Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[CH2:9][CH2:10][CH2:11][N:12]([CH3:34])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27](OC(C)(C)C)=[O:28])=[CH:17][CH:16]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(Cl)(=O)C(C)(C)C.[C:72]1([C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:79](=[O:91])[O:80][CH:81]1[CH2:86][CH2:85][N:84]([CH2:87][CH2:88][NH:89][CH3:90])[CH2:83][CH2:82]1>C(Cl)Cl>[C:72]1([C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:79](=[O:91])[O:80][CH:81]1[CH2:86][CH2:85][N:84]([CH2:87][CH2:88][N:89]([C:27](=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22][NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[N:12]([CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:35])[CH3:34])=[CH:16][CH:17]=2)[CH3:90])[CH2:83][CH2:82]1
Reactant: CN(CCCN(C)C(=O)c1ccc(NCCOCCC(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCOCCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
The compound (188 mg, 0.381 mmol) obtained in Example 28e was dissolved in methylene chloride (4 mL), trifluoroacetic acid (2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure, and moisture was removed from the resulting residue azeotropically with toluene (×2). The resulting residue was dissolved in methylene chloride (4 mL), triethylamine (0.318 mL, 2.29 mmol) and di-tert-butyl dicarbonate (183 mg, 0.838 mmol) were added, and the mixture was stirred at room temperature for 18.5 hours. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in methylene chloride (4 mL), triethylamine (79 μL, 0.572 mmol) and pivaloyl chloride (49 μL, 0.400 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. 1-[2-(Methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (296 mg, 0.838 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=50:1, v/v) to give the title compound (196 mg; yield, 66%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:17]2[CH:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:20]3=[N:21][CH:22]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed (sparging with argon for 5 minutes), stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.617 g, 2.97 mmol) and 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.97 mmol) in dioxane (12.0 ml) was added Pd(Ph3P)4 (0.171 g, 0.148 mmol), followed by a degassed aqueous solution of sodium carbonate (4.45 ml, 8.90 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and saturated aqueous ammonium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid. LRMS (ESI) calculated for C17H14N4O2S [M+H]+, 339.1; found 339.1.
Reaction SMILES: [C:1]([C:3]1C=CC(C(C2C(=O)CC(C(F)(F)F)CC=2OCC)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=CC=1)#N.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:61]2[C:66](=[O:67])[CH2:65][CH:64]([C:68]3[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][CH:69]=3)[CH2:63][C:62]=2[OH:78])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:42][CH:41]=1)#[N:39]>>[C:38]([C:40]1[CH:41]=[CH:42][C:43]([CH:46]([C:61]2[C:66](=[O:67])[CH2:65][CH:64]([C:68]3[CH:69]=[CH:70][C:71]([C:74]([F:75])([F:76])[F:77])=[CH:72][CH:73]=3)[CH2:63][C:62]=2[O:78][CH2:1][CH3:3])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:44][CH:45]=1)#[N:39]
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3ccc(C(F)(F)F)cc3)CC2=O)cc1
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-ethoxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 13), using 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(4-(trifluoromethyl)phenyl)cyclohex-1-enyl)-methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 16, 930 mg, 1.62 mmol) as starting material. Yield: 825 mg; ESI mass spectrum [M+H]+=602, Retention time HPLC: 1.37 min (V011_S01).
Reaction SMILES: [C:1]([C:3]([NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([CH3:6])[CH2:4][OH:5])#[N:2].F[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31])[C:25]#[N:26].[H-].[Na+]>O1CCCC1>[C:1]([C:3]([NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([CH3:6])[CH2:4][O:5][C:22]1[CH:23]=[C:24]([C:25]#[N:26])[CH:27]=[CH:28][C:29]=1[C:30]([F:31])([F:33])[F:32])#[N:2]
Reactant: CC(C#N)(CO)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)(COc1cc(C#N)ccc1C(F)(F)F)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
In 5 ml of dried tetrahydrofurane, 651 mg N-[1-cyano-2-hydroxy-1-methylethyl]-4-trifluoromethoxybenzamide and 427 mg 3-fluoro-4-trifluoromethylbenzonitrile are dissolved and 63 mg of sodium hydride are added under stirring at 0°. The reaction mixture is stirred for 20 h at room temperature, then quenched with 5 ml of water and finally diluted with 15 ml of brine. The crude product is extracted with 3×10 ml of ethylacetate, the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue is purified by flash chromatography to yield the title compound as white crystals of m. p. 75-8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12](N)=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:6][NH:7]2.[OH-:23].[Li+].Cl>>[CH3:1][O:2][C:3]1[C:11]([C:12]([OH:23])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:6][NH:7]2
Reactant: COc1c(C(N)=O)ccc2[nH]nc(/C=C/c3ccccc3)c12
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccccc3)c12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
22 mg of 4-methoxy-3-(E)-styryl-1H-indazole-5-carboxylic acid amide was added to 3 mL of 4N lithium hydroxide aqueous solution, and stirred at 110° C. for 4 hours. After cooling on ice, the reaction solution was neutralized with 2N hydrochloric acid under ice cooling, and the precipitated crystals were collected by filtration and washed with water. This was then dried under reduced pressure, to afford 20 mg of the title compound as brown crude crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].[Cl-].[K+].Cl[C:10]1=[C:11]([Cl:17])[C:12]([O:14][C:15]1=[O:16])=[O:13].[C:18]1([CH3:25])[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.Cl>O>[O:13]=[C:12]1[C:21]2[C:22](=[CH:23][C:18]([CH3:25])=[CH:19][C:20]=2[CH3:24])[C:10]([C:15]([OH:14])=[O:16])=[C:11]1[Cl:17]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(C)c2c(c1)C(C(=O)O)=C(Cl)C2=O
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A mixture consisting of 88 g of powdered, anhydrous AlCl3, 16 g of NaCl, 5.4 of KCl and 16.7 g (0.1 mol) of dichloromaleic anhydride is initially introduced into a stirred flask provided with a HCl outlet and is heated at 90°-100° C. for a short time (until it has melted). 10.6 g (0.1 mol) of m-xylene are added at 70°-75° C. in the course of 45 minutes. After stirring for a further 30 minutes at 75°-80° C., the melt is introduced into a mixture of 25 ml of concentrated hydrochloric acid, water and ice (final volume about 1 liter) and the product is filtered off. After washing with water and drying in vacuo at 60° C., 23.0 g (97% of theory) of yellow-orange 1-oxo-2-chloro-5,7-dimethyl-indene-3-carboxylic acid are obtained. According to the thin layer chromatogram, the product contains only slight impurities and can therefore be used direct for further reactions. When recrystallised from ethyl acetate, the product melts at 255°-256° C.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1)[C:12]([O:14][CH3:15])=[O:13].O=[C:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>ClCCl>[N:28]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30][C:25]2([O:8][C:9]3[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[CH:17][C:18]=3[N:19]3[CH:23]=[CH:22][CH:21]=[C:20]23)[CH2:26][CH2:27]1
Reactant: COC(=O)c1ccc(-n2cccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Trifluoroacetic acid (3.15 g, 2.13 mL, 27.6 mmol) was added dropwise to a solution of methyl 3-hydroxy-4-pyrrol-1-yl-benzoate (3.00 g, 13.8 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.2 mmol) in dichloromethane (60 mL) and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with water and 1N NaOH. The organics were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in Hexanes. The pure fractions were combined and concentrated to give 1′-tert-butyl 7-methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate. ESI-MS m/z calc. 398.4, found 399.5 (M+1)+. Retention time: 2.13 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2Cl.[CH3:19][O:20][C:21]1[C:22]([NH2:26])=[CH:23][S:24][CH:25]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2[NH:26][C:22]1[C:21]([O:20][CH3:19])=[CH:25][S:24][CH:23]=1
Reactant: COc1cscc1N
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1cscc1OC

Procedure:
Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (1.5 g, 0.0056 mol) and 4-methoxy-3-aminothiophene (1.46 g, 0.0112 mol) in 1,4 dioxan (20 ml) were heated under reflux for 4 hours. The solid which had formed was collected by filtration and dried. The solid was dissolved in chloroform, washed with sodium carbonate solution (50 ml), then water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.Cl>CCOCC.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:14]1([C:12]2[S:13][C:9]([C:3]3[S:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccs1
Reactant: Brc1ccc(-c2ccccc2)s1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: c1ccc(-c2ccc(-c3cccs3)s2)cc1
Reaction time: 4 h
Yield: 69.3 %

Procedure:
In 140 ml of ether, 17.4 g (0.725 mol) of magnesium shavings was reacted according to Grignard with 118 g (0.723 mol) of 2-bromothiophene, and this solution was then introduced into 280 ml of ether, 1.5 g (2.8 mmol) of 1,3-bis(diphenylphosphino)propane nickel dichloride and 140 g (0.586 mol) of 5-bromo-2-phenylthiophene. After the slightly exothermic reaction had subsided, the mixture was stirred for 4 hours at boiling point, and the solution thus obtained was then diluted with 280 ml of ether and stirred into 280 ml of 2N hydrochloric acid solution. The crystals which precipitated out were isolated and dried. There was obtained 98.4 g (69.4% of theory) of 5-phenyl-[2,2'-bithienyl], mp. 116.5°-118° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][C:41]([C:44]([OH:46])=[O:45])([CH3:43])[CH3:42])/[C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:34]([OH:36])=[O:35])=[C:15]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[C:25]([OH:27])[C:24]([OH:28])=[CH:23][C:22]=4[CH2:29][C:30](OC)=[O:31])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C>C(#N)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][C:41]([C:44]([OH:46])=[O:45])([CH3:43])[CH3:42])/[C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:34]([OH:36])=[O:35])=[C:15]([CH2:18][N:19]4[C:30](=[O:31])[CH2:29][CH:22]5[C:21](=[CH:26][C:25]([OH:27])=[C:24]([OH:28])[CH2:23]5)[CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COC(=O)Cc1cc(O)c(O)cc1CNCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN3CC4=CC(O)=C(O)CC4CC3=O)CS[C@H]12)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.6 %

Procedure:
To 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5-dihydroxy-2-methoxycarbonylmethylbenzylaminomethyl)ceph-3-em-4-carboxylic acid (800 mg) in acetonitrile (5 ml) and water (5 ml), at 0° C., was added triethylamine (260 μl). The mixture was stirred, at ambient temperature, for 90 minutes and evaporated under reduced pressure. The residue was dissolved in water (25 ml) containing acetic acid (a few drops) and sodium acetate, filtered and purified by chromatography (HPLC; Dynamax column) using 17.5% acetonitrile/water. Freeze-drying afforded the title compound (58 mg); NMR (DMSO-d6 /CF3COOH) 1.49(s,3H); 1.52(s,3H); 3.35(dd,2H); 3.4(s,3H); 4.3(m,2H); 4.5(dd,2H); 5.18(d,1H); 5.85(dd,1H); 6.58(d,1H); 6.62(s,1H); 9.7(d,1H): FAB M/S (M-H)- 645.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([N:18]([C:20]([NH:22]C(=O)OCC)=S)[OH:19])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C([O-])(=[O:30])C>>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([N:18]([OH:19])[C:20]([NH2:22])=[O:30])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:4])[CH3:3]
Reactant: CCOC(=O)NC(=S)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)[O-]
Product: CC(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(O)C(N)=O

Procedure:
[[[1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]hydroxyamino]-thioxomethyl]carbamic acid, ethyl ester, acetate;
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: CO
Reactant: O=C(O)CCCCCCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (4.7 L), 8-bromooctanoic acid (0.912 kg) and sulfuric acid (0.912 L) are charged into a suitable reactor and the mixture is heated in reflux temperature for 5 hours and is then stirred at ambient temperature overnight. The solvent is removed at reduced (3 mm Hg) pressure and the oily residue is dissolved in ether (4 L). The solution is washed with water (3×2 L), saturated NaHCO3 solution (1 L) and brine (1 L). The ether portion is dried (MgSO4) and filtered to remove dessicant. Evaporation of solvent followed by distillation of the crude oil gives methyl 8-bromooctanoate, b.p. 73°-76°/0.05 mm Hg, nD23 1.4614.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[F:25][C:26]([F:39])([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:27]([Cl:30])([Cl:29])[Cl:28].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][C:26]([F:25])([F:39])[C:27]([Cl:28])([Cl:29])[Cl:30])=[CH:38][CH:37]=3)=[O:20])=[CH:23][CH:24]=1)[CH:6]=[N:5]2
Reactant: Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1

Procedure:
A solution of 4.35 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propanoyl chloride (previously prepared from 1.5 g of the corresponding acid) in 15 ml of acetonitrile was added to a mixture prepared from 1.20 g (4.35 mmol) of 4-(1,1-difluoro-2,2,2-trichloroethoxy)aniline, 0.66 g (6.5 mmol) of triethylamine and 10 ml of acetonitrile. The mixture was warmed at reflux for a period of 2.5 hours and then poured over ice and aqueous NaOH added. The resulting precipitate was filtered and dried and then recrystallized from methylcyclohexane. This left 2.2 g (84 percent of theoretical) of the above-named product as a brown solid, m.p. 139°-141° C. (Compound 36)
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C)C=O.N1C=CN=C1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([I:27])=[CH:22][C:21]=1[OH:28]>O>[C:2]([Si:5]([O:28][C:21]1[CH:22]=[C:23]([I:27])[C:24]([Cl:26])=[CH:25][C:20]=1[Cl:19])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: Oc1cc(I)c(Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(I)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
TBDMSCl (5.22 g) was added to a dimethylformamide solution (50 mL) of imidazole (2.83 g) and 2,4-dichloro-5-iodophenol (10 g), which was synthesized according to the production method described in WO 2001/027088. The mixture was stirred at room temperature for 4 hours. Water (150 mL) was added and extracted with hexane (200 mL). The extract was then washed in succession twice with water (100 mL) and once with brine (100 mL), and was pre-dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane) to give tert-butyl-(2,4-dichloro-5-iodophenoxy)-dimethyl-silane as pale yellow oil (11.39 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].Cl.CN(C)CCCN=C=NCC.O[CH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:47][CH2:48][CH2:49][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: OCCCN1CCOCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCCN5CCOCC5)c[nH]4)c3)cc2)c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 63 mg, 0.33 mmol) in 10 ml of anhydrous tetrahydrofuran were added N-(3-hydroxypropyl)morpholine (64 mg, 0.44 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 72 mg, 56%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[C:22]=1[CH3:29])=[O:17])C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]3[CH2:20][CH:18]3[C:16]([OH:17])=[O:15])=[C:22]([CH3:29])[C:23]=2[CH3:28])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Product: Cc1c(OCc2cccnc2SC(C)C)ccc(C2CC2C(=O)O)c1C
Yield: 81.3 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.030 g, 0.149 mmol) obtained in Step C of Preparation Example 1 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 81%).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH:29]([OH:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@H:29]([OH:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
340 μl (1.89 mmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 10.58 mg (70 μmol) of (1R,2S)-1-aminoindan-2-ol in ±1 ml of tetrahydrofuran, and the mixture is stirred for another 30 min. A solution of 230 mg (0.47 mmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 21A) in 11 ml of tetrahydrofuran are then very slowly added dropwise, and the mixture is stirred overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane/dichloromethane/ethyl acetate 40:40:1→2:2:1) gives the diastereomerically pure target compounds.