Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]([OH:40])=O)[N:33]=[CH:32]1.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=1)[C:43]([N:45]1[CH2:48][C:47]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46]1)=[O:44]>CN(C=O)C>[CH:54]1([C:47]2([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46][N:45]([C:43](=[O:44])[C@H:42]([NH:41][C:38](=[O:40])[CH2:37][CH2:36][C:34]3[N:33]=[CH:32][NH:31][CH:35]=3)[CH2:60][C:61]3[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=3)[CH2:48]2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: CCCCCC1(C2CCCCC2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC1(C2CCCCC2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
100 mg (0.311 mmol) of TBTU and 0.1 ml (0.715 mmol) of triethylamine are added to 55 mg (0.311 mmol) of 3-(1H-imidazol-4-yl)propionic acid hydrochloride in 1 ml of DMF. After 10 minutes, 99 mg (0.256 mmol) of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one dissolved in 1 ml of DMF are added. After stirring for 118 hours at ambient temperature, the reaction medium is extracted with a 1/2 heptane/EtOAc mixture and washed with 1N sodium hydroxide and a saturated sodium chloride solution. The organic phase is dried over MgSO4, filtered and concentrated. The residue is purified on a silica column (eluent 9/1 DCM/MeOH). 72 mg of N—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder, with a yield of 55%.
Reaction SMILES: [C:1]1([N:7]2[CH:16]=[C:15]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C>[CH:17]1([N:12]2[CH2:13][CH2:14][C:15]3=[CH:16][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[CH2:10][CH2:11]2)[CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCC1
Reactant: c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 46) (39 mg, 0.18 mmol) in dichloromethane (4 ml) was added 3 drops of acetic acid, cyclobutanone (28 μl, 0.36 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour. The resulting reaction mixture was acidified with 2M hydrochloric acid and applied to an pre equilibrated ion exchange cartridge (SCX), washed with methanol and then a 2M ammonia in methanol solution. The basic fractions were then evaporated in vacuo to afford the title product (E45); MS (ES+) m/e 268 [M+H]+ as a 95:5 mixture of the title compound and 7-cyclobutyl-2-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-c]azepine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH2:19][Br:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(CBr)c(C#N)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (1.00 g, 3.48 mmol), N-bromosuccinimide (0.650 g, 3.65 mmol), and benzoyl peroxide (0.0421 g, 0.174 mmol) in carbon tetrachloride (10 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was diluted with dichloromethane and washed with water. The organic layers were dried over magnesium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to give the desired product (0.57 g, 45%). LCMS calculated for C16H11BrClFNO (M+H)+: m/z=366.0; Found: 366.0.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.Cl[CH2:21][CH:22]=O.C([O-])(O)=O.[Na+].CCOC(C)=O>CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:21]=[CH:22][N:12]=[C:7]3[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: O=CCCl
Reactant: CC[C@@H]1C(N)=Nc2cnc(Cl)nc2N1C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H]1c2nccn2-c2cnc(Cl)nc2N1C1CCCC1
Temperature: 68 °C

Procedure:
(R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydropteridin-6-amine (177 mg, 0.64 mmol) in MeOH (1.5 mL) treated with 50% aqueous chloroacetaldehyde (131 μL, 1.3 Eq.) and the reaction mixture heated to reflux for 6 hours. A further portion of 50% aq. chloroacetaldehyde (400 μL, 3.0 Eq.) was added, and the reaction mixture heated to 68° C. overnight. NaHCO3 (aq. sat.) and EtOAc was added, and the aqueous was further extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH:27]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33])([CH3:29])[CH3:28]>>[CH:27]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:33][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:19])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC(C)OC(=O)[C@@H](N)Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to phenylalanine isopropyl ester trifluoroacetate using the procedure described in Method 3 to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>CC(O)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-Aminophenyl)propanoic acid (8.45 g, 51.2 mmol) in AcOH (70 mL) was added HNO3 (60%, 5.66 g) at room temperature. The reaction mixture was refluxed for 4 hrs then cooled to room temperature. The mixture was poured into iced water (200 mL), and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[N+:13]=[N-:14]>>[ClH:1].[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: [N-]=[N+]=NCc1ccco1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 72.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.068 g, 0.399 mmol) was reacted with 2-azidomethyl furan (0.059 g, 0.478 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.085 g, 72%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (s, 1H), δ 7.53 (s, 1H), δ 6.59 (t, 1H), δ 6.49 (s, 1H), δ 6.44 (dd, 1H), δ 3.05 (t, 2H), δ 2.89 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 156.4, 154.9, 147.5, 144.1, 126.0, 125.1, 123.8, 110.7, 109.3, 69.8, 23.8, 17.4 ppm; HRMS (ESI) calcd for C12H14N6O (M+) 259.1301. found 259.1305.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:32])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:45][C:46]1[NH:50][N:49]=[N:48][N:47]=1>CN(C=O)C.C(#N)C>[Br:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:45][C:46]4[NH:50][N:49]=[N:48][N:47]=4)=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:32])[CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(C)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC[C@H](c1ccc(C(=O)Nc2nnn[nH]2)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoic acid (25.0 mg, 0.047 mmol) and CDI (26 mg, 0.16 mmol) in DMF (1.0 mL) was stirred at RT for 30 minutes in a sealed tube, then 5-amino-1H-tetrazole (23.0 mg, 0.260 mmol) was added. The mixture was heated at 100° C. for 12 hours, allowed to cool to RT, then diluted with acetonitrile. The mixture was purified by preparative reverse phase HPLC eluting with 47-100% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.98 (br, 1H); 7.91 (d, J=8 Hz, 2H); 7.84 (br, 1H); 7.65 (d, J=8 Hz, 2H); 7.61 (d, J=8 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 7.35 (br, 1H); 4.88 (d, J=12 Hz, 1H); 3.79 (t, J=11 Hz, 1H); 2.41 (s, 3H); 1.50-1.52 (m, 1H); 1.23-1.30 (m, 1H); 0.92 (q, J=7 Hz, 2H); 0.68 (t, J=7 Hz, 3H). LC2: 2.70 min. (M+H)+ 594.
Reaction SMILES: C1(C2(C(O)=[O:13])CCCC2)C=CC=CC=1.[C:15]1([C@@H:21]([N:23]2[CH2:27][C@@H:26]3[CH:28](N)[CH2:29][CH2:30][C@@H:25]3[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:15]1([C@@H:21]([N:23]2[CH2:27][C@H:26]3[C:28](=[O:13])[CH2:29][CH2:30][C@H:25]3[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](c1ccccc1)N1C[C@H]2CCC(N)[C@H]2C1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: C[C@@H](c1ccccc1)N1C[C@@H]2CCC(=O)[C@@H]2C1

Procedure:
The title compounds were prepared by substituting (S)-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aR,6aS)-2-((S)-1-phenylethyl)octahydrocyclopenta[c]pyrrol-4-amine for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Examples 1 and 2.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([Cl:14])=[O:4]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=O)c1cccs1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetic acid (8 g, 51.2 mmol), suspended in DCM (80 ml) and cooled to 5° C., is added oxalylchloride (5.3 ml, 61.5 mmol), followed by DMF (0.1 ml). Stirring is continued for 1 hour at 5° C. and 18 hours at room temperature. The reaction mixture is evaporated to dryness, toluene is then added and the mixture evaporated once more to give the title compound as a dark oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][N:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)[S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COc1cccc(CBr)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Product: COc1cccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C(=O)O)cc2)c1
Yield: 35 %

Procedure:
Prepared as in Example 5-5 from 1-(bromomethyl)-3-methoxybenzene and 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 572b). Yield 35%. MS M+H calculated 402.3, found 402.0.
Reaction SMILES: [S:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O)[C:2]#[N:3].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:3][C:2](=[O:18])[S:1][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: N#CSCC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 22.52 g (91.8 mmole) of 2-thiocyanato-1-(4-trifluoromethyl-phenyl)-ethanone 9 mL of 50% aqueous sulfuric acid and 45 mL of acetic acid was heated at reflux for 1.5 hours. The mixture was cooled, poured into 500 mL of ice water and stirred for 30 minutes. The solid was collected by filtration, washing with water, to give 21.33 g of 4-(4-trifluoromethyl-phenyl)-3H-thiazol-2-one as a tan solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:15]1[O:16][N:17]=[C:18]2[CH:23]=[C:22]([C:24](Cl)=[O:25])[CH:21]=[CH:20][C:19]=12>ClCCl>[CH:1]1([NH:7][C:24]([C:22]2[CH:21]=[CH:20][C:19]3=[N:15][O:16][N:17]=[C:18]3[CH:23]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1ccc2nonc2c1
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of cyclohexylamine (1 ml) and triethylamine (1.7 ml) in dichloromethane (20 ml) was added a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (730 mg, 4 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was triturated with ether to give a white solid (265 mg, yield=27%). Mp=172-173° C., 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.90 (d, 1H, J=9.0 Hz); 7.82 (d, J=9.0 Hz, 1H); 6.09 (“s”, NH, 1H), 4.05-3.97 (m, 1H) and 2.09-1.18 ppm (m, 10H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C@@H:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C@@:6]([Cl:10])([CH3:9])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:10][C@@:6]1([CH3:9])[C@H:5]([C:11]([O:13][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])[N:4]2[C:27](=[O:28])[C@@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:3]2[S:8][CH2:7]1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of benzhydryl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (209 mg) in methylene chloride (3 ml) is added triethylamine (56 mg), and the mixture is mixed with a solution of phenoxyacetyl chloride (79 mg) in methylene chloride (2 ml) under ice cooling. After being left to stand for 2 hours, the mixture is washed successively with dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate, and water, then dried, and evaporated in vacuo. Recrystallization of the residue with a mixture of ether and petroleum ether gives benzhydryl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (220 mg). Yield: 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([O:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.O.C[C@@H](N)C1C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@H:20]([O:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(C(=O)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: C[C@@H](N)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CCO[C@@H](C(=O)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 16.5 h

Procedure:
To a stirred suspension of racemic ethoxy-acid 53 (100 g, 0.27 mol) in acetone:water mixture (9:1, 900 ml) was added a solution of R-(+)-alpha methylbenzylamine (35 ml, 0.27 mol) acetone:water (9:1, 100 ml) in a dropwise manner. The resulting mixture was stirred for 16-17 hours, filtered to separate the solid and neutralise with acetic acid. The process was repeated several times to get (−)-ethoxy acid 54 (18 g, 98-99% e.e by HPLC).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Br)cc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Br)cc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4-dibromoaniline to yield 2-[(2,4-dibromophenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:15]1([CH:12]2[CH2:13][CH2:14][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCC(c2ccccc2)C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of (4-Bromo-phenyl)-(3-phenyl-pyrrolidin-1-yl)-methanone would be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would be filtered through Celite and concentrated in vacuo. The residue would be diluted with water and extracted with ethyl acetate. The combined organic phases would be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material would be purified by flash chromatography to afford product.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1ccoc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.5 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and morpholine (0.5 mL, 5.71 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (670 mg, 89%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:21]([CH2:1][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(COc2cccc(C=O)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a stirred solution of methyl 4-((3-formylphenoxy)methyl)benzoate (464 mg, 1.72 mmol) in anhydrous DCM (8 mL) was added aniline (0.63 mL, 6.87 mmol) followed by glacial acetic acid (0.46 mL, 6.87 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (1.52 g, 6.87 mmol) was added and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with DCM (100 mL). The organic layer was washed with 1 N HCl (3×30 mL) and saturated aqueous NaHCO3 (30 mL) and passed through a hydrophobic fit. The solvent was removed in vacuo to afford the title compound as an oil that solidifies on standing (380 mg, 64% yield).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH3:10][CH2:11][O:12]CC>C(O)C>[ClH:1].[CH2:8]([O:7][C:5]([CH2:4][C:2](=[NH:3])[O:12][CH2:11][CH3:10])=[O:6])[CH3:9]
Reactant: CCOCC
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCOC(=N)CC(=O)OCC
Reaction time: 8 h

Procedure:
Hydrochloric acid gas is passed at 0°-10° C. into a solution of 678 g (6 mol) of ethyl cyanoacetate in 400 ml of ethanol and 3 1 of ether for 7 h, the mixture is allowed to stand overnight at 25° C., and the deposited solid is filtered off with suction and dried in vacuo.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[K+]>C(O)C.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[CH:32][C:33]=1[CH2:38][C:49]#[N:50]
Reactant: [C-]#N
Reactant: Clc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of the (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran in ethanol (260 mL) and water (130 mL) was added potassium cyanide (31.8 g, 488 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. Purification was accomplished by chromatography to provide the titled compound 39 (105 g, 80%, ca. 2:1 mixture of anomers β:α).