Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26]>CS(C)=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: COc1ccc2nc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(OCCCCl)cc3)n(C)c(=O)c2c1
Temperature: 25 °C

Procedure:
2.8 gm (10 mmols) of 2-(4-hydroxy-phenyl)-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 20 ml of dimethylsulfoxide, and the solution was mixed, while stirring, with 1.35 gm (10 mmols+20%) of potassium tert. butylate. Subsequently, 2.8 ml of 1-bromo-3-chloropropane were added, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then poured into ice water, the aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were evaporated in vacuo after drying over sodium sulfate. The resulting oil, which solidified into crystals, was recrystallized from acetone/ether.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].[CH3:9][NH:10][NH2:11]>C1(C)C=CC=CC=1>[CH3:9][NH:10][N:11]=[C:6]([CH3:7])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: CNN
Solvent: Cc1ccccc1
Product: CNN=C(C)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
To a 100 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (4.99 g) and toluene (36.0 g) were added under a nitrogen atmosphere, and added dropwise 40 wt % of aqueous monomethylhydrazine solution (14-a) (3.96 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, and then added additional 40 wt % of aqueous monomethylhydrazine solution (0.35 g). The resulting mixture was stirred for 24 hours, and refluxed with Dean-Stark apparatus under reduced pressure at the internal temperature of 50° C. After refluxing, the resulting mixture was cooled to 0° C., and filtered to give 3.56 g of 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#N)=[CH:7][CH:8]=2)[NH:3]1.C(O)=[O:15]>[Ni]>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]=[O:15])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)NC(=O)CC2
Agent: [Ni]
Product: O=Cc1ccc2c(c1)NC(=O)CC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a formic acid (250 mL) solution of the compound (32.6 g) obtained in Step 1-3, Raney nickel catalyst (50.0 g) was added and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was filtrated by Celite, the filtrate was concentrated under reduced pressure. To the residue, a saturated aqueous NaHCO3 solution was added and the mixture was adjusted to pH 6 and filtrated to obtain solid A. The filtrate was extracted three times with CHCl3 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue and solid A were combined and suspended in a solution mixture of EtOAc/CHCl3/acetone (10/10/1; v/v/v) and the mixture was stirred at room temperature for one hour and filtrated to obtain 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (19.8 g, a light yellow solid).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:7]=[C:2]([O:22][C:15]2[CH:14]=[CH:13][C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2)[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=NS(=O)(=O)N(C)C(Oc2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-chloro-5-methoxy-2-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide (48 g) in methylene chloride (25.5 ml) is added dropwise to a stirred mixture of p-nitrophenol (38 g) and triethylamine (55 g) in methylene chloride (1 l). The mixture is stirred at RT for about 12 hours, refluxed for about 31/2 hours, concentrated in vacuo, the residue is treated with sat'd aq. Na2CO3 solution, and the resulting insoluble solid filtered and washed with water and CH2Cl2. The solid is recrystallized from ethyl acetate/acetonitrile yielding the p-nitrophenoxy compound as a crystalline solid, M.P.=220°-221° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[C:30]([F:36])[C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20]([O:37][CH3:38])[N:19]=1>CN1C(=O)CCC1>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[C:34]2[C:29]=1[CH2:28][CH2:27][N:26]2[C:24]([C:22]1[CH:21]=[C:20]([O:37][CH3:38])[N:19]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:23]=1)=[O:25]
Reactant: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(Cl)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
0.98 g (4.5 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.50 g (1.5 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone were stirred in 3 mL NMP for 12 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH2:28])[CH3:27])=[C:16]([F:29])[CH:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH:28][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:11])=[O:10])[CH3:27])=[C:16]([F:29])[CH:15]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c1
Yield: 103.3 %

Procedure:
3-Methoxybenzenesulfonyl chloride (331 mg, 1.6 mmol) was added to a solution of 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol) and triethylamine (246 μL, 1.7 mmol) in acetonitrile. The reaction was mixed at room temperature for 24 hours, afterwhich the acetonitrile was removed in vacuo. The remaining solid was dissolved in dichloromethane and purified by preparative liquid chromatogrpahy on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-50% methyl tert-butyl ether in hexane (35 min), to afford the the desired product (694 mg, 99%) as a white solid;
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=2)[C:8]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=2)[CH:6]=1)C.[OH-].[K+]>CO.Cl.O>[CH:17]([C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=3)[C:8]=2[O:19][CH2:20][O:21][CH3:22])[C:4]([OH:31])=[O:3])[CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: CCOC(=O)c1cc(-c2cccc(C=O)c2)c(OCOC)c(-c2cccc(C=O)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCOc1c(-c2cccc(C=O)c2)cc(C(=O)O)cc1-c1cccc(C=O)c1
Yield: 78.5 %

Procedure:
To a solution of 3,5-bis-(3-formylphenyl)-4-methoxymethoxybenzoic acid ethyl ester (960 mg, 2.12 mmol) in 3 mL MeOH was added 3 mL H2O and solid KOH (179 mg, 3.18 mmol). The reaction was refluxed for 5 to 6 hours then the cooled reaction mixture was diluted with 2N HCl and water. The aqueous solution was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. The solvent was removed in vacuo to give an oil that was flash chromatographed (10% MeOH:90% EtOAc) on silica gel. There yielded 650 mg of the desired acid along with some of the methyl ester of the desired acid. The methyl ester was resubjected to reaction conditions to give more of the desired acid for a total yield of 690 mg, 76.6%. 1H NMR (CDCl3) δ 2.63 (s, 3H); 4.19 (s, 2H); 7.65 (t, J=7.36 Hz, 2H); 7.87-7.95 (m, 4H); 8.06-8.26 (m, 4H); 10.10 (s, 2H).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 0.0182 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 0.0200 mol), K2CO3 (3.0 g, 0.0218 mol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and-water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=114°-116° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH2:16])[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH:16][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC(N)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Nc1ccc(C#N)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 610 mg (1.8 mmol) 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethylamine, 1.18 g (2.8 mmol) 2-bromo-5-cyano-pyridine and 0.838 g (2.8 mmol) DIPEA in 3.5 mL DMF was heated to 60° C. for 3 days. The mixture was evaporated, Na2CO3aq. was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from DCM, methanol and NH3aq. to yield after evaporation of the product containing fractions 0.526 g (66%) of the title compound as off-white foam. MS (m/e): 431.4 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[S:36][C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[S:36][C:32]([CH3:31])=[CH:33][N:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)s1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.093 g, 0.6 mmol, 1.2 eq), EDCI.HCl (0.103 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.5 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the mixture was stirred at room temperature for 18 h. The mixture was then added with water, and the organic layer was separated and washed with water, and the product was purified by preparative TLC. Yield: 25 mg (15%). 1HNMR (400 MHz, DMSO-d6): δ1.34-1.37 (m, 2H), 1.50-1.53 (m, 2H), 2.31 (s, 3H), 2.35 (s, 3H), 2.83-2.84 (d, J=4.8 Hz, 3H), 7.27 (d, J=1.2 Hz, 1H), 7.39-7.47 (m, 4H), 7.60 (d, J=1.6 Hz, 1H), 7.76-7.78 (d, J=8.4 Hz 1H), 7.83-7.85 (m, 2H), 8.02 (m, 2H), 8.45 (m, 1H), 9.51 (s, 1H) LCMS: (ES+) m/z=540 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][S:15][C:11]=3[CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][S:15][C:11]=3[CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3ncsc3c2)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3ncsc3c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide (2 mmol; prepared as in Example 141) in dioxane (5 mL) was charged with piperazine (10 mmol). The contents were heated at reflux for 10 h and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-benzothiazol-6-yl-5-nitro-2-piperazin-1-yl-benzamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]([OH:6])[C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)c2cccc(Cl)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of (R)-tert-butyl 2-(3-chlorobenzoyl)morpholine-4-carboxylate (5.5 g, 16.9 mmol) in MeOH (50 mL), NaBH4 (5.14 g, 135 mmol) was added in portions. The mixture was stirred overnight and water (50 mL) was added, The mixture was concentrated in vacuo until MeOH was removed. The aqueous residue was extracted with EtOAc. The organic extracts were washed with brine and dried over Na2SO4. The crude product was purified by chromatography to afford (R)-tert-butyl 2-((S)-(3-chlorophenyl)(hydroxy)methyl)morpholine-4-carboxylate (4.3 g, 78%)
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[N+:16]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1O)([O-:18])=[O:17].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
Triflic anhydride (4.14 mL, 24.6 mmol) was added dropwise to a solution of 2-nitro-4-tert-butyl phenol (4.00 g, 20.5 mmol) and pyridine (2.16 mL, 26.7 mmol) in CH2Cl2 (50 mL) at 0° C. The yellow solution was stirred 0.25 h at 0° C., poured onto saturated NaHCO3 and extracted with CH2Cl2. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. The residue was purified by filtration through a plug of silica-gel (methylene chloride) to provide trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (5.82 g, 87%) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([OH:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1>>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 2-bromoacetate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, CDCl3): δ 8.61 (s, 2H), 7.43 (d, 1H), 6.98 (d, 1H), 6.60 (s, 1H), 5.12 (s, 1H), 4.84 (s, 2H), 4.28 (q, 2H), 3.99 (s, 3H), 1.31 (t, 3H); MS (ESI): 438.9.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([O:17][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(OC2CCCCO2)cc(Br)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 2-bromo-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (4.52 g, 15.0 mmol) in THF (50 mL) was added potassium carbonate (2.07 g, 15.0 mmol), followed by iodomethane (4.23 g, 30.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by saturated NaHCO3 aqueous solution (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid. (4.53 g, Yield: 95.8%). 1H NMR (400 MHz, DMSO-d) δ0.19 (s, 1H), 6.98-6.98 (d, J=2.0 Hz, 1H), 6.81-6.82 (d, J=2.0 Hz, 1H), 6.73-6.74 (m, 1H), 3.88 (s, 3H), 3.60-3.75 (m, 2H), 1.75-1.89 (m, 3H), 1.53-1.67 (m, 3H). MS (ESI) m/z=315 [M+H]+.
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[Cl:10][C:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[NH:13][C:12]=1[C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]([NH2:36])=[N:34][OH:35])[CH:30]=[C:29]([Cl:37])[N:28]=2)[CH2:23][CH2:22]1)=[O:19]>C(OC(OCC)(OCC)C)C>[Cl:10][C:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[NH:13][C:12]=1[C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]3[N:36]=[CH:5][O:35][N:34]=3)[CH:30]=[C:29]([Cl:37])[N:28]=2)[CH2:23][CH2:22]1)=[O:19]
Reactant: CCOCC
Reactant: Cc1[nH]c(C(=O)OC2CCN(c3cc(C(N)=NO)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: CCOC(C)(OCC)OCC
Agent: FB(F)F
Product: Cc1[nH]c(C(=O)OC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BF3.Et2O (0.1 ml) was added to a solution of 1-{4-[amino(hydroxyimino)methyl]-6-chloropyridin-2-yl}piperidin-4-yl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (Example 114) (0.07 g, 0.15 mmol) in 1,1,1-triethoxyethane (1.0 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) mixtures to give the title compound (21 mg).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([I:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In nitrogen-purged flask is added 5.1 g (0.023 moles) of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine in 50 ml dry acetonitrile. Cool to 0° C. and add 5.54 g (0.025 moles) of NIS dissolved in 90 ml dry acetonitrile. Allow bath to come to room temperature and the reaction to stir overnight. Evaporate solvents, take up in ethyl acetate and wash two times with 50% aqueous solution of sodium sulfate then brine. Dry over sodium sulfate, filter and evaporate to a residue. Triturate in small amount of acetonitrile and filter solid. Repeat several times to obtain the title compound as light tan solid weighing 7.29 g (0.021 moles, 91.3%). 1H-NMR (DMSO-d6): δ 6.96 (s, 1H); 3.0-3.3 (m, 1H); 2.51 (s, 3H); 2.35 (s, 3H); 1.71-1.80 (m, 4H); 0.71 (t, J=7.48 hz, 6H) ppm. MS/ES+=344 (100%, M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][C:25]=2[F:39])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:25]([F:39])=[CH:26][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][C:29]=2[F:30])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)c(F)c1
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of (E)-ethyl 3-(4-(4-(N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (169 mg, 0.28 mmol) in THF (6 ml) and water (0.6 mL) under nitrogen was added trimethylphosphine (26 mg, 0.34 mmol). After stirring for 3 hours, the solvents were removed at reduced pressure and. The residue was dissolved in water (5 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated to give the title compound (162 mg).
Reaction SMILES: [CH3:1][SH:2].[Cl:3][C:4]1[C:5]([N:16]([CH2:21][CH3:22])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:6]([CH:12]=[CH:13][C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:3][C:4]1[C:5]([N:16]([CH2:21][CH3:22])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:6]([CH:12]=[CH:13][C:14]=1[S:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(F)c(Cl)c1N(CC)S(C)(=O)=O
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(SC)c(Cl)c1N(CC)S(C)(=O)=O
Temperature: -10 °C

Procedure:
A solution of methanethiol (4 ml) in dry DMF was added to a mixture of ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoate (7.4 g) and anhydrous potassium carbonate (4.71 g) in DMF at 40° C. The mixture was maintained at −10° C. for 1 hour, then warmed to ambient temperature over 2.5 hours. Water was added and the mixture extracted with ether, washed with brine solution then water, dried (anhydrous magnesium sulphate) and the solvent evaporated to give ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)benzoate (8.3 g) as a white powder, m.p. 109-110.5° C.