Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][O:17][CH2:25][CH:24]=[CH2:23])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-(benzyloxycarbonyl)-L-serine methyl ester (63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluroromethanesulfonic acid (5 mL, 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give N-(benzyloxycarbonyl)-O-2-propenyl-L-serine methyl ester.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)(=O)=O.[C-:32]#[N:33].[K+].C(OCC)(=O)C>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:32]([C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)#[N:33]
Reactant: [C-]#N
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)C(F)(F)F)C(=O)OC2
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CC/C(C)=C/Cc1c(C#N)c2c(c(C)c1OC)COC2=O
Reaction time: 18 h
Yield: 94.1 %

Procedure:
A nitrogen-flushed mixture of 5.8 g (12.4 retool) of methyl (E)-6-(1,3-dihydro-4-trifluoromethylsulfonyloxy -6-methoxy-7-methyl-3-oxoisobenzofuran5-yl)-4-methyl-4-hexenoate, 1.5 g (23.0 mmol) of potassium cyanide, and 1.11 g (0.96 mmol) of tetrakis(triphenylphosphine) palladium in 100 ml of 1,4-dioxane was heated at reflux for 18 hours. Upon cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was washed with water six times, with brine once, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting solid was stirred with hexane for 18 hours and then filtered off. This solid was further purified by silica gel chromatography using 5:4 hexane:ethyl acetate to give 4.0 g (11.7 mmol) of methyl (E)-6-(1,3-dihydro-4-cyano-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4hexenoate, mp 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13](=O)[CH2:14]Br)[CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOC(=O)c1cc(N)cc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(N)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-amino-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-amino-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH3:20])[C:12]=2[N:13]=1.CN1CCOCC1.[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31]>CN(C=O)C>[OH:31][CH2:30][C@@H:29]([NH:28][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([CH3:20])[C:12]=2[N:13]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 67.4 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzimidazole-5-carbonitrile (0.7 g, 2.19 mmol) in DMF (15 mL) were added N-methylmorpholine (0.66 g, 6.57 mmol) and (S)-(−)-2-amino-3-phenyl-1-propanol (0.40 g, 2.63 mmol). The reaction mixture was heated to 80° C. for 6 h and then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (3% MeOH/CH2Cl2) to yield the title compound (0.59 g, 68%) as a yellow foam. 1H NMR (400 MHz, CD3OD) δ 7.74 (1H, s), 7.63 (1H, s), 7.12–7.27 (6H, m), 6.07 (1H, d, J=7.5 Hz), 3.97 (1H, m), 3.74 (2H, t, J=5 Hz), 3.14 (1H, dd, J=5.5, 14.0 Hz), 2.94 (1H, dd, J=7.9, 14.0 Hz), 2.60 (3H, s). LCMS (M+H)+ m/z 400 (t=1.71 min.).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=2)[N:10]=1)([CH3:5])[CH3:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:25]([NH:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=2)[N:10]=1)([CH3:5])[CH3:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CNCc1ccccc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A solution of Example 3 (103 mg, 0.3 mmol) and benzaldehyde (30.7 mg, 0.3 mmol) in methanol (1 ml) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (76.3 mg, 0.36 mmol) was then added and the mixture stirred at room temperature for 3 hours before being diluted with ethyl acetate and sodium hydrogen carbonate solution. The aqueous layer was separated and re-extracted with additional ethyl acetate. The combined organic layers was then washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/0.880 ammonia solution (20:1:0.1) to give the title compound (22 mg, 17%) as a pale yellow solid; MS(ES+) m/e 433/435 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:23](=[O:24])[CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)CC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.25 g, 1.26 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropanoic acid (0.26 g, 1.15 mmol) under nitrogen. To the reaction was added EDC (0.48 g, 2.53 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:MeOH (5:1) to give desired product in 69% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:31][CH2:30]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Product: Cc1c(C(=O)NC2CCN(C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-{4-fluoro-2-[(S)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 1-methyl-piperidin-4-ylamine.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>O>[OH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: Oc1cccc2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)c1ccc2ccccc2c1O
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a 500-mL, three-neck, nitrogen-purged flask were added 28.8 g (0.20 mole) of 1-naphthol and 90 mL of toluene. To this stirred slurry was added 26.6 g (0.20 mole) of anhydrous aluminum chloride in portions over five minutes. The temperature of the mixture rose to 40°-50° C. during this addition. The orange slurry was heated to reflux, then 32.0 g (0.204 mole) of phenyl chloroformate was added over a period of 30 minutes. After this addition, the mixture was refluxed for 30 minutes then cooled to 30°-40° C. To the red reaction mixture was added 100 mL of water while holding the temperature at 35°-50° C. This addition is very exothermic initially, and ice bath cooling is used. During addition of the remaining water, the bath is lowered or removed in order to avoid cooling below 35° C. After this addition, 20 mL of 32% hydrochloric acid was added quickly at 35° -50° C. The mixture was stirred for 15 minutes, then the layers are allowed to separate. The lower (aqueous) layer was discarded. The top layer was washed (at 40°-50° C.) successively with: two 100-mL portions of 10% hydrochloric acid and two 100-mL portions of 40°-50° C. water. The solvent was then stripped off under vacuum (150-200 mm) to a pot temperature of 90° C. To the resulting amber liquid was added 120 mL of isopropyl alcohol at 70° C. The solution was cooled slowly to 0°-5° C. After stirring at 0°-5° C. for one hour, the slurry was filtered and the solids washed with three 25-mL portions of 0°-5° C. isopropyl alcohol. The yellow solids were air dried at 40° C. to give 31.5 g (59.7%) of phenyl 1-hydroxy-2-naphthoate.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:37][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccco1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCc2ccco2)ccn1
Yield: 63 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), furfuryl amine (19.11 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:1) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-furan-2-ylmethyl-isonicotinamide as a colorless solid (30 mg, 63% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][N:15]([C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:43]([O:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52]C)=[O:51])=[CH:48][CH:47]=1)=[O:44]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:43]([O:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=2)=[O:44])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 300 mg of tert-butyl {[4-(3-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2 mL of THF were added 0.136 mL of triethylamine and 167 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka), followed by stirring at room temperature for 2 hours. It was washed with water, and extracted with ethyl acetate, and the organic layer was then washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 8 mL of THF, 8 mL of isopropanol, and 4 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. After neutralizing by addition of 4.1 mL of 1 M hydrochloric acid, the reaction mixture was concentrated under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 387 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:19]1[S:13][C:14](=[S:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cccc(C=O)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C=C2SC(=S)NC2=O)c1OC
Yield: 95.6 %

Procedure:
A mixture of 2,3-dimethoxybenzaldehyde (5.2 g, 30 mmoles), rhodanine (4.0 g, 29 mmoles), sodium acetate (8.4 g, 102 mmoles), and acetic acid (50 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the mixture is stirred into water (250 ml) and the precipitate is filtered off, rinsed successively with water (3X), ethanol (2X), and ether (2X), and dried to afford the pure product (7.8 g), mp 268°-269° C.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.I[CH3:15].O>C1COCC1>[CH3:15][O:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([CH2:5][CH2:4][Br:3])=[CH:7][CH:8]=1
Reactant: OCc1ccc(CCBr)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a suspension of 60% NaH in paraffin (13.9 mmol; 0.56 g) in THF (20 ml) cooled to 0° C. was first added, dropwise, a solution of 4-(2-bromoethyl)benzyl alcohol (9.25 mmol; 1.99 g) in THF (20 ml) in an ice bath, followed by iodomethane (13.9 mmol; 1.972 g; 0.86 ml). The mixture was stirred at room temperature for 1 hour 30 minutes, after which it was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCl solution (3×20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on a column of alumina, eluting with ethyl acetate, to give 1.38 g of product as an oil (65%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C.[Pd]>[CH2:14]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCOC1CCN(CCN)CC1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCOC1CCN(CCNCc2ccccc2)CC1
Reaction time: 24 h
Yield: 64.8 %

Procedure:
27 g of 1-(2-aminoethyl)-4-methoxymethoxy-piperidine was dropwise added to a solution of 15 g of benzaldehyde in 300 ml of ethanol, at room temperature. The mixture was stirred at the same temperature for 1 day. To the reaction mixture was added 5 g of 10% Pd-C, and the resulting mixture was allowed to absorb hydrogen at room temperature at atmospheric pressure. After a reaction was over, the catalyst was removed by filtration. The filtrate was diluted with ethyl acetate. The dilution was subjected to extraction with 10% hydrochloric acid. The aqueous layer was made alkaline with an aqueous potassium hydroxide solution and then subjected to extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 10% methanol-chloroform) to obtain 25.50 g of 1-(2-benzylaminoethyl)-4-methoxymethoxypiperidine.
Reaction SMILES: Cl[CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:15]([OH:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][O:18][CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)N(CCl)c1ccccc1
Reactant: OCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(COCCO)c1ccccc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
212 g (1 mole) of 1-chloromethyl-1-phenyl-3,3-dimethylurea were dissolved in 100 ml of anhydrous ethyl acetate and 63 g (1.0 mole) of ethylen glycol and 60 g (1.0 mole) of triethylamine were added dropwise whilst cooling with ice. After stirring for 2 hours at 10° to 15°C, the triethylamine hydrochloride used was filtered off and the solvent was distilled off. 238 g of 1-β-hydroxyethoxymethyl-1-phenyl-3,3-dimethylurea were obtained as an oil, in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(O)C>N1C=CC=CC=1>[CH2:16]([O:18][N:19]=[C:4]1[C:3]2[C:8](=[C:9]([CH3:13])[CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1)[CH3:17]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCON=C1CCSc2c(C)cc(Br)c(C)c21
Yield: 92.6 %

Procedure:
3.0 Grams (11 mmol) of 5,8-dimethyl-6-bromothiochroman-4-one and 2.2 g (22 mmol) of O-ethylhydroxylamine hydrochloride were refluxed under heat in a mixed solvent containing 10 ml of ethanol and 10 ml of pyridine for 30 minutes. The solvents were distilled off under reduced pressure, and then the residue was treated with 5% hydrochloric acid and extracted with ethyl acetate. The so-obtained solution was consecutively washed with 5% aqueous potassium carbonate and with saturated sodium chloride solution and dried over sodium sulfate. The solvent was distilled off to give 3.2 g of 4-ethoxyimino-5,8-dimethyl-6-bromothiochroman (yield 92%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)=[O:4].[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:12](=[O:14])[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH:22]=1
Reactant: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: NCc1cccnc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc(NC(=O)C(F)(F)F)cc1)NCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 4-(trifluoroacetylamino)cinnamic acid (1.30 g) and 3-(aminomethyl)pyridine (540 mg) in 20 ml dimethylformamide was mixed with 0.9 ml diethyl cyanophosphate and subsequently with 0.8 ml triethylamine on ice, and then stirred at room temperature for 4 hours. The solid precipitated from water was then filtered, washed with water, and dried by heating under reduced pressure to give N-(3-pyridylmethyl)-4-[(trifluoroacetyl)amino]cinnamamide (1.61 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][O:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:29][C:28]4[NH:27][CH:26]=[C:25]5[C:20](=[O:19])[O:21][CH2:22][CH2:23][C:24]=45)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc3c2CCOC3=O)cc1

Procedure:
6-(4-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][CH:57]=1)[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:63]=2)=[CH:60][CH:61]=1)[CH3:54]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 55% yield: LCMS (ESI) m/z 470 (MH+).