Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][C:9]([NH2:11])=[N:10][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1.O>[Br:1][C:2]1[C:7]2[S:8][C:9]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:10][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)nc(Br)c2s1
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a solution of 4,6-dibromothiazolo[5,4-c]pyridin-2-amine (1.47 g, 56.74% as per LCMS, 2.70 mmol) in 1,4-dioxane (75 mL) was added ethylisocyanate (1.30 mL, 16.25 mmol) and the resulting reaction mixture was heated to 80° C. for 16 h. The solvent was distilled off under reduced pressure and the residue was then co-distilled with hexane (twice). The solid thus obtained was stirred in hot water at 80° C. for 30 min then filtered. The solid material was purified over silica gel (100-200 M, 30-40% EtOAc-hexane) to obtain the desired product as an off-white solid (0.85 g, 82%).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:27]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:34])=[O:5])[S:12][CH:13]=2)=[CH:20][CH:21]=1)=[O:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)Nc3ccccc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(C(=O)Nc3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
2-[(4-{2-[4-(Anilinocarbonyl)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (480 mg) obtained in Example 60-3 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (400 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].C(O)(C)C>ClCCl>[Br:1][C:2]1[C:3]([C:9]2[S:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)=[N:4][C:5]([NH:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])=[N:6][CH:7]=1
Reactant: NCCN1CCNC1=O
Reactant: Clc1ncc(Br)c(-c2ccc(CN3CCCCC3)s2)n1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C1NCCN1CCNc1ncc(Br)c(-c2ccc(CN3CCCCC3)s2)n1
Temperature: 170 °C
Yield: 61.8 %

Procedure:
5-Bromo-2-chloro-4-(5-(piperidin-1-ylmethyl)thiophen-2-yl)pyrimidine (0.3 g, 0.8 mmol), 1-(2-aminoethyl)imidazolidin-2-one (0.123 g, 0.96 mmol) and isopropyl alcohol were all placed in a microwave tube. The tube was capped and heated to 170° C. in a Personal Chemistry microwave for 10 min. The reaction then diluted with dichloromethane washed with water, saturated sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate and purified by flash chromatography using a gradient of 2 to 12% methanol in dichloromethane to give a light yellow solid (0.23 g). MS (M+H)+ 465/476.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[CH2:12]1)=[O:9])=[O:5].C(OCC)(=O)C>[Pd].CO>[NH2:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][NH:6][C:4](=[O:5])[C:3]2[CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=[CH:30][C:2]=2[NH2:1])[CH2:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine (32.6 mg), 10% Pd-activated carbone (8 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred under a hydrogen atmosphere at room temperature for 15 h. The Pd catalyst was filtered off, and the filtrate was concentrated. Solid phase extraction (Bond Elut™ SI, 20% methanol/AcOEt) afforded (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2132) (10.5 mg, 34%): The purity was determined by RPLC/MS (84%); ESI/MS m/e 470.2 (M++H, C21H23ClF3N5O2).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:9])[N:6]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1csc(Br)n1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
2-Bromo-1,3-thiazole-4-carboxylic acid (0.8 g, 3.85 mmol) was initially charged in tetrahydrofuran (10 ml). N,N′-Carbonyldiimidazole (0.94 g, 5.77 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.55 g, 5.77 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 g, 5.77 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. The aqueous phase was extracted with dichloromethane; the organic phase was dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. This gave a total of 1.0 g (89% of theory) of 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[N:22][OH:23])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[C:24]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C([O-])(=O)C.[NH4+:46]>C(O)(=O)C>[CH2:27]([O:26][C:24]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[N:22]([OH:23])[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:46]=2)[CH2:36][CH2:35]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CSc1nccc(C(=NO)C(=O)c2cccc(C(F)(F)F)c2)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CSc1nccc(-c2c(-c3cccc(C(F)(F)F)c3)nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2O)n1
Yield: 114.2 %

Procedure:
To a mixture of 1-(2-methylthiopyrimidin-4-yl)-2-(3-trifluoromethylphenyl)ethane-1,2-dione-1-oxime (5.0 g, 0.0146 mole) and N-carbobenzyloxypiperidine-4-carboxaldehyde [Amici et al Eur. J. Med. Chem. 26, 625-631 (1991)] (4.70 g, 0.019 mole), in acetic acid (140 mL) was added ammonium acetate (23 g, 0.295 mole). The mixture was heated to reflux for 11/2 hours, cooled and concentrated to remove most of the acetic acid. The residue was dissolved in water (200 mL) and ethyl acetate (400 mL) and the pH adjusted to 7.5 with 3N sodium hydroxide. The ethyl acetate layer was removed, dried over Na2SO4, filtered and concentrated to give an oil (9.5 g crude product). The oil was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:18]=2[N:19]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:29])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2cc(OC(F)(F)F)ccc2s1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3cc(OC(F)(F)F)ccc3s1)n2C
Yield: 64 %

Procedure:
1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.35 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g), 2-amino-5-(trifluoromethoxy)benzothiazole (1.17 g), 1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 424. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (s, 1H), 7.92 (s, 1H), 7.85 (br, 1H), 7.78-7.63 (m, 1H), 7.50 (d, 1H), 7.36 (d, 2H), 3.66 (s, 3H), and 3.58 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:8]1[CH:7]=[C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])[CH:11]=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)CNc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 25.5 %

Procedure:
N-(3-Phenoxyphenyl)glycine methyl ester (Intermediate 48; 10 g, 0.0389 mol) was dissolved in a mixture of glacial acetic acid (60 ml) and water (7 ml) and the solution was cooled to between 0° and 5° C. A solution of sodium nitrite (2.8 g, 0.0408 mol) in water (8.5 ml) was added to this over 15 min at the same low temperature. The solution was stirred for 1 h before being cooled to between 0° and -10° C. Zinc powder (9.9 g, 0.1517 mol) was gradually added at this temperature and the reaction was then stirred at 0° to 5° C. for 4 h. It was then poured into water (300 ml) and extracted with ethyl acetate (3×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased. It was then dried and evaporated to give a dark brown oil. This was purified by FCC on deactivated silica (200 g) eluting with hexane-chloroform (2:1) to give the title compound as a brown oil (2.7 g, 25%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([NH:27][C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[Cl:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]N(C)C=O.[H-].[Na+].CI>O>[Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:43])[C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[Cl:42])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Reaction time: 0.83 h

Procedure:
To a mixture of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene (453 mg) and N,N-dimethylformamide (2.2 ml) was added sodium hydride (60% in oil, 31 mg) under ice-cooling, and the mixture was stirred for 50 minutes. To the mixture was added methyl iodide (0.055 ml), and the mixture was stirred for 2.5 hours at ambient temperature. Water (88 ml) was added to the mixture under ice-cooling, and the resulting precipitates were collected by vacuum filtration and washed with water and ethyl acetate to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (236 mg) as powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]2[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[NH:5]2)[CH:14]=1)(=[O:36])=[O:35]
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccccc3F)c1)N2
Yield: 47.1 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 2-fluoro-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 4 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 100 mg of 2-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide yellow solid (Yield: 47%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C(OCC)(=O)C>[F:20][C:19]1[C:14]([C:10]2([CH2:9][NH:8][C:5]3[N:6]=[N:7][C:2]([C:28]4[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][CH2:11]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cccnc1C1(CNc2ccc(Cl)nn2)CCC1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a 20 dram vial was added 6-chloro-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine (1.8 g, 6.23 mmol, 1.0 equiv), 2-methoxypyridin-3-ylboronic acid (1.0 g, 6.54 mmol, 1.1 equiv), Cl2Pd(dppf) (350 mg, 0.43 mmol, 0.07 equiv), 2M potassium carbonate (8 mL, 15.5 mmol, 2.5 equiv), and dioxane (21 mL). The reaction was stirred and heated to 90° C. for 2 h and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with lithium chloride (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography to give N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine (1.7 g, 77%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(Cl)c(Cl)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3',4'-dichloroacetophenone (2.46 g, 12.8 mmol), trimethylsilyl triflate (3.0 mL, 15.4 mmol), triethylamine (3.6 mL, 26.0 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (4.0 g, 12.8 mmol) m.p. 204°-207° C.; 1H NMR (400 MHz, CDCl3) δ 1.33 (d, 6H), 3.55 (m, 1H), 6.71 (s, 1H), 7.00 (m, 1H), 7.08 (m, 1H), 7.20 (m, 1H), 7.30 (m, 1H), 7.56 (d, 1H), 7.69 (m, 1H), 7.74 (br, 1H), 7.98 (s, 1H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.C(S[S:9][CH2:10][CH3:11])C.[CH3:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][N:13]([S:9][CH2:10][CH3:11])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]
Reactant: CCSSCC
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CCSN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
A solution of 67 g of sulfuryl chloride in 100 ml of methylene chloride was added dropwise to a solution of 61 g of diethyldisulfide in 600 ml of methylene chloride cooled to -40° C. and after the temperature was raised to -5° C., the mixture was stirred for 5 minutes. The mixture was cooled to -40° C. and a solution of 57 g of N-methyl-N'-(3,4-dichlorophenyl)-urea in 460 ml of pyridine was added dropwise thereto. The mixture was stirred at -40° C. for 1 hour and for another hour at -20° C. The mixture was poured into an ice-water mixture and the pH was adjusted to 3.5 by addition of concentrated hydrochloric acid. The organic phase was decanted and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether and subjected to chromatography over silica gel. Elution with a 7-3 benzene-ethyl acetate mixture gave 22 g of N-methyl-N-ethylthio-N'-(3,4-dichlorophenyl)-urea melting at 71° C.
Reaction SMILES: C(=O)=O.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2I)=[CH:7][CH:6]=1.C([Li])CCC.[CH3:28][O:29][C:30](Cl)=[O:31]>C1COCC1.CC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2[C:30]([O:29][CH3:28])=[O:31])=[CH:7][CH:6]=1
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(I)c2c1
Reactant: COC(=O)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a cooled solution (−78° C., dry ice, acetone) containing 2-(4-fluorophenyl)-3-iodo-5-methoxybenzo[b]thiophene (1.0 g, 2.6 mmol,) and THF (26 mL) was added n-butyllithium (2.0 mL, 1.0 M THF) over 5 min. The solution was maintained at −78° C. for 1 h. Methylchloroformate (0.80 mL, 10.4 mmol) was then added quickly in a steady stream via syringe. The solution was removed from cooling and allowed to stand at ambient temperature for 1.5 h. The solution was concentrated and purified on silica gel (0-10% ethyl acetate/hexanes, 40 min. gradient) to afford methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate as a yellow residue. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.88 (d, J=2.44 Hz, 1H), 7.66 (d, J=8.85 Hz, 1H), 7.47 (dd, J=8.85, 5.19 Hz, 2H), 7.12 (t, J=8.70 Hz, 2H), 7.05 (dd, J=8.70, 2.59 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LCMS: retention time: 3.355 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 317 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C>C(#N)C>[NH2:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60° C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.09 g, 16 mmole) and TMSTF (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60° C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-β-D-ribofuranosyl) benzimidazole (43). 13C NMR (CDCl3): d 170.04 ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB): m/e 758, 718, 676, 460, 426, 259, 217, 139.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[NH:31]1[C:32]2[C:28](=[C:27]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 75.8 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (II) (100 mg, 0.35 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (70) (95 mg, 0.39 mmol) and sodium carbonate (112 mg) were suspended in toluene (2.5 mL), ethanol (1.5 mL) and water (0.7 mL). To this was added bis(triphenylphosphine)palladium(II) chloride (13.5 mg) and the reaction vessel was flushed with argon. The reaction mixture was microwaved at 120° C. for 1 h and then partitioned between DCM and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield the title compound (III) (97 mg).