Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:24][O:25][CH3:26])[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].C(N(CC)CC)C.[Cl:34][CH2:35][CH2:36][N:37]=[C:38]=[O:39]>CN(C)C=O>[Cl:34][CH2:35][CH2:36][NH:37][C:38]([O:18][CH2:17][C:14]1[CH2:15][S:16][C@@H:11]2[C@H:10]([NH:9][C:7](=[O:8])[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:24][O:25][CH3:26])[C:22](=[O:23])[N:12]2[C:13]=1[C:19]([OH:21])=[O:20])=[O:39]
Reactant: O=C=NCCCl
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NCCCl)CS[C@H]12)c1ccco1
Reaction time: 1 h

Procedure:
A solution of (6R,7R)-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) (1.50 g) in N,N-dimethylformamide (30 ml, purified by filtration through basic alumina) was cooled to 5° and was treated with triethylamine (1.1 ml) and 2 -chloroethyl isocyanate (1.66 g). The reaction was stirredfor 1 hour at 5° when the ice-bath was removed and stirring continued for 1.5 hours at ca. 20°. The solution was partitioned between aqueous sodium bicarbonate solution (3%, 100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous solution was washed with ethyl acetate (3 × 100 ml), then covered with ethyl acetate (100 ml) and acidified to pH 1.8 with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with further ethyl acetate (4 × 100 ml). The combined organic extracts were washed with water (5 × 150 ml) and saturated sodium chloride solution (100 ml) and dried (MgSO4), and the solvent was removed in vacuo to give a yellow froth which was triturated with ether (50 ml) to give the title compound as a yellow powder (0.59 g [α]D + 40° (c 1, DMSO); λmaxpH6 275 nm (ε 17,400).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:26][CH2:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: BrC1CCC1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and bromocyclobutane (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [C:1](Cl)(=[O:13])[O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[C:6]([Cl:12])[CH:5]=1.[CH3:15][N:16]([CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:17]([C:19]1[N:20]=[N:21][NH:22][CH:23]=1)=[O:18].C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:15][N:16]([CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[C:6]([Cl:12])[CH:5]=2)=[O:13])[CH2:30][CH2:31]1)[C:17]([C:19]1[N:20]=[N:21][NH:22][CH:23]=1)=[O:18]
Reactant: N#Cc1cc(Cl)cc(COC(=O)Cl)c1
Reactant: CN(CCC1CCNCC1)C(=O)c1c[nH]nn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(C#N)c2)CC1)C(=O)c1c[nH]nn1
Reaction time: 16 h

Procedure:
To 3-chloro-5-cyanobenzyl carbonochloridate (step 4) (65.5 mg, 0.285 mmol) and N-methyl-N-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide (step 3) (78 mg, 0.285 mmol) in DCM (5 mL) was added saturated aqueous sodium bicarbonate solution (5 mL, 0.285 mmol), and the mixture stirred vigorously for 16 hrs. The resulting mixture was acidified with 10% citric acid solution and the organic portion was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in DCM and applied to a 12 g silica cartridge eluting with 0-100% EtOAc/iso-hexane. The product fractions were combined and concentrated to give a gum. This was further purified by UV triggered HPLC, to give 3-chloro-5-cyanobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate as a gum;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:25][CH2:26][C:27](=[O:28])[C:9]2=3)=[C:4]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:3]=1.O.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:10]2[CH2:25][CH2:26][C:27](=[O:28])[C:9]=2[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]#[N:35])=[CH:3][C:4]=2[S:29]([CH3:32])(=[O:30])=[O:31])[NH:13]1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-(methylsulfonyl)phenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 8, 110 mg, 0.21 mmol), zinc cyanide (32 mg, 0.27 mmol) and tetrakis (triphenylphosphine)palladium(0) (24 mg, 21 μmol) in N,N-dimethylformamide (2 mL) is heated at 110° C. over night and then cooled to room temperature. Water is added and the mixture is filtered. The precipitate is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 8:2 to 3:7). Yield: 40 mg; ESI mass spectrum: [M+H]+=476; Retention time HPLC: 0.94 min (Z017_S04).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:9]=[C:10]([CH:18]=[C:19]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].C([O-])=O.[NH4+].C(O)C>[Pd].O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=[C:19]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(C=CC(=O)OCC)cc(Cc2cccnc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(Cc2cccnc2)c1
Temperature: 60 °C

Procedure:
10% Palladium on charcoal catalyst (1.30 g) was added portionwise to a stirred mixture of ethyl 3-(2-ethoxycarbonyl-1-ethenyl)-5-(3-pyridylmethyl)cinnamate Preparation 13; 13.0 g), ammonium formate (22.44 g), ethanol (100 ml) and tetrahydrofuran (100 ml) at room temperature under an atmosphere of dry nitrogen. The mixture was heated at 60° C. for 2 hours, then cooled and filtered. The filtrate was evaporated under vacuum and the residue partitioned between dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane. The organic solutions were combined, dried (MgSO4) and evaporated under vacuum to give the title compound as an oil (12.46 g); Rf 0.40 (SS 1); δ (CDCl3): 1.20(6H,t,J=7.1 Hz), 2.55(4H,t,J=7.8 Hz), 2.86(4H,t,J=7.8 Hz), 3.89(2H,s), 4.09(4H,q,J=7.1 Hz), 6.84(2H,s), 6.89(1H,s), 7.16-7.20(1H,m), 7.41-7.45(1H,m), 8.43-8.47(1H,m).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH:25][C:1](=[O:11])[CH:2]=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C=Cc2ccccc2)cn1
Yield: 4 %

Procedure:
Prepared as in Example 4-8 from cinnamic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 4%. MS M+H calculated 322.6, found 322.4.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:13])[CH:11]=[CH2:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:20]1)C[C:15]2=O>ClCCl.COC(OC)(C)C>[CH:11]([CH:10]1[O:13][C:14]([CH3:20])([CH3:15])[O:1][CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9]1)=[CH2:12]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: C=CC(O)CC(O)CC(=O)OCC
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: C=CC1CC(CC(=O)OCC)OC(C)(C)O1
Reaction time: 8 h

Procedure:
The crude β,δ-dihydroxy-6-heptenoic acid, ethyl ester from the previous step was dissolved in a mixture of 30 ml of dichloromethane and 10 ml of 2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and the mixture was stirred overnight. Concentration of the reaction mixture and flash chromatography of the residue yielded 1.1 g of 6-ethenyl-2,2-dimethyl-1,3-dioxane-4-acetic acid, ethyl ester.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:21]=2[N:20]=1>C(O)(C)C>[ClH:2].[ClH:1].[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:21]=3[N:20]=2)[C:9]=1[CH3:10]
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: FC(F)(F)c1ccc2[nH]c(S)nc2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
Following the procedure described in Example 12, the reaction of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride with 2-mercapto-5-trifluoromethyl-1H-benzimidazole in isopropanol gives the title compound as a colorless solid; m.p. 173° C (decomp.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[CH:9]1>C(Cl)Cl>[NH:20]1[CH2:19][CH2:18][CH:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][CH:9]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
TFA (5.0 mL, 3.58 mmol) was added in one portion at ambient temperature to a stirred suspension of tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylate (1.08 g, 3.58 mmol) in DCM (8 mL). The resulting solution was stirred for 30 minutes then applied to an SCX column and eluted with MeOH followed by 2M ammonia in methanol. Pure fractions were combined and concentrated by evaporation, then triturated with ether to give a solid which was collected by filtration and air-dried to give 3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.64 g, 88%) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1.O1CCOCC1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100° C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 274 [M+H]+, rt 5.20 min).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[NH:4][N:3]=1.[H-].[Na+].[CH3:19][CH:20]([CH3:23])[CH2:21]Br>CN(C=O)C.O>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:12])=[O:13])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH2:19][CH:20]([CH3:23])[CH3:21])[N:3]=1
Reactant: CC1=NNS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=NN(CC(C)C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
The product from step B (0.9 g, 2.85 mmol) was dissolved in DMF (10 mL). Sodium hydride (0.17 g, 4.28 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then 2-methyl bromopropane (0.47 mL, 4.28 mmol) was added. The mixture was warmed to 80° C. and stirred for 2h. And then cooled to 0° C. and stirred for 12h. DMF was evaporated under high vacuum. The residue obtained was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4 and evaporated to provide an oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give the desired compound as a white solid (0.54 g, 50%). mp: 140°-142° C. 1H NMR (DMSO-d6): δ:0.89 (6H, d, 2CH3); 2.03 (1H, m, CH); 2.49 (3H, s, CH3); 3.64 (2H, δ, CH2); 7.94 (1H, s, CH); 8.21 (2H, s, NH2 exchangeable). Analysis calculated for C9H13N3O4S3 : C, 35.59; H, 4.78; N, 12.45 Found: C, 35.56; H, 4.44; N, 12.36.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:36]1[C:44]2[CH:43]=[CH:42][C:41]([Cl:45])=[C:40]([NH2:46])[C:39]=2[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([N:36]1[C:44]2[C:39](=[C:40]([NH:46][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[C:41]([Cl:45])=[CH:42][CH:43]=2)[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(N)c12
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(NC(=O)c3cnc4cc(OCCOC)ccn34)c12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a magnetically stirred, ice cooled, suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (6.76 mg, 0.0286 mmol) (prepared as in Example 1, steps A-D) in dichloromethane (1 mL) was added N,N-dimethylformamide (1 μL) followed by oxalyl chloride (18.3 μL, 0.0365 mmol; 2M solution in dichloromethane). The mixture was allowed to warm to ambient temperature with occasional venting to allow gases to evolve. After stirring for 30 minutes, 1-benzyl-5-chloro-3-ethyl-1H-indazol-4-amine (8.70 mg, 0.0304 mmol) was added as a solution in dichloromethane (0.5 mL). The mixture was stirred for 60 minutes and then concentrated under reduced pressure. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol in dichloromethane to give N-(1-benzyl-5-chloro-3-ethyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (5.4 mg). MS (APCI), positive scan, m/z=504.3 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:13])[F:14])=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)CN1C(=O)CCc2cc(C(F)(F)F)ccc21
Product: O=C(CN1C(=O)CCc2cc(C(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was synthesized from 2-(2-oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.373, method [7], MS (ESI) 500.0 (M+H); 1H NMR (300 MHz, CD3C1) δ 7.90 (s, 1H), 7.50 (s, 1H), 7.48 (d, J=6.6 Hz, 1H), 7.03 (d, J=9.34, 1H), 6.90 (s, 1H), 4.92 (s, 2H), 3.20-3.14 (m, 2H), 2.93-2.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([C:5]2[N:4]=[C:3]3[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[NH:1][C:2]3=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2nc(N)c(C#CCCCCC(=O)O)nc2-c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(-c2nc3cc(CCCCC(=O)O)[nH]c3nc2-c2ccc(C)cc2)cc1

Procedure:
7-(3-Amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid (step 1) (137 mg, 0.343 mmol) in tert-BuOH (3 ml) was treated with potassium tert-butoxide (154 mg, 1.372 mmol) and stirred at reflux for 3 hours. The mixture was added to water (50 ml) and extracted with DCM (×3). The organic solvent was removed under reduced pressure and the crude material was dissolved in EtOH (minimal) and excess of water was added. The resulting suspension was sonicated and filtered, rinsing the filter cake with water (×3). Purification of crude product by chromatograpy on silica eluting with 0-1% MeOH in DCM afforded the titled compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 84.4 %

Procedure:
Prepared according to the procedure described for Example 121 using 2,4-difluorobenzenesulfonyl chloride (2.19 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.532 g); m.p. 198-200° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH2:18][C:19]([CH3:24])([OH:23])[CH:20]([F:22])[F:21])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:27]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:34]#[C:33][C@:31]([C:28]4[N:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:15]=3)[C:10]([CH2:18][C:19]([OH:23])([CH3:24])[CH:20]([F:22])[F:21])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(O)(Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12)C(F)F
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CC(C)(O)C(F)F)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 65 °C

Procedure:
To a solution of 3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol (75 mg, 0.19 mmol) in piperidine (1 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for 1.5 hr under an atmosphere of nitrogen. After cooling to RT, the reaction mixture was re-treated with additional tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for a further 3 hr. After cooling to RT, the reaction mixture was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, eluent 9:1 DCM/MeOH) furnished a partially purified product. Further purification by reverse phase preparative HPLC gave the title compound as a brown solid: 1H NMR (500 MHz, DMSO) delta 1.17 (3H, s), 1.90 (3H, s), 2.63 (3H, s), 3.09 (1H, d, J 14.2), 3.21 (1H, d, J 14.2), 5.50 (1H, s), 5.92 (1H, t, J 56.1), 6.78 (1H, s), 7.01 (2H, s), 7.08 (1H, d, J 5.5), 7.36 (1H, dd, J 8.3, 1.2), 7.94 (1H, d, J 8.3), 8.29 (1H, d, J 5.5), 8.89 (1H, s); LC-MS: m/z=+470.05 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[O:17]C)=[C:4]([F:22])[CH:3]=1>Br.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(SC)ccc1C(=O)NCc1ccc(Br)cc1F
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)NCc2ccc(Br)cc2F)c(O)c1
Temperature: 100 °C
Yield: 50 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-2-methoxy-4-methylsulfanyl-benzamide (11g crude, from step 1) was dissolved in a 25% HBr in glacial acetic acid solution (400 mL) and heated to 100° C. for 4 h. The solution was diluted with ethyl acetate (750 mL) and washed with saturated NaCl (500 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) gave N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-4-methylsulfanyl-benzamide (5.0 g, 50%). Rf 0.57 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 12.57 (s, 1H), 9.22 (t, J=5.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.52 (dd, J1=9.8 Hz, J2=1.7 Hz, 1H), 7.40-7.27 (m, 2H), 6.77-6.71 (m, 2H), 4.46 (d, J=5.7 Hz, 2H), 2.46 (5, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]1[O:11][C@H:10]1[CH2:12]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C@@H:10]2[CH2:9][O:11]2)=[CH:4][CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: Oc1ccc(Br)cc1
Product: Brc1ccc(OC[C@@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-bromophenol and R-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])[CH:17]=1
Reactant: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 26 %

Procedure:
The title compound was prepared by condensing 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76A) with 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 26% yield, mp>260° C. 1H-NMR (DMSO-d6) δ 8.73 (s, 1H), 8.31 (dd, J=1, 4 Hz, 1H), 8.26 (d, J=8 Hz, 2H), 8.05 (d, J=16 Hz, 1H), 7.89–7.97 (m, 3H), 7.82 (d, J=16 Hz, 1H), 7.17–7.21 (m, 1H), 6.89 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H). MS m/z=465([M+H]+, 65%), 256 (100%). HRMS (ES+) Calcd. for C23H20N4O5S: 465.1232. Found: 465.1240.