Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:20]=3[C:19]3[C:30](=[O:33])[NH:31][CH2:32][C:18]=3[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])(C)(C)C.O1CCOCC1>Cl>[C:6]([CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:20]=3[C:19]3[C:30](=[O:33])[NH:31][CH2:32][C:18]=3[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CCn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)NC3
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)NC3

Procedure:
147 mg (0.33 mmole) 12-(2-tert.-butoxycarbonylethyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole are stirred for 16 hours at 20° C. in 5 mL 18% hydrochloric acid and 5 mL dioxan and then for 2 hours at 50° C. The product formed is filtered off, washed with a little water and ethanol and dried in a vacuum at 90° C. 12-(2-Carboxyethyl)-6,7,12,13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of pale beige crystals which decompose above 320° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH3:51])[CH2:47][C:48](O)=[O:49]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:48](=[O:49])[CH2:47][N:46]([CH3:51])[CH3:45])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Temperature: 60 °C
Yield: 33.5 %

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (70 mg, 230 μmol), HATU (210 mg, 552 μmol), and 2-(dimethylamino)acetic acid (45 mg, 436 μmol) in DMF (2.5 mL) was heated to 60° C. for 2 h. The solution was diluted with H2O (20 mL) until it became cloudy and cooled to rt. The mixture was filtered, washed with H2O (10 mL), Na2HCO3 (saturated, 5 mL), and H2O (5 mL). The filter was dissolved in MeOH (10%) in DCM and dried over MgSO4. The organic was filtered, concentrated to a yellow solid. This was further purified on silica using MeOH in EtOAc (0-5%) to give a light yellow solid. A second purification with 1:1 hexane-acetone removed the less polar impurity (NAc) effectively, affording a white solid (30 mg). MS (ESI, POS. ION) M/Z: calc'd for C18H20ClN5OS: 389.1. found: 390.1. 1H NMR (400 MHz, chloroform-d) δ ppm 2.43 (s, 3H) 2.93 (s, 3H) 3.25 (s, 2H) 7.52 (d, J=2.15 Hz, 1H) 7.63 (dd, J=8.41, 1.76 Hz, 1H) 7.87 (d, J=8.41 Hz, 1H) 7.99 (d, J=1.56 Hz, 1H) 8.27 (d, J=2.15 Hz, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>ClCCl>[C:12]1([C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][S:21](=[O:6])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(C2(c3ccccc3)CCSCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=S1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 20.3 g of 3-chloroperoxybenzoic acid (at 85%) in 300 cm3 of dichloromethane is added over 40 minutes to a solution, cooled to 0° C., of 25.4 g of 4,4-diphenyltetrahydrothiapyran in 130 cm3 of dichloromethane After stirring for 2 hours at 0° C., 250 cm3 of a 5% aqueous solution of potassium hydrogen carbonate are added to the mixture and it is then stirred for 15 minutes. The organic phase is again washed with 250 cm3 of a solution of potassium hydrogen carbonate and it is then dried over magnesium sulphate and concentrated to dryness (after verifying the absence of peroxides) under reduced pressure (2.7 kPa). 26.9 g of 4,4-diphenyltetrahydrothiapyran 1-oxide are obtained in the form of a white solid; melting point 122° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[O:7][C:8](/[CH:11]=[CH:12]/[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:10]=1)[OH:5].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C(Cl)Cl>[CH:13]1(/[CH:12]=[CH:11]/[C:8]2[O:7][C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])=[CH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCC(O)c1ccc(/C=C/C2CCCCC2)o1
Solvent: ClCCl
Product: O=C(NCCC(O)c1ccc(/C=C/C2CCCCC2)o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E)-3-amino-1-(5-(2-cyclohexylvinyl)furan-2-yl)propan-1-ol (0.25 g, 1.0 mmol) was dissolved in CH2Cl2 (5 mL) and ethyl trifluoroacetate (0.5 mL) was added. The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc—hexanes gradient) gave (E)-N-(3-(5-(2-cyclohexylvinyl)furan-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.26 g, 75%). (E)-N-(3-(5-(2-Cyclohexylvinyl)furan-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.15 g, 0.434 mmol) was dissolved in MeOH:H2O (3:1, 8 mL) and K2CO3 (0.13 g, 0.94 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Flash chromatography purification (2%-16% 7N NH3/MeOH—CH2Cl2 gradient) gave Example 14 as a light yellow oil. Yield (0.025 g, 23%); 1H NMR (400 MHz, CD3OD) δ 6.00-6.40 (m, 4H), 4.64-4.74 (m, 1H), 2.70-2.80 (m, 2H), 2.01-2.14 (m, 1H), 1.90-2.00 (m, 2H), 1.50-1.80 (m, 5H), 1.10-1.40 (m, 5H); RP-HPLC tR=10.06 min; ESI-MS m/z 232.2 [M−H2O+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[Cl:18][C:19]1[N:23]([CH3:24])[N:22]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH3:32])[CH:26]=2)[C:20]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][S:9][C:8]1[C:3]([CH2:2][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:21]3[C:20]([CH3:33])=[C:19]([Cl:18])[N:23]([CH3:24])[N:22]=3)=[CH:26][C:27]=2[CH3:32])=[C:4]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cccc(-n2nnn(C)c2=O)c1CBr
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cccc(-n2nnn(C)c2=O)c1COc1ccc(-c2nn(C)c(Cl)c2C)cc1C

Procedure:
A mixture of 1-(2-bromomethyl-3-methylthiophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Preparation example 13) 1.5 g, 4-(5-chloro-1,4-dimethyl-1H-pyrazol-3-yl)-2-methyl-phenol 1 g, potassium carbonate 0.9 g and acetonitrile 20 ml was stirred with heating under reflux for five hours. The reaction mixture was concentrated and the resulting residue was subjected to a silica gel column chromatography to give 1-{3-methylthio-2-[2-methyl-4-(5-chloro-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 38”) 2.1 g.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCOCC.[Cl-].[NH4+]>[F:31][C:32]1[CH:39]=[CH:38][C:35](/[CH:36]=[CH:2]/[O:3][CH3:4])=[CH:34][C:33]=1[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: CCOCC
Product: CO/C=C/c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (2.48 g) in ether (50 ml) at room temperature under nitrogen is added phenyllithium (4 ml of a 1.8 M solution in ether, 7.2 mmol) and the resulting mixture stirred for 20 minutes. 4-fluoro-3-phenoxybenzaldehyde (1.30 g, 6.0 mmol) is then added and the reaction is stirred for 4 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 ml) and diethyl ether (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (5:95) to afford the title compound as a colorless liquid (1.30 g, 89%) which is characterized by 1HNMR, IR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[C:9]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (5.6 g, 20.97 mmol) in ethanol (40 mL) was added ammonium chloride (5.6 g, 104.6 mmol) dissolved in water (30 mL) and iron powder (4.67 g, 85.16 mmol). The resulting mixture was heated at 80° C. for 1 h. On completion, water was added to the reaction then the mixture was filtered through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were dried then concentrated under reduced pressure to give methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])C.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[CH:13]=1
Reactant: CCOC(=O)CCCc1cc(F)ccc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1CCCC=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of ethyl-4-(5′-fluoro-2′-methoxyphenyl)butyrate (2.25 g, 9.4 mmol) in dry toluene (30 mL) under Ar(g) was added DIBAL solution (1 M in toluene, 11 mL, 11 mmol) at −78° C. Then the reaction was stirred at this temperature for 2 h. Methanol (2 mL) was then added to the reaction mixture and the reaction was allowed to warm to 0° C. The reaction mixture was poured into a separatory funnel containing HCl solution (1 N, 100 mL). The organic function was extracted with ethyl acetate (3×60 mL) and the combined organic layers were washed with brine (80 mL) and dried over sodium sulfate. The crude product that obtained by removal of the solvent in vacuo was purified by flash column chromatography (10% EtOAc in hexane, Rf=0.10) to give the product (1.30 g, 70%).
Reaction SMILES: [Br-].[Br-].[Br-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1>ClCCl>[C:5]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[CH2:17][C:18]([OH:20])=[O:19])(=[O:7])[CH3:6]
Reactant: COc1cccc(CC(=O)O)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(CC(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of aluminum tribromide (57.6 g, 216 mmol) in dichloromethane (90 mL) at 0° C. was slowly added acetyl chloride (11.5 mL, 162 mmol). To the reaction mixture was added (3-methoxy-phenyl)-acetic acid (17.9 g, 108 mmol) in dichloromethane (20.0 mL). The reaction mixture was stirred for one hour and then poured over ice (100 mL). The organic layer was separated and 1N aqueous sodium hydroxide was added (100 mL). The biphasic mixture was stirred vigorously for 90 minutes and the layers were separated. The organic layer was discarded and concentrated hydrochloric acid was added to the aqueous layer until the pH reached 1. A solid precipitated and was filtered and air-dried to afford (2-acetyl-5-methoxy-phenyl)-acetic acid (16.8 g, 75%). M.p. 153-155° C. 1H NMR (300 MHz, CDCl3) δ2.68 (s, 3), 3.91 (s, 3), 3.92 (s, 2), 6.92-6.95 (m, 2), 7.88 (d, 1, J=9.5). 13C NMR (100 MHz, CDCl3) δ28.33, 41.43, 55.46, 112.54, 118.26, 129.17, 133.08, 136.94, 162.65, 174.80, 200.96. IR 3435, 1704, 1663, 1609, 1568, 1258 cm−1. Analysis calculated for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.35; H, 5.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]1([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]([CH:34]=O)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]([CH2:34][NH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH2:12]3)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: Fc1ccccc1N1CCN(CCNCc2cc(-c3ccccc3)n(-c3ccccc3)n2)CC1
Yield: 74.5 %

Procedure:
Compound 68 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([CH:18]([OH:28])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH:18]([O:28][C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CCCCC(O)C(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Phenyl chloroformate (14.1 g) was added dropwise to a mixture of ethyl 6-(4-chlorobenzoyl)-6-hydroxyhexanoate (24.5 g), pyridine(7.14 g) and tetrahydrofuran(200 ml) with cooling with ice. After stirring for 3 hours at room temperature, the reaction mixture was poured into ice water, and neutrized by 2N-hydrochloric acid. This was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanate(32.3 g, 94%) as an oily substance.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH2:12]1[O:20][C:19]2[C:14](=[CH:15][CH:16]=[C-:17][CH:18]=2)[O:13]1.[Mg+2].[Br-]>ClCCl>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]([C:17]3[CH:16]=[CH:15][C:14]4[O:13][CH2:12][O:20][C:19]=4[CH:18]=3)[OH:8])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [c-]1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of piperonal (0.75 g) in solution in dichloromethane (25 ml) was added dropwise 3,4-(methylenedioxy)phenylmagnesium bromide (5 ml, 1M solution in toluene/THF). The mixture was stirred at room temperature overnight, then poured onto water, extracted with dichloromethane, dried and evaporated in vacuo to give the crude alcohol as a brown gum. Purification by column chromatography over silica gel eluting with ethyl acetate in CH2Cl2 (10 to 20%) gave the pure alcohol as a white gum (1.18 g, 87%).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])(C)C)(C)(C)C.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O>[Cl:16][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([Cl:15])[C:11]=1[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl-(2,4-dichloro-phenoxy)-dimethyl-silane (113, 4.00 g, 0.0144 mol) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 6.06 mL) was added slowly. After 30 minutes, N,N-dimethylformamide (1.34 mL, 0.0173 mol) was added to the reaction. After 1 hour, the reaction was allowed to warm to room temperature. 1N HCl (40 mL) was added to the reaction. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid (114, 2.0 g, 72.6%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[NH2:25]>>[CH3:21][O:22][C:23](=[O:28])[C:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])[CH3:26]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 377.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:24][C:25]([NH2:27])=[O:26])=[O:9])=[C:4]([OH:30])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>O1CCOCC1>[C:42]([O:41][C:39](=[O:40])[CH2:38][O:30][C:4]1[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[CH2:24][C:25](=[O:26])[NH2:27])=[O:9])([CH3:45])([CH3:44])[CH3:43]
Reactant: NC(=O)C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1CC(N)=O
Reaction time: 60 h
Yield: 87.5 %

Procedure:
(2R)-2-[1-[(4-Chloro-2-hydroxy-phenoxy)-acetyl]-4-(4-fluoro-benzyl)-piperazin-2-yl]-acetamide (0.070 g, 0.16 mmol), cesium carbonate (0.078 g, 0.24 mmol) and tert-butyl bromoacetate (0.038 g, 0.028 mL, 0.193 mmol) were stirred in dioxane (2 mL). After 2.5 days, the solution was filtered, concentrated and chromatographed on silica gel to yield the title compound as a white solid (0.077 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCCCl)cc1
Yield: 93.3 %

Procedure:
A mixture of para-nitrophenol (0.83 g, 6 mmoles), 1-bromo-4-chloro-butane (1.23 g, 7.2 mmoles), and K2CO3 (1.24 g, 9 mmoles) was stirred together in DMF at 80° C. for 1 hour. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.28 g, 5.6 mmoles).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(Br)c(C=O)c2)O1
Temperature: 150 °C
Reaction time: 10 h
Yield: 52 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (62; 5 g, 0.025 mol) in DMF (100 ml) was added (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (63; 4.87 g, 0.032 mol) and K2CO3 (7.0 g, 0.05 mol). The resulting reaction mixture was stirred at 150° C. for 10 h, cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether/EtOAc=10:1 to afford the desired product, namely (S)-2-bromo-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde 64 (4.1 g, 56%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32]>CCOC(C)=O>[Cl:36][C:35]([Cl:38])([Cl:37])[CH2:34][O:33][C:31](=[O:32])[NH:27][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101 %

Procedure:
To a solution of Intermediate 53a (445 mg, 1.13 mmol) in EtOAc (4 mL) and 1N sodium hydroxide solution (2.40 mL, 2.40 mmol) was added 2,2,2-trichloroethyl chloroformate (165 μL, 1.20 mmol), and the mixture stirred vigorously at RT for 1.5 h. The aqueous layer was extracted with EtOAc (2×10 mL), and then the combined organics dried and concentrated in vacuo. The residue was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound (650 mg, 100%). LCMS (Method 3): Rt 4.90 min, m/z 568, 570, 572 [MH+].
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:17][CH2:16][CH:15]([OH:18])[CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)Cc1cccc(Cc2ccccc2)c1OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cccc(Cc3ccccc3)c2OCc2ccccc2)cc1
Yield: 70.2 %

Procedure:
Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]propane-1,2-diol (9.76 g, 0.028 mol) with p-toluenesulfonyl chloride (5.87 g, 0.031 mol) in pyridine (250 mL) generally according to the procedure described for Intermediate 3 gave 9.88 g (70%) of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C30H30O5S: C, 71.69; H, 6.02. Found: C, 70.41; H, 6.14.