Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1N=CC=N1)C#C.N1C=CN=N1.C(Br)C#C.[Li]CCCC.[CH3:23][C:24](=[O:45])[C@@H:25]1[C@:42]2([CH3:43])[C@H:28]([C@H:29]3[C@H:39]([CH2:40][CH2:41]2)[C@:37]2([CH3:38])[C@@H:32]([CH2:33][C:34](=[O:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1>C1COCC1.C(Cl)Cl>[CH3:23][C:24](=[O:45])[C@@H:25]1[C@:42]2([CH3:43])[C@H:28]([C@H:29]3[C@H:39]([CH2:40][CH2:41]2)[C@:37]2([CH3:38])[CH:32]([CH2:33][C:34](=[O:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C#CCBr
Agent: C#CCn1nccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-propynyl)-2H-1,2,3-triazole (prepared by the reaction of triazole with propargyl bromide) (35 mg, 0.33 mmol) in dry THF (10 mL) was treated with n-BuLi (2.5M in THF, 0.33 mmol, 0.15 mL) at -70° C. After stirring the mixture at -75° C. for 0.5 hr, a solution of 5β-pregnan-3,20-dione, cyclic 20-(1,2-ethanediyl acetal) (60 mg, 0.16 mmol) in THF (10 mL) was added and the mixture was stirred at -78° C. for 1 hr. The cooling bath was removed and the mixture was quenched with NH4Cl solution (1 mL). The solvent was removed and the residue was then dissolved in acetone (25 mL). After adding 2N HCl (2 mL) the solution was stirred at rt for 30 min. Sat. NaHCO3 soln. was added to neutralize the acid. The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (85:15) gave pregnan-3,20-dione (20 mg) as a first fraction. Further elution with the same solvent yielded 3α-hydroxy-3β-[3-(2'H-1,2,3-triazol-2'-yl)-1-propynyl]-5β-pregnan-20-one (20 mg) as a colorless solid; mp 139-140° C.; TLC Rf (hexane:acetone 4:1)=0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.S(Cl)([Cl:13])=O>ClC(Cl)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([Cl:13])=[O:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)ccn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-pyridine-2-carboxylic acid (2.0 g, 12.8 mmol) in dichloroethane (43 mL) was added thionyl chloride (2.8 mL, 38.5 mmol) and DMF (2-3 drops). The suspension was warmed to 85° C. After 1 h, the resulting clear, yellow solution was cooled to rt and concentrated. The residue was dissolved in DCE and concentrated. This process was repeated two additional times to give a yellow liquid which crystallized upon standing to give a yellow solid.
Reaction SMILES: [NH:1]1[S:6](=[O:8])(=[O:7])[NH:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:2]1[C:3]=23.[H-].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.O>CN(C)C=O.C(OCC)(=O)C>[C:28]1([C:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][N:1]3[S:6](=[O:8])(=[O:7])[N:5]([CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH:24]=[C:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH2:27]4)[C:4]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:2]3[C:3]=45)[CH2:27][CH:26]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Reactant: O=S1(=O)Nc2cccc3cccc(c23)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)N(CCCN2CC=C(c3ccccc3)CC2)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 19.4 %

Procedure:
A solution of 1H,3H-naphtho[1,8-cd]-1,2,6-thiadiazine 2,2-dioxide (8.8 g) in dry N,N-dimethylformamide (20 cc) is added dropwise to a suspension of sodium hydride (1.2 g, 80% suspension in oil) in N,N-dimethylformamide (50 cc). After 15 minutes' stirring, a solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (9.36 g) in N,N-dimethylformamide (50 cc) is added. The reaction mixture is heated to 100° C. for 1 hour and is then cooled and poured into a mixture of water (500 cc) and ethyl acetate (300 cc). The organic phase is washed with water, is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is redissolved in N,N-dimethylformamide (40 cc) and the solution is diluted with ethanol (300 cc). The precipitate is filtered off, washed with ethanol and dried and then taken up in a 0.1 N aqueous sodium hydroxide solution (200 cc) in which it partially dissolves. The mixture is filtered. The insoluble material is filtered off, washed with water and dried. After recrystallization from ethyl acetate (60 cc), 1,3-bis[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H,3H-naphtho[1,8-cd]-1,2,6-thiadiazine 2,2-dioxide (2.38 g) is obtained, melting at 140° C. The filtrate obtained above is acidified to pH 4 with 1 N hydrochloric acid. The precipitate is redissolved in N,N-dimethylformamide (30 cc) at 100° C., the hot solution is filtered and is then diluted with ethanol (150 cc). The precipitate is filtered off, washed with ethanol (3×50 cc) and dried. 1-[3-(4-Phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H,3H-naphtho[1,8-cd]-1,2,6-thiadiazine 2,2-dioxide (0.95 g) is obtained, melting at 240° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].F[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].Cl>CN(C=O)C.O>[NH2:8][C:6](=[O:7])[CH:5]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21])[C:3]#[N:4]
Reactant: N#CCC(N)=O
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
NaH (3.41 g, 85 mmol) was added portionwise to a cold solution of 2-cyanoacetamide (7.18 g, 85 mmol) in DMF (53 mL). After 30 minutes at room temperature, a solution of methyl 4-fluoro-3-nitrobenzoate (8.5 g, 42.7 mmol) in 15 mL of DMF was added dropwise. After 3 hours a mixture of ice, water and 12 mL HCl (10%) were added. The resulting solid was filtered, rinsed with water and dried under high vacuum overnight to give 9.1 g of methyl 4-(2-amino-1-cyano-2-oxoethyl)-3-nitrobenzoate: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H) 5.78 (s, 1H) 7.77 (s, 1H) 7.91 (d, J=7.83 Hz, 1H) 8.04 (s, 1H) 8.39 (dd, J=8.02, 1.76 Hz, 1H) 8.56 (d, J=1.56 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[N:13]=[N:14][N:15]([C:18]4[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=4)[C:16]=3[CH3:17])[CH:8]=2)[C:3]1=[O:25].[H][H]>[C].[Pd].C(O)C>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[N:13]=[N:14][N:15]([C:18]4[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=4)[C:16]=3[CH3:17])[CH:8]=2)[C:3]1=[O:25]
Reactant: [H][H]
Reactant: Cc1c(-c2ccc3c(=O)n(C)ccc3c2)nnn1-c1cccnc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C)C3=O)nnn1-c1cccnc1F
Yield: 19.9 %

Procedure:
20 mg of palladium carbon was added to 10 ml solution of ethanol with 5 mg of 4-(2-methyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, and hydrogen was added under 4 atm of hydrogen atomosphere. 8 hours later, the reaction solution was filtered, and after distilling out the solvents of the filtrate, the residues were separated and purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 1 mg of the above compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:12])[CH:10]=[CH2:11])=[C:4]([Cl:13])[C:3]=1[Cl:14].FC(F)(F)C(C)=[O:18].C(=O)(O)[O-].[Na+].OOS([O-])=O.[K+]>O.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH:10]2[CH2:11][O:18]2)[CH3:12])=[C:4]([Cl:13])[C:3]=1[Cl:14]
Reactant: C=CC(C)Oc1ccc(Br)c(Cl)c1Cl
Reactant: CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(Oc1ccc(Br)c(Cl)c1Cl)C1CO1
Temperature: 0 °C
Yield: 91 %

Procedure:
1-Bromo-2,3-dichloro-4-(1-methyl-allyloxy)-benzene (2.5 g), 1,1,1-trifluoroacetone (6.05 mL) and sodium bicarbonate (2.12 g) were taken up in a solvent mixture of acetonitrile and water (2:1, 45 mL) and cooled to 0° C. Oxone (5.19 g) was added in three portions and the reaction was slowly warmed to room temperature. Upon completion the reaction was filtered and concentrated and re-dissolved in ethyl acetate. This solution was washed with saturated NH4Cl, brine and dried over sodium sulfate. Upon filtration, it was concentrated and purified by flash column chromatography eluting with EtOAc in hexanes to get the desired product (2.39 g) in 91% yield as white solid. 1H-NMR (400 MHz, CDCl3) : 7.48 (d, 2H), 6.97 (d, 1H), 6.83 (d, 1H), 4.40-4.38 (m, 1H), 4.15-4.08 (m, 1H), 3.25-3.21 (m, 1H), 3.18-3.16 (m, 1H), 2.89 (t, 1H), 2.85-2.68 (m, 3H), 1.49-1.44 (m, 6H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([P:10]([Cl:13])([Cl:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[N+:14](C1C=C(P(=O)(O)O)C=CC=1)([O-:16])=[O:15]>>[N+:14]([C:9]1[CH:8]=[C:7]([P:10]([Cl:12])([Cl:13])=[O:11])[CH:6]=[CH:5][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(P(=O)(Cl)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(P(=O)(O)O)c1
Product: O=[N+]([O-])c1cccc(P(=O)(Cl)Cl)c1

Procedure:
Prepared according to the procedure described for (4-nitrophenyl)phosphonic dichloride using (3-nitrophenyl)phosphonic acid.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:22])[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>>[ClH:1].[ClH:1].[CH3:3][O:4][C:5](=[O:22])[CH2:6][CH2:7][N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)[CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)CCNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)CCN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]-β-alanine methyl ester dihydrochloride, phenylacetaldehyde and sodium cyanoborohydride.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nnc(C(F)(F)F)s2)c1
Temperature: 80 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.032 g, 0.1 mmol), 2-chloro-5-(trifluoromethyl)-1,3,4-thiadiazole (0.019 g, 0.1 mmol) and K2CO3 (0.018 g, 0.13 mmol) in DMF was heated at 80° C. overnight. The mixture was purified via preparative-HPLC to obtain the title compound. ESI-MS (m/z): 466 [M+1]+.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[N:21]#[C:22][NH2:23]>C(O)C>[ClH:1].[CH3:2][CH:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:22]([NH2:23])=[NH:21])[CH:15]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: N#CN
Reactant: CC(Cc1cccc(N)c1)C(=O)Oc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(Cc1cccc(NC(=N)N)c1)C(=O)Oc1ccccc1

Procedure:
In 200 ml of ethanol were dissolved 24.3 g of the phenyl α-methyl-β-(m-aminophenyl)-propionate hydrochloride obtained and 4.2 g of cyanamide, and the solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure to obtain phenyl α-methyl-β-(m-guanidinophenyl)-propionate hydrochloride in the form of an oily matter. This was dissolved in 50 ml of ethanol and then added to saturated aqueous NaHCO3 solution, upon which colorless crystals precipitated. The crystals were collected by filtration and washed with water and acetone, to obtain phenyl α-methyl-β-(m-guanidinophenyl)-propionate carbonate. Yield: 22.6 g (75%); melting point: 97°-98° C.; IR (cm-1): 3500-2500, 1745, 1682, 1625; MS: M+= m/e 297 (M.W.-H2CO3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>CN(C)C=O>[C:7]([NH:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16]([NH:15][CH2:14][CH2:13][Cl:12])=[O:17])=[CH:11][CH:10]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C=NCCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=O)NCCCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1800 g of p-aminoacetanilide in 7000 ml of dimethylformamide is stirred at room temperature. The solution is then cooled to 10°-15° in an ice-water bath. To the stirred cooled solution is added 1440 g of 2-chloroethyl isocyanate in a thin stream over a 50-minute period, keeping the reaction mixture temperature between 20° and 25°. The reaction mixture is stirred at room temperature for 90 minutes; 8000 ml of ice-water is added over a 20-minute period. After stirring for an additional 2 hours, the solid is filtered off and washed with 4000 ml of water. The crude product is slurried with 7000 ml of 95% alcohol. The solid is filtered off and air-dried overnight at room temperature to give 1-(p-acetamidophenyl)-3-(2-chloroethyl)-urea, m.p. 207°-9° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>N1C=CC=CC=1>[C:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution 3-[4-(4-chlorophenyl)-2-oxazolyl] propanol (0.5 g) in pyridine (5 ml) was added acetic anhydride (1.0 ml), followed by stirring for 30 minutes at 50° to 60° C. The reaction mixture was poured into water. The precipitated crystals were collected by filtration to obtain 3-[4-(4-chlorophenyl)-2-oxazolyl]propyl acetate (0.535 g, 91%). Recrystallization from ether-hexane gave colorless prism crystals of mp 37°-37.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH:23]([OH:26])[CH2:24][CH3:25].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. A sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (9 mg, yield 4%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N+:15]([C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=1)([O-:17])=[O:16]>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:27]=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Product: O=C(CSc1nc2ccc([N+](=O)[O-])cc2s1)N1CCCc2ccccc21
Yield: 33 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 6-nitrobenzo[d]thiazole-2-thiol as the nucleophile to yield 21 as a yellow solid (33%): MS m/z: 386 (M+H)+. Anal. Calcd. For, C18H15N3O3S2: C, 56.09; H, 3.92; N, 10.90; S, 16.64. Found: C, 55.98; H, 3.75; N, 10.94; S, 16.41.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:19])=O>CCCCCC>[CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:19])=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C2CC2C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: CCCCc1ccc(C2CC2C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylic acid (9.0 g, 0.04 mol) and oxalyl chloride (6.35 g, 0.05 mol) in hexane (70 ml) was stirred at room temperature for 2 hours and then warmed at 60° C. for 3 hours. The hexane and excess oxalyl chloride were removed in vacuo to give 2-(5-n-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (9.7 g, 100%) as a pale yellow liquid which was used in the next stage without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:2].[NH2:20][OH:21].Cl.C([O-])(O)=O.[Na+]>CCO>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NO
Reactant: CCOC(=O)CCCn1ccc2c(C#N)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCn1ccc2c(C(=N)NO)cccc21
Temperature: 55 °C

Procedure:
Ethyl 4-(4-cyano-1H-indol-1-yl)butanoate (D56) (8.25 g, 32.2 mmol) was dissolved in EtOH and treated with NH2OH.HCl (4.47 g, 64.4 mmol) and NaHCO3 (8.11 g, 97 mmol) and heated to 55° C. for 1 day and two nights. Further NH2OH.HCl (500 mg) and NaHCO3 (500 mg) were added and the reaction was heated for another 3 hours and then separated the inorganics by filtration, washing well with EtOH. The solvent was evaporated and the residue dried under high vacuum. Trituration with ether and dcm afforded two batches of the title compound N2668-20-A8 (5.14 g) and N2668-20-A9 (976 mg). δH (400 MHz, d6-DMSO) 1.15 (3H, t), 1.98 (2H, apparent quin), 2.25 (2H, t), 4.03 (2H, q), 4.21 (2H, t), 5.73 (2H, br s), 6.82 (1H, dd), 7.15 (1H, apparent t), 7.27 (1H, dd), 7.35 (1H, d), 7.51 (1H, d), 9.58 (1H, br s). MS (ES): C15H19N3O3 requires 289; found 290 (MH+).
Reaction SMILES: C([O:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[NH:13])C1C=CC=CC=1.C.CCOC(C)=O.CCCCC.C(O)(=O)C>CO.[Pd]>[OH:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:17])=[O:16])=[NH:13]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCO)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
83.8 mg (0.24 mmol) of N—(N-(2-(benzyloxy)ethyl)carbamimidoyl)-4-methylbenzenesulfonamide were dissolved under nitrogen in MeOH. A few mg of 10% Palladium over activated charcoal were added. 3 vacuo hydrogen flush were done before stirring vigorously the reaction under a H2 atmosphere. After 2 hours, no conversion was found by TLC (eluant AcOEt:pentane 9:1) and approximatively 5 times the amount of starting Palladium over activated charcoal was added. The rection was stirred overnight. The TLC showed the formation of a more polar product unless the reaction was far from being complete. 1 mL of acetic acid was added. One hour after the reaction was complete. The reaction was filtered over celite and the solvent evaporated to afford 62.8 mg (0.24 mmol) of N—(N-(2-hydroxyethyl)carbamimidoyl)-4-methylbenzenesulfonamide as a white solid (yield=100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:14])[CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccc2c(N)ncnn12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 190.7 %

Procedure:
To a cooled (0° C.) solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanone (262.0 mg, 1.49 mmol) in DMF (21 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (212.6 mg, 0.74 mmol). The mixture was stirred for 80 min and then quenched by addition of saturated aqueous sodium sulphite (10 mL) and water (60 mL). The mixture was allowed to warm to rt and the precipitate was collected by filtration. The solid was air-dried to yield 360.0 mg (95%) of the title compound. 1H-NMR (DMSO-d6) δ 9.49 (bs, 1H), 8.49 (bs, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 2.56 (s, 3H); MS [M+H]+=255.3; LCMS RT=1.96 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1.[F-].[Cs+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[N:22]=2)[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: COc1cccc(-c2cc(Cl)cc(-c3ccc(OC(C)C)cc3)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (50 mg, 0.18 mmol), 2-methoxy-6-(tributylstannyl)pyridine (701 mg, 0.178 mmol), CuI (9 mg, 0.05 mmol), CsF (82 mg, 0.54 mmol), and Pd(PPh3)4 (10 mg, 8.9 μmol). The vial was sealed with a septum screw-cap and then placed under N2 atmosphere. To the vial was added degassed DMF (1 mL). The vial was placed in a 80° C. heating block with stirring for 1 hour. The reaction mixture was allowed to cool to room temperature and was then directly purified via C18 chromatography (water:MeOH w/0.1% TFA) to afford 4-chloro-6-(4-isopropoxyphenyl)-6′-methoxy-2,2′-bipyridine as a dark solid (58 mg, 92%). 1H-NMR (500 MHz, CDCl3) 8.29 (d, J=1.7 Hz, 1H), 8.21 (dd, J=7.4, 0.5 Hz, 1H), 8.09-8.04 (m, 2H), 7.74 (t, J=7.8 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.03-6.99 (m, 2H), 6.82 (dd, J=8.2, 0.5 Hz, 1H), 4.66 (spt, J=6.1 Hz, 1H), 4.08 (s, 3H), 1.40 (d, J=6.0 Hz, 6H); MS: MS m/z 355.2 (M++1).