Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=2)[CH:3]=1.CI.N12CCCN=C1CCCC[CH2:21]2.C(=O)([O-])O.[Na+]>C(#N)C.CN1CCCC1=O.C(OCC)(=O)C>[OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([O:17][CH3:21])=[O:16])[CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1ccc2cc(O)c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-3,6-di-hydroxycarbonylnaphthalene (11.6 g) was dispersed in anhydrous acetonitrile (116.0 g) and N-methyl-2-pyrrolidone (39.0 g). Then, methyl iodide (7.85 g) was added and 1.8-diazabicyclo[5.4.0]undec-7-ene (hereinafter referred to as "DBU") (8.37 g) was added dropwise over 5 minutes, followed by heating at 50° C. overnight. Further methyl iodide (2.32 g) and DBU (2.42 g) was added and mixture was stirred overnight. The deposited crystal was filtered and then dried under reduced pressure to obtain 7.29 g of a crude crystal of 2-hydroxy-3-hydroxycarbonyl-6-methoxycarbonylnaphthalene. Aliquot of this crystal (1.52 g) was dissolved in ethyl acetate (30.2 g) and an aqueous 5% sodium hydrogencarbonate. The solution was separated into the organic layer and the aqueous layer, and then the organic layer was extracted with an aqueous 5% sodium hydrogencarbonate solution (10.3 g) and aqueous extract was combined with the above aqueous layer. To this aqueous layer was added dropwise 10% hydrochloric acid until the pH becomes 7 while ice-cooling. The deposited crystal was filtered and then dried under reduced pressure to obtain 1.02 g of 2-hydroxy-3-hydroxycarbonyl-6-methoxycarbonylnaphthalene (DSC analysis value: 295.1° C.).
Reaction SMILES: [CH2:1]([OH:14])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>CCOCC>[CH2:1]([OH:14])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC#CCO
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCCCC/C=C/CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-tridecyn-1-ol (2 g, 10 mmol) in Et2O (50 mL) was added LiAlH4 (1 g, 26 mmol, 2.6 equiv). The resulting mixture was refluxed for 12 hours and allowed to cool to 25° C. A saturated solution of sodium-potassium tartrate was then added and the resulting mixture was stirred for an additional 3 hours. The organic layer was separated, dried (MgSO2) and concentrated by rotary evaporation to yield trans-2-tridecen-1-ol (50) as a colorless oil: 1H NMR (CDCl3) δ 5.62 (dt, J1 =15.3 Hz, J2 =5.1 Hz, 1 H), 5.70 (dt, J1 =15.3 Hz, J2 =5.7 Hz, 1 H), 4.08 (t, J=4.2 Hz, 2 H), 2.04 (q, J=6 Hz, 2 H), 1 30 (m, 16 H), 0.88 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 133.72, 128.92, 63.96, 32.31, 32.01, 29.72, 29.60, 29.43, 29.28, 29.24, 22.78, 14.20. ##STR24##
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pt](=O)=O>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH:20]([CH3:38])[CH2:19][CH2:18][CH:17]([CH3:39])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: [H][H]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1COCCO1
Product: CC(CCC(C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 99.6 %

Procedure:
A solution of 593 mg (1.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 15 ml dioxane was stirred with 25 mg (0.11 mmol) platinum (IV) oxide under 1 atm of hydrogen for 72 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and azeotroped three times with chloroform on a rotary evaporator to remove last traces of dioxane, then triturated in ether to afford 400 mg (100%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH3:4].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][S:36]([C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[Cl:28])(=[O:38])=[O:37])[CH:8]=[CH:7][C:6]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:20])=[O:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(N)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: CCCCc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 6-butyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-ylamine and 2,4-dichlorobenzenesufonyl chloride using General Method 11 step 2 to give N-{6-butyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-2,4-dichloro -benzenesulfonamide. 1HNMR CDCl3 8.10 (1H, d), 7.58 (2H, d), 7.47 (1H, s), 7.36 (1H, d), 7.07 (2H, d), 6.81 (1H, d), 2.97 (4H, m), 2.80 (2H, t), 1.15-1.65 (10H, m), 0.81 (3H, t). LCMS (Luna 2, ): rt=8.11 minutes, 612 (M−H)−.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].ClC(OCC)=O.[CH2:15]([N:17](CC)CC)[CH3:16].C(N)C.[Cl-].[Na+]>C1COCC1>[CH2:15]([NH:17][C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH3:16]
Reactant: CCN(CC)CC
Reactant: C/C=C/C=C/C(=O)O
Agent: CCN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C/C=C/C=C/C(=O)NCC
Yield: 26 %

Procedure:
2E,4E-Hexadienoic acid 1 eq, ethyl chloroformate 1.12 eq, triethylamine 1.2 eq, ethylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=26%. 1.16 ppm (t, 3H, J=7.27 Hz), 1.82 ppm (d, 3H, J=6.09 Hz), 3.36 ppm (q, 2H, J=7.26 Hz, of d, J=5.73 Hz), 5.77 ppm (d, 1H, J=14.96 Hz), 5.93 ppm (br. s, 1H), 6.01-6.18 ppm (m, 2H), 7.19 ppm (d, 1H, J=14.94 Hz, oft, J=10.14 Hz).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(N(CC)CC)C>[C:22]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(c2ccccc2)c2ccccc21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture comprising 4.0 g of 3-phenylindoline, 40 ml of benzene, 5 ml of triethylamine and 4.0 g of acryloylchloride was stirred at 10°-15° C for 15 minutes. The mixture was then washed with water, the benzene solution dried and the solvent removed. 4.1 G of resin which was crystallized from ether to give 2.3 g of the desired N-acryloyl-3-phenylindoline which was found to have a melting point of 77°-8° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1ccc(CO)cc1
Yield: 46 %

Procedure:
This compound was prepared by reduction of 4-cyanobenzaldehyde according to the procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 46%: MP 102-123° C.; 1H NMR (Acetone-d6, 500 MHz) 7.27 (m, complex 4H), 4.58 (s, 2H), 3.72 (s, 2H), 3.69 (s, 1H) 2.77 (br, 1H), 2.45 (br, 1H);
Reaction SMILES: I[CH2:2][CH2:3][C:4]([C:7]([C:10]([S:13]([O:15][Na])=[O:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5].[OH-].[K+]>C(O)C>[CH2:2]=[CH:3][C:4]([C:7]([C:10]([S:13]([OH:15])=[O:14])([F:11])[F:12])([F:8])[F:9])([F:6])[F:5]
Reactant: O=S(O[Na])C(F)(F)C(F)(F)C(F)(F)CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(F)(F)C(F)(F)C(F)(F)S(=O)O
Temperature: 20 °C
Yield: 88.8 %

Procedure:
The above ICH2CH2(CF2)3SO2Na wet solid was dissolved in ethanol and treated with 8.7 g KOH (MW=56, 85%, 0.132 mol) at room temperature, then the mixture was reacted at 50° C. for 8 hrs to precipitate a solid (KI). The reaction mixture was cooled to 20° C. and filtered to remove solids. No significant change in 19F NMR was observed. The solvent was stripped and the resulting solid was acidified with 2NH2SO4 to a pH<2. The acidified solution was extracted with t-butylmethyl ether (three times, 100 mL each) and the combined ether solution was dried over MgSO4. Finally, the solution was filtered and the solvent was stripped to yield 21.5 g (MW=242, 88.8 mmol) desired semisolid product, CH2═CH(CF2)3SO2H, which is soluble in water. The structure of the product was confirmed by NMR analyses, 19F NMR, −115 (dxt, 2F, ═CHCF2-), −125 (txm, 2F), −127 (t, 2F, —CF2SO2H). 1H NMR, 4.4˜5.6 (m) ppm, indicating no more ICH2CH2— signal. The isolated yield is ˜88.8% from ICH2CH2CF2CF2CF2I.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=[O:39])CCCCCCC/C=C\C/C=C\C/C=C\CC>>[OH:39][CH:13]([CH2:14][CH:15]=[CH:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCC=CCC(O)CCC=CCCCCCCCC(=O)O

Procedure:
The same procedure as in Example 2 was repeated, except that linoleic acid was replaced by α-linolenic acid, whereby 13-hydroxy-9,15-octadecadienoic acid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][CH2:29]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[CH2:29]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:16]=1)[CH:28]=[CH2:27]
Reactant: Cc1cccc(-c2nn3cc(CO)ccc3c2-c2ccc(F)cc2)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOCc1ccc2c(-c3ccc(F)cc3)c(-c3cccc(C)n3)nn2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A solution of EXAMPLE 99 (0.13 g, 0.39 mmol) and 1-bromo-3-chloropropane (0.06 g, 0.39 mmol) in DMF (10 mL) was treated with cesium carbonate (0.14 g, 0.43 mmol) and heated to 80° C. The reaction is stirred overnight and is diluted with EtOAc and water. The organic phase is separated and washed with brine. After drying over Na2SO4, the organic phase is filtered, and the solvent removed to afford 0.04 g (27%) of product. MS ES+ m/e 374.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][CH2:13][CH2:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:16]([C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[C:26](=[O:31])[N:25]([C:32]1[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:33]=1[CH2:34][O:35]C(=O)C)[N:24]=[CH:23]2)([CH3:19])([CH3:18])[CH3:17].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[C:16]([C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[C:26](=[O:31])[N:25]([C:32]1[CH:42]=[CH:41][CH:40]=[C:39]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[O:12][CH2:13][CH2:14][N:15]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:33]=1[CH2:34][OH:35])[N:24]=[CH:23]2)([CH3:19])([CH3:17])[CH3:18]
Reactant: Cn1cc(Br)cc(NC2=NCCO2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(NC2=NCCO2)c1=O
Temperature: 100 °C
Yield: 11.8 %

Procedure:
A mixture of 5-bromo-3-(4,5-dihydro-oxazol-2-ylamino)-1-methyl-1H-pyridin-2-one (111 mg, 0.41 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (201 mg, 0.41 mmol), X-Phos (15 mg, 0.033 mmol) and potassium phosphate tribasic (174 mg, 0.82 mmol) was taken up in n-butanol/water (4:1, 8.1 mL) and vacuum degassed. Palladium(0) bis(dibenzylideneacetone) (10 mg, 0.02 mmol) was added and the mixture was vacuum degassed and then heated to 100° C. under argon atmosphere. After 3 hours the material was cooled to ambient. The material was taken up in dichloromethane (40 mL) and water (40 mL) and shaken in a separatory funnel. The dichloromethane phase was collected and washed with brine solution (40 mL). The aqueous phase was back extracted with methylene chloride (2×30 mL) and the organic phases combined, dried over magnesium sulfate, filtered and stripped. Residual n-butanol was removed on the pump/rotary evaporator. Chromatography (Preparative TLC [3 plates], 11% methanol/dichloromethane—methanol contains 5% triethylamine) provided semi-pure product. The material was chromatographed a second time (Preparative TLC [2 plates], using 12% methanol/dichloromethane—methanol contains 5% triethylamine) which provided the title compound as an off-white crystalline solid (25 mg). (M+H)+=518 m/e; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 3.56 (s, 3 H) 3.69-3.83 (m, 2 H) 4.25 (t, J=8.5 Hz, 2 H) 4.29-4.36 (m, 2 H) 4.65 (m, 1 H) 7.35-7.54 (m, 5 H) 7.74 (dd, J=13.3, 1.7 Hz, 1 H) 7.87 (d, J=1.7 Hz, 1 H) 8.49 (d, J=2.6 Hz, 1 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]([CH3:57])[CH2:43][CH2:44][N:45]([CH3:56])[C:46]1[S:47][C:48]2[CH:54]=[C:53]([NH2:55])[CH:52]=[CH:51][C:49]=2[N:50]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:41][N:42]([CH3:57])[CH2:43][CH2:44][N:45]([CH3:56])[C:46]1[S:47][C:48]2[CH:54]=[C:53]([NH:55][C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH:52]=[CH:51][C:49]=2[N:50]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Yield: 59.6 %

Procedure:
Prepare according to Method A, using 4-(4-fluorophenyl)benzoic acid (572 mg, 2.65 mmol), HATU (1.06 g, 2.79 mmol), N2-(2-dimethylamino-ethyl)-N2-methyl-benzothiazole-2,6-diamine (500 mg, 2.00 mmol), DIEA (1.15 mL, 6.60 mmol), and a chromatography gradient of MeOH in CH2Cl2 (7-17%) to afford the title compound (535 mg, 60%). mass spectrum (m/e): 449.0 [M+H]. 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.26 (d, 1H, J=2.2 Hz), 8.06 (d, 2H, J=8.4 Hz), 7.84-7.78 (m, 4H), 7.57 (dd, 1H, J=8.8, 2.2 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.34 (t, 2H, J=8.8 Hz), 3.61 (t, 2H, J=6.8 Hz), 3.14 (s, 3H), 2.52 (m, 2H), 2.20 (s, 6H).
Reaction SMILES: C[Zn]C.[C:4]1(C)C=CC=CC=1.Cl[C:12]([CH2:14][O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:13].Cl>[Cl-].[Na+].O.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[O:13]=[C:12]([CH3:4])[CH2:14][O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)COCC(=O)Cl
Reactant: Cc1ccccc1
Agent: Cl[Pd+]
Agent: C[Zn]C
Agent: Cl
Solvent: O
Product: COC(=O)COCC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A solution of 2M dimethyl zinc in toluene (21 mL, 42 mmol) was cooled to 0° C. under nitrogen, treated with trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0.57 g, 76 mmol), treated with methyl 2-(chloroformylmethoxy)acetate (12.6 g, 76 mmol) dropwise over 0.5 hours, stirred for 0.5 hours at 0° C., stirred for 16 hours at ambient temperature, treated with 1M HCl (40 mL) and then brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography over silica gel (1:2 ethyl acetate/hexanes) to provide the title compound (5.2 g).
Reaction SMILES: C(O)(=O)C.O.[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18]2=[O:42])=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1>[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:42])=[CH:43][CH:44]=1)=[O:9]
Reactant: COC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
1700 ml of acetic acid and then 400 ml of water were added at room temperature to a suspension of 344 g of 5-(4-methoxycarbonylmethoxybenzyl)-3-triphenylmethyl-thiazolidine-2,4-dione [prepared as described in step (f) above] in 400 ml of 1,4-dioxane and the resulting mixture was stirred for 5 hours at 80° C. At the end of this time, the reaction mixture was freed from the solvent by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of ethyl acetate and hexane, a 2 1 by volume mixture of ethyl acetate and hexane and then ethyl acetate as eluents, to give 161.7 g of the title compound, melting at 100°-106° C.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:20])[CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]([CH3:20])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: Cc1ccccc1
Product: C[C@@H](CN)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL, 86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90° C.-95° C. for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropylamine, (5.58 g, 94.9%) an oil; 1H nmr (CDCl3, 300 MHz) δ 1.21 (d,3H), 1.40-1.60 (b, 2H), 2.68-2.80 (m, 1H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2c(F)cccc2Cl)C1
Solvent: CC#N
Product: O=C(Cc1c(F)cccc1Cl)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-chloro-6-fluorophenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: C(OC(=O)N[C:8]([CH3:29])(C)[CH2:9][C:10]1[C:18]2[C:13](=[C:14](OC3C(C#N)=CC=CN=3)[CH:15]=[CH:16][CH:17]=2)[NH:12]C=1)(C)(C)C.Cl.O1CCO[CH2:34][CH2:33]1>>[CH3:33][CH2:34][CH2:29][CH2:8][CH2:9][CH2:10][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:12]
Reactant: C1COCCO1
Reactant: CC(C)(Cc1c[nH]c2c(Oc3ncccc3C#N)cccc12)NC(=O)OC(C)(C)C
Agent: Cl
Product: CCCCCCCCCCCCN
Reaction time: 5 h
Yield: 83 %

Procedure:
{2-[7-(3-Cyano-pyridin-2-yloxy)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (119 mg, 0.293 mmol) is dissolved in 10 mL of 1,4 dioxane. The mixture is cooled to zero degrees Celsius in an ice/water bath. To the mixture is added 10 mL of 4N hydrochloric acid in 1,4 dioxane, and the resulting mixture is stirred at zero degrees, under nitrogen, for five hours. The solvent is evaporated, and the residue is taken up in water. The pH of the water is adjusted to 9 using sodium bicarbonate, and is extracted three times with 50 mL of ethyl acetate. The organic layers are combined, dried with sodium sulfate, filtered, and the solvent removed in vacuo to give 218 mg of the title amine (83%). FDMS m/e=307 (M++1).
Reaction SMILES: [CH2:1]([N-]CC)C.[Li+].[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].IC.O>C1COCC1>[CH3:1][CH:13]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[C:8]1=[O:7]
Reactant: O=C1CCCCN1c1ccccc1O
Reactant: CC[N-]CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC1CCCN(c2ccccc2O)C1=O
Reaction time: 0.5 h

Procedure:
Lithium diethylamide (2M solution in THF) (3.92 mL, 7.84 mmol) was added to a solution of 2-(2-oxo-piperidin-1-yl)-phenol (as described in Example 1, Step F) (0.50 g, 2.61 mmol) in THF (5 mL) at −78° C. with stirring under Ar. After 30 min, iodomethane (0.488 mL, 7.84 mmol) was added and the reaction left to come to room temperature overnight. The reaction was treated with H2O, concentrated to remove the THF, then partitioned between diethyl ether and H2O. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound after chromatography (silica gel, 1% CH3OH, 29% EtOAc, 70% hexane).
Reaction SMILES: [OH-].[K+].C(OC(C)C)(C)C.[CH:10]#[C:11][CH:12]([OH:14])[CH3:13].[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1=[O:25])[CH3:16]>O>[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1=[O:25])[CH3:16].[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1([OH:25])[C:10]#[C:11][CH:12]([OH:14])[CH3:13])[CH3:16]
Reactant: C#CC(C)O
Agent: CCC1CCCC(C)(C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCC1CCCC(C)(C)C1(O)C#CC(C)O
Yield: 78 %

Procedure:
448 g (8 mole) of KOH and 1100 ml of di-isopropyl-ether were first introduced into a reaction vessel fitted with cooling and stirring devices. 154 g (2.2 mole) of but-1-yn-3-ol were then added to the above mixture (temperature 25°-30°; addition period:30 min), followed by 308 g (2.0 mole) of 2-ethyl-6,6-dimethyl-cyclohexanone (addition period:30 min; dropwise). The reaction mixture was then stirred at 35° for 17 hours and, after cooling, 500 ml of water were progressively added thereto. After separation of the organic phase, washing with 5% aqueous H2SO4 (200 ml), drying over Na2SO4, concentration and final distillation, there were isolated a first portion of unreacted 2-ethyl-6,6-dimethyl-cyclohexanone (46 g) and 313 g (78% yield) of 2-ethyl-6,6-dimethyl-1-hydroxyl-1-(3-hydroxy-but-1-yn-1-yl)-cyclohexane.