Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[CH2:8]([C@H:15]([NH2:24])[C@@H:16]([OH:23])[C@@H:17]([OH:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([N:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])=[O:36])[CH:34]=1)[C:29](O)=[O:30].CCN(C(C)C)C(C)C>>[CH2:8]([C@H:15]([NH:24][C:29](=[O:30])[C:28]1[CH:27]=[C:26]([CH3:25])[CH:34]=[C:33]([C:35]([N:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])=[O:36])[CH:32]=1)[C@@H:16]([OH:23])[C@@H:17]([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCC[C@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(C)cc(C(=O)N(CCC)CCC)c1

Procedure:
The trifluoroacetate salt of (1S,2R,3S)-1-benzyl-2,3-dihydroxyheptylamine (0.1 mmol) was reacted with 3-methyl-5-[(dipropylamino)carbonyl]benzoic acid as described in method A (addition of an extra equivalent of DIEA to neutralize the amine salt) to give N1-[(1S,2R,3S)-1-benzyl-2,3-dihydroxy-octyl]-5-methyl-N3,N3-dipropyl-isophthalamide. MS (ESI+) for C29H42N2O4 m/z 483 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:52][CH2:51][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:55][CH2:54]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:8]1=[O:27]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.42 g, 1.3 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (1.2 mmol), and N,N-diisopropylethylamine (0.32 g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and water. Separate the layers and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give a residue. Partition the residue between dichloromethane and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.19 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH2:37][CH3:38])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 1-iodopropane (107 μL). The reaction mixture is allowed to stir at room temperature for 4 h. Additional 1-iodopropane (107 μL) is added and the mixture is heated to 60° C. for 2 h. The mixture is allowed to cool to room temperature and stand for 18 h. The resulting suspension is poured into water (25 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 335 mg (73%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29][C@@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCN(C(=O)CO)C[C@@H]1O

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].CC1(C)C(C)(C)OB([C:26]2[CH:35]=[CH:34][C:29]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=2)O1>>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([C:26]3[CH:35]=[CH:34][C:29]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=3)[C:3]([CH3:17])=[N:4]2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: CC(=O)Nc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide: MS (EI) m/z 385 [M]+, 1H-NMR (CDCl3) δ 7.44-7.26 (8H, m), 3.92-3.90 (2H, br), 3.08 (3H, s), 2.94 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.29 (3H, s).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1C.Cl.[S:17]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18].[CH2:29](O)C>O>[CH3:29][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[N:27]([C:24]3[CH:23]=[CH:22][C:21]([S:17]([NH2:18])(=[O:20])=[O:19])=[CH:26][CH:25]=3)[N:28]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)=[CH:11][CH:10]=1
Reactant: CCO
Reactant: Cc1ccccc1C#CC(=O)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
A solution of 1,1,1-trifluoro-4-(methylphenyl)-3-butyn-2-one (3, 10 mmol) in ethanol (100 mL) is refluxed with 4-sulfamylphenyl hydrazine hydrochloride (4, 12 mmol) for 4 h. The reaction mixture is cooled and diluted with water. The precipitated crude 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide is filtered and recrystallized.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](=[O:23])[CH3:22].[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]1[CH2:3][C:2](=[O:1])[CH2:22][C:21](=[O:23])[CH2:20]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC(=O)CC(c2ccccc2Cl)C1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (170.1 g) was added diethyl malonate (80.1 g) at room temperature (immediately precipitated material was observed), and then a solution of crude 2-chlorobenzalacetone (94.6 g) in ethanol (40 ml). The mixture was stirred at 90° C. for 2 hours, cooled at room temperature and under-ice-cooling (for 1 hour). Precipitated materials were filtered and washed with ethyl acetate and isopropylether to give crude ethyl 6-(2-chlorophenyl)-2-hydroxy-4-oxo-2-cyclohexene-1-carboxylate monosodium salt (151.0 g) as pale yellow powder. To said powder was added 2 M sodium hydroxide (350 ml), and the mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5 M sulfuric acid (350 ml) for 15 minutes, and the mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added ethyl acetate (1.4 l), and the mixture was subjected to extraction. The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and ethyl acetate was evaporated under reduced pressure. Precipitated crystals were washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2-chlorophenyl)cyclohexane-1,3-dione (82.1 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.[CH3:22][O:23][CH2:24]OC.O=P(Cl)(Cl)Cl.CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][O:23][CH3:24])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1
Reactant: O=c1cc(Oc2c(Cl)cccc2Cl)c2cc(O)ccc2o1
Reactant: COCOC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCOc1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
A mixture of 4-(2,6-dichlorophenoxy)-6-hydroxycoumarin (1.2 g, 32 mmole), dimethoxymethane (0.565 g, 7.4 mmole), POCl3 (0.74 g, 4.8 mmole) and dimethylformamide (0.43 g, 5.94 mmole) in toluene is heated at 90°-100° C. for 4 hours, cooled to room temperature, poured onto ice water and filtered. The filtercake is dried and recrystallized from acetonitrile/water to afford the title product, 0.45 g (38% yield), mp 302°-305° C. (dec), identified by 1HNMR, 13 CNMR and IR analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].Br[CH2:31][CH:32]=[CH2:33]>COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:11]([O:13][CH3:14])=[O:12])([CH2:33][CH:32]=[CH2:31])[C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=1[O:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CCBr
Reactant: COC(=O)C(Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCC(Cc1ccc(OC)c(OCCc2ccccc2)c1)(C(=O)OC)C(=O)OC
Yield: 94 %

Procedure:
To a solution of the crude methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylpropionate (7.45 g) in 75 ml of 1,2-dimethoxyethane, 0.80 g of 60% sodium hydride (oily) was added little by little at room temperature under stirring. The resultant solution was stirred further at 40° C. for 1.5 hours. To this solution, 2.66 g of 3-bromo-1-propene was added and stirred at room temperature for 1.5 days. The reaction solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to obtain 7.76 g of methyl 3-[4-methoxy-3-(2-phenylethoxy) phenyl]-2-methoxycarbonyl-2-(2-propen-1-yl)propionate.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([CH:22]=O)=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)=[O:7])[CH2:3][CH2:2]1.C(O)C.[NH:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[O:29].N1CCCCC1>O>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([CH:22]=[C:33]5[C:31](=[O:32])[NH:30][C:28](=[O:29])[NH:27]5)=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2ccc(-c3ccc(C(=O)NCC4CC4)s3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccc(C(=O)NCC5CC5)s4)nc23)N1
Temperature: 80 °C
Yield: 29 %

Procedure:
To the reaction flask, N-(cyclopropylmethyl)-5-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxamide (10 mg, 0.030 mmol) was added to ethanol (0.5 mL) along with hydantoin (3 mg, 0.03 mmol) and piperidine (3 uL, 0.03 mmol). The reaction was heated at 80° C. for 1 hour in the microwave then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, N-(cyclopropylmethyl)-5-(3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxamide, was recovered as a solid in 29% yield. LCMS (M+1=409)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]#[N:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]#[N:20]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CSCC#N
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1N
Temperature: -69 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a slurry of 29.6 g (0.15 mole) of 2-aminobenzophenone and 13.1 g (0.15 mole) of (methylthio)acetonitrile in 400 ml of methylene dichloride at a temperature of -68° C. was added dropwise 16.8 g (0.155 mole) of t-butyloxychloride at a rate to ensure that the reaction temperature did not exceed -64° C. The resulting solution was stirred at -69° C. for one hour, treated with 15.7 g (0.155 mole) of triethylamine and allowed to warm to ambient temperature. The solution obtained was washed twice with water, dried over sodium sulphate, and concentrated to give 45.2 g of a dark oil as the residue. This residue was chromatographed on 1 kg of silica gel to yield 22.5 g (53%) of the title compound as tan crystals, m.p. 107°-108° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].[CH2:19](I)[CH3:20].O>C1COCC1>[CH2:19]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH3:20]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (500 mg) was dissolved in THF (5 ml), and NaH (174 mg) was added thereto under ice-cooling, and subsequently, ethyl iodide (680 mg) was added thereto, followed by elevating the temperature to room temperature and stirring overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% to 20% EtOAc/hexane) to obtain tert-butyl 4-(2-ethoxyethyl)piperidine-1-carboxylate (496 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>C(O)C>[O:19]1[CH2:20][CH2:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:17][CH2:18]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCOCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Diethyl malonate (32.0 g) was added to a solution of sodium ethoxide (1 equivalent) in ethanol and the solution was stirred for 30 min. 2-Bromoethyl ether (46.0 g) was then added and the mixture was stirred at reflux for 3 h. The mixture was then cooled, evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water and brine, then dried (MgSO4) and evaporated. The residue was then purified by flash column chromatography on silica gel, eluting with 4:1 hexanes/ether, to give the title compound (28.0 g) as colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8].[Na].[C:15](Cl)(=[O:17])[CH3:16]>C(OCC)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]([C:15](=[O:17])[CH3:16])([C:7](=[O:9])[CH3:8])[C:10](=[O:12])[CH3:11]
Reactant: COC(=O)CCC(C(C)=O)C(C)=O
Reactant: CC(=O)Cl
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)CCC(C(C)=O)(C(C)=O)C(C)=O
Reaction time: 6 h

Procedure:
92.5 g of 4-acetyl-5-oxohexanoic acid methyl ester was reacted with 11.5 g of metallic sodium in 200 ml of diethyl ether. After the dissolving of sodium was finished, 39.25 g of acetyl chloride was dropped in, and the resulting boiling mixture was stirred for 6 hours. Then, the reaction mixture was filtered, washed with aqueous potassium hydroxide and water, following by evaporation of solvent. The final vacuum distillation yielded the subject compound as a yellowish liquid having a purity of above 90%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4].[C:23](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[O:14][CH3:23])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1c(OC)c2cc(OC)ccc2n1-c1ccccc1

Procedure:
A mixture of 10.8 g (0.036 mole) of 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984)] and 5.5 g (0.040 mole) of anhydrous potassium carbonate in 100 ml of acetone was treated with 3.7 ml (4.9 g; 0.039 mole) of dimethyl sulfate. The mixture was stirred and heated at reflux for 16 hours, cooled, and filtered. The filter cake was washed several times with fresh acetone, and the combined filtrates were evaporated (vacuum) to yield a crude residue of 3,5-dimethoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[F:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:19]=[C:20]([SH:22])[CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]#[N:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:19]=[C:20]([S:22][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=[CH:5]3)[CH:21]=1
Reactant: Ic1ccc2c(ccc3nccn32)c1
Reactant: N#CC1(c2cc(F)cc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2cc(F)cc(Sc3ccc4c(ccc5nccn54)c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
1g (230 mg, 0.82 mmol) and 4-(3-Fluoro-5-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1h, 230 mg, 0.99 mmol) were dissolved in 1,4-dioxane (10 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.35 mL, 2.0 mmol), Pd2dba3 (20 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.04 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by silica gel chromatography to give the desired product, 1k.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5].C([Li])(C)(C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]=[O:31])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N:21]2>C(OCC)C.O1CCCC1.[Cl-].[NH4+]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH:30]([OH:31])[CH2:2][CH2:3][C:4]([CH3:6])=[CH2:5])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:32][C:33](=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N:21]2
Reactant: C=C(C)CCI
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)CCC(O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
A solution of 4-iodo-2-methylbut-1-ene (942 mg, 4.8 mmol) in diethyl ether (5 mL) was added to a solution of tert-butyllithium (1.7 M in pentane, 5.65 mL, 9.6 mmol) in diethyl ether (15 mL) at −78° C. The reaction mixture was stirred at −78° C. for 35 minutes and then N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (400 mg, 0.96 mmol) in diethyl ether (5 mL) and tetrahydrofuran (4 mL) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for 15 minutes, then allowed to warm to 0° C. and stirred at 0° C. for 1 hour. The mixture was allowed to warm to room temperature, then stirred at room temperature for 15 minutes. The mixture was diluted with a saturated aqueous solution of ammonium chloride (35 mL) and extracted with ethyl acetate (3×35 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated to afford a yellow oil. Purification via silica gel chromatography (Gradient: 0% to 90% ethyl acetate in heptane) afforded the product as a white solid. Yield: 108 mg, 23%. LCMS m/z 487.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.22 (br d, J=6.8 Hz, 2H), 7.31-7.53 (m, 4H), 6.68-6.96 (m, 2H), 4.72-4.73 (m, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.80-3.87 (m, 1H), 3.76 (br s, 1H), 3.61-3.65 (m, 1H), 3.56 (br d, J=8.2 Hz, 1H), 3.13 (br s, 1H), 3.03 (dd, J=12.7, 4.1 Hz, 1H), 2.68 (m, 1H), 2.0-2.29 (m, 4H), 1.74 (s, 3H), 1.59-1.69 (m, 2H).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:40][CH2:41][CH:42](CO)[OH:43]>>[CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH2:26][CH:42]([OH:43])[CH2:41][OH:40])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(CC)C(=O)OC)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(CC)C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(4-tetradecenylamino)phenylbutyrate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.