Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[Na+].C1(CC([O-])=O)C=CC=CC=1.[C:24]1([NH:30][C:31](=[O:54])[CH:32]([CH:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=O)[C:33](=O)[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:30][C:31]([C:32]2[C:38]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[C:39]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[N:2]([CH2:3][CH2:4][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[O:6])[C:33]=2[CH:34]([CH3:36])[CH3:35])=[O:54])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCC(=O)N1CCOCC1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)N1CCOCC1
Yield: 78 %

Procedure:
A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3A molecular sieves (4-8 mesh; 36 g), is charged with 3-amino-1-morpholin-4-yl-propan-1-one hydrochloride (170 mmol), phenylacetic acid sodium salt (170 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]4-methyl-3-oxo-pentanoic acid phenylamide (100 mmol). THF (150 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for ca. 24 hours, during which time the product begins to precipitate. Aqueous NaHCO3 (100 mL) is added slowly, and the reaction mixture is cooled with continued stirring to ca. 0° C. MtBE (100 mL) is added, and the solids are collected via filtration. The yellow-colored solid is washed with distilled water (15 mL) and MtBE (2×15 mL), collected, and dried under vacuum at ≦50° C. to afford 5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white solid (42.1 g). This material is carried on to subsequent steps without further purification.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([O:13]CC2C=CC=CC=2)[C@H:10]([O:21]CC2C=CC=CC=2)[CH:9]1[CH:29]([OH:31])[CH3:30])C1C=CC=CC=1.Cl>[Pd].C(O)C>[OH:31][CH:29]([CH:9]1[C@@H:10]([OH:21])[C@H:11]([OH:13])[CH2:12][NH:8]1)[CH3:30]
Reactant: CC(O)C1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(O)C1NC[C@@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 111.2 %

Procedure:
To a solution of (3R,4R)-1-benzyl-3,4-dibenzyloxy-2-(1-hydroxyethyl)pyrrolidine (90 mg, 0.22 mmol) in abs. ethanol (10 ml) was added palladium on activated charcoal (10% Pd, 30 mg) and 37% hydrochloric acid (0.1 ml). The mixture was hydrogenated in a Parr apparatus at 40 psi for 20 hours. The mixture was filtered and evaporated to dryness in vacuo to give (3R,4R)-2-(1-hydroxyethyl)-3,4-pyrrolidinediol (36 mg, yield: 90%) as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:24][CH2:25][N:26]([C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:27][CH2:28]1
Reactant: O=C(c1ccccc1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccccc1)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 48 h

Procedure:
In a 25 ml round-bottomed flask, 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is dissolved in 15 ml of methanol in the presence of 0.2 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 48 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (1/1 heptane/ethyl acetate).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24]/[N:25]=[C:26](\[C:33]3[N:37]([CH3:38])[C:36](=[O:39])[O:35][N:34]=3)/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][NH:9][C:17]2[N:18]=[C:19]([CH2:23][O:24]/[N:25]=[C:26](/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)\[C:33]3[N:37]([CH3:38])[C:36](=[O:39])[O:35][N:34]=3)[CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(/C(=N\OCc2cccc(N(CCC3CCCCC3)C(=O)OC(C)(C)C)n2)c2ccccc2)noc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(/C(=N\OCc2cccc(NCCC3CCCCC3)n2)c2ccccc2)noc1=O
Yield: 63.8 %

Procedure:
A solution of tert-butyl (2-cyclohexylethyl){6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (100 mg, 0.187 mmol, 1 eq.) in dichloromethane (5 ml) was treated with trifluoroacetic acid (0.144 mL, 1.867 mmol, 10 eq.) and refluxed overnight. The reaction was quenched by addition of NaHCO3 sat. aq. and extracted with EtOAc (3×20 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. After concentration, the residue was purified by chromatography on silica gel to give 3-[(Z)-[({6-[(2-cyclohexylethyl)amino]pyridin-2-yl}methoxy)imino](phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (52 mg, 63% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(C)(=O)=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.475 g, 3.769 mmol) in tetrahydrofuran/methanol (30 mL/30 mL) was added sodium hydroxide (26.5 mL, 53.126 mmol, 14.1 eq.). The mixture was heated to reflux and stirred for 0.5 h. LC-MS indicated that the reaction was completed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid. The precipitation was filtered, washed with water and dried to give 1.45 g of 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as off-white solid, yield: 86.3% (for two steps). MS (ESI+APCI) M+1=375.1.
Reaction SMILES: [OH:1][CH:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CCn2c(cc3ccccc32)C1O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCn2c(cc3ccccc32)C1OC(C)=O
Temperature: 50 °C
Yield: 99556.3 %

Procedure:
A solution of 75 g (0.29 mmol) of ethyl 6,7,8,9-tetrahydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 1000 ml of pyridine is treated dropwise within 10 minutes with 59.2 g (0.58 mol) of acetic anhydride. The reaction mixture is heated at 50° C. for 24 hours and the solvent is subsequently evaporated. The residue is taken up in a mixture of ethyl acetate and water (2:1, total 750 ml) and the organic phase is washed with 250 ml of water and twice with 100 ml of 1N hydrochloric acid each time, dried over anhydrous sodium sulfate and evaporated to dryness. In this manner, there are obtained 87 g (100%) of ethyl 9-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate as a pale yellow solid, m.p. 98°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1F)[C:35]([O:37][CH3:38])=[O:36].[H-].[Na+].O>CS(C)=O>[F:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 17.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (485 mg, 1.127 mmol) synthesized in Example (38d) and commercially available methyl 3,4-difluorobenzoate (540 mg, 3.137 mmol) were dissolved in dimethyl sulfoxide (10 mL), and sodium hydride (60%, 180 mg, 4.50 mmol) was added, followed by stirring at 100° C. for 2.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, and extraction was carried out with diethyl ether (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-30%) to afford the desired compound (97 mg, yield 18%) as a white solid.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Na].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([Cl:4])(=[O:25])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)c1ccc(OCc2ccccc2)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 55 ml (639 mmol) of oxalyl chloride in 250 ml of dichloromethane is added dropwise to a solution of 61 g (213 mmol) of the sodium salt of 4-benzyloxybenzenesulfonic acid in 200 ml of dimethylformamide, while maintaining the temperature between −20° C. and −10° C. After addition, the reaction medium is slowly brought back to ambient temperature and then stirred for 18 h, poured onto ice and extracted with ethyl acetate. The organic phase is washed with water and with a saturated aqueous solution of sodium chloride and concentrated under vacuum. 54 g (89%) of 4-benzyloxybenzenesulfonyl chloride are obtained in the form of a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.C[O:19][C:20]([CH:22]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23]1)=O>C(OCC)C.C(O)(=O)C>[O:19]=[C:20]([CH:22]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCCC1CCC(C(=O)OC)C1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC1CCC(C(=O)CP(=O)(OC)OC)C1

Procedure:
17 ml. of a 2 M solution of n-butyllithium in diethyl ether were added dropwise with stirring, under an atmosphere of nitrogen, to a solution of 4.2 g. of dimethyl methylphosphonate in 40 ml. of dry tetrahydrofuran at -50° to -60° C. After stirring for 10 minutes, 2.9 g. of 1-methoxycarbonyl-3-propylcyclopentane in 10 ml. of dry tetrahydrofuran were added dropwise at -78° C. and the reaction mixture was stirred for 4 hours at -78° C. and further stirred overnight at 0° C. The reaction mixture was then acidified with acetic acid and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give 3.1 g. of the title compound having the following physical characteristics:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[CH:15][N:14]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccnc(Cl)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccnc(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloropyridin-4-ol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:12])=[CH:14][CH:15]=2)[N:5]=[C:4]([NH:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: Nc1nc(Nc2ccc3c(c2)OCO3)nn1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc3c(c2)OCO3)nn1-c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.5 %

Procedure:
A mixture of 4-[5-amino-3-(benzo[1,3]dioxol-5-ylamino)-[1,2,4]triazol-1-yl]-benzoic acid (0.15 g, 0.44 mmol), morpholine (0.05 mL, 0.55 mmol) and HBTU (0.21 g, 0.55 mmol) in THF (5 mL) was stirred at room temperature for 4 h. The reaction was diluted with water, extracted with methanol/dichloromethane, dried (sodium sulfate) and evaporated. Purification by 2 successive semi-preparative HPLC's provided the title compound (0.008 g, 5% yield) as a pale pink lyophilate.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:22]=1>>[F:20][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH:18]=[CH:19][C:2]=1[NH:1][C:39]([NH:38][C:29]1[CH:30]=[C:31]([C:34]([F:36])([F:35])[F:37])[CH:32]=[CH:33][C:28]=1[O:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)=[O:40]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Oc1cccnc1)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Nc1cc(C(F)(F)F)ccc1Oc1cccnc1
Reaction time: 40 h

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (30.6 mg, 0.112 mmol) and a 60.6 mM solution of phenyl 2-(pyridin-3-yloxy)-5-(trifluoromethyl)phenylcarbamate (1.6 ml, 0.097 mmol). After 40 h, the mixture was evaporated onto silica gel, loaded onto a Biotage 12+M column, which was eluted with 40%-100% EtOAc in DCM. Yield: 4 mg (7%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[O:19]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.O>[CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1O

Procedure:
A solution of 1.73 g of 1-benzyl-1-(n-butyl)-3-(2-methoxy-3-chlorophenyl)urea and 1.0 ml of boron tribromide in 40 ml of methylene chloride was stirred at ambient temperature for 3 days and diluted with water. The organic layer was separated, dried, and evaporated. The residue was crystallized from hexane to yield 1-benzyl-1-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea, m.p. 59°-62° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=[O:6])[CH3:2].[C:8]([O:11][CH:12]1[C:13]([O:50][CH:51]([O:53][CH2:54][CH3:55])[CH3:52])([CH3:49])[CH2:14][CH2:15][CH:16](O)[CH2:17][C:18]([O:20][CH:21](/[C:26](/[CH3:47])=[CH:27]/[CH:28]=[CH:29]/[CH:30]([CH3:46])[CH2:31][CH:32]2[O:45][CH:33]2[CH:34]([CH3:44])[CH:35]([O:38][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:36][CH3:37])[CH:22]([CH3:25])[CH:23]=[CH:24]1)=[O:19])(=[O:10])[CH3:9].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>ClCCl.C(OCC)(=O)C>[C:8]([O:11][CH:12]1[C:13]([O:50][CH:51]([O:53][CH2:54][CH3:55])[CH3:52])([CH3:49])[CH2:14][CH2:15][CH:16]([O:6][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH2:17][C:18]([O:20][CH:21](/[C:26](/[CH3:47])=[CH:27]/[CH:28]=[CH:29]/[CH:30]([CH3:46])[CH2:31][CH:32]2[O:45][CH:33]2[CH:34]([CH3:44])[CH:35]([O:38][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:36][CH3:37])[CH:22]([CH3:25])[CH:23]=[CH:24]1)=[O:19])(=[O:10])[CH3:9]
Reactant: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Reactant: CCOCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: CCOCC(=O)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCC(=O)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of ethoxyacetic acid (8.2 mg, 0.079 mmol) in dichloromethane (1.6 mL) was added to (8E,12E,14E)-7-acetoxy-6,21-di(1-ethoxyethoxy)-3-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (13 mg, 0.016 mmol) at room temperature, and dicyclohexylcarbodiimide (20 mg, 0.094 mmol) and dimethylaminopyridine (1.9 mg, 0.016 mmol) were further added at room temperature. The mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by silica gel column chromatography (Kanto silica gel 60N, spherical, neutral, 40 to 100 μm, eluate; hexane:ethyl acetate=70:30) to obtain the title compound (11 mg, 91%) as a colorless oil. ESI-MS m/z 789 (M+Na)+.
Reaction SMILES: F[C:2](F)(F)[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][S:3]([O:6][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][C:19]=1[CH:24]([CH3:26])[CH3:25])(=[O:5])=[O:4]
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1cc(Br)ccc1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.47 mL) was added to an ice-cooled mixture of 4-bromo-2-isopropylphenol (0.5 g) and pyridine (0.28 mL) in methylene chloride (5 mL) with stirring. The mixture was stirred for 10 min, and poured into a mixture of ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford 4-bromo-2-isopropylphenyl methanesulfonate (0.71 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10]C(C)(C)C)=[O:9])[N:5]([C:15](=[O:28])[C@H:16]([CH3:27])[CH2:17][S:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]1=[O:29])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([OH:10])=[O:9])[N:5]([C:15](=[O:28])[C@H:16]([CH3:27])[CH2:17][S:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]1=[O:29])[CH3:2]
Reactant: CCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1C[C@@H](C(=O)O)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Yield: 95.2 %

Procedure:
4.0 g of tert.-butyl (4S)-1-ethyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate and 15 ml of trifluoroacetic acid are treated in the same manner as described in Example 2-(3). 3.3 g of (4S)-1-ethyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 95.2% The physico-chemical properties of this product are identical with those of the sample obtained in Example 4-(4).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OC1C=C(C=CC=1)CN1CCCCC1.BrCCCC(OCC)=O.[OH-].[K+].Cl>O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCCOc1cccc(CN2CCCCC2)c1
Agent: CCOC(=O)CCCBr
Agent: Cl
Agent: Oc1cccc(CN2CCCCC2)c1
Solvent: O
Product: O=C(O)CCCOc1cccc(CN2CCCCC2)c1

Procedure:
In a similar manner to that described above in Example 17 ethyl 4-(3-piperidinomethylphenoxy)butyrate (b.p. 190°-200° C./0.005 mm Hg) was prepared from N-3-hydroxybenzylpiperidine and ethyl 4-bromobutyrate. The resulting ester (21.4 g) was then hydrolysed by heating under reflux with potassium hydroxide (3.6 g), water (210 ml) and industrial methylated spirit (210 ml) for 30 minutes. 5N Hydrochloric acid (13.7 ml) was then added and the solvent removed by evaporation in vacuo. The residue was dried by azeotropic distillation with toluene and then with ethanol. The residue was digested with ethanol (420 ml). The ethanolic liquor was filtered and the solvent removed from the filtrate to give a yellow oil which was crystallised from a mixture of methanol and ether to give 4-(3-piperidinomethylphenoxy)butyric acid (m.p. 73°-77° C.).
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[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH2:24]>>[F:32][C:22]([F:21])([F:31])[CH:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 503173-14-6) as starting materials, MS (EI): m/e=443.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40])/[C:31](=[N:33]/O)/[NH2:32]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([C:31]2[N:33]=[C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=3)[O:9][N:32]=2)[CH:35]=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1Cl
Temperature: 140 °C
Yield: 74.4 %

Procedure:
To a slurry of 4-(hydroxymethyl)benzoic acid (0.220 g, 1.443 mmol) in DMF (1.640 ml) was added EDC (0.277 g, 1.443 mmol) followed by HOBT hydrate (0.195 g, 1.443 mmol). After about 45 min. a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.300 g, 1.31 mmol) in DMF (1.640 ml) was added and the reaction mixture was heated to about 140° C. for about 2 h. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol (0.336 g, 71%) as an off-white solid. LCMS (Table 1, Method c) Rt=2.80 min, m/z 345 (M+H)+.