Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[C:7]([O:11]C)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1([CH3:13])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1
Reactant: COc1cccc2c1C(C)(C)CO2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2cccc(O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 3,3-dimethyl-4-(methyloxy)-2,3-dihydro-1-benzofuran (Intermediate 49, 4.0 g) in dichloromethane (100 ml, SCRC) was added BBr3 (6.37 ml, 67.3 mmol, SCRC) dropwise under ice-cooling. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature and then water (20 ml) was added. The resulting mixture was extracted with ethyl acetate (3 times 100 ml, SCRC) and the combined organic layers were dried, evaporated and purified by silica gel chromatography with EtOAc/PE as eluents (1/20) to afford the title compound (2.8 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=O>>[F:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-fluoro-5-(trifluoromethyl)benzoic acid: MS (ESI): m/z 455 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18].ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:18])=[O:27]
Reactant: CSc1ccccc1-c1nc2ccccc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2ccccc2S(C)=O)nc2ccccc21
Temperature: 25 °C

Procedure:
The product of step (b) above (2 g) was dissolved in dichloromethane (50 mls) and cooled to -10° with stirring. 85% m-chloroperbenzoic acid (1.6 g) was added portionwise. The reaction mixture was slowly warmed to room temperature and after 3 hours the reaction was complete. The reaction mixture was washed with aqueous metabisulphite solution, then bicarbonate solution and finally brine, dried over magnesium sulphate and evaporated to dryness in vacuo, then the residue was purified by flash chromatography (SiO2 /ethyl acetate 3:2 CH2Cl2) to afford the sub-title compound as a yellow crystalline solid, mp 157°-159°.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH2:20][CH2:21]I>CN(C)C=O>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]3[CH2:21][CH2:20][CH2:19][S:1][C:2]3=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: ICCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)nc1n2CCCS1
Yield: 25.3 %

Procedure:
To a flask were added 2 g 2-mercapto-5-methylbenzimidazole, 4.2 g potassium carbonate, 4.0 g 1,3-diiodopropane and 60 ml N,N-dimethylformamide. The mixture was heated to 50 C under nitrogen for 5 hours and then cooled to 22 C. The reaction was quenched with 100 ml water and the product was extracted twice with ethyl acetate and washed twice with water. Following removal of the solvent, the product was recrystallized by dissolving in a hot mixture of 50 ml hexane with 10 ml 2-propanol. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 0.63 g of an off-white solid.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)[CH3:13].[NH3:21]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:10]([C:9]2[C:4]3[C:5](=[N:1][O:2][N:3]=3)[CH:6]=[CH:7][CH:8]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([CH3:19])[NH:21][C:17]=1[CH3:19])=[O:20])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: N
Reactant: O=Cc1cccc2nonc12
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc2nonc12

Procedure:
3.2 g of 2,1,3-benzoxadiazole-4-aldehyde, 5.7 g of acetoacetic acid ethyl ester, 2.5 ml of concentrated ammonia and 10 ml of ethanol are refluxed for 6 hours. The mixture is subsequently evaporated and the residual oil is chromatographed on silica gel with chloroform/acetic acid ethyl ester (9:1) to yield the title compound. The product is recrystallised from toluene, m.p. 153°-155°.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C@:5]1([CH2:16][CH:17]=[O:18])[CH2:7][C@H:6]1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].S(=O)(=O)(O)O>O1CCCC1>[CH3:4][C@:5]1([CH2:16][CH:17]([OH:18])[CH3:1])[CH2:7][C@H:6]1[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[Mg]Br
Reactant: CC(c1ccccc1)[C@@H]1C[C@]1(C)CC=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(O)C[C@@]1(C)C[C@H]1C(C)c1ccccc1
Reaction time: 0.5 h
Yield: 7 %

Procedure:
Under a nitrogen atmosphere, methyl magnesium bromide (0.97 mol/L tetrahydrofuran solution, 3.0 ml, 2.9 mmol) was placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer. In the dropping funnel, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetaldehyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol) and tetrahydrofuran (1 ml) were placed, and added dropwise in 5 minutes, with the temperature kept at 20° C. At the same temperature, the mixture was stirred for 30 minutes. Next, a 5% aqueous sulfuric acid solution (2.9 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. The results of a GC analysis showed that the condensed residue was a mixture of four isomers. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2). Thus, a component (0.016 g, 0.07 mmol, 7% yield) with the longest retention time in the GC analysis was obtained. Results of evaluation based on gas chromatography-olfactometry (GC-O) showed that this component was a component having the lowest odor threshold, among the 4 isomers.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[O:31][C:32]([O:34][CH3:35])=[O:33])[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=C[C@H]4O)CC2)C)OC1>>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[C@H:15]([O:31][C:32]([O:34][CH3:35])=[O:33])[CH:16]=3
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C=O)CC[C@H]3[C@H]12
Yield: 62.7 %

Procedure:
The procedure of Example 36 was repeated except that 2.5 mg (0. 005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α, 2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol to give 1.3 mg of 1α,2α-epoxy-3β-hydroxy-7α-methoxycarbonyloxypregn-5-ene-20-carbaldehyde (yield: 62%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:43][CH:42]=1
Reactant: COc1ccc(CN)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-methoxybenzylamine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.44 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=395 m/e.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][O:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][O:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Reactant: Nc1cnccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
A solution of triphenylphosphine (118 mg, 0.45 mmol) in methylene chloride (5 mL) cooled to 0° C. was treated with N-bromosuccinimide (91 mg, 0.51 mmol). Upon complete dissolution, the cooled, purple solution was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (100 mg, 0.30 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min then warmed to 25° C., where it was stirred for another 30 min. The purple reaction mixture was then treated with 2-aminopyrazine (43 mg, 0.45 mmol) and pyridine (0.07 mL, 0.90 mmol) and stirred for 16 h at 25° C. The reaction was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 1.5/98.5 methylene chloride/methanol) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-3-yl)-propionamide (46 mg, 37%) as a light orange foam: (ES)+-HRMS m/e calcd for C18H20ClN3O4S (M+H)+ 410.0936, found 410.0940.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[CH2:30]([S:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:34])=[O:33])[CH3:31]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
((R)-1-Ethanesulfonyl-pyrrolidin-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and ethanesulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [C:1]([CH2:3][NH:4][CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2].IC.[C:22](=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH3:22][N:4]([CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:1]#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#CCNCCC(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: CN(CC#N)CCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A mixture of 0.72 g (2.9 mmol) N-cyanomethyl-3,3-diphenylpropylamine (from step 1), 0.49 g (3.4 mmol) iodomethane and 1.6 g potassium carbonate in 5 ml acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, the solvent evaporated, and the residue chromatographed on silica gel column with 20% ethyl acetate in hexanes to give 0.33 g (yield 43%) N-methyl-N-cyanomethyl-3,3-diphenylpropylamine as an oil which solidified on standing. 1H NMR ((CDCl3, 300 MHz) 7.30-7.10 (m, 10 H), 4.02 (t, 1 H, 3.47 (s, 3 H), 2.38 (t, 2 H), 2.32 (s, 3H), 2.19 (dt, 2H);
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH:34]4[O:38][CH2:37][CH2:36][O:35]4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OCC4OCCO4)cc3)cc3ccccc23)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.53 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and 2-bromomethyl-1,3-dioxolane (250 ml), and the mixture was stirred at 90° C. overnight. Water was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.47 g of the title compound as a pale yellow oil.
Reaction SMILES: ClCC([NH:5][C:6](C)(C)[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.NC(N)=S.[C:20](O)(=O)[CH3:21]>CCO>[CH3:10][C:9]1[C:20]([CH3:21])=[N:5][CH:6]=[CH:7][C:8]=1[CH2:13][CH2:12][NH2:11]
Reactant: CC(C)(Cc1ccncc1)NC(=O)CCl
Reactant: CC(=O)O
Agent: NC(N)=S
Solvent: CCO
Product: Cc1nccc(CCN)c1C
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of 260B (1.30 g, 5.75 mmol), thiourea (524 mg, 6.90 mmol), acetic acid (2 ml) and EtOH (10 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and the solid that separated out was filtered. The filtrate was concentrated and made acidic using 1N HCl. The aqueous solution was washed with EtOAc (2×25 mL), cooled to 0° C. and basified with 2N NaOH. The sodium hydroxide layer was re-extracted with EtOAc (2×25 mL), washed with water (25 mL), dried over Na2SO4 and concentrated under reduced pressure to give 260C (390 mg, 45%) 1NMR (CDCl3) δ 8.45 (d, 2H), 7.06 (d, 2H), 2.58 (s, 2H), 1.06 (s, 6H)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][CH2:16][CH2:17][C:10](=[CH:11]2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH2:22].C[C:29](C)=[O:30]>>[CH2:1]([NH:8][C:13](=[O:14])[C:12]1[CH2:11][CH2:10][CH2:17][CH2:16][C:15]=1[C:29]([NH:22][C:21]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=1[F:19])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)=O
Reactant: O=C1C2=CC(CCC2)C(=O)N1Cc1ccccc1
Product: O=C(NCc1ccccc1)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 2 h

Procedure:
In acetone (50 ml) was dissolved N-benzyl-3,4,5,6-tetrahydroisophthalimide (2.4 g), followed by addition of 2-fluoro-4-chloroaniline (1.5 g). The mixture was stirred at 40°-50° C. for 2 hours, after which time the precipitate was recovered by filtration and washed with acetone. Yield 3.0 g.; m.p. 121°-123° C.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OCC)=O.[Cl:40]C1C=CC=CC=1S(Cl)(=O)=O>>[Cl:40][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[S:7]([NH:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2Cl)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 2-chlorobenzene-sulphonyl chloride
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].N.C([N:38](CC)CC)C>O1CCOCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH2:38])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: N
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(N)(=O)=O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 7 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. dioxane (5 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 60 mg, 75 μmol) was added and the solution was cooled to 7° C. Dry ammonia gas was then introduced for 15 min, and the mixture was then cooled to 0° C. Triethylamine (11 μl, 75 μmol, 1 eq.) was added, and the reaction was then stirred for 12 h, during which time the mixture gradually warmed to RT. The solvent was then distilled off under reduced pressure, and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (33 mg, 90% of theory).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:29]1[CH:28]=[CH:24][CH:23]=[C:22]([Br:21])[CH:30]=1)=[O:5])[CH3:9]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To potassium ethyl malonate (3.25 g, 19.13 mmol) in acetonitrile (50 mL) was sequentially added triethyl amine (4.1 mL, 29.16 mmol) and magnesium chloride (2.16 g, 22.78 mmol) at room temperature. After stirring the reaction mixture at room temperature for 2 hours, 3-bromobenzoyl chloride (2.0 g, 9.11 mmol) was added and the mixture was heated at 60° C. for 18 hours, concentrated under reduced pressure and partitioned between ethyl acetate (100 mL) and 1N HCl (25 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (2.45 g, 99 %). 1H NMR (CDCl3): δ 8.1 (s, 1H), 7.85 (d, 1H), 7.7 (d, 1H), 7.35 (t, 1H), 4.3 (m, 2H), 3.4 (s, 1H), 1.3 (m, 3H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=1)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.O>C(COC)OC.C(OCC)(=O)C>[C:26]([O:25][C:24]([NH:23][CH2:22][C:21]1[CH:20]=[C:19]([CH:33]=[CH:32][CH:31]=1)[CH:17]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C=Cc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
374 mg of 60% sodium hydride was suspended in 20.0 mL of dimethoxyethane, and 1.91 g of ethyl diethylphosphonoacetate was added dropwise thereto at −5° C., followed by stirring at room temperature for 10 minutes. To the reaction liquid was added dropwise a solution of tert-butyl (3-formylbenzyl)carbamate in dimethoxyethane (5.00 mL), followed by stirring at 60° C. for 4 hours. The reaction liquid was cooled to room temperature, followed by addition of water and extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain ethyl 3-{[(tert-butoxycarbonyl)amino]methyl}cinnamate. This was dissolved in 5.00 mL of ethyl acetate, and 8.50 mL of a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring at room temperature for 6 hours. The resulting precipitate was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain 1.71 g of ethyl 3-(aminomethyl)cinnamate hydrochloride.
Reaction SMILES: [Fe:1].[C:2]([OH:6])(=[O:5])[CH:3]=[CH2:4]>>[C:2]([O-:6])(=[O:5])[CH:3]=[CH2:4].[Fe+2:1].[C:2]([O-:6])(=[O:5])[CH:3]=[CH2:4]
Reactant: [Fe]
Reactant: C=CC(=O)O
Product: C=CC(=O)[O-]
Product: [Fe+2]

Procedure:
No. 10 - Iron acrylate was prepared by heating 5 g. of iron powder with 100 g. of glacial acrylic acid at 100° C. for 2 hrs. The solution was cooled and filtered to remove any undissolved iron. Analysis showed the solution to contain 1.2% by weight of iron.
Reaction SMILES: Br.Br[CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH:9]=[CH2:10].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[CH:9]([C:5]1[N:6]=[CH:7][S:8][C:4]=1[CH2:3][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1)=[CH2:10]
Reactant: C=Cc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a 0° C. mixture of 5-(bromomethyl)-4-ethenyl-1,3-thiazole hydrobromide (2.6 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (275 mg, 1.4 mmol) in absolute ethanol (15 mL) was added triethylamine (1.5 mL, 10.8 mmol). The mixture was stirred at room temperature overnight. The solution was evaporated, and the residue was treated with diethyl ether (100 mL). The solid material was removed by filtration. The filtrate was evaporated, and the crude product was purified by flash chromatography (0-5% MeOH/DCM), affording 2-{[(4-ethenyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (270 mg, 60%); 1H NMR (500 MHz, DMSO-d6): δ 4.75 (s, 2H), 5.42 (dd, 1H, J=2.3 Hz, 10.8 Hz), 6.06 (dd, 1H, J=2.3 Hz, 16.9 Hz), 6.68 (s, 1H), 8.95 (s, 1H); M+ 320.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[C:25]([OH:29])(=[O:28])[CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:26][C:25]([OH:29])=[O:28]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: O=CC(=O)O
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CC(=O)O)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxylic acid.