Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]([F:22])([F:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O-:20])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[CH:62][C:61]=1[C:73]([F:76])([F:75])[F:74])([O-:59])=[O:58]>CN(C)C=O.ClCCl.O1CCCC1>[N+:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:68][CH2:69][N:70]([C:18](=[O:20])[CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:21])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH2:71][CH2:72]2)=[CH:62][C:61]=1[C:73]([F:76])([F:74])[F:75])([O-:59])=[O:58]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCN1CCC(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCC(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Trifluoromethyl-phenyl)-piperidin-1-yl]-propionic acid lithium salt (118 mg; 0.38 mmol, prepared in accordance with Example 13), diisopropylethyl amine (137 μL; 0.76 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (145 mg; 0.38 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (12 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (114 mg; 0.35 mmol, prepared in accordance with Example 8) in dimethylformamide (4 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (50 mL), the organic layer is sequentially washed with water (15 mL), aq. sat. sodium hydrogen carbonate (15 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The desired product is finally obtained in pure form (103 mg; 0.18 mmol) following purification by preparative HPLC. The structure was confirmed using Protocol II-A. Calculated mass=572; observed mass=573; HPLC retention time=3.62 min.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH2:19])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Br[C:22]1[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[CH:25]=[N:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].COCCOC.O>C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:19][C:14]1[N:15]=[CH:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:22]1[C:27]([CH3:28])=[N:26][CH:25]=[C:24]([CH:23]=1)[C:29]([O:31][CH3:32])=[O:30])[CH:18]=2
Reactant: COC(=O)c1cnc(C)c(Br)c1
Reactant: CC1(C)OB(c2ccc3cc(N)ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C)c(-c2ccc3cc(N)ncc3c2)c1
Yield: 74 %

Procedure:
A mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine (337.3 mg; 0.8742 mmol), methyl 5-bromo-6-methyl-pyridine-3-carboxylate (214.2 mg; 0.9311 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (63.3 mg; 0.0894 mmol), potassium carbonate (307.2 mg; 2.223 mmol), 1,2-dimethoxyethane (3.0 mL; 28 mmol), and water (0.3 mL; 20 mmol) was subjected to microwave irradiation at 110° C. for 90 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 189.8 mg (74%) of the title compound. LCMS (ESI): M+H=294.2; 1H NMR (400 MHz, DMSO) δ 8.98 (d, J=1.9 Hz, 1H), 8.88 (s, 1H), 8.10 (d, J=1.9 Hz, 1H), 7.88 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 6.67 (s, 1H), 6.03 (s, 2H), 3.90 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane. N-Methyl-4-piperidone (5 g) was added to the mixture, followed by NaHB(OAc)3 (12 g) and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. A saturated NaHCO3 (200 mL) solution was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel. The organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.3.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH2:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:26][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH2:25]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: C=CCC=CCC=CCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: C=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12,15-hexadecatrienol, and 84 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the mixture is refluxed at 110° C. with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-hexadecatrienyloxy)-2-furoic acid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29]C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]>CN(C=O)C.N1CCCCC1>[NH2:29][C:13]1([C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:2]([NH2:1])=[O:3])[C:12]=3[N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCN(C(=O)OCc4ccccc4)CC3)nc12
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: NC(=O)c1cccc2[nH]c(C3(N)CCN(C(=O)OCc4ccccc4)CC3)nc12
Yield: 35.6 %

Procedure:
A mixture of Example 49A (0.035 g, 0.1 mmol) in DMF (2 ml) and piperidine (0.5 ml), was stirred at room temperature for 2 h. The mixture was concentrated under vacuum then crystallized from MeOH to provide 0.014 g (64%) of the desired product. MS (ESI) m/e 416 (M+Na)+. 1H NMR (DMSO-D6) δ ppm 8.14 (s, 1H), 7.84 (d, J=7.02 Hz 1H), 7.73 (s, 2H) 7.37-7.40 (m, 4H), 7.31-7.37 (m, 2H), 5.11 (s, 2H), 3.51-3.68 (m, 6H), 2.32 (s, 2H), 1.88 (d, J=13.43 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(Cl)cc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(Cl)cc3)c2CC1)C(F)(F)F
Yield: 68.8 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (700 mg, 1.6 mmol) with 4-chlorobenzylamine (354 mg, 2.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) and then SCX chromatography to give 7-chloro-6-(4-chlorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (459 mg, 69%). MS (ES+) m/z: 417 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:20])[CH:18]=O>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]2[N:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:7][CH2:18][N:17]2[C:20]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CN(C)C=O
Product: c1ccc(-c2[nH]c3ccccc3c2C2N(c3ccccc3)CCN2c2ccccc2)cc1

Procedure:
4.44 parts by weight of bis-[1,3-diphenyl-imidazolidin-(2)-ylidene] and 3.86 parts by weight of 2-phenylindole in 20 parts by volume of dimethylformamide are heated under nitrogen for 5 hours to boiling point. A little unreacted bis-[ 1,3-diphenyl-imidazolidin-(2)-ylidene] is filtered off while still warm, the solvent is removed partly in vacuo and 2-(2-phenylindol-3-yl)-1,3-diphenyl-imidazolidine is obtained in the form of colourless crystals melting at 237°-238° C (from toluene) ##STR15##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[O:33][C:32]1=[O:44].[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[O:33][C:32]1=[O:44]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(C)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (30.1 mg, 0.050 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added 1M aqueous LiOH (0.498 mL, 0.498 mmol). The mixture was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude material was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]-methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=591.2; found=591.1 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.83 (s, 1 H); 8.02 (s, 1 H); 7.94 (t, J=10.0 Hz, 1 H); 7.72 (s, 0.5 H); 7.69 (t, J=6.0 Hz, 1 H); 7.64 (s, 0.5 H); 7.49-7.43 (m, 3 H); 7.40 (d, J=5.2 Hz, 0.5 H); 7.35 (d, J=5.4 Hz, 0.5 H); 7.31 (m, 1 H); 7.16 (dd, J=2.1, 6.0 Hz, 1H); 7.12 (t, J=8.8 Hz, 1 H); 5.56 (d, J=8.1 Hz, 0.5 H); 5.26 (d, J=8.2 Hz, 0.5H); 4.94 (dd, J=8.7, 15.7 Hz, 1H); 4.77 (br s, 1 H); 4.20 (d, J=15.8 Hz, 0.5 H); 4.00 (d, J=15.7 Hz, 0.5 H); 3.90 (s, 1.5 H); 3.89 (s, 1.5 H); 3.89-3.81 (m, 1 H); 2.82 (s, 1.5 H); 2.81 (s, 1.5 H); 2.41 (s, 1.5 H); 2.36 (s, 1.5 H); 0.62 (d, J=6.5 Hz, 1.5 H); 0.49 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[C@@H:32]([OH:33])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O[C@@H](c1ccccc1)[C@H]1COCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3[C@@H](O)c3ccccc3)sc21
Temperature: 90 °C
Yield: 68.7 %

Procedure:
N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1, 134 mg) and (S)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 9, 111 mg) in DMF (3 mL) is treated with diisopropylethylamine (0.5 mL). The mixture is heated at 90° C. overnight. After cooling to room temperature, the solution is poured into ethyl acetate (75 mL) and washed with dilute pH 4 phosphate buffer (10 mL), dilute pH 7 phosphate buffer (10 mL), and brine (10 mL). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (methanol/CH2Cl2, 1-3%) and ethyl acetate-hexanes crystallization to afford 0.13 g of the title compound Physical characteristics. M.p. 129-134° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.60, 8.67, 7.41-7.25, 5.33, 5.07, 4.54, 4.17, 3.88, 3.81, 3.73, 3.6, 3.5-3.4, 2.94, 2.6, 2.4-2.3; HRMS m/z 538.1561 (M+H)+. Anal. Found: C, 62.33; H, 5.25; N, 7.75.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1)=O.C[O:15][C:16](=[O:30])/[C:17](=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH2:18][C:19]([O:21][CH3:22])=[O:20].CC(C)([O-])C.[K+].C(OC(C)C)(C)C>C(O)(C)(C)C.O>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1)=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([C:16]([OH:30])=[O:15])=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C/C(=C\c1ccccc1)C(=O)OC
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=Cc1ccccc1)C(=O)O)=C(C)c1cc(OC)cc(OC)c1
Temperature: 25 °C
Yield: 111.1 %

Procedure:
3,5-Dimethoxyacetophenone (246 g) and (E)-benzylidenesuccinic acid dimethyl ester (320 g) are dissolved in tert-butyl alcohol (1300 ml), and thereto is added potassium tert-butoxide (168.6 g) at room temperature, and the mixture is stirred. The mixture is allowed to cool to room temperature, and the mixture is further stirred at the same temperature for two hours. To the reaction mixture are added water (3 L) and diisopropyl ether (700 ml), and the aqueous layer is separated. To the remaining organic layer is added water, and the aqueous layer is separated. The aqueous layers are combined, and the pH value thereof is adjusted to pH 2-3 with conc. hydrochloric acid. The resulting oily product is extracted with ethyl acetate, and the extract is dried, and concentrated to give oily 1-methyl-1-(3,5-dimethoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (580 g) which is a mixture of (1Z,3E)-isomer and (1E,3E)-isomer. The oily product thus obtained is dissolved in diisopropyl ether-hexane, and the mixture is stirred at room temperature, and the precipitated crystals are collected. To the crystals is added ethyl acetate (1 L), and the mixture is heated at about 80° C., and the remaining crystals are collected by filtration to give (1E,3E)-1-methyl-1-(3,5-dimethoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (the same compound as the compound of Example 135) (117 g). The mother liquor (the filtrate) is concentrated, and ethyl acetate (700 ml) is added to the residue, and the (1Z,3E)-isomer is inoculated thereto. The mixture is stirred, and the precipitated crystals are collected to give (1Z,3E)-1-methyl-1-(3,5-dimethoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (the same compound as the compound of Example 121) (192 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:3]=1[NH2:4].C(C1C([NH2:20])=CC=CC=1)C.ClN1C(=O)CCC1=O>C(#N)C>[Cl:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Cl:1])[CH:8]=1)[NH:4][N:20]=[C:10]2[CH3:11]
Reactant: CCc1cc(Cl)cc(Cl)c1N
Reactant: CCc1ccccc1N
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1n[nH]c2c(Cl)cc(Cl)cc12

Procedure:
5,7-Dichloro-3-methyl-1H-indazole was prepared using a procedure similar to that described in Example 98, part a and b, except starting from 2,4-dichloro-6-ethylaniline (2.9 g) that was prepared by chlorination of 6-ethylaniline (10 g) with N-chlorosuccinimide (22 g) in acetonitrile (80 mL).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5].FC(F)(F)C([O-])=O.[CH2:28]([O:35][C@H:36]([CH3:39])[CH2:37]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)[C@@H](C)O)C>>[CH2:28]([O:35][C@H:36]([CH3:39])[CH2:37][NH:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](CO)OCc1ccccc1
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Agent: CCOC(=O)[C@@H](C)O
Agent: O=C([O-])C(F)(F)F
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1

Procedure:
Prepared from 3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide, trifluoroacetate (Example 107, Step C) and (R)-2-benzyloxypropanol (prepared from ethyl-D-lactate according to the procedure of Hanessian and Kloss, Tetrahedron Lett. 1985, 26, 1261-1264.) by the procedure described in Example 86, Step A. 1H NMR (200 MHz,CD3OD): 1.31 (d,6 Hz,3H), 1.4 (s,3H), 1.43 (s,3H), 2.17 (m,1H), 2.30 (m,1H), 2.6-3.1 (m,5H), 3.22 (dd;3,12 Hz;1H), 3.86 (m,1H), 4.48 (dd;7,12 Hz;1H), 4.50 (d,12 Hz,1H), 4.70 (d,12 Hz,1H), 7.11 (d,8 Hz,1H), 7.15-7.45 (m,8H). FAB-MS: calculated for C25H33N3O3 423; found 424 (M+H, 100%).
Reaction SMILES: ClC1C(OC2C3CC4CC(Cl)(CC2C4)C3)=C[C:5](F)=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:24][C:25]1[C:26]([O:35][CH2:36][C:37]2([C:41]([F:44])([F:43])[F:42])[CH2:40][CH2:39][CH2:38]2)=[CH:27][C:28]([F:34])=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]>>[Cl:24][C:25]1[C:26]([O:35][CH2:36][C:37]2([C:41]([F:42])([F:43])[F:44])[CH2:40][CH2:39][CH2:38]2)=[CH:27][C:28]([F:34])=[C:29]([CH:33]=1)[C:30]([O:32][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:31]
Reactant: O=C(O)c1cc(Cl)c(OC2C3CC4CC2CC(Cl)(C4)C3)cc1F
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 2 and making variations as required to replace 5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoic acid with 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoic acid, the title compound was obtained as clear liquid (2.41 g, 99%): MS (ES+) m/z 327.1, 329.1 (M−55).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]1[CH:37]=[C:38]([NH2:45])[C:39](=[CH:43][CH:44]=1)[C:40](O)=[O:41]>O.CN(C=O)C>[NH2:45][C:38]1[CH:37]=[C:36]([F:35])[CH:44]=[CH:43][C:39]=1[C:40]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:41]
Reactant: C1CCNC1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(F)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.9 %

Procedure:
A DMF solution (4 ml) of pyrrolidine (1.93 g, 27.1 mmol), a DMF solution (4 ml) of triethylamine (3.79 g, 37.5 mmol), 1-hydroxybenzotriazole (HOBt) (3.11 g, 23.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (3.91 g, 20.4 mmol) were added to a DMF solution (4 ml) of 4-fluoroanthranilic acid (2.0 g, 12.8 mmol) in that order. The mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure to thereby obtain 1.65 g of oily orange 1-(2-amino-4-fluorobenzoyl)pyrrolidine (yield: 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(OC(C)(C)C)=O)=[N:9][CH:10]=1)=[O:4].C(O)=O>C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N(Cc2cc([N+](=O)[O-])ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nc1
Solvent: O=CO
Solvent: CCOCC
Product: COC(=O)c1ccc(NCc2cc([N+](=O)[O-])ccc2OCc2ccccc2)nc1

Procedure:
A mixture of methyl-2-[N-(2-benzyloxy-5-nitrobenzyl)-N-t-butoxycarbonylamino]pyridine-5-carboxylate (5.2 g) and formic acid (20 ml) was heated on a steam bath to give a clear solution. The mixture was evaporated to dryness and the residue obtained was dissolved in diethylether (100 ml) and washed with saturated sodium bicarbonate. The organic layer was dried and evaporated to give methyl-2-[N-(2-benzyloxy-5-nitrobenzyl)-amino]pyridine-5-carboxylate, yield 3.3 g. This same procedure was used to prepare ethyl-2-[N-(2-benzyloxy-5-bromobenzyl)-amino]thiophene-5-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O.CCOC(C)=O>[N:20]([CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[C:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCCBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCCN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of crude diethyl 1-(3-bromopropyl)-1H-pyrrole-2,4-dicarboxylate in DMF (30 mL) was added sodium azide (1 g, 15.4 mmol). The resulting mixture was stirred at rt overnight then diluted with water (30 mL) and EtOAc (150 mL). After separation, the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Purification via flash chromatography (petroleum ether:EtOAc, 20:1 to 15:1) afforded diethyl 1-(3-azidopropyl)-1H-pyrrole-2,4-dicarboxylate (2 g, 75%). 1H NMR (CDCl3, 300 MHz) δ7.42 (s, 1H), 7.36 (s, 1 H), 4.40 (t, J=6.6 Hz, 2 H), 4.26 (m, 4 H), 3.30 (m, J=6.2 Hz, 2 H), 2.04 (m, 2 H), 1.36 (m, 6 H).