Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[C:11]([CH:12]=O)=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:3]([C:7]1[C:11]([CH2:12][NH:2][CH3:1])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CN
Reactant: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(C)(C)C)n2)sc2c1CCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NC)CCCC3)nc1C(C)(C)C
Reaction time: 17 h
Yield: 31.9 %

Procedure:
Methylamine (45.0 mg, 50 μl, 1.449 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (100 mg, 0.248 mmol) and acetic acid (100 μl, 1.74 mmol) in DMF (1 mL). Sodium triacetoxyborohydride (527 mg, 2.484 mmol) was added and the reaction stirred for 17 h. The reaction was quenched with water (500 μl) and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and eluted with 2M NH3 in MeOH. Volatiles were blown down under a nitrogen atmosphere to yield the title product (33 mg, 0.079 mmol, 32%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9](Cl)=[O:10])(=[O:6])=[O:5].[CH:12]([S:14][CH2:15][CH2:16][NH2:17])=[CH2:13].C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:17][CH2:16][CH2:15][S:14][CH:12]=[CH2:13])=[O:10])(=[O:6])=[O:5]
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Reactant: C=CSCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CSCCNC(=O)CCS(=O)(=O)CCCl
Reaction time: 2 h

Procedure:
A solution of 5.92 g 3-(2-chloroethylsulphonyl)-propionyl chloride in 75 ml dichloromethane was treated dropwise with a solution of 2.65 g 2-vinylthioethylamine and 2.6 g triethylamine in dichlormethane. After 2 hours, the solution was evaporated and the residue recrystallised from aqueous ethanol. Yield 6.1 g; Mp. 102° to 103° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19]C)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1>Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[OH:19])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: COc1ccc(Cc2ccc(C(=O)O)nc2)cc1OC
Agent: Br
Product: O=C(O)c1ccc(Cc2ccc(O)c(O)c2)cn1
Yield: 59.4 %

Procedure:
Twenty milliliters of 48% hydrobromic acid were added to 1.5 g of 5-(3,4-dimethoxybenzyl)picolinic acid. The mixture was heated under reflux for 6 hours. After allowing to cool, crystals formed were collected by filtration. The crystals were dissolved in 10% aqueous ammonia, treated with active carbon and adjusted to pH 2-3 with dilute hydrochloric acid to form crystals. The crystals were collected by filtration to obtain 0.8 g of 5-(3,4-dihydroxybenzyl)picolinic acid as reddish brown crystals of a decomposition point of 246°~249° C.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH:19]=[CH:18][NH:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30]>CN(C)C=O>[CH2:29]([NH:31][C:32]([N:17]1[C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH:19]=[CH:18]1)=[S:33])[CH3:30]
Reactant: CCN=C=S
Reactant: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=S)n1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of pyrrolo-pyridine 16 in dimethylformamide under an atmosphere of nitrogen and 3 equivalents of di-iso-propylethylamine (3 eq.) was added 3 equivalents of ethylisothiocyanate. The reaction mixture was stirred in a microwave at 100° C. for 3 hours. The crude reaction mixture was concentrated in vacuo and purified by column chromatography to afford compound 17e. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.42 (m, 3H) 3.68-3.93 (m, 2H) 6.72-6.90 (m, 1H) 7.19-7.38 (m, 1H) 7.42-7.64 (m, 2H) 7.77-7.96 (m, 2H) 8.27-8.59 (m, 1H) 8.61-8.81 (m, 1H) 12.10-12.38 (m, 1H) 12.37-12.57 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.O.[SH2:17].[Na]>CO>[SH:17][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Reactant: S
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(S)n2nc(C)nc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
Methyl 7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate (0.80 g) (3.53 mmol) are suspended in 35 ml of methanol and treated with 0.78 g (10.6 mmol) of sodium hydrogen sulphide hydrate. After stirring at 60° C. for 5 hours the mixture is concentrated and the residue is dissolved in 20 ml of water. The solution is acidified to pH 3 with 3N aqueous hydrochloric acid. The separated product is filtered off under suction and washed with water and methanol. After recrystallization from methanol/dichloromethane there is obtained 0.66 g of methyl 7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxylate as yellow crystals of melting point 237° C. (dec.).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>CN(C)C=O.C(OCC)(=O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(I)cc1
Temperature: 115 °C

Procedure:
To a solution of 4-iodoaniline (4.03 g, 18.4 mmol) in N,N-dimethylformamide (20 mL) was added isatoic anhydride (3.00 g, 18.4 mmol), and the reaction mixture was heated at 115° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give 2-amino-N-(4-iodo-phenyl)-benzamide as white solid. Yield: 1.50 g (24%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([C:14]1[C:15](/[N:23]=[CH:24]/[N:25]([CH3:27])C)=[N:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)#N.O>C(O)(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]2[C:27]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:25][CH:24]=[N:23][C:15]=2[N:16]=1)([CH3:21])[CH3:22]
Reactant: CC(C)c1ccc(C#N)c(/N=C/N(C)C)n1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cccc(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
To methyl 3-aminobenzoate (0.50 g, 3.31 mmol) in acetic acid (10 mL) was added (E)-N′-(3-cyano-6-isopropylpyridin-2-yl)-N,N-dimethylformimidamide (0.71 g, 3.31 mmol) and the mixture was stirred at 120° C. for 25 minutes. Reaction mixture was cooled to room temperature and a solid formed. Water was added and solid was collected by filtration. Purification by chromatography on silica gel eluting with 0-30% methanol in dichloromethane gave the title compound (1.05 g, 98% yield).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([N+:16]([O-:18])=[O:17])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N:19]12[CH2:26][CH2:25][CH2:24][C:23]1([CH2:27][NH2:28])[CH2:22][CH2:21][CH2:20]2>>[N:19]12[CH2:26][CH2:25][CH2:24][C:23]1([CH2:27][NH:28][C:2]1[C:3]3[C:8]([C:9]([N+:16]([O-:18])=[O:17])=[C:10]4[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21][CH2:20]2
Reactant: O=[N+]([O-])c1c2ccccc2c(Br)c2ccccc12
Reactant: NCC12CCCN1CCC2
Product: O=[N+]([O-])c1c2ccccc2c(NCC23CCCN2CCC3)c2ccccc12
Yield: 51.5 %

Procedure:
9-Bromo-10-nitroanthracene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 51.5%.
Reaction SMILES: [C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([O:7]CC)=[O:6])#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: CCOC(=O)CC(C#N)=CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C=C(C#N)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-cyano-5-methylhex-3-enoate (mixture of E and Z isomers) and lithium hydroxide hydrate are suspended in a mixture of tetrahydrofuran and water. The slurry is vigorously stirred for 4 hours at room temperature. The mixture is acidified to pH 2 (3N HCl) and extracted into ethyl acetate (3×150 mL). The combined organic layers are dried (MgSO4), and the solvent is removed in vacuo to give crude 3-cyano-5-methylhex-3-enoic acid. The crude acid is dissolved in ethyl acetate (400 mL), and a solution of tert-butylamine in ethyl acetate (20 mL) is added. The temperature of the solution rises approximately 10° C. as a mass of white crystalline solid precipitates. The product is collected by filtration and dried in vacuo. Yield 22.15 g, 97.9 mmol, 89%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1
Reactant: C1CCNCC1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccccc3)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
100 mg of 6-[[2-chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2.5 ml of piperidine, and the mixture was stirred for 5 hours at 100° C. It was concentrated by evaporation to a very large extent in a vacuum, mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 30 mg was obtained.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]1=2.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O>[C:19]1([CH2:18][N:1]2[C:10](=[O:11])[CH2:9][CH2:8][C:7]3[N:6]=[CH:5][C:4]4[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=4[C:2]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ncc3ccccc3c2N1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2ncc3ccccc3c2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A stirred solution of 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (3.97 g) in dimethylsulfoxide (sieve dried, 80 ml) was treated sequentially with powdered potassium hydroxide (2.64 g of 85% KOH) and benzyl bromide (3.76 g). The solution was stirred for 1.5 hours at ambient temperature, transferred to a separatory funnel, diluted with water (400 ml) and extracted with ethyl acetate (2×250 ml). The organic phase was washed with water (2×200 ml), dried (Na2SO4), filtered and evaporated to give a solid (4.9 g). Recrystallization from 95% ethanol (32 ml) gave 3.35 g of crystals, m.p. 153.5°-155.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:14]([O:21][CH2:22]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOCCOC>[CH2:14]([O:21][CH2:22][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)C(=O)c1cccn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
Methyl pyrrol-2-ylglyoxylate (306 mg) in diglyme was treated with sodium hydride (63 mg) and stirred at room temperature for 3 hr. Benzyloxymethyl chloride (376 mg) was added and the mixture stirred at room temperature for a further 3 hr. The suspension was filtered and the filtrate evaporated. The residue, in ether, was washed with sodium bicarbonate solution, water and dried. Evaporation gave the crude product as a brown oil (530 mg). Purification by preparative thin-layer chromatography gave the title compound as a colourless oil (250 mg, 46%); τ values (DMSO-d6) include 6.10 (--CH3), 4.20 (>N-CH2 -), 5.47 (--OCH2 --), 2.70 (-Ph).
Reaction SMILES: [H-].[Na+].[S:3]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:6]1)(=[O:5])=[O:4].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:6]1[C:7](=[O:8])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:3]1(=[O:4])=[O:5]
Reactant: BrCCCCBr
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A 60% sodium hydride in mineral oil (1.1 g) was added to dry dimethylformamide (50 ml) at room temperature while stirring. Saccharin (5 g) was gradually added to the suspension at room temperature, followed by stirring for 30 minutes. To the resultant mixture, 1,4-dibromobutane (29.5 g) was dropwise added, and the mixture was kept at an inner temperature of 90° to 100° C. for 5 hours. After completion of the reaction, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform as an eluent to give the objective compound (7.98 g). IR νmaxfilm (cm-1): 1730, 1595, 1460, 1440, 1330.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([N+:21]([O-])=O)=[C:19]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([NH2:21])=[C:19]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (647 mg, 1.3 mmol) was dissolved in ethyl acetate under nitrogen and then 10% Pd/C was added. The mixture was stirred at room temperature for 4 hours to afford 4-[5-amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester as a tan solid (535 mg, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.77-1.67 (m, 4H), 1.48 (s, 9H), 3.04 (s, 3H), 3.31-3.24 (m, 2H), 3.82 (m, 2H), 5.32 (m, 1H), 6.96 (s, NH), 7.53 (t, NH), 7.70 (t, 1H), 7.71 (d, 2H), 8.16 (s, 1H). Exact mass calculated for C21H29N5O5S 463.19, found 464.3 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][Mg]Br>C1COCC1>[CH3:12][C:8]1([OH:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a cooled (−78° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (1 equiv) in THF (0.64 M) was added a solution of methylmagnesium bromide (1.8 equiv, 3 mol/L in ether) dropwise under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 20 minutes, then warmed to −30° C. for 30 minutes and then stirred at 0° C. for 30 minutes. After the reaction was complete, the resulting mixture was quenched with saturated aqueous ammonia chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a white solid (92% yield), which was used in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-d1) δ ppm 4.00-3.91 (m, 4H), 1.95-1.80 (m, 3H), 1.77-1.67 (m, 4H), 1.59-1.58 (m, 1H), 1.27 (s, 3H), 1.17 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[C:18](=[O:25])[O:19][C:20]2=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([N:16]1[C@H:17]([C:18](=[O:25])[NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22][C@@H:21]1[C:20]([OH:19])=[O:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)C2CCC1N2Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)[C@H]1CC[C@@H](C(=O)NCc2ccccc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzylamine (25.7 g, 0.24 mol) was added to an ice cold solution of 8-benzyl-3-oxa-8-azabicyclo[3.2.1]octan-2,4-dione (0.24 mol; from step (a) above) in CH2Cl2 (1 L). The solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in Et2O and extracted with 2 N NaOH solution. The aqueous base layer was separated and acidified to pH 4. The precipitated product was collected and dried to afford 49.5 g (61% for two steps) of the sub-title compound as a tan solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:15][OH:16]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
To a solution of 3-(trifluoromethoxy)phenol (3 g, 16.8 mmol) in DMF (30 mL) was added 2-bromoethanol (3.16 g, 25.3 mmol), potassium carbonate (4.65 g, 33.7 mmol). The mixture was heated at 80° C. overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by a column chromatography eluting with petroleum ether and ethyl acetate (10:1) to give 2-(3-(trifluoromethoxy)phenoxy)ethanol (3.5 g, 94.5% yield) as a yellow oil. 1H-NMR (DMSO-d6) δ 7.28-7.30 (t, 1H), 6.81-6.86 (m, 2H), 6.78 (s, 1H), 4.07-4.09 (t, 2H), 3.95-3.99 (m, 2H), 2.58 (t, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[C:19]([CH2:20]O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[CH2:20][O:22]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccnc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(CN2CCC3(CC2)OCc2cccnc23)cc1
Yield: 63.2 %

Procedure:
To a solution of 1.1 g (3.5 mmol) 1′-benzyl-3-hydroxymethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol and 1.0 ml (7.4 mmol) triethylamine in 35 ml dry tetrahydrofuran were added 0.26 ml (3.3 mmol) methane sulfonyl chloride at room temperature. The reaction mixture was heated at reflux for 1 h and then quenched with water. The aqueous layer was basified with aqueous 1 M sodium hydroxide and extracted with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (0.62 g, 62%) as a light yellow amorphous solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:23][C:22]([C@:8]2([F:25])[C@@H:7]3[C@H:9]2[CH2:10][C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C@@:6]3([NH2:5])[C:26]([OH:28])=[O:27])=[O:24])=[CH:32][CH:31]=1
Reactant: OCc1ccc(F)cc1
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Solvent: O=S(Cl)Cl
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
23 μL of thionyl chloride was added to 30 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 0.3 mL of 4-fluorobenzyl alcohol at room temperature, and the mixture was stirred for 3 days at 60° C. After standing to cool, the reaction solution was purified by reverse phase chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.) eluent: water, a 70% aqueous solution of acetonitrile), thereby yielding 5 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(4-fluorobenzyl)ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CS(O)(=O)=O>C(Cl)Cl>[C:11]12([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([O:9][CH3:10])[C:5]=3[OH:8])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: COc1cc(Br)ccc1O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1O
Temperature: 54 °C
Yield: 75.3 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (2.00 g, 9.85 mmol), 1-adamantanol (1.50 g, 9.85 mmol), and MeSO3H (0.8 mL) in CH2Cl2 (8 mL) was stirred with heating at 54° C. (oil-bath) for 18.3 h. The resulting solution was quenched with H2O (30 mL) and extracted with EtOAc (120 mL). The extract was washed with 5% NaHCO3 and brine and dried. The residue obtained on concentration was purified on silica gel (4% EtOAc/hexane) to give 2.5 g (76%) of 2-(1-adamantyl)-4-bromo-6-methoxyphenol as a white solid, mp 157-159° C. IR 3510, 2903, 2850, 1413, 1217 cm−1; 1H NMR δ (CDCl3) 1.76 (bs, 6H, AdCH2), 2.07 (bs, 9H, AdCH and AdCH2), 3.87 (s, 3H, OCH3), 5.90 (s, 1H, OH), 6.86 (d, J=2.4 Hz, 1H, 5-ArH), 6.95 ppm (d, J=2.4 Hz, 1H, 3-ArH).