Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(=O)CC>[CH2:22]([N:9]1[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][N:8]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Reaction time: 2 h

Procedure:
To a slurry of 7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (35.0 g) and potassium carbonate (66.34 g) in 150 ml of 2-butanone was added benzyl bromide (44.47 g) and the mixture was stirred at 50° for 2 h. The reaction was quenched with 750 ml of H2O, mixture was neutralized with 2N HCl to pH 8 and extracted with chloroform. The organic layer was washed successively with dilute HCl, H2O and brine and thereafter dried (MgSO4), charcoaled, filtered and concentrated. The yellow-orange residue was purified by flash chromatography (silica, dichloromethane) and recrystallized from ethanol to give 2.0 g of light yellow microcrystals, mp 163°-165°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[O:26]=[C:27]([CH:29]=[C:30]([CH3:32])[CH3:31])[CH3:28]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:30]([CH3:32])([CH3:31])[CH2:29][C:27](=[O:26])[CH3:28])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: CC(=O)C=C(C)C
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(C)(C)P(=O)(O)CCCCc1ccccc1
Yield: 37.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and mesityl oxide (0.32 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. CHCl3 was removed in vacuo. The residue was diluted with ether and washed with 5% aqueous NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. Organic layers were combined and extracted with brine, dried over Na2SO4 and solvent was removed to give 0.28 g of the product an an oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH2:12]([CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[CH3:13]>C(Cl)Cl>[CH2:12]([CH:14]([CH2:17][CH3:18])[CH2:15][O:16][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)[CH3:13]
Reactant: O=C(Cl)c1ccc(CBr)cc1
Reactant: CCC(CC)CO
Solvent: ClCCl
Product: CCC(CC)COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title A compound, 4-bromomethyl-benzoyl chloride (466 mg, 2 mmol) in 3 mL of CH2Cl2 is added dropwise to a solution of 2-ethyl-1-butanol (204 mg, 2 mmol) and TEA (202 mg, 2 mmol) in 10 mL of CH2Cl2 at 0˜5° C. over 30 min. The reaction is allowed to warm to RT and stirred overnight. The solvent is evaporated and the residue is partitioned between hexane and water. The organic phase is dried over anhydrous MgSO4 and concentrated. The residue is chromatographic on silica gel using EtOAc/hexane (gradient 90-70) to give 4-bromomethyl-benzoic acid 2-ethyl-butyl ester as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCBr
Temperature: 120 °C
Reaction time: 6 h
Yield: 51.8 %

Procedure:
A suspension of 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane in 100 ml of dimethylformamide was heated under stirring at 120° C. for 6 hours to react them. Insoluble matters were then filtered off from the reaction mixture and the filtrate was then concentrated to dryness under reduced pressure. The residue was washed with hexane and then recrystallized from ethanol-water. Resulting crystals were collected by filtration, washed and then dried to obtain 13.8 g of N-(3-bromopropyl)phthalimide.
Reaction SMILES: N1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2C=N1.FC(F)(F)C(OCC)=[O:17].C[O-].[Na+]>CO>[C:9]1(=[O:17])[C:8]2[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: c1ccc2c(c1)CCc1cn[nH]c1-2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCCc2ccccc21

Procedure:
Synthetic Scheme III shows the procedure for preparation of 4,5-dihydrobenz[g]indazole compounds embraced by Formula I. In step 1, ethyl trifluoroacetate is reacted with base, such as 25% sodium methoxide in a protic solvent, such as methanol, and a 1-tetralone derivative (9) to give the intermediate diketone (10). In step 2, the diketone (10) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the free base or hydrochloride salt of a phenylhydrazine at reflux for 24 hours to afford a mixture of pyrazoles (11) and (12). Recrystallization gives the 4,5-dihydro benz[g]indazolyl-benzenesulfonamide (11). ##STR12##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=O)[C:22](F)(F)F)[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ICC[CH2:36][S:37]([N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)(=[O:39])=[O:38]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH2:21][CH2:22][CH2:36][S:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC(=O)C(F)(F)F
Reactant: O=S(=O)(CCCI)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCS(=O)(=O)N1CCCC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-[(trifluoroacetyl)amino]-2-pyridinecarboxylate (206 mg, 0.556 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (362 mg, 1.11 mmol) and 1-[(3-iodopropyl)sulfonyl]pyrrolidine (253 mg, 0.834 mmol), respectively. The reaction mixture was stirred at 80° C. for 5 hours, after which additional cesium carbonate (362 mg, 1.11 mmol) and 1-[(3-iodopropyl)sulfonyl]pyrrolidine (253 mg, 0.834 mmol) were added. The reaction mixture was stirred at 80° C. for an additional 7 hours. The reaction mixture was cooled and diluted with toluene. The resulting mixture was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5% gradient, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(1-pyrrolidinylsulfonyl)propyl]amino}-2-pyridinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=1.3 Hz, 1 H), 7.79 (t, J=5.7 Hz, 1 H), 7.13 (dd, J=8.5, 5.4 Hz, 2 H), 6.97 (t, J=8.7 Hz, 2 H), 6.86 (s, 1 H), 4.41 (q, J=7.2 Hz, 2 H), 4.26 (t, J=6.2 Hz, 2 H), 3.91 (s, 2 H), 3.37-3.31 (m, 4 H), 3.03 (m, 2 H), 2.19-2.09 (m, 2 H), 1.95-1.89 (m, 4 H), 1.42 (t, J=6.9 Hz, 3 H); MS m/z 450 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[NH2:13][C:14]1[C:15]([I:28])=[C:16]([C:25]([Cl:27])=[O:26])[C:17]([I:24])=[C:18]([C:22]=1[I:23])[C:19]([Cl:21])=[O:20]>C1C=CC=CC=1.CC(C)=O>[C:1]([NH:13][C:14]1[C:22]([I:23])=[C:18]([C:19]([Cl:21])=[O:20])[C:17]([I:24])=[C:16]([C:15]=1[I:28])[C:25]([Cl:27])=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 1 h

Procedure:
A mixture of 50 ml. of acetic anhydride and 0.1 ml. of conc. sulfuric acid was stirred at room temperature for 5 minutes. To this mixture was added 15 g. (0.025 mole) of 5-amino-2,4,6-triiodoisophthaloyl chloride in one portion and stirring was continued at room temperature for one hour. The mixture was stored overnight at 0°. Filtration furnished 16 g. of solid material. The product was recrystallized from ethyl acetate to furnish 10 g. (63%) of pure product. The compound was shown to be pure by tlc (silica plate-benzene/acetone 80/20).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]([CH:28]([CH3:30])[CH3:29])[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH2:40]Cl>CN(C=O)C>[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH2:40][N:25]1[CH2:26][CH2:27][CH:22]([C:20]2[CH:19]=[CH:18][C:15]3[C:16]4[N:10]([CH:9]=[C:8]([C:6]([N:5]([CH2:4][CH2:3][OH:2])[CH:28]([CH3:30])[CH3:29])=[O:7])[N:17]=4)[CH2:11][CH2:12][O:13][C:14]=3[CH:21]=2)[CH2:23][CH2:24]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Reaction time: 72 h
Yield: 19.8 %

Procedure:
To a stirred mixture of 8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride (127 mg, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (127 mg, 0.92 mmol), N,N-dimethyl-2-chloroacetamide (36 mg, 0.3 mmol) and KI (catalytic) and stirring continued at RT for 72 h before concentrating in vacuo. The resultant residue was diluted with ethyl acetate and washed with water followed by brine, then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was passed down an Isolute SCX-2 cartridge eluting with DCM/methanol then 2M NH3 in methanol. Basic fractions were combined and concentrated in vacuo, the residue subjected to RPHPLC (C18 column, gradient 5 to 95% CH3CN in water+0.1% HCO2H) to give 356 as a colourless glass (22 mg, 20%). LCMS: RT=1.90 min, [M+H]+=484 1H NMR 400 MHz (CDCl3) δ: 8.42 (2H, s), 8.20 (1H, br, s), 8.34 (1H, d, J=8.32 Hz), 7.81 (1H, s), 7.04 (1H, dd, J=8.40, 1.77 Hz), 6.90 (1H, d, J=1.69 Hz), 4.63 (2H, m), 4.45-4.44 (4H, m), 3.38 (3H, m), 3.32 (2H, m), 3.16 (2H, d, J=11.21 Hz), 3.11 (3H, s), 2.99 (3H, s), 2.56 (1H, m), 2.48 (2H, m), 1.87 (4H, m), 1.42 (6H, d, J=6.46 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc(Cl)ccc1Cl
Yield: 45 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,5-dichlorobenzenesulfonyl chloride (13.5 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 45% yield (8.3 mg). MS (ESI+) calcd mass for C13H9Cl2N5O2S 368.985401, found 368.985761.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nc(C)cc(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nc(C)cc(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.56 g) in methylene chloride (16.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.22 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. The mixture was allowed to be warmed up to 0° C., and an aqueous solution of saturated sodium thiosulfate was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 230) (165 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1nn(-c2ccccc2)nc1CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccc2)nc1CBr
Temperature: 120 °C
Yield: 91.5 %

Procedure:
To a solution of (5-Methyl-2-phenyl-2H-[1,2,3]triazol-4-yl)-methanol (0.25 g, 1.30 mmol) in 10 ml of toluene was added PBr3 (0.53 g, 1.90 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.30 g, 90%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21][CH3:22])=[N:17][CH:18]=3)[N:13]([CH2:23][CH3:24])[C:12]2=[O:25])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1(C2[O:34]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21]([CH3:22])=[O:34])=[N:17][CH:18]=3)[N:13]([CH2:23][CH3:24])[C:12]2=[O:25])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(SC)nc21
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfanyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (5.61 g, 15.57 mmol) in dichloromethane (100 mL) at ambient temperature was added 3-phenyl-2-(phenylsulfonyl)oxaziridine (4.88 g, 18.69 mmol, PD 0191006, Org. Synth., 1987; 66:203-210) in portions. The reaction mixture was stirred overnight, then washed with brine and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a solvent mixture of 3% methanol in dichloromethane to yield 4.6 g (78%) of the titled compound: mp 167-169° C. Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe=450° C.) (m+1)/z 377.1
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C1COCC1>[CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]2[O:15][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1NC(=O)c1snnc1C1CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2snnc2C2CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
2-(4-Cyclopropyl-1,2,3-thiadiazol-5-ylcarbonylamino)benzoic acid (0.77 g; 2.7 mmols), triethylamine (0.54 g; 5.3 mmols) and 2-chloro-1-methylpyridinium iodide (0.82 g; 3.2 mmols) were dissolved or suspended in THF (15 ml), followed by stirring at room temperature for 10 hours. Subsequently, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Crystals thus formed were washed with methanol to obtain 0.63 g of 2-(4-cyclopropyl-1,2,3-thiadiazol-5-yl)-4H-3,1-benzoxazin-4-one.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[O:14])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:15][C:16]([CH3:18])=O.IC#N>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[O:14])[C:11](=[C:16]([CH3:18])[CH3:15])[CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc3c(c2o1)C(=O)CC3
Reactant: CC(C)=O
Agent: N#CI
Solvent: C1CCOC1
Product: CC(C)=C1Cc2ccc3nc(C)oc3c2C1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 32.7 %

Procedure:
2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (1.87 g, 10.0 mmol), acetone (3.68 mL, 50.0 mmol) and ICN Alumina B (manufactured by ICN, Akt.1, 20 g) were suspended in tetrahydrofuran (50 mL), and the mixture was stirred at 50° C. for 9 hr. Acetone (3.68 mL, 50.0 mmol) was added, and the mixture was further stirred for 12 hr. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (742 mg, yield 33%).
Reaction SMILES: O[C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:25])C>>[CH3:16][C:2]1([CH3:17])[C:3](=[O:25])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:6]1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCNCC
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=CC1=O
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one (1.74 g, 7.46 mmol, 1 eq) in ethanol (30 mL), a solution of diethylamine (778 mg, 7.46 mmol, 1 eq) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 90 min. The ethanol was removed, and the mixture was then diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (1.6 g, 92%) which was used in the next step without further purification.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>ClCCl>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo [5,1-c][1,4]benzodiazepine and 1.5 g of triethylamine in 20 ml of dichloromethane is added a solution of 2.11 g of 6-chloropyridine-3-carbonyl chloride in 5 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature diluted with 20 ml of dichloromethane and washed with 30 ml of 1N NaOH. The organic layer is washed twice with 20 ml of 1N NaOH, dried (Na2SO4) and the solvent removed. The residue is triturated with ether to give 3 g of solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[C:16]1([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[K+].CN(C=O)C>CCOC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:29][CH2:28][CH:25]2[CH2:24][CH2:23][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)=[CH:10][CH:11]=1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: NCC1CCN(c2ccccc2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCC(O)(CCNCC1CCN(c2ccccc2)CC1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 66 %

Procedure:
1-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol (223 mg, 0.97 mmol), (1-phenylpiperidin-4-yl)methanamine (295 mg, 1.6 equiv.), potassium iodide (178 mg, 1.1 equiv.) and DIEPA (186 μL, 1.1 equiv.) were mixed with DMF (5 mL) and heated at 80° C. for overnight. The mixture was diluted with EtOAc (50 mL), washed by water (2×15 mL), brine (2×10 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge eluted with a 0˜20% methanol in CH2Cl2 gradient to afford 3-(4-fluorophenyl)-1-((1-phenylpiperidin-4-yl)methylamino)hex-5-en-3-ol (245 mg. 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][S:29](=[O:32])(=[O:33])[CH2:30][CH2:31]2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cn1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
[6-(Dimethylamino)-3-pyridinyl]boronic acid (34 mg, 0.202 mmol), 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (75 mg, 0.202 mmol) and potassium carbonate (84 mg, 0.606 mmol) were suspended in 4 mL of dioxane:water (3:1) and degassed for a few minutes with nitrogen gas. Pd(PPh3)4 (23 mg) was then added and the reaction mixture was heated in a microwave oven at 150° C. for 40 minutes on ‘high’ absorption setting. After heating, LCMS of all crude reaction mixtures showed the desired m/z with few impurities. The crude reaction mixtures were filtered through 500 mg Stratospheres SPE Thiol cartridges eluting with 10 mL methanol/DCM (1:1) and concentrated. The residues were dissolved in DMSO (˜3 mL) and purified via RP-HPLC using an XBridge Prep C18 column with water/acetonitrile (0.1% NH4OH buffer). The desired fractions were concentrated, giving 0.029 g (34.8%) of the title compound.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].CC(C)=O.[CH3:11][C:12]1[C:16]([S:17](Cl)(=[O:19])=[O:18])=[C:15]([CH3:21])[O:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:11][C:12]1[C:16]([S:17]([O-:19])=[O:18])=[C:15]([CH3:21])[O:14][N:13]=1.[Na+:5]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1noc(C)c1S(=O)[O-]
Temperature: 80 °C
Yield: 101.1 %

Procedure:
A solution of sodium sulfite (680 mg, 5.40 mmol) in water (5 mL) was added to an acetone (5 mL) solution of 3,5-dimethylisoxazole-4-sulfonyl chloride (530 mg, 2.70 mmol). The mixture was heated to 80° C., then a solution of sodium carbonate (430 mg, 4.05 mmol) in water (5 ml) was added dropwise. The mixture was refluxed for 16 hours then evaporated to dryness. The residue was refluxed with ethanol (20 mL), the inorganics were removed by filtration. Evaporation of the filtrate afforded 500 mg of crude sodium 3,5-dimethylisoxazole-4-sulfinate. It was used in the next steps without further purification. 1H NMR (400 MHz, DMSO-d6): δ 2.37 (s, 3H) and 2.22 (s, 3H).