Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[I:20]I>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([I:20])[S:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cscn1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1csc(I)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole (106.4 mg, 0.465 mmol) in THF (5 mL) was added dropwise a solution of n-BuLi (465 μL of a 1.6M solution in hexanes, 0.744 mmol). The reaction was stirred at −78° C. for 30 minutes, and then a solution of iodine (295 mg, 1.16 mmol) in THF (5 mL) was added by cannula. The reaction was warmed to room temperature for 15 minutes and then quenched by pouring into aq. NaHSO3 (20 mL). The mixture was extracted with EtOAc (60 mL) and the organic layer was washed with brine, saturated NaHCO3, and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (15% EtOAc/hexanes) afforded 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole. Rf=0.55 (15% EtOAc/hexanes). LCMS=356.0 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.16 (s, 1H), 4.86 (s, 2H), 0.93 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16].CCCCCC.CCOC(C)=O>CC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([N:11]=[C:15]=[S:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: S=C=Nc1cccc(Oc2ccccc2)c1

Procedure:
To a stirring solution of 3-phenoxyaniline (185 mg, 1.0 mmol) in acetone (4.0 mL) at 0° C. was added thiophosgene (0.23 mL, 3.0 mmol) and the resulting reaction maintained for 30 min. The reaction determined complete by TLC (4:1 hexane/EtOAc). The reaction was concentrated, azeotroped with toluene and taken on without further purification.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[S:18][CH:19]=[C:20]2[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][C:21]=12.O>O1CCCC1>[N:17]1[S:18][CH:19]=[C:20]2[C:25](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:24][CH:23]=[CH:22][C:21]=12
Reactant: O=Cc1cccc2nscc12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccc2nscc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 380.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (60%, 1.16 g, 26.6 mmol) in tetrahydrofuran (30 mL) was added a solution of ethyl diethylphosphonoacetate (4.83 mL, 5.41 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2,1-benzisothiazole-4-carbaldehyde (3.94 g, 24.1 mmol) in tetrahydrofuran (8.3 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (4.80 g, yield 85%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]([C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)[CH:11]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:10]([CH:11]=[CH2:1])[C:9]=1[O:18][CH3:19]
Reactant: CC(C)(C)[O-]
Reactant: COc1c(Br)ccc(SC)c1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(SC)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
At 0° C., potassium tert-butoxide (6.2 g, 55.4 mmol) was added to a solution of methyltriphenylphosphoniumbromide (19.7 g, 55.4 mmol) in THF (180 ml). At from −10 to −5° C., 3-bromo-2-methoxy-6-methylsulfanylbenzaldehyde (12 g, 46 mmol) dissolved in THF (180 ml) was then added, and the mixture was stirred overnight at RT for 7 h. The mixture was filtered, and the solution was admixed with H2O (200 ml) and MTBE (200 ml) and then extracted with MTBE (200 ml). The combined organic phases were dried over MgSO4 and concentrated. Chromatography (cyclohexane→cyclohexane/EtOAc 9:1) gave 1-bromo-2-methoxy-4-methylsulfanyl-3-vinylbenzene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)[N:9]=2)[CH2:2]1.Br[C:24]1[N:28]=[CH:27][NH:26][N:25]=1>>[N:25]1[N:26]=[C:27]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]3[CH:13]=[CH:12][N:11]=[C:10]([C:14]4[CH:15]=[N:16][N:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=45)[N:9]=3)[CH2:2]2)[NH:28][CH:24]=1
Reactant: c1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: Brc1nc[nH]n1
Product: c1ccn2ncc(-c3nccc(N[C@@H]4CCCN(c5nnc[nH]5)C4)n3)c2c1
Temperature: 150 °C
Yield: 52.1 %

Procedure:
A mixture of (R)—N-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-amine (Preparation 34, 298 mg, 1.01 mmol) and 3-bromo-1H-1,2,4-triazole (75 mg, 0.51 mmol, prepared as described in Journal of Medicinal Chemistry, 2004, 47 (19), 4645-4648) was heated at 150° C. overnight. The crude mixture was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (96 mg, 52%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C@@H:5]([CH3:7])[N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:3]1[CH3:18].C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:18][C@H:3]1[C:2](=[O:1])[CH2:6][C@@H:5]([CH3:7])[N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@@H]1C[C@H](O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: C[C@@H]1CC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a solution (20 mL) of benzyl (2S,3S,5R)-3-hydroxy-2,5-dimethylpyrrolidine-1-carboxylate (1.30 g) in acetonitrile were added tetrapropylammonium perruthenate (92 mg), 4-methylmorpholine N-oxide (1.22 g) and molecular sieves 4A powder (1.32 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/1) to give the title compound as colorless oil (yield: 1.30 g, yield: 100%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[O:21])=[CH:18][CH:17]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(C(CC)=O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=4)[NH:6][CH:5]=3)[CH2:24]2)=[O:21])=[CH:28][CH:29]=1
Reactant: O=C(CC1CCNC1)c1ccc(F)cc1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: COc1ccc2[nH]cc(CCN3CCC(CC(=O)c4ccc(F)cc4)C3)c2c1

Procedure:
A mixture of 5 g (0.0197 mol) of the product obtained in Stage 2, 4 g (0.0216 mol) of 3-(4-fluorobenzoylmethyl)pyrrolidine, 0.1 g of sodium iodide and 3 g of potassium carbonate in 100 ml of diethyl ketone is brought to reflux for 24 hours. The inorganic salts are then filtered off, the solvent is evaporated under vacuum, the residue is taken up in 100 ml of dichloromethane and this organic phase is washed with 100 ml of water. After drying over magnesium sulfate and evaporation of the solvent, the residue is purified by chromatography on a silica column, Merck 70-230 mesh, using a dichloromethane/methanol/aqueous ammonia (97/3/0.3) mix-ture as eluent.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1.[CH3:19][C:20]([CH3:46])([O:22][C:23]([NH:25][C:26]([CH3:45])([CH3:44])[C:27]([NH:29][C@H:30]([CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])=[O:24])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:10]3([CH2:11][CH2:12][N:13]([C:31]([C@H:30]([NH:29][C:27](=[O:28])[C:26]([NH:25][C:23]([O:22][C:20]([CH3:46])([CH3:21])[CH3:19])=[O:24])([CH3:45])[CH3:44])[CH2:34][C:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[NH:37][CH:36]=4)=[O:32])[CH2:14][CH2:15]3)[CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1ccc2c(c1)C(=O)CC1(CCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1)O2

Procedure:
Prepared by the procedure described in Example 3, Step B. 3,4-Dihydro-6-methylspiro[2H- 1 -benzopyran-2,4'-piperidine]-4-one hydrochloride (20 mg, 0.058 mmol), (Hashigaki et al Chem. Pharm. Bull. 32 pg 3561-3568 (1984)) α(R)-[[2-[[(1,1-dimethylethoxy)-carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3propanoic acid) (32 mg, 0.082 mmol), HOBT (1 eq.), N-methyl morpholine (0.03 mL, 0.28 mmol), and EDC (40 mg, 0.21 mmol). Reaction time: 8 hours. Yield: 34 mg (86%).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1)/[CH:11]=[C:12]1/[C:13](=[O:17])[NH:14][CH2:15][CH2:16]/1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:41]Br>C(OCC)(=O)C.O>[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:41][N:14]1[CH2:15][CH2:16]/[C:12](=[CH:11]\[C:10]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:8]([O:7][CH3:6])[CH:9]=2)/[C:13]1=[O:17]
Reactant: COc1cc(/C=C2\CCNC2=O)ccc1-n1cnc(C)c1
Reactant: Fc1ccc(CBr)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCN(Cc3ccc(F)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a DMF (6.0 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)pyrrolidin-2-one (100 mg), lithium bis(trimethylsilyl)amide (1M hexane solution, 0.53 mL) was added at 0° C., and the reaction solution was agitated for 30 minutes at 0° C. 3,4-difluorobenzylbromide (0.060 mL) was added to this solution at 0° C., and that reaction solution was agitated at room temperature for 1 hour. The reaction solution was added to iced water and ethyl acetate, and the organic layer was partitioned. The obtained organic layer was washed with a saturated salt solution, and it concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system), and 80 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.COB(OC)OC.B.CSC.[OH-].[Na+]>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Agent: B
Agent: COB(OC)OC
Agent: [Na+]
Solvent: CSC
Product: OCc1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.5 %

Procedure:
To a mixture of 4-chloro-2,5-difluoro-benzoic acid (15 g, 78 mmol) tetrahydrofuran (THF) (75 mL) and trimethylborate (26 mL, 230 mmol) was added borane-methylsulfide complex (86 mL, 86 mmol, 10 M solution in DMS), and the mixture was stirred for 18 hours at ambient temperature. Additional borane-methylsulfide complex (2.47 mL, 24.7 mmol) was added to drive the reaction to completion. The mixture was poured into 1M aqueous NaOH, extracted 3× with ether, and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. Trituration of the solid residue with ether-hexane afforded 14 g of (4-chloro-2,5-difluoro-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) 67 7.26 (dd, 1H, J=6, 8.8 Hz), 7.11 (dd, 1H, J=6, 9.2 Hz), 4.71 (d, 2H, J=6.0 Hz), 1.80 (t, 1H, J=6.0 Hz) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[C].[Pd]>[O:11]=[C:10]1[NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][C@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
10% palladium carbon (1 g) was added to a solution of (R)-(−)-2-tert-butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (7.6 g) in tetrahydrofuran (100 ml), and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure, to thereby obtain (R)-2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid. The residue was dissolved in toluene (100 ml), the solution was refluxed overnight. After allowed to cool, the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:1), to thereby obtain 5.16 g of the title compound (Yield 80%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)(=O)C>CN(C=O)C.N1CCCCC1>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:20])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=2)=[O:16])[CH3:19]
Reactant: COc1cc(C=O)c(O)cc1O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(OC)c(O)cc2oc1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxy-5-methoxybenzaldehyde (1.68 g) and diethyl malonate (1.76 g) in DMF (5 ml) was treated with a few drops of piperidine and acetic acid and kept at 80-95° C. overnight. The reaction mixture was poured into ice water, acidified and filtered. Yield: 2.2. g.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]([NH2:40])[CH2:38][NH2:39]>COC(C)(C)C>[NH2:39][CH2:38][CH2:37][NH:40][C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCCN
Solvent: COC(C)(C)C
Product: Cc1cc(F)ccc1-c1cc(NCCN)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 87 %

Procedure:
A mixture of 1.0 g (1.9 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 5.0 ml (75 mmol) ethylenediamine was heated at 130° C. for 6 h. After cooling to room temperature the reaction mixture was diluted with 20 ml tert-butyl methyl ether and washed with 20 ml of a saturated aqueous solution of sodium carbonate, 20 ml of water and 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 0.92 g (88%) of the title compound as a white foam.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:23]([O:25]C)=[O:24])[C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1COCC1.O.[OH-].[Na+]>CO>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:23]([OH:25])=[O:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 30 (274 mg) is dissolved in 5 ml of methanol, 2.5 ml of THF and 5 ml of water. A 2M solution of sodium hydroxide is added (1.8 ml) and the reaction mixture is stirred for 4 days at ambient temperature. The solvents are then evaporated off under reduced pressure, and the resulting residue is taken up in water and extracted with ethyl acetate. The aqueous phase is cooled to 0° C. and acidified with a 2M hydrochloric acid solution, and the resulting solid is filtered off.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[C:23]1([C:29]2[N:30]=[N:31][N:32]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)[CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:36]4[CH2:37][CH2:38][CH:34]([N:32]5[CH:33]=[C:29]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:30]=[N:31]5)[CH2:35]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ccc(-c2cn(C3CCNC3)nn2)cc1
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: c1ccncc1
Product: Cc1c(F)c(N2CCC(n3cc(-c4ccccc4)nn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (100 mg, 0.37mmol),3-(4-phenyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (160 mg, 0.67 mmol) and diazobicycloundecane (102 mg, 0.67 mmol) in (5 ml) pyridine was heated at 90° C. for 24 hrs. The reaction mixture was concentrated and diluted with water. The separated solid was filtered and washed with water followed by ether and was crystallized from methanol. Yield: 89 mg (55%), m.p. 221.4° C. 1H NMR (TFA) δ: 1.20-1.70 (m, 4H), 2.76-3.80 (m, 2H), 4.20-4.96 (m, 5H), 5.74-5.90 (m, 1H), 7.52 (dd, 5H), 8.70 (s, 1H), 9.27 (s, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.Br[CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].CN(C)C(=O)C>O>[CH:14]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[CH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Over a period of 2 hours, 672 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were added dropwise to a solution of 1016 g of N-(2-bromoethyl)phthalimide in 2.81 of N,N-dimethylacetamide. During the addition, the temperature increased to 60° C. After the addition had ended, stirring was continued for 12 hours. The batch was poured into 9 l of water and filtered, and the filtration residue was dried at 50° C. This gave 621 g of product (=90% of theory) of melting point 79-80° C.
Reaction SMILES: O[C:2]1([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>C(O)C>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccsc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccsc3)C(C)(C)O4)CC2)cc1
Yield: 77 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(3-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 36, the title compound was synthesized in the same manner as in Example 46. Yield 77%. mp. 128–131° C. (ethanol).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])([CH3:4])[CH3:3].O1CCCC1>[Fe].O>[C:2]([C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH2:19])[CH:13]=1)=[O:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O

Procedure:
Iron metal powder (50.2 g; 0.897 mole) and 10M-hydrochloric acid (92 ml; 0.92 mole) were added alternatively over 11/2 hr. to a mixture, of the nitro compound (60.6 g; 0.149 mole) from (a), tetrahydrofuran (520 ml) and water (52 ml), heated under reflux. Heating was continued for a further 31/2 hr. after which the mixture was filtered. The filtrate was evaporated to dryness and the residue partitioned between toluene (500 ml) and water (400 ml). The layers were separated and the toluene solution filtered through kieselguhr, dried and evaporated to give a solid. This material was crystallized from methanol (100 ml) to give the product (41 g; 75%) as a white solid, m.p. 64°-66° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][C:20]([F:19])([F:31])[F:32])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3ccccc3OC(F)(F)F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2-Trifluoromethoxybenzoyl chloride (1.64 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days.
Reaction SMILES: C([Li])CCC.Br[C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O>CCCCCC.O1CCCC1>[CH3:13][C:7]([CH3:14])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: BrCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccccc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
25 ml of a 1.6M solution of n-butyllithium in n-hexane were added dropwise to a solution of 5.3 ml (7 g, 36 mmol) of ethyl bromoisobutyrate in 20 ml of tetrahydrofuran at -75° to -70° C. The mixture was then warmed to -20° C., 6.42 ml (9.43 g, 54 mmol) of benzylbromide were added dropwise and the mixture was subsequently stirred at room temperature for a further 3 hours. Dilute sulfuric acid was then added to the reaction mixture and the mixture was extracted twice with ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude product (6.6 g) was purified by distillation.