Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]([OH:25])[CH2:13][O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.O[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)([OH:39])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>C(O)C>[N+:7]([C:5]1[N:6]=[C:2]2[N:3]([CH:4]=1)[CH2:10][CH2:11][C@H:12]([CH2:13][O:14][C:27]1[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][C:36]([C:40]4[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:47])[F:49])=[CH:44][CH:45]=4)([OH:39])[CH2:35][CH2:34]3)=[CH:31][CH:32]=1)[O:25]2)([O-:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: Oc1ccc(N2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(O)(c4ccc(C(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 60 °C
Reaction time: 15 h
Yield: 41 %

Procedure:
A mixture of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (1.16 g), 1-(4-hydroxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (1.0 g), tripotassium phosphate (2.52 g) in ethanol (10 ml) was stirred at 60° C. for 15 hours under an argon atmosphere. The reaction mixture was added to an ammonium chloride aqueous solution, and the mixture was stirred for a while. The precipitated crude crystal was collected by filtration and dried at 60° C. The crude product thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:1) and recrystallized from acetone-water to afford the title compound as a beige powder (0.63 g).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][CH2:14][O:15][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>CCO>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:2]3[C:11]4[CH:10]=[C:9]5[O:12][CH2:13][CH2:14][O:15][C:8]5=[CH:7][C:6]=4[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:27]=2)[CH:23]=[N:24]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc2cn[nH]c2c1)OCCO3
Yield: 75.9 %

Procedure:
A mixture of 1.00 g (4.07 mmol) of 9-chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile and 0.649 g (4.88 mmol) of 6-aminoindazole in 25 mL of EtOH was refluxed under N2 for 5.7 h. Satd NaHCO3 was added and the solvent was removed. The residue was slurried with H2O, filtered, washed with H2O and cold EtOH and dried. The crude product was boiled with EtOH, filtered and dried in vacuo (50° C.) to yield 1.06 g of 9-(1H-indazol-6-ylamino)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbonitrile as tan crystals: mass spectrum (electrospray, m/e): M+H 344.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:20][C:21]1([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:24]3[CH2:25][CH2:26][C:21]([OH:27])([CH3:20])[CH2:22][CH2:23]3)=[O:17])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)c1=O
Reactant: CC1(O)CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCC(C)(O)CC3)cn2)c1=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 12.6 %

Procedure:
In a 250 mL round-bottomed flask, 6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid (195 mg, 695 μmol), 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT (138 mg, 903 μmol) and Hunig's base (269 mg, 364 μl, 2.08 mmol) were combined with DMF (13 ml) to give a light yellow suspension. EDC (173 mg, 903 μmol) was added and the reaction mixture was heated to 100° C. and stirred for 24 h. Additional 4-methylpiperidin-4-ol (80.0 mg, 695 μmol), HOBT (106 mg, 695 μmol) and EDC (133 mg, 695 μmol) were added with 2 ml DMF. The reaction mixture was heated to 100° C. and stirred for 24 h. The reaction was cooled to 25° C. and quenched with water. The aqueous layer was back-extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was taken up in DCM/MeOH 9:1 and filtered. The filtrate was conc. in vacuo to give a light yellow solid. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to afford 0.033 g (13%) of the title compound as a yellow solid. (M+H)+=378/380 m/e.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[Si:14]([O:21][CH2:22][C@@H:23]([N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][N:41]=[C:40](S(C)(=O)=O)[N:39]=2)=[CH:34][C:33]1=[O:48])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1>[Si:14]([O:21][CH2:22][C@@H:23]([N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:39]=2)=[CH:34][C:33]1=[O:48])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: Cc1cc(N)ccn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
2-Methylpyridin-4-amine (0.28 g, 2.6 mmol) was placed in THF (5 mL) and cooled to −78° C. t-BuLi (1.5 mL, 2.6 mmol) was added dropwise, and the solution was warmed to 0° C. for 30 minutes. This solution was then added dropwise to a −78° C. THF solution (5 mL) of (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 0.13 mmol). The reaction was stirred for an additional 30 minutes at −78° C., then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:10-500:20 DCM/MeOH) to give the product (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.028 g, 38% yield).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH2:26][CH2:27][CH3:28])C(OCC(Cl)(Cl)Cl)=O)[C:14]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[CH:31][CH:30]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.O1CCCC1.C(O)(=O)C>[Zn].CO>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:26][CH2:27][CH3:28])[C:14]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[CH:33][CH:34]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reaction time: 2 h

Procedure:
To 22 g (35 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 585) was added 100 ml of tetrahydrofuran, 100 ml of methanol, 4.6 g (70 mmole) of zinc dust, and finally 6.4 g (106 mmole) of acetic acid. After stirring for 2 hours, the starting material had been consumed as shown by TLC. The mixture was filtered from unreacted zinc, concentrated in vacuo, dissolved in 200 ml of diethyl ether, washed twice with 100 ml of water, washed once with 100 ml of dilute aqueous sodium hydroxide and washed once with brine. The resulting ether solution was dried over anhydrous magnesium sulfate, concentrated in vacuo, and chromatographed over silica gel using hexanes, diethyl ether, and ethyl acetate yielding 1 g of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propyl-N-(2,2-dichloroethoxycarbonyl)-amino)-4,5,-dihydro-1H-pyrazole-1-carboxamide and 12 g of the desired compound, mp 130°-133° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]([OH:33])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(Cc1ccccc1F)C1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccccc1F)C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Yield: 72.4 %

Procedure:
After dissolving 7.5 ml of oxalyl chloride in 130 ml of dichloromethane, the solution was cooled to −78° C. and a solution of 6.1 ml of dimethylsulfoxide in dichloromethane (20 ml) was added dropwise while stirring. After stirring for 20 minutes, a solution of 13.4 g of 1-(1-benzylpiperidin-4-yl)-2-(2-fluorophenyl)ethanol in dichloromethane (40 ml) was added dropwise. After stirring for 30 minutes, 24 ml of triethylamine was added and the temperature was raised to room temperature. Water was added to the reaction solution, the organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (9.64 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O(CCCC)CCCC>[Fe].O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CCCCOCCCC
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Temperature: 80 °C
Yield: 64 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8nitro-5-(9-phenylnonoxy) quinoline (11 g, 0.025 mol), degreased 40 mesh Fe filings (30 g), H2O (100 ml), HOA c (20 ml) and n-Bu2O (20 ml) was heated at 80° C. for 2 h, cooled and filtered. The solid residue and the filtrate were thoroughly extracted with warm Et2O and the combined extracts were dried (Na2SO4), treated with Darco, and concentrated. The resulting solid was dissolved in pet ether (Darco) and cooled in dry ice--Me2CO to give 6.5 g (64) of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline as pale yellow crystals, mp 32°-32.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[SH2:16]>CO.C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[S:16])[NH2:2]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: S
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2C(N)=S)cc1
Reaction time: 72 h

Procedure:
First, 2.00 g of 2-cyano4′-methyl-1,1′-biphenyl was dissolved in a mixture of 15 ml of methanol and 4.18 g of triethylamine, and hydrogen sulfide gas was bubbled thereinto at room temperature to the point of saturation. After keeping at room temperature for 3 days, the solution was kept at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate containing 1% hydrochloric acid. The organic layer was concentrated to give 2.18 g of 2-thiocarbamoyl-4′-methyl-1,1′-biphenyl. Yield, 92%; m.p., 111-115° C.; m/z, 227
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]1.[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[ClH:43]>[I-].[K+].C(C(C)=O)C(C)C>[ClH:43].[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5]2([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1cc(F)ccc1C1(CCCBr)OCCO1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1cc(F)ccc1C1(CCCN2CCC(O)(c3cccc(C(F)(F)F)c3)CC2)OCCO1
Yield: 91.2 %

Procedure:
A mixture of 4-bromo-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane (3.3 g), 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (1.96 g), potassium carbonate (1.1 g), potassium iodide (20 mg) and methyl isobutyl ketone (25 g) was heated under refluxing for one hour. To the resulting mixture, 13% hydrochloric acid (8.2 g) was added under cooling, and the precipitated crystals were collected by filtration, washed with toluene and dried to give 3.9 g (91.1%) of 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane hydrochloride. M.P. 229° C (decomp.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23](O)=O.[F:26][C:27]1[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=1>C1(C)C=CC=CC=1.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]2[NH:33][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:14]5=[CH:15][C:16]6[O:20][CH2:19][O:18][C:17]=6[CH:21]=[C:13]5[O:12][CH2:11]4)[C:2]3=[O:1])=[N:34][C:29]=2[CH:28]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N(Cc2nc3cc(F)ccc3[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 25.7 %

Procedure:
A mixture of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.50 g, 1.47 mmol) and 4-fluorobenzene-1,2-diamine (0.15 g, 1.18 mmol) in anhydrous toluene (20.0 mL) was refluxed overnight under N2. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/1) to give the title compound (0.13 g, 22%): mp 138-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.47-7.39 (m, 1H), 7.32-7.22 (m, 2H), 7.16-6.93 (m, 3H), 6.18 (s, 1H), 6.07 (s, 1H), 5.84-5.78 (m, 2H), 5.20-5.14 (m, 2H), 4.98 (d, 1H), 4.60 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 179.2, 161.3, 158.1, 156.2, 149.2, 149.1, 142.5, 141.2, 131.5, 129.5, 124.4, 124.0, 118.0, 111.6, 111.2, 109.9, 103.1, 101.7, 93.5, 80.5, 58.5, 38.9; MS (ES+) m/z 430.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]([CH3:39])[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:21]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:38])[CH:20]([CH3:39])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1)C(C)C

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [rac]-2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-(6-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as light yellow gum.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:11][C@@H:12]1[C@H:17]2[CH2:18][O:19][C@H:15]([O:16]2)[C@H:14]([CH:20]=C)[C@H:13]1[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+]>C(O)C.C(O)C.O>[CH2:4]([O:11][C@@H:12]1[C@H:17]2[CH2:18][O:19][C@H:15]([O:16]2)[C@H:14]([CH2:20][OH:1])[C@H:13]1[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[O+][O-]
Reactant: C=C[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1O
Reaction time: 0.5 h

Procedure:
A stream of ozone (0.36 mmol/min) was passed through a solution of 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-vinyl-β-D-glucopyranose (8, 3.36 g, 12.8 mmol) in ethanol (100 ml) for 43.5 minutes. The solution of the ozonide was transferred to a three-necked round bottomed flask equipped with a thermometer and a dropping funnel containing a solution of NaBH4 (3.87 g, 102 mmol) in ethanol/water 1:1 (35 ml). The solution of NaBH4 was added dropwise in such a manner to keep the temperature below 20° C. (cooling on ice bath). After stirring for 45 min Amberlite IR 120, H+ (100 ml) was added. After stirring for another 30 minutes, the ion exchange resin was filtered off and rinsed with water. The solution was evaporated and co-concentrated with methanol (3×80 ml). The residue was a colorless syrup obtained in 96% (3.28 g) yield. This syrup was flash chromatographed using ethyl acetate/pentane 2:1 and ethyl acetate as eluent to give 9 in a 63% (2.14 g) yield as a crystalline compound. In some runs the crude syrup crystallized and was recrystallized from chloroform: mp. 111°-113°; [α]D20 =41.4° (c; 2.05, CH3OH). 13C-NMR (50 MHz, D2 O):δ139, 130.1, 129.8 (Ph); 102.0 (C-1);, 80.5 (C-4), 76.1 (C-3), 72.9 (OCH2Ph), 67.4 (C-5), 66.2 (C-6), 61.7 (C-2'), 49.0 ppm (C-2). Anal. Calc. for C14H18O5 : C, 63.15; H, 6.81. Found: C, 63.14; H, 6.79.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:24]([OH:36])[CH2:25][S:26][C:27]3[S:28][C:29]4C=CC=C[C:30]=4[N:31]=3)[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+]>O.C1COCC1>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:24]([OH:36])[CH2:25][S:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)C(CC(O)CSc1nc2ccccc2s1)NS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(O)CSc1nccs1)NS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
2-[(4′-Trifluoromethyl[1,1′-biphenyl]-4-yl)sulfonyl]amino-4-hydroxy-5-[2-benzothiazolylthio]-pentanoic acid: To a solution of 3-[(4′-trifluoromethyl[1,1′-biphenyl]-4-yl)sulfonyl]amino-[2-oxo-5-(thiazol-2-yl)thio]methyl]-tetrahydrofuran 14c (1.13 g, 2.2 mmol) in water (5 mL) and THF (5 mL) is slowly added lithium hydroxide (0.53 g, 22 mmol). The reaction is stirred for 2 hr, then concentrated to dryness. The reaction mixture is diluted with water and then the mixture is extracted with ethyl ether (2×25 mL) The ethyl ether layer is discarded and the aqueous layer is slowly acidified with 1N HCl to pH 5, and then extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The solid is purified by prep HPLC to give the desired white solid product.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:14]O)[CH2:12][CH3:13])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O.[Pd]>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: CCC(=NO)c1ccc(OC)cc1
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(N)c1ccc(OC)cc1
Yield: 82.5 %

Procedure:
To a N2 flushed solution of 4′-methoxypropiophenone oxime (4 grams, 22.3 mmol) in glacial acetic acid (40 milliliters) was added 0.8 grams of 5% Pd/C. The mixture was treated with 60 psi of H2 in a Parr Type Shaker for 23 hours. The catalyst was filtered off through celite and the filtrate was concentrated to afford a yellow oil. The oil was taken up in water, the pH was adjusted to 12 using a saturated solution of sodium carbonate, and extracted with methylene chloride. The organic extract was dried over magnesium sulfate and concentrated to afford 3.04 grams (83%) of product as a yellow oil: 1H NMR (CDCl3) δ7.32-7.20(m, 2H), 6.94-6.82(m, 2H), 3.79(s, 3H), 1.88-1.54(m, 4H), 0.87(t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:18])[C:6]2[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:7]=2[N:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)CO.C(N(CC)CC)C>O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[NH:4][C:5](=[O:18])[C:6]3[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:7]=3[N:8]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1sc2nc(CCl)[nH]c(=O)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O
Product: CCOC(=O)c1sc2nc(CN3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c2c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A mixture of 1.15 g of ethyl 2-chloromethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 745 mg of tert-butoxycarbonylpiperazine, 20 mL of ethylene glycol and 400 mg of triethylamine was stirred at 80° C. for 3 hours. Thereafter water was added to the reaction mixture, followed by extraction with chloroform, drying over anhydrous magnesium sulfate, and removal of the solvent by distillation under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:chloroform:hexane=2:1:1) to provide 1.36 g (78%) of the title compound.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:7]1)(=O)=O.[Br:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][N:8]3[CH2:9][CH2:10][C@@H:6]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[O:28][CH2:27][C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[Br:24])[CH2:7]3)=[CH:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1OCc1ccccc1Br
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccccc1COc1ccccc1N[C@@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1

Procedure:
(S)-3-Methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine (0.30 g, 0.89 mmol) was added to 2-(2-bromobenzyloxy)aniline (1.15 g, 4.13 mmol) in argon stream. The obtained mixture was dissolved in acetonitrile (50 ml). Potassium carbonate (1.62 g, 11.7 mmol) was added to the obtained solution, and they were refluxed for 85 hours. Acetonitrile (15 ml) was added to the reaction mixture, and they were refluxed for additional 48 hours. The reaction mixture was filtered through Celite to obtain the filtrate. The solvent was evaporated under reduced pressure to obtain the title compound in the form of a brown oily mixture (1.40 g).