Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:10][CH:11]=1.[BH4-].[Li+].O>C1COCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][OH:2])=[CH:11][CH:10]=1
Reactant: COC(=O)COc1ccc(-c2ccccc2F)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccc(-c2ccccc2F)nc1

Procedure:
Under argon, 675 mg (2.58 mmol) of (6-(2-fluorophenyl)pyridin-3-yloxy)acetic acid methyl ester and 112.5 mg (5.17 mmol) of lithium borohydride were stirred in 20 ml of THF at 60° C. for 2 h. After cooling, the mixture was cautiously hydrolyzed with water and concentrated, and water and ethyl acetate were added. The organic phase was separated, washed with water and concentrated. Yield: 350 mg (58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C(Cl)(Cl)Cl>C(Cl)Cl>[C:40]([O:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])[CH:24]=1)(=[O:42])[CH3:41]
Reactant: COc1ccc(O)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC(C)=O)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(5-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-2, 62.5 mg, 0.14 mmol) and triethylamine (154 μL, 1.11 mmol) were dissolved in anhydrous methylene dichloride (1 mL), acetic anhydride (52 μL, 0.55 mmol) was added thereto, and then the mixture was stirred at room temperature for 1.5 hours. Chloroform (10 mL) was added to the reaction mixture, the mixture was washed with water (10 mL) and saturated brine (300 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (56.6 mg) as a colorless amorphous product. (Yield 83%)
Reaction SMILES: [C:1]1([CH:7]=[C:8]([CH3:20])[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH2:18][CH3:19])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[C].[Pd]>[C:1]1([CH2:7][CH:8]([CH3:20])[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH2:18][CH3:19])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CCc1cnccc1C(C)CC(C)=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCc1cnccc1C(C)CC(C)Cc1ccccc1
Yield: 90.8 %

Procedure:
1.2 g (4.53 mmol) of 1-phenyl-2-methyl-4-(3-ethyl-4-pyridyl)-1-pentene (Compound 63) obtained in Example 46 was dissolved in 30 ml of methanol, 250 mg of 5% palladium carbon was added thereto and the resulting mixture was stirred for 8 hours at room temperature in an atmosphere of hydrogen. Palladium-carbon was filtered out and methanol was distilled away under reduced pressure, to obtain 1.1 g (yield: 91.2%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12](CC3C=CC=CC=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:7]2[C:14]([CH3:15])=[C:13]([CH3:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncnc(Nc3cccc(Cl)c3)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g (2.76 mmol) of 4-(m-chloroanilino)-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine and 2.57 g (19.32 mmol) of AlCl3 are heated at reflux in 20 ml of toluene for 2 hours, until all starting material has disappeared in a TLC. The reaction solution is cooled to RT, poured onto ice-water and stirred at 0° C. for 2 hours. The precipitate is filtered off with suction and dissolved in hot ethyl acetate. The ethyl acetate solution is washed twice each with 5% sodium hydrogen carbonate solution and sat. NaCl solution, is dried and is concentrated by evaporation. The residue is crystallised from ethyl acetate/hexane, yielding 4-(m-chloroanilino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine in the form of colourless crystals having a melting point of 239-240° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:21][S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])([CH2:11]/[C:12](=N/N(C)C)/[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)(O)[O-:30].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:21][S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])([CH2:11][C:12](=[O:30])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CN(C)/N=C(/CC(CF)(N[S@](=O)C(C)(C)C)c1cccc(Br)c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)NC(CF)(CC(=O)C(F)(F)F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
(R)-N-((Z)-2-(3-bromophenyl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (1.47 g, 3.10 mmol) was dissolved in THF 16 mL and 2N hydrochloric acid (1.549 ml, 3.10 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was worked up with saturated sodium bicarbonate solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 15-50% EtOAc/hexane to give (R)-N-(2-(3-bromophenyl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide (1.13 g, 84% yield). MS m/z=433.9 [M+H]+. Calculated for C15H18BrF4NO2S: 432.3
Reaction SMILES: [CH2:1]=[C:2]1[S:6]/[C:5](=[N:7]\[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])/[N:4]([C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)[CH2:3]1.ICl.C(=O)([O-])[O-:32].[Cs+].[Cs+].OS([O-])=O.[Na+].II>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.C(O)(=O)C>[OH:32][CH2:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])/[N:4]([C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)[CH:3]=1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/C(=N/C(=O)N2CCCC2)S1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClI
Agent: II
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(/N=c1\sc(CO)cn1-c1ccc2c(c1)OC(F)(F)C(F)(F)O2)N1CCCC1
Reaction time: 0.25 h

Procedure:
The alkene (Example 22D, 23 mg, 55 μmol) and tetrabutylammonium chloride (1.2 mg, 4 μmol) were dissolved into acetic acid (500 μL) and treated with 1 M iodine monochloride (110 μL, 110 μmol) in CH2Cl2, dropwise over 1 minute. After 15 minutes, cesium carbonate (18 mg, 55 μmol) was added. After another 10 minutes, solid NaHSO3 (16 mg, 150 μmol) was added, and the resulting suspension was thoroughly stirred until the deep iodine color had changed to a light orange (15 minutes). The suspension was diluted with CH2Cl2, stirred for 2 minutes, and filtered through a glass-fritted funnel with a CH2Cl2 rinse. The filtrate was concentrated, concentrated twice from EtOAc, dissolved into 20% EtOAc/CH2Cl2, and filtered through a pad of Aldrich basic alumina (activated, Brockmann 1, ˜150 mesh, CAS #1344-28-1) with a 20→50% EtOAc/CH2Cl2 rinse. The intermediate mixture was concentrated to 13 mg, dissolved into MeOH (500 μL), and treated with 1 M aqueous Cs2CO3 (30 μL). After ˜15 minutes, the mixture was concentrated and partitioned between CH2Cl2 and pH 7 potassium phosphate buffer. The aqueous phase was separated and extracted with CH2Cl2, and the combined organic phases were dried (Na2SO4), concentrated, and chromatographed through silica (20% EtOAc/CH2Cl2, then 5% MeOH/CH2Cl2) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.86 (4H), 3.44 (4H), 4.65 (2H), 6.89 (1H), 7.23 (1H), 7.37 (1H), 7.48 (1H); MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[C:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:28]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:20]=[C:21]2[CH2:26][CH2:25][N:24]([C:34]([NH:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:23][CH2:22]2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: C#CCCCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
5-(Pent-4-ynyloxy)-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.26 g, 0.746 mmol) and phenyl pyridin-3-ylcarbamate (0.159 g, 0.746 mmol) were dissolved in DMSO (3 mL) and triethylamine (0.3 mL) was added dropwise. The reaction was stirred for 12 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (acetone:hexane, 2:5) to give the title compound (0.23 g, 65%). 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.88 (s, 1H), 7.29 (m, 3H), 6.98 (d, J=7.5 Hz 2H), 6.93 (d, J=11 Hz, 2H), 6.86 (d, J=9 Hz, 1H), 6.38 (s, 1H), 4.07 (t, J=6 Hz, 2H), 3.64 (m, 2H), 3.53 (m, 2H), 2.59 (m, 2H), 2.46 (m, 2H), 2.40 (d, J=7 Hz, 2H), 1.98 (t, J=7 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 157.51, 155.22, 154.49, 151.84, 143.19, 140.58, 138.81, 137.68, 136.57, 133.71, 129.44, 127.90, 126.87, 124.84, 124.63, 123.78, 120.59, 118.35, 112.56, 83.15, 69.15, 67.28, 45.74, 44.74, 35.76, 29.17, 28.09, 15.08; m/z (469.2, MH+); HPLC: 97.8%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Mg]Br.C(OCC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])([CH3:35])[CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)=O)cc3)ccc2C1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)(C)O)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[(S)-6-(4-Acetyl-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-carbamic acid tert-butyl ester (400 mg, 0.71 mmol) was dissolved in tetrahydrofuran (15 ml) at 0° C. A 3 molar solution of methylmagnesium bromide in diethyl ether (2.82 ml, 7.12 mmol) was added slowly and the reaction mixture was stirred for 3 hours at room temperature. Another portion of a 3 molar solution of methylmagnesium bromide in diethyl ether (0.5 ml, 1.26 mmol) was added. Since no further conversion was observed, the reaction mixture was evaporated to dryness. Water (20 ml) was added to the residue and the aqueous phase was extracted with diethyl ether (50 ml) twice. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude product was purified by MPLC chromatography using dichloromethane/methanol (100:0-70:30) as eluent, yielding the product (300 mg, 47% purity, 39%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]2[CH2:17][CH2:16]2)[C:10]=1[CH3:18].Cl.C[O-].[Na+]>CO>[CH:15]1([C:11]2[C:10]([CH3:18])=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][OH:7])[CH2:16][CH2:17]1
Reactant: Cc1c(COC2CCCCO2)cccc1C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)cccc1C1CC1
Yield: 80.9 %

Procedure:
Elimination of the protective group: 16.7 g of 3-cyclopropyl-2-methylbenzyl tetrahydro-2-pyranyl ether in 180 ml of methanol are stirred overnight at room temperature with 10.8 ml of concentrated hydrochloric acid. The mixture is neutralized with sodium methylate solution while cooling with ice and is then evaporated down. Water is added to the residue, which is then extracted several times with ether. The combined ether extracts are washed with water, dried and evaporated down. The crude product (11.5 g) is purified by column chromatography over silica gel using toluene as the mobile phase. 8.9 g of 3-cyclopropyl-2-methylbenzyl alcohol (Example 100) are obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)C=C.[C:14]1(C)[C:15](C)=CC=C[CH:19]=1>>[CH2:15]([C:10]1[CH:9]=[C:8]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:14]=[CH2:19]
Reactant: Cc1ccccc1C
Reactant: C=CCOc1ccc(C(C)=O)cc1
Product: C=CCc1cc(C(C)=O)ccc1O

Procedure:
A solution of 4′-allyloxyacetophenone (6.0 g, 34.1 mmol) in 10 mL xylene is introduced into a thick walled pyrex tube, which is sealed with a teflon cap. After heating to 230° for 5 hours, the solution is cooled to 0°. The precipitated white solid is filtered and the solid is washed with cold toluene and hexane to yield 3′-allyl-4′-hydroxyacetophenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(Br)cc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1ccc(-c2ncnn2-c2ccc(Br)cc2)cc1

Procedure:
A mixture of 9.0 g. of 1-(p-bromophenyl)-5-(p-nitrophenyl)-1H-1,2,4-triazole, 18.0 g. of sodium hydrosulfite, 40 ml. of water and 150 ml. of acetone is stirred at room temperature overnight. The acetone is removed in vacuo and the residue is extracted with hot chloroform. Cooling produces 2.1 g. of the desired product as pale yellow crystals, mp. 128°-130° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[OH:10][C:9]1[C:2]([O:1][CH3:11])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(O)cccc1C=O
Yield: 61.7 %

Procedure:
2,3-Dihydroxybenzaldehyde (1.00 g, 7.24 mmol), potassium carbonate (1.00 g, 7.24 mmol) and iodomethane (0.59 ml, 1.34 g, 9.4 mmol) in dry DMF (10 ml) were stirred at ambient temperature for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N aqueous sodium hydroxide (3×). The basic extracts were combined and acidified by addition of 3N hydrochloric acid, then extracted with ethyl acetate. The ethyl acetate layer was washed with water (4×), brine and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 3-hydroxy-2-methoxy-benzaldehyde (0.68 g, 62%) as a yellowish-tan solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=1[F:31])[O:21][CH2:22][C:23]([O:25]CC)=[O:24].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=1[F:31])[O:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of ethyl 2-[3-[[2,6-difluoro-3-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (240 mg, 0.53 mmol, 1.0 eq) in THF (10 mL) was added a solution of aqueous NaOH (1M aqueous solution, 5 mL, 5 mmol, 9.4 eq). The reaction mixture was stirred at room temperature for 3 h. The organic solvent was removed in vacuo and the residue diluted with water and adjusted to pH 5-6 by addition of diluted HCl. The precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a solid (180 mg, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:35])=[C:24]([CH:27]=[N:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)[CH:25]=2)[NH:20][C:19](=[O:36])[C:18]=1[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:35])=[C:24]([CH2:27][NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)[CH:25]=2)[NH:20][C:19](=[O:36])[C:18]=1[C:37]1[CH:38]=[C:39]([CH3:44])[CH:40]=[C:41]([CH3:43])[CH:42]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C=Nc4ccncn4)c(Cl)cc3[nH]c2=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CNc4ccncn4)c(Cl)cc3[nH]c2=O)c1
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrimidin-4-yliminomethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl )-piperidine-1-carboxylic acid tert-butyl ester (36 mg in 2 mL dry tetrahydrofuran) at -10° C. was added a 1M solution of lithium aluminum hydride (2 mL) and the mixture stirred at low temperature. After 2 hours, the reaction was quenched by the addition of water, filtered and the organic portion concentrated in vacuo. Purification by preparative tic on silica gel gave the title compound.(12 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23](OCC)(OCC)(OCC)[CH3:24]>>[CH3:23][C:24]1[N:11]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: CO[C@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Reactant: CCOC(C)(OCC)OCC
Product: CO[C@H]1C[C@@H](n2c(C)nc3cnc4ccsc4c32)CC[C@@H]1CC#N

Procedure:
This compound was prepared according to the procedure of Example 34, steps 12, using {(1R,2S,4S)-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-methoxycyclohexyl}acetonitrile (racemic) and triethyl orthoacetate as the starting material. LCMS calculated for C18H21N4OS (M+H)+: m/z=341.1. Found: 341.1.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:10][O:9][C:4]1[C:3]([CH2:2][N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]([CH3:29])=[CH:12][CH:13]=3)=[CH:23][CH:22]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1ncccc1CCl
Reactant: Cc1ccc(Oc2ccc(NS(C)(=O)=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncccc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 70 °C

Procedure:
A mixture of 3-chloromethyl-2-methoxy-pyridine (0.2 g, 1.29 mmol) from Step A, N-(4-p-tolyloxy-phenyl)-methanesulfonamide (0.38 g, 1.35 mmol) from Step B and K2CO3 (0.44 g, 3.22 mmol) in dry DMF (5 mL) was heated at 70° C. overnight. The reaction was then diluted with EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2) and the combined organics were brought to the usual work-up. The resulting crude material was purified by chromatography (silica gel, 40% EtOAc/hexanes) to give the desired product. MS (EI) 399 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Clc1cccc(Br)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cccc(Cl)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 1-bromo-3-chlorobenzene.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([C:25]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26]4)=[CH:20][C:19]=3[F:32])=[CH:14][CH:13]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4].C(O)(=O)C>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([C:25]4([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[CH:20][C:19]=3[F:32])=[CH:16][CH:17]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4]
Reactant: COC(=O)C1(c2cc(F)c(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(F)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3c(F)cc(C4(C(=O)O)CC4)cc3F)cc2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
Powdered potassium hydroxide (91 mg, 1.62 mmol) was added in one portion to methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylate (Intermediate 28-1; 142 mg, 0.32 mmol) in tert-butanol (10 mL). The resulting yellow cloudy suspension was stirred at 40° C. for 1 hour. The reaction mixture was quenched with acetic acid (0.149 mL, 2.60 mmol) in ethanol (2 mL) and the resulting solution stirred for a further 10 minutes before being evaporated to dryness. The resulting solid was partitioned between water (20 mL) and ethyl acetate (20 mL). An insoluble solid was filtered off. The organic layer was separated and the aqueous re-extracted with ethyl acetate (20 mL). The combined organics were evaporated in vacuo to give crude product as an off white solid. The crude solid was triturated with mixture of DCM (3 mL) and methanol (3 mL) to give a solid which was collected by filtration and dried under vacuum to give 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)cyclopropanecarboxylic acid (52.0 mg, 37.8%) as a white solid.