Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[C:17]([NH:19][C:20]2[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH:29]([CH3:31])[CH3:30])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:26]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:29]([CH3:30])[CH3:31])[C:20]=1[NH:19][C:17](=[O:18])[N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1)([CH3:27])[CH3:28]
Reactant: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1ccc(N(Cc2ccc(O)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 17.9 %

Procedure:
A solution of N-[(4-benzyloxyphenyl)methyl]-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (5.23 g), 10% Pd—C (0.6 g) and ammonium formate (3.1 g) in methanol was stirred at room temperature for 5 hr. Pd—C was filtered off from the reaction system and the filtrate was concentrated and the residue was purified by silica gel column chromatography to give N′-(2,6-diisopropylphenyl)-N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)urea (0.78 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[S:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1cccc(F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCN(CC)C(=S)c1cccc(F)c1
Yield: 142 %

Procedure:
A mixture of N,N-diethyl-3-fluorobenzamide (4.69 g, 24 mmol) (cf Mills, et al., “Directed Ortho Metalation of N,N-Diethylbenzamides. Silicon Protection of Ortho Sites and the o-Methyl Group,” J. of Organic Chemistry 54: 4372-4385, 1989), Lawesson's reagent (6.47 g, 16 mmol) and xylenes (150 mL) was refluxed overnight, then was concentrated and kugelrohr distilled (105-110° C. at 0.25 torr) to yield 4.8 g N,N-diethyl-3-(fluoro)thiobenzamide as a yellow oil, a 95% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(C=O)cc3OC)c(C)s2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(CO)cc3OC)c(C)s2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of ethyl 1-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (1.56 g) in tetrahydrofuran (30 mL)-ethanol (5 mL) was gradually added sodium borohydride (70 mg) at 0° C. After stirring at 0° C. for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (1.48 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 84-85° C.
Reaction SMILES: [CH3:1][Li].Cl[CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9]>CCOCC>[CH3:1][C:8]1[C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5][CH2:4][N:9]=1
Reactant: CC(C)(C#N)CCCCl
Reactant: [Li]C
Solvent: CCOCC
Product: CC1=NCCCC1(C)C
Reaction time: 0.5 h

Procedure:
0.1 mol of methyl lithium dissolved in 200 ml of ether anhydride is added drop by drop in an inert atmosphere (argon or nitrogen) to 15 g of 5-chloro-2,2-dimethyl pentane nitrile diluted in 60 ml of anhydrous ether. The reaction mixture is maintained between 0° and 5° C. during the addition and then for a further 30 minutes and then kept at room temperature for 4 hours. After hydrolysis it is extracted with ether. The 2,3,3-trimethyl-3,4,5,6-tetrahydropyridine is then isolated by distillation. A colorless liquid of B.P.14 =60° C. is obtained in a yield of 76% of 1-piperideine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27]([CH3:29])([CH3:28])[CH2:26][N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:39])=[CH:19][C:18]=3[F:40])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27]([CH3:28])([CH3:29])[CH2:26][NH:25][C:24]4=[O:39])=[CH:19][C:18]=3[F:40])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2CC(C)(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4(C)C)cc3F)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114, 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (112 mg) described in Preparation Example 54, cesium carbonate (261 mg) and copper(I) iodide (38 mg) were added 1,4-dioxane (10 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was stirred with heating under reflux for 32 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one. The obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one was dissolved in dichloromethane (5 mL), trifluoromethanesulfonic acid (75 μL) was added, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (30 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[CH2:12]([N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:39][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:22]=2)[CH:16]=1)[CH2:10][CH2:9][CH2:8][NH2:7])[CH3:13]
Reactant: NCCc1cccc(F)c1
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2nc(Cl)ncc2F)c1
Product: CCN(CCCN)Cc1cccc(-c2nc(NCCc3cccc(F)c3)ncc2F)c1

Procedure:
Intermediate 78 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 426. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H), 8.19 (s, 2H), 7.66 (m, 2H), 6.97 (m, 4H), 4.49 (s, 2H), 3.64 (t, 2H), 3.24 (m, 4H), 2.97 (t, 2H), 2.92 (t, 2H), 2.07 (m, 2H), 1.36 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1>>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C:11]=3[O:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]([O:7][CH3:8])=[O:6])(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3c(c2)OCO3)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1

Procedure:
Analogously to Example 77, by condensing methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate with benzo[1,3]dioxol-5-sulphonyl chloride there was obtained methyl 3-(benzo[1,3]dioxol-5-sulphonyl-amino)-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate und therefrom by treatment with 5.5M HCl there was obtained methyl 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-benzoate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][N:13]=[C:12]1[CH3:16])=[O:10])[CH3:3].[C:17]1([CH3:28])[CH:22]=[CH:21][C:20]([S:23]([O:26]C)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C>[C:17]1([CH3:28])[CH:18]=[CH:19][C:20]([S:23]([O-:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1.[CH3:1][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][N:13]=[C:12]1[CH3:16])=[O:10])([CH3:17])[CH3:3]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC1=NCCN1C(=O)CCCCCN(C)C
Solvent: CC#N
Product: CC1=NCCN1C(=O)CCCCC[N+](C)(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
6-(N,N-Di-methylamino)hexanoyl 2-methyl-2-imidazoline (50.00 g, 0.222 mol), acetonitrile (150 mL), and methyl ρ-toluenesulfonate (41.32 g, 0.222 mol) are combined in a 500 mL three-necked round-bottomed flask equipped with reflux condenser, argon inlet, and magnetic stirrer. The mixture is heated for 1.3 h, cooled to room temperature, and concentrated by rotary evaporation at 50° C. to give a gold-brown solid. Drying at room temperature at 0.2 mm Hg for 18 h affords the title QSBA, 91.41 g as a solid.
Reaction SMILES: [OH-].[Na+].C(OC([NH:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:21]([C:34]([O:36]CC)=[O:35])=[C:20]([Cl:39])[CH:19]=2)[CH:12]=1)=O)(C)(C)C>CO.O1CCCC1.O>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:21]([C:34]([OH:36])=[O:35])=[C:20]([Cl:39])[CH:19]=2)[CH:12]=1
Reactant: CCOC(=O)c1c(Cl)cc(Nc2cc(NC(=O)OC(C)(C)C)ncn2)c(=O)n1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2c(C(=O)O)c(Cl)cc(Nc3cc(N)ncn3)c2=O)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide (0.26 g, 6.6 mmol) was added to a suspension of ethyl 5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (0.70 g, 1.32 mmol) in methanol/tetrahydrofuran/water (2:1:1, 30 mL). The mixture was stirred at 80° C. for 16 h. After completion, the solvent was evaporated to dryness under reduced pressure. The crude was diluted with 1 N hydrochloric acid. The precipitate obtained was collected by filtration, dried, washed with pentane and dried further to afford 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (5) as brown solid. Yield: 0.45 g, 85%; MS (ESI) m/z 402.09 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.67 (brs, 2H), 7.19 (d, J=8.16 Hz, 2H), 6.87 (d, J=8.12 Hz, 2H), 6.39 (s, 1H), 5.18 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[C:15]([O:19][C:20]1[CH:21]=[C:22]([C@H:33]([OH:40])[CH2:34]OS(C)(=O)=O)[C:23]2[S:27][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[N:25][C:24]=2[CH:32]=1)([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]1[CH:21]=[C:22]([C@H:33]([OH:40])[CH2:34][NH:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N:10]([CH3:11])[CH3:12])=[CH:6][CH:5]=2)[C:23]2[S:27][C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[N:25][C:24]=2[CH:32]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@H](O)COS(C)(=O)=O)c2s1
Reactant: CN(C)c1ccc(CC(C)(C)N)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@H](O)CNC(C)(C)Cc3ccc(N(C)C)cc3)c2s1
Temperature: 80 °C

Procedure:
[4-(2-Amino-2-methyl-propyl)-phenyl]-dimethyl-amine (210 mg) and Methanesulfonic acid (S)-2-(5-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-hydroxy-ethyl ester (120 mg) are dissolved in toluene (2 ml). The reaction mixture is heated to 80° C. for 20 hours. The solvent is removed by vacuo to give (S)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-[2-(4-dimethylamino-phenyl)-1,1-dimethyl-ethylamino]-ethanol. MS (ES+) m/e. 500
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([N:15]1[CH2:23][C@H:22]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH:35]=[CH2:36])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)[CH2:21][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:37].O1CCOCC1>>[ClH:37].[NH2:8][C@H:9]([C:13]([N:15]1[CH2:23][C@H:22]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH:35]=[CH2:36])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)[CH2:21][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](N)C(C)C)C3)c2c1

Procedure:
A 0.27 M solution of carbamate from Step 1 in 4N HCl/dioxane was stirred at RT for 2 h. The volatiles were then removed under reduced pressure to give the title compound as an off-white solid that was used directly in the next step. MS (ES+) C22H27N3O4 requires: 397. Found: 398 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11](=[O:16])(=[O:15])[NH:12][CH2:13][CH3:14])[CH:6]=1.O[Li].O>C1COCC1.O.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:13]([NH:12][S:11]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:17])=[O:2])[CH:10]=[CH:9][CH:8]=1)(=[O:16])=[O:15])[CH3:14]
Reactant: CCNS(=O)(=O)c1cccc(CC(=O)OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
(3-Ethylsulfamoyl-phenyl)-acetic acid methyl ester (0.28 g, 1.1 mmol) was dissolved in THF and LiOH hydrate (63 mg, 1.5 mmol) in water was added. The reaction mixture was stirred at room temperature for 4 hours and then diluted with ethyl acetate and 10% citric acid. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to a solid. 0.25 g, 1.1 mmol 99% yield. 1H NMR 500 MHz (DMSO) 7.71 ppm, 1H, s; 7.70 ppm, 1H, m; 7.50 ppm, 3H, m; 4.11 ppm, 1H, br s; 3.70 ppm, 2H, s; 2.81 ppm, 2H, m; 0.99 ppm, 3H, t.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7]CC)=[O:6])#[N:3].Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)C.C1(C)C=CC=CC=1>[C:2]([CH:4]([CH2:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6])#[N:3]
Reactant: O=C(CCl)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CC(CC(=O)c1ccccc1)C(=O)O
Temperature: 30 °C

Procedure:
10 g of sodium was dissolved in 200 ml of ethanol. The solution was cooled to 30° C. and 45.2 g of ethyl cyanoacetate was added rapidly. The resulting mixture was cooled to -15° C. and stirred while a warm solution of 62 g of 2-chloroacetophenone in 100 ml of toluene was added over a 15-minute period, with cooling, allowing the temperature of the mixture to rise to 20° C. over a 1-hour period. The mixture was poured in ice/3 N hydrochloric acid, the organic phase was separated, the solvent was evaporated under reduced pressure and the residue was distilled under reduced pressure to give a liquid, bp: 130°-160° C., at 0.01 Torr., which solidified on standing. Recrystallization from cold ether gave the ethyl ester of 2-cyano-4-oxo-4-phenylbutanoic acid (16A), mp: 53°-54° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: CN(C)CCO
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-hydroxy-1-tetralone (Aldrich, 1.0 g, 6.17 mmol, 1.0 eq), N,N-dimethylethanolamine (Aldrich, 0.93 mL, 9.26 mmol, 1.5 eq), and triphenylphosphine (Aldrich, 2.43 g, 9.26 mmol, 1.5 eq) in THF (10 mL) was added diethyl azodicarboxylate (Aldrich, 1.94 mL, 12.34 mmol, 2.0 eq) at 0° C. The reaction mixture was gradually warmed to RT and continued to stir overnight. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (3%-5% MeOH—CH2Cl2) to provide the product as orange oil. MS (ESI): 234 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: COCCCCC(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCCC(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Yield: 84.7 %

Procedure:
To a mixture of methyl 4-{[5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}benzoate (1.07 g) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred with heating under reflux for 1 day, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (875 mg, 85%) as a brown solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:7]2[N:8]([N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]>ClCCl.[O-2].[O-2].[Mn+4]>[C:2]([C:6]1[C:7]2[N:8]([N:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCC(=O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
The compound of Example 136 (265 mg) was dissolved in dichloromethane (5.00 mL). To this solution, activated manganese dioxide (801 mg) was added and the mixture was stirred at room temperature for 16 hours. Subsequently, a second portion of activated manganese dioxide (801 mg) was added and the mixture was stirred at room temperature for 10 hours. A third portion of activated manganese dioxide (801 mg) was then added and the mixture was stirred at room temperature for 10.5 hours. Finally, a fourth portion of activated manganese dioxide (400 mg) was added and the mixture was stirred for 13.5 hours. Subsequently, the reaction mixture was filtered through Celite and the filtrate was evaporated to afford the title compound as a pale yellow powder (174 mg).
Reaction SMILES: [C:1]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl[CH2:19][C:20]([O-:22])=[O:21].[Na+]>>[C:1]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:19][C:20]([OH:22])=[O:21])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C([O-])CCl
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: [Na+]
Product: CCOC(=O)C1(c2ccccc2)CCN(CC(=O)O)CC1
Reaction time: 7 h
Yield: 58 %

Procedure:
4-Carbethoxy-4-phenylpiperidine (4.01 g.) was dissolved in 13 ml. absolute alcohol and refluxed together with 2.01 g. sodium chloroacetate. After 7 hours no starting material was present as evidenced by TLC. The precipitated sodium chloride was removed by filtration and washed with 3 ml. ethanol. On cooling of the filtrate white crystals appeared. Filtration and drying gave 2.9 g. (58%) of the title compound. m.p. 148°-150°C. Evaporation of the mother liquor gave a glass which did not crystallize from acetone/hexane.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])=[N:19][NH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])=[N:19][NH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1)#[N:30]
Reactant: Fc1ccc(-c2n[nH]nc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)-c1sc(-c3n[nH]nc3-c3ccc(F)cc3F)cc1CCO2
Temperature: 200 °C
Yield: 84 %

Procedure:
To solution containing 4-(2-chloro-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-5-(2,4-difluorophenyl)-2H-1,2,3-triazole (0.085 g, 0.20 mmol), zinc cyanide (47.9 mg, 0.408 mmol;), and tetrakis(triphenylphosphine)palladium(0) (11.8 mg, 0.0102 mmol;) in N,N-dimethylformamide (2.83 mL, 36.6 mmol;) was evacuated then back-filled with nitrogen. The reaction mixture was heated in microwave to 200° C. for 10 min. The reaction mixture was quenched with sat. NH4Cl then extracted EtOAc (3×). The crude product was purified by column chromatography (EtOAc/Hex) to give 367 (84% yield). MS: (ESI+)=408.2
Reaction SMILES: C[O-].[Na+].C([S:7][C@H:8]1[CH2:13][CH2:12][CH2:11][O:10][C@H:9]1[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C.CS(O)(=O)=O.O>CO>[CH2:16]([O:15][CH2:14][C@H:9]1[C@@H:8]([SH:7])[CH2:13][CH2:12][CH2:11][O:10]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)S[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: S[C@H]1CCCO[C@H]1COCc1ccccc1
Reaction time: 2 h

Procedure:
1.04 ml of an approximately 28% w/v methanolic solution of sodium methoxide was added dropwise at -10° C. to 1.422 g of dl-S-(cis-2-benzyloxymethyltetrahydropyran-3-yl) thioacetate (prepared as described in Preparation 38) dissolved in 30 ml of methanol. The reaction mixture was stirred at -10° to 0° C. for 2 hours, and then 0.33 ml of methanesulfonic acid was added. The reaction mixture was then poured into water and extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure to give an oily residue. The residue was subjected to column chromatography through 30 g of silica gel. Those fractions eluted with mixtures of diethyl ether and hexane ranging from 3:97 to 5:95 by volume were worked up, to give 1.146 g of the title compound as an oil.