Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([N:12]([CH2:14][C:15](O)=[O:16])[CH3:13])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)(O)[O-].[Na+].O>C(O)C>[C:8]([O:7][C:5](=[O:6])[N:12]([CH2:14][C:15](=[O:16])[NH:4][CH2:1][CH:2]=[CH2:3])[CH3:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Allylamine (0.377 ml, 5.03 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) (1.89 g, 6.04 mmol) were added to a solution of Boc-sarcosine (1.0 g, 5.29 mmol) in ethanol, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction solution, followed by extraction with ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give allylcarbamoylmethyl-methyl-carbamic acid tert-butyl ester (712 mg).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].CC([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][N:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:20]=2)=[CH:12][CH:11]=1)(C)C.[H][H]>C(O)C.[Pd]>[CH3:12][C:13]([CH3:16])([O:4][C:1](=[O:5])[CH2:2][CH2:3][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][N:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[N:20]=2)=[CH:12][CH:11]=1)[CH3:14]
Reactant: CC(C)(C)c1ccc(-c2nnn(C(C)(C)C)n2)cc1
Reactant: C=CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(-c2nnn(C(C)(C)C)n2)cc1
Yield: 157.1 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]benzene propenoate (1.6 g. 5.6 mmol) and 100 mg of 10% Pd/c in ethanol (17 mL) was stirred under a blanket of hydrogen (1 atm). After hydrogen uptake ceased, the mixture was filtered through a pad of Celite washing with ethanol (30 mL). The filtrate was concentrated to give 5-[4-(3-(1,1-dimethylethoxy)-3-oxopropyl)phenyl]-2-(1,1-dimethylethyl)-2H-tetrazole (1.2 g. 4.4 mmol) in 78% yield.
Reaction SMILES: [C:1]([C:4](=[C:9](OC)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:23][C:24]([CH3:27])([O-:26])[CH3:25].[K+:28].Cl>C1COCC1.CO.CC(C)=O>[CH3:23][C:24]([CH3:27])([O-:26])[CH3:25].[K+:28].[CH3:2][C:1]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:9]([CH3:10])[N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:21]=1
Reactant: N=C(N)c1ccccc1
Reactant: COC(=O)C(C(C)=O)=C(C)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-acetyl-3-methoxy-2-butenoate (34.4 g, 0.2 mole), benzamidine hydrochloride (37.4 g), acetone (136 ml) and methyl alcohol (100 ml) were charged into a 1 L 3-necked, flask (fitted with addition funnel, condenser, agitator and nitrogen inlet). The reaction was blanketed with nitrogen, the agitator started and the batch cooled to between −5 and 0°C. While the batch was cooling, a solution of potassium t-butoxide was prepared (27 g in THF, 100 ml) under nitrogen. When the batch had reached the correct temperature, the potassium t-butoxide solution was charged slowly, keeping the temperature below 5° C. The batch was allowed to warm to about 25° C. The reaction was complete after about 1.5 hours. Concentrated hydrochloric acid was charged dropwise to bring the pH to 7. The batch was concentrated under vacuum until no more volatiles were collected. Methyl t-butylether (300 ml), 150 ml ethyl acetate and water (200 ml) were charged. The batch was agitated for 10 minutes, a small amount of solid was filtered off, and the layers were then separated. The organic layer was concentrated under vacuum to afford a solid residue of methyl 4,6-dimethyl-2-phenylpyrimidine-5-carboxylate, 48.7 g. m. p. 54–55° C., 1H NMR (CDCl3): δ2.58 (6H, s, CH3), δ3.89 (3H, s, OCH3), δ7.42 (3H, s, ArH), δ8.40 (2H, s, ArH). 13H CMR (CDCl3): δ168.78, δ165.24, δ164.11, δ137.57, δ131.34, δ128.93, δ128.92, δ124.12, δ52.86, δ23.65. HR-MS; Calculated for C14H15N2O2, m/z=243.1134. Found 243.1134.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][NH:3][C:2]1=[S:6].N12CCCN=C1CCCCC2.Br[CH2:19][C:20]1[C:21]([C:30]([F:33])([F:32])[F:31])=[N:22][N:23]([CH3:29])[C:24]=1[O:25][CH:26]([F:28])[F:27].O>C(#N)C>[F:28][CH:26]([F:27])[O:25][C:24]1[N:23]([CH3:29])[N:22]=[C:21]([C:30]([F:33])([F:32])[F:31])[C:20]=1[CH2:19][S:6][C:2]1[O:1][CH:5]=[CH:4][N:3]=1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Reactant: S=c1[nH]cco1
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Oxazole-2(3H)-thione (2.960 g, 29 mmol; prepared as described in WO 2003/006442 A) is initially charged in 50 ml of acetonitrile. With ice-bath cooling, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 4.81 ml, 32 mmol) is added dropwise. The mixture is stirred at 25° C. for 30 minutes. A solution of 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (9.045 g, 29 mmol) dissolved in acetonitrile is added dropwise. The mixture is stirred at 25° C. for a further 4 hours and allowed to stand overnight. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptan:ethyl acetate, gradient 10:0 to 7:3). This gives 7.6 g of product (74.9% of theory).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[ClH:19].[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: OCCN1CC=C(c2ccc(F)cc2)CC1
Solvent: c1ccccc1
Product: Cl
Product: Fc1ccc(C2=CCN(CCCl)CC2)cc1

Procedure:
0.5 g. of 1-(2-hydroxyethyl)-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine are dissolved in 10 ml. of absolute benzene and 0.4 g. of thionyl chloride are added with stirring and cooling with ice. The mixture is heated under reflux conditions for 30 minutes and the solvent is evaporated. The 1-(2-chloroethyl)-4 -(p-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride obtained melts at 226°C. after recrystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>>[Br:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Reactant: Nc1ncccc1Br
Product: C[Si](C)(C)C#CCCc1cn2cccc(Br)c2n1
Yield: 61.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 3-bromopyridin-2-amine (280 mg, 1.60 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 870 mg, 3.5 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 315 mg of 8-bromo-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 61%) as a yellow oil.
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16](OC)[O:17]C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)c1ccc(S(=O)(=O)C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(S(=O)(=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1112.1 %

Procedure:
To a solution of 1-(cyclohexylsulfonyl)-4-(dimethoxymethyl)benzene (117 mg, 0.392 mmol) in THF (4 mL) was added an aqueous solution of sulfuric acid (2% v/v, 2 mL) and the resulting mixture stirred for 18 hours at room temperature. Excess solid potassium carbonate was then added, and the mixture diluted with water. Finally, the aqueous solution was extracted with ethyl acetate (×3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 4-(cyclohexylsulfonyl)benzaldehyde (1100 mg, quantitative yield) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([NH2:24])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25](=O)[CH3:26].[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([N:24]([CH2:25][CH3:26])[CH2:28][CH3:29])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Reactant: CC(N)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(C)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 122.6 %

Procedure:
4-[2-(2-Amino-propoxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.35 g, 0.75 mmol) was dissolved in methanol (25 mL), and the reaction was cooled to 0° C. Acetaldehyde (0.363 g, 8.25 mmol) and sodium triacetoxyborohydride (0.795 g, 3.75 mmol) were added. A reflux condenser was fitted and the flask was stirred at r.t. for about 24 hours. The solution was extracted with diethyl ether (3×50 mL) and then concentrated under reduced pressure to afford the final compound (0.360 g, 90%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[CH3:19][NH:20][CH3:21].O>O1CCCC1>[CH3:19][N:20]([CH3:21])[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2sc(Cl)nc2c1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 16.5 h

Procedure:
In 7.4 ml of tetrahydrofuran was dissolved 160 mg of 2-chloro-5-nitro-1,3-benzothiazole, and thereto was added 1.86 ml of a 1M dimethylamine tetrahydrofuran solution, followed by 16.5 hours of stirring. Water was added to the reaction solution and the organic layer was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 173 mg of N,N-dimethyl-5-nitro-1,3-benzothiazol-2-amine as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C.[NH4+].[Cl-]>O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][NH:2][C:30](=[O:33])[CH2:31][CH3:32])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), propionyl chloride (49 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4-0 mL). After stirring at 25° C. for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (240 mg, 91%) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.3 (t, J=5.8 Hz, 1H), 7.6 (q, J=8.7 and 6.58 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.3 (dd, J=2.6 and 7.6 Hz, 1H), 7.22 (d, J=7.51 Hz, 1H), 7.12 (td, J=2.0 and 6.5 Hz, 1H), 6.65 (s, 1H), 5.3 (s, 2H), 4.23 (d, J=3.6 Hz, 2H), 2.1 (q, J=7.7 Hz 2H), 1.98 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) ppm. ES-HRMS m/z 465.1203 (M+H calcd for C23H21ClF3N2O3 requires 465.1187).
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([C:38]([F:37])([F:46])[F:47])[CH:40]=2)=[O:16])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg), triethylamine (0.40 mmol, 0.056 mL), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 3-(trifluoromethyl)aniline (0.30 mmol, 0.037 mL) was added and the reaction stirred at rt for 24 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was recrystallized from EtOAc/hexane to give the title compound as a light yellow solid (59 mg, 66%).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.[NH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:29].C(Cl)(Cl)(Cl)[Cl:35]>C(Cl)Cl>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:29])=[O:13])=[CH:10][CH:9]=1.[NH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:35])=[O:24])=[CH:21][CH:20]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: NCc1ccc(C(=O)Cl)cc1
Reaction time: 2.5 h
Yield: 84 %

Procedure:
Twenty grams of p-aminomethylbenzoic acid hemisulfate was suspended in 400 ml of methylene chloride, and 75 g of phosphorus pentachloride was slowly added to the suspension. The reaction was carried out at 40° to 45° C. for 2.5 hours. The solution was cooled with ice, and 300 ml of carbon tetrachloride was added, followed by filtration to give 18.3 g (yield 84%) of p-aminomethylbenzoyl chloride hemisulfate as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15](O)=[O:16])[CH:6]=1.Cl.[CH3:34][O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH2:40][S:41][CH3:42])[NH2:38].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15]([NH:38][C@@H:37]([CH2:39][CH2:40][S:41][CH3:42])[C:36]([O:35][CH3:34])=[O:43])=[O:16])[CH:6]=1
Reactant: Cc1cn(CC(Oc2ccc(CCc3ccc(F)cc3)c(C(=O)O)c2)c2nccs2)cn1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cc(OC(Cn2cnc(C)c2)c2nccs2)ccc1CCc1ccc(F)cc1
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of 5-[2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoic acid (0.4 g; 0.89 mM), L-methionine methyl ester hydrochloride (0.27 g, 1.35 mM) and DMAP (0.54 g, 4.43 mM) was stirred until solution and EDC (0.026 g, 1.35 mM) in dichloromethane was added and the mixture stirred for 18 hours. It was purified on silica using dichloromethane then methanol/dichloromethane (5:95) as eluant to give the title product (0.47 g, 89%) as a foam.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.CC(C)=O.C([N-]C(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[CH3:38][S:39]SC>O1CCCC1>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:13])[CH:3]([S:39][CH3:38])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CSC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.50 g, 2.8 mmol, from Reference Example 22) in tetrahydrofuran (5 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 3.1 mL, 6.2 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.37 mL, 3.1 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Dimethyl disulfide (0.38 mL, 4.2 mmol) is then added neat via syringe and the reaction mixture is allowed to stir for two days while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/dichloromethane/methanol) is performed to give a clear light brown oil which solidified upon standing (0.54 g, 86%). TOF MS (ES−): (M−H)=222.9
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:16])[CH:10]=3)[C:5]([CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)(O)[C:4]=2[CH:3]=1.S(C1C=CC=CC=1C(OC(=O)C1C=CC=CC=1S(O)(=O)=O)=O)(O)(=O)=O.C(O)(=O)CC>>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:16])[CH:10]=3)[C:5](=[C:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:4]=2[CH:3]=1
Reactant: CN1CCC(C2(O)c3ccc(F)cc3Sc3ccc(F)cc32)CC1
Agent: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Solvent: CCC(=O)O
Product: CN1CCC(=C2c3ccc(F)cc3Sc3ccc(F)cc32)CC1

Procedure:
The thioxanthene-9-ol (2.6 g., 0.0075 mol) prepared as above is heated with 2.8 g. (0.015 mol) of o-sulfobenzoic anhydride in 80 ml. of propionic acid. The product is isolated by the usual procedure to give 4-(2,6-difluoro-9-thioxanthenylidene)-1-methylpiperidine, m.p. 120°-123° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[H-].[Na+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cccc2cccnc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4cccnc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 100-mL round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.30 g, 1.2 mmol) and 8-hydroxyquinoline (0.17 g, 1.2 mmol, Aldrich) in DMF (5 mL), was added NaH (56 mg, 1.4 mmol, 60% in mineral oil, Aldrich) at room temperature and the mixture was then stirred at room temperature for 48 h. After the solvent was removed in vacuum, EtOAc (25 mL) was added to the residue, and the mixture was washed with water (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (4:1 hexanes/EtOAc) afforded the title compound as a white solid. Mp: 155–157° C. MS (ESI, pos. ion) m/z: 368 (M+1). Anal. Calcd for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.29; H, 3.25; N, 11.41.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.CN(C)C=O.[OH-].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1
Reactant: BrCCCCBr
Reactant: O=C1CSCN1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSCN1CCCCBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-oxothiazolidine (25 g,) dimethylformamide (500 ml), and KOH (27.16 g) was stirred under N2 at room temperature for 1.5 hours. To the resulting mixture was added 1,4-dibromobutane (101 ml) and stirring was continued at room temperature for 44 hours. The reaction mixture was poured into H2O (1000 ml) and the aqueous mixture was extracted three times with 300 ml portions of ethyl acetate. The combined extracts were washed with H2O (300 ml) and brine (300 ml), dried over Na2SO4, and concentrated in vacuo to an oil. HPLC of a 44.95 g aliquot yielded 7.15 g of an oil which upon distillation yielded a clear liquid, b.p. 134°-137° C/0.12 mmHg.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4](I)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:13]([C:15]1[CH:16]=[N:17][N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:19]=1)#[CH:14]>CC#N.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:14]#[C:13][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C#Cc1cnn(Cc2ccc(OC)cc2)c1
Reactant: COc1ccc(I)c(OC)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(C#Cc3ccc(OC)c(F)c3OC)cn2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 3-fluoro-2,4-dimethoxy-iodobenzene (200 mg, 0.71 mmol) and 4-ethynyl-1-(4-methoxy-benzyl)-1H-pyrazole (180 mg, 0.85 mmol) in dry MeCN (4 ml) and NEt3 (2 ml) was added Pd(Ph3P)2Cl2 (15 mg, 3 mol %) and the reaction vessel was evacuated and backfilled with N2 (g) three times. Copper (I) iodide (6 mol %) was added and the reaction rapidly became dark. Stirring was continued at room temperature for 3 hours, then the crude mixture was concentrated directly onto silica-gel and purified by flash chromatography (silica-gel, eluted sequentially with hexanes:EtOAc, 3:1, 2:1) to give the product as a resin that crystallised slowly upon standing in the freezer (230 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 7.66 (s, 1H), 7.50 (s, 1H), 7.19 (d, J=8.6 Hz, 2H), 7.10 (dd, J=8.7, 2.1 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.61 (t, J=8.2 Hz, 1H), 5.24 (s, 2H), 4.01 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H).