Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.[BH3-]C#N.[Na+]>CO>[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][N:33]([CH:40]3[CH2:42][CH2:41]3)[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCN(C5CC5)CC4)cc3)c(Cl)sc2[nH]c1=O

Procedure:
A mixture of 2-chloro-4-hydroxy-3-{4-[(4-hydroxy-piperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (70 mg, 0.128 mmol),[(1-ethoxycyclopropyl)oxy]trimethylsilane (0.103 mL, 0.513 mmol), 3A molecular sieves (30 mg), and NaCNBH3 (32 mg, 0.513 mmol) in MeOH (1 mL) was heated to reflux for 12 h. The reaction was then quenched by the addition of H2O (1 mL) and EtOAc (1 mL). The layers were separated, and the aqueous was extracted with additional EtOAc (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound. MS (ESI) m/e 472 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (m, 2H), 0.94 (m, 2H), 1.80 (d, J=12.0 Hz, 2H), 1.94 (m, 2H), 2.97, (m, 1H), 3.40 (m, 4H), 3.86 (s, 2H), 5.22 (s, 1H), 6.92 (d, J=8.82 Hz, 2H), 7.22 (d, J=8.82 Hz, 2H), 8.81 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[CH:31][CH:30]=1>>[CH3:24][CH:23]([CH3:25])[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]3[C:33]4[C:32](=[CH:31][CH:30]=[C:29]([CH3:28])[CH:34]=4)[NH:35][CH:2]=3)[CH2:14][CH2:13]2)[CH:16]=1)=[O:26]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]cc(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 404.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(N(C)C2CCOCC2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-[methyl(oxan-4-yl)amino]benzoate (413 mg, 1.32 mmol) in THF (13 ml) and MeOH (2 ml) was added 4M NaOH (13.16 ml). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 385 mg (98%) of the title compound as a thick yellow oil. LC-MS 94%, m/z=300.0/302.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.74 (d, J=2.0 Hz, 1H), 7.30-7.12 (m, 1H), 4.11-4.02 (m, 2H), 4.01 (s, 3H), 3.54 (t, J=11.6 Hz, 1H), 3.40 (t, J=11.3 Hz, 2H), 2.76 (s, 3H), 1.97-1.78 (m, 2H), 1.63 (d, J=11.8 Hz, 2H).
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C>[S:8]([O:11][CH2:7][C@H:2]([C@@H:3]([CH2:4][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:12])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[OH:1])[OH:1])([C:5]1[CH:4]=[CH:3][C:2]([CH3:12])=[CH:7][CH:6]=1)(=[O:9])=[O:10]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To an ethanol (100 mL) suspension of 1,4 di-O-tosyl-2,3-O-isopropylidene-L-threitol (10.0 g, 21.25 mmol), p-toluenesulfonic acid monohydrate (0.40 g) was added, and the mixture was heated to reflux for 4 days with stirring. The reaction liquor was cooled, and then the solvent was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, to obtain the title compound as a solid. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:11]=1.CN(C)P(=O)(N(C)C)N(C)C.O>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][Cl:3])[CH:11]=1
Reactant: OCCCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: ClCCCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.31 ml of thionyl chloride was added under ice-cooling to a solution of 0.86 g of 4-[5-chloro-2-(2-phenylethoxy)phenyl]butanol and 4 ml of hexamethylphosphoric triamide in 20 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 ml), extracted with ethyl acetate, successively washed with water twice and a saturated aqueous solution of sodium hydrogencarbonate 4 times and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 0.91 g of crude 4-chloro-2-(4-chlorobutyl)-1-(2-phenylethoxy)benzene was obtained. This compound was not purified any more but used in the subsequent reaction.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1(=[O:12])[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:11][C:7]1[CH2:8][CH2:9][CH2:10][C:5](=[O:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1CCCC(=O)C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
According to Scheme 4 Step 1: Acetyl chloride (19.6 mmol, 1.39 mL) was added to a solution of cyclohexane-1,3-dione (17.8 mmol, 2.00 g) and pyridine (17.8 mmol, 1.28 mL) in CHCl3 (60 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with the addition of water and the organic phase was washed with a solution of HCl (0.1 M, 30 mL), a saturated solution of NaHCO3 (30 mL) and water (30 mL). The organic phase was dried over Na2SO4 and concentrated to yield 3-oxocyclohex-1-enyl acetate (13.2 mmol, 2.04 g, 74%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=O)[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2F)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2F)C1
Yield: 89.9 %

Procedure:
To a solution of 3-(2-fluorophenylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (2) (1.13 g, 3.5 mmol) in THF (4 ml) at 0° C. was added BH3-THF solution (1.0 M, 3.5 ml) slowly. The mixture was refluxed for 2 hrs. The reaction was quenched by slow addition of MeOH at 0° C. The solvent was removed by evaporation. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 85:15) to give 3-[(2-Fluorophenylamino)methyl]piperidin-1-carboxylic acid tert-butyl ester (3) as a colorless oil (0.97 g, 90%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: COc1ccc2c(c1)CCNC2C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(c1nc(Cl)nc(C)c1C)C2C
Temperature: 85 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
After 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline(1.3 g, 7.3 mmol) and triethylamine(1.0 ml, 7.3 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(1.2 g, 6.64 mmol) in dimethylformamide, the reaction mixture was stirred for 3 hours at 85° C. The reaction mixture was cooled to a room temperature and diluted with ethyl acetate. The organic layer was washed with water and aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, concentrated under a reduced pressure, and then purified by a silica gel column chromatography to give 1.7 g of the titled compound. (Yield: 78.5%)
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>COCCOC.C(O)C.C1COCC1.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>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
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: CCO
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 0.08 h

Procedure:
A room temperature solution of ethyl 4-bromobenzoate (0.70 mL, 4.3 mmol) in DME (20 mL) was treated with Pd(PPh3)4 (246 mg, 0.2 mmol), stirred for 5 minutes, treated with a solution of 4-methylphenylboronic acid (870 mg, 6.4 mmol) in ethanol (10 mL), stirred for 5 minutes, treated with 2M Na2CO3 (18.0 mL, 36.0 mmol), heated to reflux, stirred for 16 hours, and concentrated. The concentrate was dissolved in water (75 mL) and diethyl ether (50 mL), filtered through celite, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 33% acetone/hexanes. The resulting product was dissolved in methanol (10 mL) and THF (5 mL), treated with 1M NaOH (4.3 mL, 4.3 mmol), stirred for 48 hours, concentrated, dissolved in water (10 mL), adjusted to pH 1 with 12M HCl, and filtered. Recrystallization from ethyl acetate provided the desired product. MS (APCI(+)) m/e 213 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C:17]([CH:23]=[O:24])([CH2:20][CH2:21][CH3:22])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C:17]([CH:23]([C:4]2[S:3][C:2]([Cl:1])=[C:6]([Cl:7])[CH:5]=2)[OH:24])([CH2:20][CH2:21][CH3:22])[CH2:16]1)=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCC1(C=O)CCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1ccsc1Cl
Product: CCCC1(C(O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-[(4,5-Dichloro-thiophen-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2,3-dichloro-thiophene and 3-formyl-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester using the procedure of step 1 of Example 20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (158 mg, 0.35 mmol, see step (b) Example 9) and 4-trifluoromethylphenylboronic acid. Yield 135 mg (65%).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:35]([O:43][CH2:44][C:45]1[O:49][N:48]=[C:47]([CH3:50])[C:46]=1Br)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(CC)CC.[CH3:59][C:60]1([CH3:67])[C:64]([CH3:66])([CH3:65])[O:63][BH:62][O:61]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:35]([O:43][CH2:44][C:45]1[O:49][N:48]=[C:47]([CH3:50])[C:46]=1[B:62]1[O:63][C:64]([CH3:66])([CH3:65])[C:60]([CH3:67])([CH3:59])[O:61]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1noc(COC(=O)c2ccccc2)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1noc(COC(=O)c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a resealable vial was added Pd(OAc)2 (3.87 mg, 0.017 mmol) and X-phos (16.42 mg, 0.034 mmol) before the vial was sealed and evacuated and purged with N2 (3×). To this vial was added (4-bromo-3-methylisoxazol-5-yl)methyl benzoate (102 mg, 0.344 mmol) in dioxane (1 mL), Et3N (144 μl, 1.033 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution (517 μl, 1M in THF, 0.517 mmol). The reaction was stirred overnight at 80° C., cooled to room temperature and filtered. The filtrate was concentrated to afford crude (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl benzoate. To a resealable vial was added K2CO3 (47.5 mg, 0.344 mmol), PdCl2(dppf)-CH2Cl2 Adduct (20.06 mg, 0.025 mmol), (2-bromophenyl)(4-chlorophenyl)methanone (72.6 mg, 0.246 mmol). The vial was sealed and evacuated and purged with N2 (3×) before addition of crude (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl benzoate (118 mg, 0.344 mmol) dissolved in dioxane (2 mL). Water (0.5 mL) was then added to this solution before the vial was heated to 110° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 432 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CN=C1>CN(C=O)C>[C:23]([Si:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Cl

Procedure:
4-Chloro-3-methylphenol (33.22 g, 0.233 mol), tert-butyldiphenylsilyl chloride (62.89 g, 0.233 mol), and imidazole (47.59 g, 0.699 mol) in DMF (200 mL) were heated at 70° C. for 18 h. The reaction mixture was partitioned between EtOAc/hexane and H2O, the organic layer separated, washed with H2O, brine, and dried(Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([C:26]([F:29])([F:28])[F:27])=[N:18]2)=[CH:13][CH:12]=1>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19]([C:26]([F:29])([F:27])[F:28])=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=1
Reactant: Cc1cn[nH]c1
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(Cc2ccc(-n3nc(C(F)(F)F)c4c3CCCC4)cc2)c1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
Sodium hydride (60% in mineral oil, 10.0 mg; 0.25 mmol) was added in one portion to a room temperature stirring solution of 4-methyl-1H-pyrazole (15.0 mg; 0.18 mmol) in anhydrous DMF (1 mL). After stirring at this temperature for 15 minutes, a solution of 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (52.0 mg; 0.16 mmol) in anhydrous DMF (1 mL) was added and the resulting mixture stirred at room temperature for a further 23 hours. The reaction was quenched with aqueous hydrochloric acid (2M; 1 mL), concentrated in vacuo and purified by MDAP, giving the title compound (35.6 mg; 60%).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[N:6]1[CH2:14][C:13]2[C:8](=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:18].[OH-].[Na+].Cl>CO>[CH:31]1([CH2:30][O:29][C:21]2[CH:20]=[C:19]([CH:5]([N:6]3[CH2:14][C:13]4[C:8](=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:18])[CH2:4][C:3]([OH:34])=[O:2])[CH:24]=[CH:23][C:22]=2[O:25][CH:26]([F:28])[F:27])[CH2:33][CH2:32]1
Reactant: COC(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a suspension of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (550 mg, 1.2 mmol) in methanol (5 ml) was added dropwise 10 N NaOH (0.23 ml, 2.3 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then it was allowed to warm up to room temperature and stirred for 2 hours. 4N HCl was added until pH=5. The mixture was extracted with methylene chloride (30 ml) and 1N HCl (30 ml). The organic layer was washed with water (2×30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a yellow solid (480 mg, 90%). 1HNMR (CDCl3): δ 0.31–0.37 (m, 2H), 0.59–0.67 (m, 2H), 1.22–1.28 (m, 1H), 3.11 (dd, J=6.5, 15 Hz, 1H), 3.33 (dd, J=9, 15 Hz, 1H), 3.78–3.87 (m, 2H), 4.18 (d, J=17.5 Hz, 1H), 4.46 (d, J=17.5 Hz, 1H), 5.83 (dd, J=6.5, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 6.91–7.17 (m, 3H), 7.59–7.76 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[CH:9]1[O:31][CH:12]2[CH2:13][O:14][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:18][CH:11]2[CH:10]1[O:32][C:33](=[O:35])[CH3:34].C(N(CC)CC)C.F.F.F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[CH:9]1[CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([OH:18])[CH:12]([CH2:13][OH:14])[O:31]1
Reactant: CC(=O)OC1C2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OCC2OC1n1ccc(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1C(O)C(CO)OC1n1ccc(=O)[nH]c1=O

Procedure:
The Tips protecting group is removed from Compound 5 as illustrated in the literature (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 239 and references therein, Greene, T. W. and Wuts, P. G. M., eds, Wiley-Interscience, New York). To a solution of 5 (1 eq.) in anhydrous dichloromethane is added triethylamine (2 eq.) and triethylamine trihydrofluoride (2 eq.). The reaction mixture is monitored by thin layer chromatography until complete at which point the reaction mixture is diluted with additional dichloromethane, washed with aqueous NaHCO3, dried over anhydrous Na2SO4, and evaporated. The resulting Compound 6 is optionally purified by silica gel chromatography.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([CH2:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1.N1C=CC=CC=1>O>[CH:5]1([CH2:13][Br:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: OCC1C=CCCCCC1
Reactant: BrP(Br)Br
Solvent: O
Solvent: c1ccncc1
Product: BrCC1C=CCCCCC1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
A solution of phosphorus tribromide (1.02 cm3 ; 0.0105 m) in 40 to 60 petroleum ether (5 cm3) was added dropwise to a solution of 2-cyclooctenylcarbinol (2.8 g; 0.02 m) (fraction 9 above) and AR. Pyridine (0.104 g; 0.0013 m) in petroleum ether (15 cm3) stirred and cooled to -10° C. After addition the mixture was allowed to warm to room temperature and stood for 2 days. The reaction mixture was treated with water (50 cm3) and the organic layer separated. The aqueous layer was extracted with 40 to 60 petroleum ether (3×25 cm3) and the combined organic layer and petrol extracts washed with 2 N-NaOH (25 cm3) and water (25 cm3). The petrol extracts were combined and dried over anhydrous MgSO4 and the solvent removed under vacuum to leave a crude product 2.3 g. The crude product was distilled to give 0.7 g of pure product b.p. 48°-50°/0.25 mmHg.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH3:2].[OH:30]O>C(O)(=O)C>[CH2:1]([S:3]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)=[O:30])[CH3:2]
Reactant: CCSCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CCS(=O)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 24 h

Procedure:
2.01 g (5.0 mmol) of 4'-[(2-ethylthiomethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid are dissolved in 25 ml of glacial acetic acid and treated with 0.51 ml of 30% strength hydrogen peroxide. The solution is allowed to stand for 24 hours at ambient temperature and is then evaporated to dryness. The residue is purified over a silica gel column (grain size: 40-63 μm, eluting agent: methylene chloride/ethanol/glacial acetic acid=50/1/0.15). The homogeneous fractions are combined, the solvents, are distilled off, the residue is dissolved in methylene chloride and washed three times using water. The organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue is mixed with diethylether, the mixture is filtered under suction and the crystals are dried at 75° C. in vacuum.