Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13])(=[O:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:1]([NH:13][CH2:12][C:11]1[CH:10]=[C:9]([C:6](=[O:8])[CH3:7])[CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(CN)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.1 %

Procedure:
Acetyl chloride (2.5 g) was added slowly to a suspension of 3-acetylbenzylamine hydrochloride (5.0 g) and triethylamine (6.0 g) in dichloromethane (50 ml) with cooling on an ice-water bath. The mixture was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (100 ml). The solution was alkalified with an aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate (150 ml). The solution was dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3'-acetylaminomethylacetophenone (3.2 g) (oil).
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](=O)[CH2:18]Br>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[C:17]([C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[O:14][CH3:13])[N:2]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: N=C(N)NN=Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1-c1cn(N=Cc2ccccc2)c(N)n1

Procedure:
A solution of 41.7 g (0.257 mol) of benzaldehyde guanylhydrazone (see Thiele, A., Liebigs Annalen der Chemie 270, 35) and 30.12 g of 2-methoxyphenacyl bromide (Aldrich, Buchs, Switzerland; 98%, Cat. no. 10,085-4) in 130 ml of ethanol is boiled under reflux for one hour. After cooling, the product that has crystallised out is filtered off with suction and recrystallized from ethanol. In that manner there is obtained the title compound, m.p. 166°-167° C., 1H-NMR (DMSO): δ=8.61 (s, 1H); 8.0 (m, 3H); 7.88 (s, 1H); 7.5 (m, 3H); 7.19 (m, 1H); 7.03 (d, 1H); 6.96 (t, 1H); 6.16 (s, 2H); 3.94 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:17])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])[N:3]=1.C(O)(=[O:20])C>>[CH:12]([C:11]1[C:2](=[O:20])[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:15][CH3:16])[CH:7]=[CH:6][C:5]=2[CH3:17])([CH3:14])[CH3:13]
Reactant: COc1ccc(C)c2nc(Cl)c(C(C)C)cc12
Reactant: CC(=O)O
Product: COc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Temperature: 120 °C
Reaction time: 15 h

Procedure:
2-Chloro-3-isopropyl-5-methoxy-8-methylquinoline (2.65 g, 10.6 mmol) was dissolved in acetic acid (70 ml), and the solution was stirred at 120° C. for 15 hours. The reaction solution was condensed under reduced pressure, and the resultant residue was recrystallized from chloroform-ethyl acetate. 2.10 g of the title compound was obtained as pale yellow powdery crystals (85.6%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:31]#[N:32].[Na+].O>CS(C)=O>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:32]
Reactant: BrCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
1-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6 g) in dry dimethylsulphoxide (70 ml) was added over 10 minutes to a mixture of sodium cyanide (3.68 g) in dimethyl-sulphoxide (50 ml) and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5-triphenylimidazole (24.19 g, 99%) as a white solid, m.p. 104°-6°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]=2[S:14][CH:13]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(C(C)C)CC)(C)C>C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)[C:15]=2[S:14][CH:13]=1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCNCC4)ncnc23)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4F)csc23)CC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
30 mg (0.0736 mmol) of 7-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine was dissolved in 1 ml of dimethylchloride, and 20 (0.147 mmol) of acetyl chloride and 19 μl (0.110 mmol) of diisopropylethylamine were added thereto. The mixture was stirred at room temperature for 13 hr. The resulting mixture was dissolved in ethylacetate and washed with sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to obtain 17 mg of the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[N-:15]=[N+]=[N-].[Na+]>CS(C)=O>[NH:15]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C=CC1=C(Cl)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c([nH]1)CCCC2
Temperature: 105 °C
Yield: 93.1 %

Procedure:
To a mixture of ethyl 3-(2-chlorocyclohex-1-enyl)acrylate (21.4 g, 100 mmol) in DMSO (100 mL) was added sodium azide (9.75 g, 150 mmol). The reaction mixture was heated at 105° C. for 4 h. After cooling to room temperature, the mixture was poured into ice water. The resulting precipitate was collected by filtration to afford 195a (18.0 g, 93.3%). MS-ESI: [M+H]+ 194.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8](O)=[O:9])(=[O:4])=[O:3].S(Cl)([Cl:19])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8]([Cl:19])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1S(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Cl)cc1S(C)(=O)=O

Procedure:
4.0 g of 3-methylsulfonyl-4-i-propylbenzoic acid, 1.5 ml of thionyl chloride and 3 drops of DMF are heated under reflux for 10 h in 30 ml of toluene. The solvent is subsequently removed in vacuo and the product is taken for further use without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A N,N-dimethylacetamide (30 ml) solution containing 4-nitrofluorobenzene (1.69 g) and trans-1,4-cyclohexanediamine (4.1 g) was stirred at 144-C for 3 days. After cooling, an aqueous saturated potassium carbonate solution was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and then, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-ammonia (90:10:1)), and the solvent was removed to obtain trans-N-(4-nitrophenyl)-1,4-cyclohexanediamine (Reference Example 3-41 in Table 5) (2.31 g).
Reaction SMILES: [H][H].[CH2:3]([N:5]1[CH2:15][CH:14]2[O:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)[CH3:4]>[Pd].C(O)C.C(Cl)Cl>[CH2:3]([N:5]1[CH2:15][CH:14]2[O:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1)[CH3:4]
Reactant: CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCN1CC2OC(C1)c1cc(N)ccc12
Reaction time: 18 h
Yield: 87.4 %

Procedure:
Hydrogen was bubbled through a mixture of 10-ethyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (115 mg, 0.56 mmol) and 10% palladium on carbon (53 mg, 0.050 mmol) in ethanol (3 mL) and CH2Cl2 (3 mL) for 5 min. The reaction was then stirred under a hydrogen atmosphere for 18 h. Filtration through Celite and concentration gave 10-Ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine as an off-white foam (100 mg, 100%). MS (m/e) 205 (M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:26])[C:19]([CH2:24][CH3:25])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:26])[C:19]([CH2:24][CH3:25])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: CCC(C)(CCCl)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
79.7 g (0.62 mole) of 4-chlorophenol and 85.6 g (0.62 mole) of potassium carbonate in 600 ml of toluene are heated under reflux for 2 hours, using a water separator. 104 g (0.53 mole) of 1,5-dichloro-3-ethyl-3-methyl-2-pentanone in 100 ml of toluene are then added at 70° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool and is stirred with 500 ml of water. The organic phase is separated off, washed with dilute sodium hydroxide solution and with water, dried over sodium sulphate and concentrated. 110 g (71.8% of theory) of 1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone of refractive index nD20 1.5092 are obtained. ##STR101##
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCCCCCC>CO>[O:2]1[C:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:23][N:22]=[CH:21]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CO
Product: N#Cc1ccc(-c2cnco2)cc1
Yield: 97 %

Procedure:
To a solution of 4-Formyl-benzonitrile (5 g, 38.17 mmol) and tosylmethyl isocyanide (TosMIC) (from Aldrich, 8.33 g, 42 mmol) in MeOH (200 mL) was added K2CO3 (6.85 g, 49.62 mmol) and the mixture was stirred at reflux for 1 h. The solvent was then evaporated and saturated aqueous NaHCO3 was added. The resultant suspension was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4 and concentrated to leave a yellow solid. Trituration with heptane afforded a solid that was collected by filtration and dried under vacuum to give the title compound (6.3 g, 97%). m.p.=140° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCOCc1c(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)oc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOCc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a mixture of methyl 4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]benzoate (482 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (437 mg, 93%) as a pale-red solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: c1ncc(-c2ncc[nH]2)cn1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cncnc3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate B instead of Intermediate C and with 5-(1H-imidazol-2-yl)pyrimidine instead of 2-phenyl-1H-imidazole. LCMS: 405.2 m/z (M+H)+; ret. Time: 5.44 min (Analytical Method C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][CH2:29][CH3:30]
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: CCCOC(=O)Cl
Solvent: C1CCOC1
Product: CCCOC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added propyl chloroformate (108 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 15%-40%, 25 min) to give the title compound (246 mg, 46%) as TFA salt. 1H NMR DMSO 400 MHz δ 9.99 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.42 (s, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 6.48 (s, 1H), 6.35 (q, 1H), 4.84 (s, 2H), 4.50 (s, 2H), 3.93 (q, 2H), 1.57 (q, 2H), 0.63 (t, 3H).
Reaction SMILES: Cl.[S:2]1[CH2:6][C@@H:5]([C:7]([N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[O:8])[NH:4][CH2:3]1.Cl.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:15]([N:4]1[C@H:5]([C:7]([N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[O:8])[CH2:6][S:2][CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C([C@@H]1CSCN1)N1CCSC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([C@@H]1CSCN1C(=O)c1ccncc1)N1CCSC1
Yield: 74.6 %

Procedure:
To a solution of 0.48 g of 3-[(R)-(-)-thiazolidine-4-carbonyl]thiazolidine hydrochloride and 0.36 g of isonicotinoylchloride hydrochloride in 10 ml of dichloromethane was added 1.6 ml of triethylamine with stirring under cooling. The reaction mixture was stirred for 24 hours at room temperature, and then washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/acetonitrile=1/1) to obtain 0.46 g of 3-[(R)-(-)-3-isonicotinoylthiazolidine-4-carbonyl]thiazolidine (yield: 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1>>[CH3:22][O:21][C:18]1[N:19]=[CH:20][C:15]([NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:16][CH:17]=1
Reactant: COc1ccc(N)cn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cn1
Yield: 68 %

Procedure:
The title compound (1.05 g, 3.4 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) and 5-amino-2-methoxypyridine (683 mg, 5.5 mmol) using the methods of (IntA1), step 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)[CH:6]=[CH:7][CH:8]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: COc1cccc(CCOc2cccc3[nH]c(C(=O)O)cc23)c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1cccc(CCOc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(3-methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid 16k and amine 14.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][Si:7]([C:10]#[C:11][C:12]([CH2:14][CH2:15][CH2:16][Cl:17])=[O:13])([CH3:9])[CH3:8]>CCOCC>[Cl:17][CH2:16][CH2:15][CH2:14][C:12]([OH:13])([C:11]#[C:10][Si:7]([CH3:8])([CH3:9])[CH3:6])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: C[Si](C)(C)C#CC(=O)CCCCl
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCCl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 grams of magnesium and 10 mg. of mercuric chloride in 12 ml. of ether is added 0.4 ml. of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The solution of 11.2 grams of 3-chloropropyl trimethylsilylethynyl ketone and 3.51 ml. of propargyl bromide in 13 ml. of ether is added dropwise so that the mixture is very gently boiled during a period of about 40 minutes. After addition is complete, the cooling bath is removed and the mixture is stirred at room temperature for about 1.5 hours. The mixture is recooled in an ice bath and 10 ml. of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquid is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving a red liquid. The liquid is Kugelrohr-distilled to afford the pale yellow liquid distillate which is the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[C:24]([N:25]=[C:26]=S)=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1>C(#N)C>[Cl:18][C:19]1[C:24]([NH:25][C:26]2[NH:1][C:2]3[C:7]4[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=4[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=3[N:17]=2)=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Reactant: Cc1ccnc(Cl)c1N=C=S
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(C)ccnc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 229.8 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 1.00 g, 0.450 mmol), acetonitrile (10.0 mL), 2-chloro-3-isothiocyanato-4-methylpyridine (Step 1 product, 0.95 g, 0.521 mmol) and N,N-di-isopropyl carbodimide (2.0 mL) to afford 0.400 g of the desired product. 1HNMR (DMSO-d6): δ 1.42 (s, 6H), 2.24 (s, 3H), 2.98 (s, 2H), 3.72 (s, 3H), 7.31 (s, 1H), 7.37 (d, J=4.8 Hz, 1H), 8.15 (d, 1H), 10-11 (s, 2H); MS [M+H]+: 387.24.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH3:11])=[O:9]>C1C=CC=CC=1>[CH3:11][O:10][C:8]([CH2:12][CH2:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc[nH]1
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc[nH]1

Procedure:
The 2-(2-methoxycarbonylethyl)pyrrole is prepared as follows: A solution of pyrrole-2-carboxaldehyde (3.9 g, 41 mmol) and (carbomethoxymethylene)triphenylphosphorane (14 g, 42 mmol) in 160 mL of dry benzene is heated at reflux for 18 hours under a nitrogen atmosphere. After cooling, the reaction mixture is concentrated under vacuum and the resulting oil is purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and hexane (1:9) to give 5.11 g of a mixture of cis- and trans-methyl 2-(2-pyrrolyl)acrylate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
To 4-fluorobenzonitrile (11.56 g) in DMSO (200 ml) was added piperidine-4carboxylic acid ethyl ester (15 g) and potassium carbonate (14.4 g) and the reaction was heated to 120° C. for 4 h. After cooling solvent was evaporated and the residue taken up into EtOAc (150 ml) and washed with HCl (1M, 2×100 ml), sodium hydrogen carbonate solution (2×100 ml) and brine (100mI). Evaporation of the organic layer provided the subtitled compound (22.6 g). LCMS electrospray(+ve) 259 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([Cl:31])=[O:24])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 0 °C

Procedure:
A suspension of 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoic acid (1.50 g, 3.56 mmol) in DCM (35 mL) was stirred at 0° C. and oxalyl chloride (340 μL, 3.9 mmol) was added, followed by a catalytic amount of DMF (<50 μL). The mixture was allowed to warm to room temperature and stirred for two days, during which time the solid dissolved to form a light yellow clear solution. The mixture was evaporated under reduced pressure and the residue was azeotroped with toluene (3 mL), then hexane (10 mL) and the title compound obtained as a light brown, slightly gummy, solid (1.5 g) which was used without further purification.