Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].O1CCCC1.[CH3:11][C:12]1[NH:24][C:15]2=[N:16][C:17]3[C:22]([N:23]=[C:14]2[N:13]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3>N1C=CC=CC=1>[CH3:5][O:4][C:2]([N:13]1[C:14]2=[N:23][C:22]3[C:17]([N:16]=[C:15]2[N:24]=[C:12]1[CH3:11])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:3]
Reactant: COC(=O)Cl
Reactant: Cc1nc2nc3ccccc3nc2[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)n1c(C)nc2nc3ccccc3nc21
Reaction time: 17 h

Procedure:
A solution of 6 parts of methyl chloroformate in 50 parts of tetrahydrofuran was added over 30 minutes to a suspension of 4 parts of 2-methyl-1H-imidazo[4,5-b]quinoxaline in 200 parts of tetrahydrofuran and 6 parts of pyridine. The heterogeneous reaction mixture was stirred at 25° for 17 hours. Concentration in vacuo, addition of 200 parts of CH2Cl2, washing with 500 parts of 5% HCl, drying over sodium sulfate, and concentrating in vacuo left a pale yellow solid. Recrystallization from chloroform-hexane gave almost colorless 1-methoxycarbonyl-2-methyl-1H-imidazo[4,5-b]quinoxaline, m.p. 184° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)=[O:21])=[CH:5][CH:4]=1.[C:33]1([NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:40][C:28]([C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:20]([C:10]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:21])=[CH:25][CH:26]=1)=[O:30]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A solution of 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoic acid (0.213 g, 0.5 mmol) and phenylenediamine (0.108 g, 1.0 mmol) in DMF (10 ml) was cooled to 0° C. Triethylamine (0.40 ml, 2.87 mol), 1-hydroxybenzotriazole (0.101 g, 0.75 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.144 g, 0.75 mmol) were added subsequently, and the mixture was stirred for 2 h at 0° C., and for an additional 96 h at room temperature. Ethyl acetate (40 ml) was added, and the obtained solution was washed with water (7 ml), Na2S2O3 1N (7 ml, aqueous solution), water (7 ml), NaHCO3 (7 ml, saturated aqueous solution), and NaCl (7 ml, saturated aqueous solution), dried over Na2SO4 and evaporated under reduced pressure, to obtain 0.142 g (0.27 mmol) of N-(4-{[(2-aminophenyl)amino]carbonyl}benzyl)-3-(4-methoxyphenyl)-5-Phenyl-1H-pyrrole-2-carboxamide: Yield 55%; m.p. 142-143° C. (dec); IR 3407, 3296, 1627, 1530, 1493, 1246 cm−1; 1H-NMR (300 MHz, δ ppm, DMSO-d6) 11.54 (s, 1H), 9.61 (s, 1H), 7.95 (d, J=7.8 Hz, 3H), 7.80 (d, J=7.4 Hz, 2H), 7.45-7.38 (m, 6H), 7.26 (t, J=7.3 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 6.97 (dt, J=8.0 Hz, J′=1.4 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.79 (dd, J=7.9 Hz, J′=1.1 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 6.60 (dt, J=7.5 Hz, J′=1.0 Hz, 1H), 4.86 (s, 2H), 4.49 (d, J=5.7 Hz, 2H), 3.77 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 165.0, 161.1, 157.9, 143.0, 142.9, 133.1, 132.9, 131.5, 129.9, 128.6, 127.9, 127.8, 127.7, 127.1, 126.7, 126.6, 126.4, 124.5, 123.3, 122.6, 116.2, 116.1, 113.4, 108.3, 55.0, 42.1.
Reaction SMILES: Br[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:32])=[O:28]
Reactant: O=C(O)CC1(Br)OC2=CC=CC2=CC1c1ccccc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: C1=CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid (12.1 g., 0.0365 mole) and cyclohexene (3.3 g., 0.04 mole) in 100 ml. of chloroform is treated with 5 g. of dinitrogen tetroxide in 20 ml. of chloroform dropwise. The mixture is stirred for 16 hours at about 25° C. then at 50°-55° C. for about 20 minutes. The mixture is washed with water, and the organic layer is treated with an aqueous base. The aqueous layer is acidified, then extracted with dichloromethane. The organic layer is washed thrice with water, dried and evaporated. Two recrystallizations from benzene give light yellow solid 2-nitro-3-phenyl-4-benzofuranacetic acid, m.p. 187.5°-189.5° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:26]C4C=CC=C(O)C=4)[CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])=O)(C)(C)C.[ClH:34].[O:35]1[CH2:40][CH2:39]OCC1>>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:26])[CH:21]=3)[NH:16][C:15]=2[CH:14]1[C:15]1[CH:14]=[C:40]([OH:35])[CH:39]=[CH:22][CH:23]=1)=[O:12].[ClH:34]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCc2c([nH]c3ccc(Cc4cccc(O)c4)cc23)C1
Agent: Cl
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CCN)C3c1cccc(O)c1

Procedure:
(tert-Butoxy)-N-{3-[1-(3-hydroxyphenyl)-6-methyl-(1,2,3,4-tetrahydro-beta-carbolin-2-yl)]-3-oxopropyl}carboxamide was treated with HCl in dioxane (4 N, 10 equiv) for 30 min, and the solvent was removed to give 3-(2-beta-alanyl-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)phenol 15 as its HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCCC1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.ClC1C=CC(O)=CC=1[F:78].ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C@H:14]([C@H:13]2[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:15])=[CH:18][C:19]=1[F:78]
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)c(F)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 4-Chloro-3-fluoro-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 581.5 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:21]([O:24]C(=O)C)(=O)[CH3:22].C([O-])(=O)C.[K+].[N:33](OCCC(C)C)=O>C1(C)C=CC=CC=1>[C:21]([N:1]1[C:2]2[C:3](=[C:4]([O:5][C:6]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:7]=3[C:8]([O:10][CH3:11])=[O:9])[CH:17]=[CH:18][CH:19]=2)[CH:20]=[N:33]1)(=[O:24])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCON=O
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(N)c1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1cnn2C(C)=O
Temperature: 80 °C

Procedure:
A mixture of EXAMPLE 446A (1.0 g), acetic anhydride (0.734 mL), and potassium acetate (0.428 g) in toluene (20 mL) was stirred at room temperature for three hours. To the flask was added isoamyl nitrite (1.03 mL). The reaction mixture was heated at 80° C. for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:20])[C:10]=2[C:16]([F:19])([F:18])[F:17])[N:5]=1.C(C1C(C)=C([O:34][C:35]([CH:37]2[CH2:39][CH2:38]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([O:15][C:35]([CH:37]2[CH2:39][CH2:38]2)=[O:34])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:20])[C:10]=2[C:16]([F:17])([F:19])[F:18])[N:5]=1
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: Cc1nc2ccc(F)c(C(F)(F)F)c2c(O)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(F)c(C(F)(F)F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h

Procedure:
In 3 ml dimethyl formamide was suspended 18.8 mg of 60% sodium hydride. The mixture of 2,3-dimethyl-4-hydroxy-5-trifluoromethyl-6-fluoroquinoline with 2,3-dimethyl-4-hydroxy-6-fluoro-7-trifluoromethylquinoline (starting material 1) (100 mg) was suspended in 3 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 40.8 mg of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on a silica gel packed column (Varian) (20 g; elution solvent=n-hexane-ethyl acetate (40:1) to (20:1)) to give 27.9 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5-trifluoromethyl-6-fluoroquinoline (compound 61) and 51.3 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-trifluoro -methylquinoline (compound 63). 1H-NMR data are shown in Table 3.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.C([N:36]1[CH2:40][CH2:39][C:38](=O)[CH2:37]1)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:43].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:43])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH:38]2[CH2:39][CH2:40][NH:36][CH2:37]2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)([O-])[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(C2CCNC2)C[C@@H]1CCCB(O)O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 112.2 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-BOC-pyrrolidine-3-one (0.185 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 2.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1,3′-bipyrrolidine-3-carboxylic acid (160 mg, 81%) as an amber solid. NMR (D2O) δ 4.25-4.35 (m, 1 H), 4.00 (dd, J1=12 Hz, J2=5 Hz, 1 H) 3.70-3.95 (m, 3 H), 3.25-3.60 (m, 4 H), 2.45-2.65 (m, 2 H), 2.15-2.25 (m, 1 H), 1.50-1.65 (m, 1 H), 1.15-1.35 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 286.1; MS (m−H2O+1): 268.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].CO>CCOCC>[ClH:25].[CH3:24][O:23][C:22]1[C:17]2[O:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cccc2c(C3CCNCC3)noc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of 4-(7-Methoxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.00 g, 9.03 mmol), HCl (35 mL of a 1 M ether solution, 35.0 mmol), and methanol (25 mL) was stirred at room temperature under nitrogen for 18 h. Ether (75 mL) was added, the mixture stirred at room temperature for 15 min, and the product collected by filtration to afford 2.37 g (98%) of the desired product as a white powder, mp: >250° C.
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].Br[C:15]1[CH:16]=[C:17]([Cl:23])[C:18]([Cl:22])=[C:19]([CH3:21])[CH:20]=1.O1CCCC1.CCCCCC>CN(C)C=O>[Cl:23][C:17]1[CH:16]=[C:15]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])[CH:20]=[C:19]([CH3:21])[C:18]=1[Cl:22]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: Cc1cc(Br)cc(Cl)c1Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=C(c1cc(C)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
In a nitrogen atmosphere, to 19 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, a solution of 2.2 g of 5-bromo-2,3-dichlorotoluene in 10 mL of N,N-dimethylformamide was added and tetrahydrofuran was distilled off under reduced pressure. To the remaining N,N-dimethylformamide solution, 0.26 g of dichlorobis(triphenylphosphine) palladium (II) was added and the resultant mixture was stirred at 100° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 200 mL of a tetrahydrofuran-hexane (2:5) mixture was added to the reaction mixture, followed by filtering off the deposited insoluble substance. The resultant filtrate was washed with water (100 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 2.3 g of the objective substance as a brown oily substance.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH2:7]([OH:10])[CH:8]=[CH2:9]>C1C=CC=CC=1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([O:10][CH2:7][CH:8]=[CH2:9])[OH:1]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C=CCO
Solvent: c1ccccc1
Product: C=CCOC(O)C(Cl)(Cl)Cl

Procedure:
A mixture of 7 g of chloral, 2.9 of allyl-alcohol and 15 ml of benzene is left standing for a night at room temperature, then distilled.
Reaction SMILES: [C:1](O)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)(C)C(Cl)=O.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC>C1COCC1>[C:1]([N:27]1[C@@H:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:30][O:29][C:28]1=[O:31])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 222 g (1.5 mol) of trans-cinnamic acid and 250 mL (1.77 mol) of TEA in 3 L of THF at −78° C. was treated with 200 mL of trimethylacetyl chloride maintaining the internal temperature at less than −65° C. The resulting mixture was warmed to 0° C., then cooled to −78° C. In a separate flask, a solution of 4-(S)-benzyl-oxazolidin-2-one in 2.05 L of THF at −20° C. was treated with 660 mL of 2.5 M n-butyllithium in hexanes over 45 min. The resulting turbid mixture was cooled to −78° C. and then transferred via cannula to the flask containing the mixed anhydride. The resulting mixture was allowed to warm to rt and was stirred for 20 h. The reaction was quenched with 300 mL of sat'd NH4Cl; the resulting mixture was partitioned between EtOAc and H2O and the layers were separated. The organic layer was dried over MgSO4. The aqueous layer was extracted with 2×EtOAc; the extracts were dried and all of the organic extracts were combined. Partial concentration in vacuo caused precipitation of a solid; the mixture was diluted with hexanes and allowed to stand at rt for 1.5 h. The precipitate was filtered and dried to afford the title compound: 1H NMR (500 MHz, CDCl3) δ2.86 (dd, J=13.5, 9.5, 1H), (3.38, J=13.5, 3.5, 1H), 4.20-4.27 (m, 2H), 4.78-4.83 (m, 1H), 7.24-7.42 (5H), 7.63-7.65 (m, 1H), 7.92 (app d, J=2.5, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:18](O)([CH3:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)CCc1nc(-c2ccc(Cl)cc2)co1
Yield: 91 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) and isopropanol (30 ml) was added conc. sulfuric acid (0.3 ml), and the resultant was refluxed for 5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer was washed succesively with a saturated sodium hydrogen carbonate aqueous solution and water, and dried over MgSO4. The ether was distilled off to give crystals of isopropyl 4-(4-chlorophenyl)-2-oxazolepropionate (530 mg, 91%). Recrystallization from hexane gave colorless prism crystals of mp 30°-31° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=2)=[C:13]([O:18][CH3:19])[CH:12]=1
Reactant: COc1cc(Br)ccc1O
Reactant: Cn1ccnc1CCl
Agent: Cl
Product: COc1cc(Br)ccc1OCc1nccn1C

Procedure:
The title compound was prepared by substituting 2-chloromethyl-1-methyl-1H-imidazole hydrochloride and 4-bromo-2-methoxyphenol for Example 627A and Example 474, respectively, in Example 627B. MS (ESI) m/e 329 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 7.17 (d, J=1.2 Hz, 1H), 7.11-7.15 (m, 2H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 6.85 (d. J=1.0 Hz, 1H), 5.09 (s, 2H), 3.77 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC(COC(=O)CCCCCCCCCCCCCCC)CSCCC(NCC1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)=O)(=O)CCCCCCCCCCCCCCC.[C:110]([O:114][C:115](=[O:123])[C:116]1[CH:121]=[CH:120][C:119]([NH2:122])=[CH:118][CH:117]=1)([CH3:113])([CH3:112])[CH3:111].P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:110]([O:114][C:115](=[O:123])[C:116]1[CH:117]=[CH:118][C:119]([NH:122][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:120][CH:121]=1)([CH3:113])([CH3:111])[CH3:112]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (2.0 g), 4-aminobenzoic acid t-butyl ester (600 mg) and phosphorus trichloride (207 mg) in pyridine (40 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform) to yield the title compound (2.157 g, yield 99%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4])=[N+:21]=[N-:22]
Reactant: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 68.3 %

Procedure:
A solution of 4.0 g of N-chloracetyl-3-phenylindoline and 1.1 g of sodium azide in 70 ml of 80% aqueous ethanol was refluxed for one hour. After cooling, the solution was diluted with 100 ml of water and extracted with methylene chloride. Evaporation of the solvent gave 2.8 g of the desired N-azidoacetyl-3-phenylindoline having a melting point of 72°-3° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:16]([O:27][C:28](=[O:38])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[C:30]=3[OH:37])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[OH:46]>CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:16]([O:27][C:28](=[O:38])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[OH:46])[C:30]=3[OH:37])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: Nc1ccccc1O
Reactant: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1O
Solvent: CO
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccc(CNc2ccccc2O)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]3-formyl-2-hydroxy-benzoate (800 mg, 1.41 mmol), MeOH (5 mL) AcOH (0.5 mL) and 2-aminophenol (184 mg, 1.69 mmol) was stirred at room temperature for 16 hours before adding NaBH3(CN) (444 mg, 7.05 mmol) in one portion. The resulting mixture was stirred at room temperature for 3 h, concentrated in vacuo to a sticky pink oil. The residue was used in the next step without further purification. LCMS (Method 2): [MH+]=661 at 3.68 min.