Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]([C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[N+]=[N-].C(=O)([O-])[O-]>O1CCCC1>[F:11][C:9]1[CH:10]=[C:5]([NH2:2])[C:6]([NH2:12])=[N:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1cc(F)cnc1N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1cc(F)cnc1N
Reaction time: 1 h
Yield: 92.8 %

Procedure:
The HCl salt of 3-azido-5-fluoropyridin-2-amine (1.90 g, 10.0 mmol) was dissolved in tetrahydrofuran (100 mL) and treated with MP-Carbonate (Argonaut, 11.5 g). After 1 h, the mixture was filtered, rinsed with more tetrahydrofuran, and concentrated. This residue was dissolved in ethanol (50 mL), purged with argon, and 10% palladium on carbon was added (0.15 g). Hydrogen was introduced (1 atm) and the reaction stirred until complete. The catalyst was filtered and the solvent evaporated from the filtrate to give the title compound (1.18 g). MS 128.0 (M+1)
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[NH:33])=[CH:30][CH:29]=2)[C:15]2[NH:19][C:18](=[O:20])[N:17]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:16]=2)=[CH:10][C:9]=1[O:37][CH3:38])[CH3:6]>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH2:34])=[NH:33])=[CH:35][CH:36]=2)[C:15]2[NH:19][C:18](=[O:20])[N:17]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)[N:16]=2)=[CH:10][C:9]=1[O:37][CH3:38])[CH3:6]
Reactant: CCOc1ccc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Solvent: CC(=O)O
Product: CCOc1ccc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Yield: 26.7 %

Procedure:
A SUMICHIRAL OA-2500 column was used for optical resolution of 75 mg of 4-{[(4-ethoxy-3-methoxyphenyl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (produced by the same procedure as in Example (18g), using 0.1% acetic acid instead of the 0.1% trifluoroacetic acid in Example (18g)), and the first eluting enantiomer (20 mg) of the title compound was obtained as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>>[C:1](/[C:3](=[C:17](/[N:19]([CH3:21])[CH3:20])\[CH3:18])/[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2]
Reactant: CCc1ccccc1NC(=O)CC#N
Reactant: COC(C)(OC)N(C)C
Product: CCc1ccccc1NC(=O)/C(C#N)=C(/C)N(C)C

Procedure:
As for Example 1, 2-cyano-2'-ethylacetanilide is heated with N,N-dimethylacetamide dimethylacetal to give 2-cyano-3-dimethylamino-2'-ethylcrotonanilide as colorless prisms, m.p. 79°-81.5° C.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].S(OCC)(O[CH2:17][CH3:18])(=O)=O>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:17][CH3:18])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Brc1nc2ccccc2[nH]1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(Br)nc2ccccc21
Yield: 91.9 %

Procedure:
To a flask were added 4 g 2-bromo-1H-benzimidazole and 60 ml tetrahydrofuran, and the mixture was cooled to 10 C. To this mixture was added 1.2 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 4.7 g of diethyl sulfate were added. The reaction mixture was heated to 40 C for several hours, then cooled to 22 C and quenched with 100 ml water. The product was extracted twice with 50 ml ethyl acetate and following removal of the solvent, the product was purified by silica gel chromatography using a gradient from 100% hexane to 25% ethyl acetate in hexane. An oil was obtained that crystallized on standing which was dried resulting in 4.2 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]2)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(c2nc(Cl)nc3c2COC3c2ccc(F)cc2)C[C@H](C)O1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) was reacted as described in Preparation Xa with (2R,6S)-2,6-dimethylmorpholine to give 2-chloro-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation Mh). LC-MS (M+H)+=364.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.39 (dd, J=8.70, 5.34 Hz, 2H) 7.07 (t, J=8.70 Hz, 2H) 5.90 (br. s., 1H) 5.34-5.42 (m, 1H) 5.24-5.34 (m, 1H) 4.14 (q, J=7.02 Hz, 2H) 3.67 (ddd, J=10.38, 6.41, 2.44 Hz, 4H), 1.20 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O[C:14]([S-])=[S:15])C.[K+]>N1C=CC=CC=1>[SH:15][C:14]1[O:10][C:9]2[C:2](=[C:3]([C:4]#[N:5])[CH:6]=[CH:7][CH:8]=2)[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1cccc(O)c1N
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1cccc2oc(S)nc12
Yield: 45.5 %

Procedure:
A solution of 2-amino-3-hydroxybenzonitrile (298 mg) and potassium ethylxanthate (427 mg) in pyridine (7.4 ml) was heated under reflux for 3 hr. To the reaction mixture was added distilled water, the mixture was acidified with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (178 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (370 mg, 0.827 mmol) (obtained as described in Reference Example 53(7)) in methylene chloride (19 ml) were added methanesulfonyl chloride (192 μl, 2.48 mmol) and triethylamine (348 μl, 2.48 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (422 mg, yield 97%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]3=[O:27])=[C:12]([S:28][CH3:29])[CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].BrBr.C([O-])(=[O:34])C.[Na+]>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]3=[O:27])=[C:12]([S:28]([CH3:29])=[O:34])[CH:11]=2)=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CC(=O)[O-]
Reactant: COC(=O)CCN1CCN(c2ccc(-c3ccc(C(=N)N)cc3)cc2SC)C1=O
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CCN1CCN(c2ccc(-c3ccc(C(=N)N)cc3)cc2S(C)=O)C1=O

Procedure:
Prepared from 1-(4'-amidino-3-methylthio-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one by oxidation with bromine in glacial acetic acid in the presence of sodium acetate at ambient temperature.
Reaction SMILES: [OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25]Cl)=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9].[CH3:29][NH2:30]>CO>[OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][NH:30][CH3:29])=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9]
Reactant: CN
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CCl)n2Cc2ccccc2)n(C)c1=O
Solvent: CO
Product: CNCc1nc2c(c(=O)n(CCCC[C@H](C)O)c(=O)n2C)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (prepared as described for the synthesis of CT 30289) (2.3 g, 5.68 mmol) in methanol (50 ml) was added methylamine (40% in water, 50 ml). After stirring at room temperature for 2 hours, the solvent and excess reagent were evaporated under reduced pressure. A solution of triethylamine and ethanol (1:4) (100 ml) was added and then evaporated under reduced pressure to give (S)-1-(5-hydroxyhexyl)-7-benzyl-8-methylaminomethyl-3-methylxanthine as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7](F)[C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CC(N(C)C)=O>C(OCC)(=O)C>[C:4]([C:3]1[C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=[CH:8][C:7]=1[NH:29][CH2:28][CH2:27][NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:5])[NH2:6]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: NC(=O)c1c(F)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1ccc(Cl)c(Cl)c1C(N)=O
Temperature: 140 °C
Yield: 81.8 %

Procedure:
A mixture of 2,3-dichloro-6-fluorobenzamide (4.0 g, 19.32 mmol.), K2CO3 (5.33 g, 38.64 mmol), and N-Boc-ethylenediamine (3.41 g, 21.25 mmol) and dimethylacetamide (50 mL). was heated at 140° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with a solution of aqueous saturated sodium bicarbonate (3×100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give the title compound (5.50 g, 82% yield) as a brown gum.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A solution of potassium phthalimide (627 mg, 3.38 mmol) and 7-bromohept-1-ene in dry DMF (10 mL) was stirred at 100° C. under nitrogen for 1 h. Then, the reaction mixture was successively cooled to room temperature, filtered, diluted with ether, and filtered again. The filtrate was concentrated under reduced pressure to give the target product 75 as an oil, which was used without further purifications in the next step: m/z=244 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (Example 7) gave 317. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.30 (td, J=7.9, 1.8 Hz, 1H), 7.87 (s, 1H), 7.48-7.26 (m, 5H), 7.02-6.56 (m, 1H), 4.84 (dd, J=10.6, 3.5 Hz, 1H), 4.58-4.39 (m, 1H), 4.36-4.22 (m, 1H), 4.20-3.98 (m, 1H), 3.76 (s, 3H), 2.09-1.91 (m, 2H), 1.87-1.67 (m, 3H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:12]>ClCCl>[Br:12][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCc1cccc(Cl)c1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: Clc1cccc(CCBr)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
Add triphenylphoshpine (3.90 g, 14.9 mmol) to a stirred solution of 3-chlorophenethyl alcohol (2.0 mL, 14.8 mmol), carbon tetrabromide (4.91 g, 14.8 mmol) and anhydrous dichloromethane (100 mL). Stir for 5 h under nitrogen at room temperature, and then wash with water (100 mL) and brine (100 mL). Dry the dichloromethane layer over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% hexanes to yield 2.30 g (71%) of 1-(2-bromo-ethyl)-3-chloro-benzene: TLC: Rf in 100% hexanes: 0.27; 1H NMR (CDCl3): 7.26-7.11 (m, 3H), 7.09-7.07 (m, 1H), 3.54 (t, 2H), 3.12 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]([C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:12]([OH:14])=[O:13])=[O:4].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C@@H:11]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[C:12](=[O:14])[O:13][CH:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sccc1NC(C(=O)O)c1ccc(OC)nc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1sccc1N[C@@H](C(=O)OC1CN2CCC1CC2)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
To a solution of 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I59) (548 mg, 1.70 mmol) in THF (20 ml), were added N,N′-methanediylidenedicyclohexanamine (421 mg, 2.04 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (276 mg, 2.04 mmol), and (R)-quinuclidin-3-ol (259 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 15 hours, and then the solvent was evaporated. The residue was taken up with DCM, and the insoluble was removed by filtration. The organic phase was washed twice with Na2CO3 and then brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (DCM/MeOH=95/5) collecting first diastereomer 1 of C60 (140 mg, 19 yield) and then a mixture of diastereomers 1 and 2 of C60 (100 mg, 14% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].N#N.[CH3:20][C:21](=[CH2:23])[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)C>[NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([O:6][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1

Procedure:
10 g (42 mmol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken in an autoclave at 20 atm. N2 pressure for 3 days in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4Excess isobutylene was blown out and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted twice using 100 ml of diethyl ether each time. The combined organic phases were washed with 2×100 ml of H2O and dried over Na2SO4. After removing the solvent in vacuo, (1.1) were obtained as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][Cl:24])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NCCc1ccccc1CO)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1ccccc1CCl)c1ccc([N+](=O)[O-])cc1
Yield: 96.7 %

Procedure:
1-(4-Nitrobenzoyl)amino-2-(2-hydroxymethylphenyl)ethane (15.3 g) was dissolved in 200 ml of chloroform, and with stirring under ice cooling, 15.9 g of phosphorus pentachloride was added gradually. The mixture was stirred at room temperature for 8 hours, and then the solvent was distilled off. The residue was dissolved in benzene, washed in water, and dried, followed by distilling off the solvent. The residue was recrystallized from benzene-n-hexane to afford 15.7 g of 1-(4-nitrobenzoyl)amino-2-(2-chloromethylphenyl)ethane having a melting point of 125.9° to 126.3° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([O:14][C:15](=[O:23])[CH:16]=[CH:17]N1CCCC1)[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[N:2][O:1][CH:17]=1)=[O:23])[CH3:13]
Reactant: Cc1ccccc1C(Cl)=NO
Reactant: CCOC(=O)C=CN1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1conc1-c1ccccc1C
Yield: 47 %

Procedure:
To a stirred solution of N-hydroxy-2-methylbenzenecarboximidoyl chloride (2.07 g, 12.2 mmol, 1.0 equiv) in diethyl ether (15 mL) was added a solution of 3-pyrrolidin-1-yl-acrylic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 4,187,099) (2.06 g, 12.2 mmol, 1.0 equiv) and triethylamine (1.48 g, 12.2 mmol, 1.0 equiv) in diethyl ether (30 mL) dropwise over 15 minutes. The resultant mixture was stirred at ambient temperature for 16 hours, partitioned between water and diethyl ether and separated. The aqueous phase was extracted with diethyl ether (2×), and the combined ethereal extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane) gave 1.32 g (47%) of 3-o-tolyl-isoxazole-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 9.02 (s, 1H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 3H), 4.19 (q, 2H), 2.23 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[C:30]([CH3:36])=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1>>[CH3:36][C:30]1[C:29]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:34][CH:33]=[C:32]([CH3:35])[N:31]=1
Reactant: Cc1ccc(Br)c(C)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c(C)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 3-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method 2 tR=1.012, m/z=463.1; 1H NMR (CDCl3) 1.32 (m, 2H), 1.49 (d, 3H), 1.62 (m, 2H), 1.86-1.96 (m, 2H), 2.17-2.29 (m, 3H), 2.31 (s, 3H), 2.49 (s, 3H), 2.93 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.88-7.03 (m, 7H), 7.25 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=O.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: [H][H]
Reactant: COc1c(C(=O)CCC(=O)O)ccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: COc1c(CCCC(=O)O)ccc2c1CCCC2
Reaction time: 6 h

Procedure:
42 g (0.15 mol) of 3-(1-methoxy-2-naphthoyl)propionic acid [cf. W. I. Awad, F. G. Badder, A. E. Marei, J. Chem. Soc. 1954, p. 4538] are hydrogenated for 6 h at 60° C. and 30 bar of hydrogen in 800 ml of ethanol in the presence of 12 g of palladium/animal carbon (10% strength) as a catalyst. The catalyst is filtered off, the solution is evaporated and the residue is flash chromatographed on silica gel using methylene chloride/methanol 10:1 as the eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Yield: 78.6 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL COCl2. The resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) and pyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:20](O)(=O)[CH:21]=[O:22].C(O)C>C(O)(=O)C>[Cl:15][C:14]1[C:9]([C:4]2[CH:3]=[C:2]3[C:7]([N:8]=[CH:20][C:21](=[O:22])[NH:1]3)=[CH:6][CH:5]=2)=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=1
Reactant: O=CC(=O)O
Reactant: Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1N
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1cnc2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
A mixture of 10.0 g of 2-(3,4-diaminophenyl)-3-chloro-5-trifluoromethylpyridine, 5.7 g of a 50% strength by weight aqueous glyoxalic acid solution, 100 ml of ethanol and 50 ml of glacial acetic acid was stirred at 23° C. for 2.5 hours. The solid portion formed was separated off, washed with ethanol and dried. After concentrating, the filtrate gave a further amount of the products. Total yield: 87% (9.9 g of colorless crystals); isomeric ratio according to 1H-NMR=about 1:1).