.1 parts of N-methylmorpholine and, after 20 min, 20.6 parts of N,N-methanetetraylbis-[cyclohexanamine] under a nitrogen atmosphere. The whole was kept at 0° C. for 1 hour and at room temperature for 12 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and NaHCO3 (sat.). The organic layer was separated, washed with NaCl (sat), dried, filtered and evaporated, yielding 24.2 parts (99.9%) of (1,1-dimethylethyl) (S)-[1-methyl-2-[(2-methyl-2-propenyl)amino]-2-oxoethyl]carbamate (interm. 63).