Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:24]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:24])[C:3](=[O:2])[N:13]([CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)CNC(C)=C(C=CC(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Cn1c(C)c(C(=O)OC)cc(Br)c1=O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
MeOH (240 mL) was added to a flask containing 4-[1-(2-ethyl-butylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (7.32 g, 25.9 mmol). NaOMe solution (5.9 mL, 25.9 mmol, 4.375 M in MeOH) and N-bromosuccinimide (5.52 g, 31.0 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 5.72 g of the title compound. MS: (+) m/z 352.18, 354.19 (M+Na, 7″81Br).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C:3]([NH:6][C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])([CH3:4])[CH3:5])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxy-1,1-dimethylethyl)carbamate (5.1 g, 27 mmol, 1 equiv) in CH2Cl2 (100 ml) at room temperature were added NEt3 (11.3 ml, 81 mmol, 3 equiv) and methanesulfonyl chloride (28.3 mmol, 2.2 ml, 1.05 equiv) and the resulting solution was stirred for 2 h then partitioned between AcOEt and a saturated aqueous NaHCO3 solution. The two layers were separated and the organic phase dried over MgSO4 and concentrated in vacuo to give 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) (7.8 g, 108%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:34]([CH3:38])[C:35](=[O:37])[CH3:36]>C(#N)C>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:34]([CH3:38])[C:35](=[O:37])[CH3:36])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(C)C(C)=O)CC2)CC1
Yield: 88.6 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) in acetonitrile (30 ml) are added potassium carbonate (80 mg) and 3-chloro-2-butanone (220 mg), and the mixture is heated under reflux for 16 hours, and concentrated to dryness under reduced pressure. The residue is dissolved in chloroform, and the mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=15:1) to give the desired compound (640 mg) as a yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6]2
Reactant: CCCCC(=O)Cl
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a stirring mixture of 2-(6-methoxy-2-naphthyl)-1-benzofuran (4.02 g, 14.7 mmol) in chloroform (70 mL) chilled in an ice bath was added valeryl chloride (2.6 mL, 22 mmol). The reaction mixture was chilled to −20° C. and tin (IV) chloride (2.2 mL, 19 mmol) was added, dropwise. The mixture was then stirred at room temperature for one hour and then refluxed for 3 hours, 20 minutes. It was allowed to cool to room temperature and poured into ice. The organic phase was diluted with excess ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified twice by flash chromatography (Biotage apparatus) using 2% ethyl acetate in hexane and 10-50% chloroform in hexane to afford 1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow gum (3.17 g). Mass spectrum (+EI, M+) m/z358. 1HNMR (400 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0-8.05 (m, 3H), 7.8 (dd, 1H, J=8.5 Hz and 1.7 Hz), 7.7-7.75 (m, 1H), 7.4-7.45 (m, 3H), 7.25-7.3 (m, 1H), 3.9 (s, 3H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[CH3:31].C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Yield: 48.8 %

Procedure:
A mixture of 0.03 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.015 g (0.0001 mole) of 4-amino-3-methylbenzoic acid, 0.3 mL of ethanol, 0.8 mL of water, and 1 drop of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.020 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methyl-benzoic acid (I-7) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH2:15][CH3:16]>>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH2:14][CH2:15][CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: CCCSC(C)(C)C=O
Product: CCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 35.5 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.40 g, 2.06×10-3 mol) and 0.452 g (3.09×10-3 mol, 150 M %) of 2-propylthio-2-methylpropanal were reacted by the method of Example 2 to give 0.239 g (40% yield) of 2-(2-mercapto-2-methylpropylamino)-1-[2-propylthio-2-methylpropylamino]benzene as a colorless oil after purification by radial chromatography on a 4 mm silica gel plate eluting with 200 ml 5% diethyl ether/petroleum ether and 100 ml 7% diethyl ether/petroleum ether.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][C:9]([N:11]2[CH2:22][CH2:21][C:14]3[N:15]=[N:16][C:17]([NH:19][NH2:20])=[CH:18][C:13]=3[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30]([CH3:32])=O>>[C:23]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:11]2[CH2:22][CH2:21][C:14]3[N:15]=[N:16][C:17]([NH:19][N:20]=[C:30]([CH3:32])[CH3:29])=[CH:18][C:13]=3[CH2:12]2)=[O:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNc1cc2c(nn1)CCN(C(=O)CC(c1ccccc1)c1ccccc1)C2
Reactant: CC(C)=O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)CC(c1ccccc1)c1ccccc1)C2

Procedure:
A solution of 1.5 g of 6-(3,3-diphenylpropionyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 40 cc of absolute acetone is heated on a water bath for 35 minutes. The title compound has a M.P. of 172°-175° (decomp., from absolute ethanol).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[F-:23]>CN1CCCC1=O.C(Cl)Cl>[F:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1ccc(N(C)c2nc(F)nc3ccccc23)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine 0.150 g (0.5 mmol) and NH4F 0.5 g in 1-methyl-2-pyrrolidinone 3 mL was stirred at 120° C. for 16 h. The reaction mixture was diluted with CH2Cl2 10 mL and directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 100%) to give the crude titled compound product in 10% yield, which was further purified with preparative HPLC. 1H NMR (CD3OD, 400 MHz): δ 7.48-7.43 (m, 1H), 7.25-7.19 (m, 3H), 7.02 (d, 2H, J=9.0 Hz), 6.82-6.73 (m, 2H), 3.84 (s, 3H), 3.58 (s, 3H). 19F NMR (CD3OD):−77 (s). m/e: 284.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:17]1[CH2:27][CH2:28][O:29][CH:16]1[C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(C2OCCO2)c(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 14 h

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (15.99 g, 33.3 mmol) prepared in Step F in anhydrous THF (150 ml) were added ethylene glycol (70 ml) and p-toluenesulfonic acid monohydrate (316.6 mg, 1.66 mmol) at room temperature, and the mixture was stirred for 14 hours. Then ethylene glycol (100 ml) was added, and the reaction mixture was stirred for additional 8 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 5-[1,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (21.69 g) as a crude product.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=O)=[CH:5][CH:4]=[C:3]([Br:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[S:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]1[S:19][CH:9]=[C:7]([C:6]2[CH:5]=[CH:4][C:3]([Br:11])=[CH:2][CH:1]=2)[N:18]=1)[CH3:13]
Reactant: CCOC(=O)CC(N)=S
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(Br)cc2)cs1

Procedure:
A mixture of p-α-dibromoacetophenone (13.9 g, 0.05 mole) and 2-thiocarbamoylacetic acid ethyl ester in ethanol (65 ml) was heated under reflux for 21/2 hours. On cooling, there was obtained the title compound (12.2 g) mp 189°-191° C. (dec). An analytical sample recrystallization from ethanol had mp 191°-193° C.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:10][C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]3[O:10][C:9](=[O:28])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:12]=3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)cc1
Yield: 87.8 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a 1.16 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6c, 1.42 g, 94%). Nitro compound (6c, 1.52 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 1.23 g, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7d, 0.35 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8d, 405 mg, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][C@H:26]([C@H:28]([N:36]1[CH:40]=[C:39]([C:41]([NH2:43])=[O:42])[N:38]=[CH:37]1)[CH2:29][CH2:30]OS(C)(=O)=O)[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:25][C@H:26]([C@H:28]([N:36]1[CH:40]=[C:39]([C:41]([NH2:43])=[O:42])[N:38]=[CH:37]1)[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc2ncccc2c1)n1cnc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
Under N2, to a solution of 6-hydroxyquinoline (43 mg, 0.296 mmol) in DMF (3 ml) was added potassium carbonate (82 mg, 0.593 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide was added and the resulting mixture was stirred for 6 h at 70° C. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (8 g) chromatography eluting with chloroform/methanol (100:1 to 30:1) to give 1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide (1) (62.5 mg, 48.9%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3[nH]cc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A solution of 2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl 4-methylbenzenesulfonate (0.20 g, 0.44 mmol) in anhydrous DMF (2.5 mL) was added sodium azide (0.14 g, 2.2 mmol) and heated to 100° C. for 6 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (1×15 mL), dried (MgSO4), filtered concentrated under reduced pressure. Silica gel chromatography (40% Ethyl acetate/petroleum ether) gave the azide as a clear glass (0.13 g, 86%) which was used directly in the next step.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([Cl:22])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH:10]([Cl:22])[CH2:11][S:12]([C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[O:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(Cl)CSc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cl)CS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step B, 2.II, 207 mg, in 9 ml of CH2Cl2 is treated dropwise at 0° C. over 70 minutes with 121 mg of m-chloroperbenzoic acid (MCPBA) (85%) in 9 ml of CH2Cl2 under N2. The solution is stirred 1 hour at 25° C., washed with aqueous NaHCO3, dried with MgSO4, filtered, evaporated (209 mg) and purified by preparative thin layer chromatography on silica gel with 4:1 (v/v) CHCl3 -ethylacetate, affording 97 mg of pure product, Rf 0.25.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CSc1ccc(I)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(I)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A flask was charged with 10 g of 4-iodothioanisole and 5.5 mL of dimethylsulfate and warmed to ca. 90° C. for 10 min. The resulting solution was dissolved in conc. sulfuric acid (30 mL) and cooled to ca. 0-4° C., whereupon it was treated, with extreme caution, slowly with conc. HNO3 (ca. 2 mL) while maintaining the reaction temperature below 4° C. After stirring it for ca. 10 min, the reaction mixture was stirred at ca. 90° C. for ca. 3 d. The reaction was monitored with HPLC, TLC, and LC-MS, and if needed, smaller portions of nitric acid were added to the reaction mixture to force it to completion. Use of fuming sulfuric acid is also helpful. After the complete consumption of the aromatic starting material, the reaction mixture was cooled, poured over crushed ice, treated with 30% aq. perchloric acid at 4° C. The light colored precipitate was filtered, washed thoroughly with water, and dried under vacuum. The perchlorate salt was stirred with saturated aq. NaCl solution at 95° C. for 3-6 h. Upon cooling to room temperature, the precipitate was filtered, washed thoroughly with water to get rid of any inorganic salts, and dried under vacuum to obtain 4-iodo-3-nitrothioanisole in >80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:34][C:35]1([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:38]3[CH2:39][CH2:40][C:35]([CH3:34])([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:42])[CH2:36][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CN(C)CCOC(=O)C1(C)CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)C1(C)CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (3 mL) was added 2-(dimethylamino)ethyl 4-methylpiperidine-4-carboxylate hydrochloride (87 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% MeCN up to 42.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 49.7 mg (41%) of the formic acid salt of 2-(dimethylamino)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate. LCMS (Method 28) [M+H]+=659.2, RT=1.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.2, 7.2 Hz), 8.68-8.64 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 4.16 (t, 2H, J=5.6 Hz), 3.97-3.93 (m, 1H), 3.75-3.71 (m, 1H), 3.25-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.47 (m, 2H), 2.33 (s, 6H), 2.16-1.95 (m, 2H), 1.49-1.44 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]4[CH:26]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]4[CH:26]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(Cl)nc4)cc3)cn2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)nc4)cc3)cn2c1
Temperature: 170 °C
Yield: 73.5 %

Procedure:
A stirred mixture of 6-chloro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pyridine-3-carboxamide (0.15 g, 0.414 mmol), dimethylamine hydrochloride (0.845 g, 10.36 mmol) and K2CO3 (1.43 g, 10.36 mmol) in dry DMSO (10 ml) was heated at 170° C. for 16 h under an atmosphere of argon. The cooled reaction mixture was added to water (200 ml) and the precipitate was collected by filtration and dried in the air. The solid was purified by flash chromatography (12:1 DCM/MeOH) to give the title compound (0.113 g, 73%) as a pale yellow solid.