Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=O)C.Cl.C([O-])(O)=O.[Na+]>CO.O>[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([S:16]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])(=[O:18])=[O:17])=[CH:14][CH:13]=1
Reactant: NCCOCCO
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H) 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8ethoxymethylene-6,8-dihydro-I-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (brt, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H,4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:19](=[O:23])[C:20]([OH:22])=[O:21])[N:13]([CH3:18])[C:14]=2[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:25](O)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:19](=[O:23])[C:20]([O:22][CH2:25][CH3:26])=[O:21])[N:13]([CH3:18])[C:14]=2[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cn1c(C(=O)C(=O)O)cc(CSc2cccc(Cl)c2)c1C(=O)O
Agent: Cl
Product: CCOC(=O)C(=O)c1cc(CSc2cccc(Cl)c2)c(C(=O)O)n1C

Procedure:
4-(m-Chlorophenylthio)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetic acid (1.0 g, 2.82 mmol) is dissolved in hot ethanol (7 ml) and concentrated HCl (150 μl) is added. The reaction is heated to reflux for 30 minutes, then the mixture is cooled, the solvent is removed in vacuo to give a red oill whih solidifies on standing. The solid is recrystallized from cyclohexane:chloroform to give 395 mg purple solid, i.e. ethyl 4-(m-chlorophenylthio)methyl-5-hydroxycarbonyl-1-methyl-α-oxo-pyrrole-2-acetate (36%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[CH:7]=1)[CH3:2].IC.[CH3:42][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:39])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@@H:30]([CH3:31])[C@@H:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:38])[CH:7]=1)[CH3:42])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To {4-methoxy-3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid ethyl ester (0.242 g, 0.45 mmol) and iodomethane (0.03 mL, 0.45 mmol) in THF (5 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1M in THF; 0.45 mL, 0.45 mmol). The reaction was stirred at −78° C. for 1 hour, and then at room temperature for 1 hour. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.C=O.[C:31]([BH3-])#N.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:31][NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: [BH3-]C#N
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a 5 mL round bottom flask were added commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (100 mg, 0.26 mmol), formaldehyde (0.12 g of 37% H2O solution, 1.6 mmol), dimethylformamide (2 mL) and glacial acetic acid (1 drop). The reaction mixture was stirred at room temperature for 1 h, after which time sodium cyanoborohydride (1M THF solution (Aldrich), 2 mL, 2 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1 h. Formation of product was confirmed by LC/MS and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 25 mg (25%) of the title compound. 1H-NMR (400 MHz, d6-DMSO): δ 11.78 (s, 1H), 8.62 (s, 1H), 8.04 (d, 1H), 7.61 (d, 1H), 7.49 (t, 1H), 7.30 (d, 1H), 7.19 (d, 1H), 7.10 (m, 2H), 6.23 (q, 1H), 3.85 (d, 2H), 2.86 (d, 3H), 2.01 (m, 1H), 0.93 (d, 6H). MS (EI) for C22H23N5O2: 390 (MH+).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8](Cl)=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.[CH3:24][O-:25].[Na+].C1(C)C=CC=CC=1>C(Cl)Cl>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:25][CH3:24])=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1cc2ccccc2s1

Procedure:
A heterogeneous mixture of 3-(benzo[b]thiophen-2-ylmethyl)-6-bromo-2,4-dichloroquinoline (7.5 g, 17.73 mmol, Intermediate 51: step a), sodium methoxide (4.79 g, 88.62 mmol), and toluene (25 mL) was heated at 110° C. in a sealed tube for 6 hours. The resulting black tar was diluted with DCM, then filtered through Celite®, rinsing with dichloromethane. The filtrate was concentrated and the crude product purified by chromatography (heptanes/DCM, gradient) to provide the title compound as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][CH:7]=[CH:6][N:5]2[C:20]=1[CH3:21].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:20]([CH3:21])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[CH:7][C:8]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Solvent: CC(=O)O
Product: Cc1cccc(C)c1CNc1c([N+](=O)[O-])ccn2c(C)c(C)nc12
Temperature: 82.5 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine (2.0 g, 7.16 mmol) was dissolved in acetic acid (30 ml) and nitric acid (0.53 g, 7.57 mmol) was added. The mixture was heated to 80-85° C. and stirred for 3 h at this temperature. After evaporation of the major part of the acetic acid, the residue was partitioned between methylene chloride and water. The organic layer was washed with a solution of sodium carbonate and the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and filtered through silica gel (10 g) whereupon the methylene chloride was removed under reduced pressure. Chromatography with methylene chloride (100%) gave 0.4 g (17%) of the title compound.
Reaction SMILES: [H-].[Na+].C(S)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:26]=[C:27]([Cl:31])[C:28]=1[O:29]C)[C:10]([N:13]1[CH2:17][C:16]([CH3:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:25])([CH3:12])[CH3:11].Cl>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:26]=[C:27]([Cl:31])[C:28]=1[OH:29])[C:10]([N:13]1[CH2:17][C:16]([CH3:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:25])([CH3:12])[CH3:11]
Reactant: COc1c(Cl)cc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)c(O)c(Cl)c2)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A DMF suspension of 2.2 g (0.05 mol) of sodium hydride (about 60% in oil) was cooled with ice water, and 5.1 g (0.05 mol) of ethyl mercaptan was dropwise added thereto at a temperature not higher than 10° C. under stirring. The reaction mixture was returned to room temperature and left to stand for about 30 minutes. Then, a DMF solution of 15.7 g (0.04 mol) of 1-(3,5-dichloro-4-methoxy-α,α-dimethylbenzyl)-4-methyl-3-phenyl-3-pyrrolin-2-one (Compound No. 143) prepared in Example 2, was added thereto. The solution was heated at about 80° C. and reacted for three hours. After completion of the reaction, the reaction solution was poured into a large amount of ice water, acidified with a 10% hydrochloric acid aqueous solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The solid thereby obtained was washed with isopropyl ether to obtain 11.0 g (yield: 73.3%) of the desired compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH2:19]([O:27][C:28](Cl)=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:28]([O:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[N+:7]([O-:8])=[C:6]([NH:9][C:28]([O:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCCCCCCCC)[n+]1[O-]
Temperature: 5 °C

Procedure:
10 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are suspended in 150 ml. of methylene chloride and 20 ml. of triethylamine. The suspension is cooled to 5° C. and 28 g. of chloroformic acid octyl ester are added dropwise while stirring. The mixture is cooled for 30 minutes and then stirred at room temperature for 1 hour. The mixture is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride/ethanol, there being obtained dioctyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 64° C.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:45].[Ca+2].[OH-:47]>C(Cl)Cl>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[O:18])=[CH:15][CH:14]=2)(=[O:47])=[O:45])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Example 1 (400 mg, 0.845 mmoles) was taken up in methylene chloride (30 ml) to which was added m-chloroperbenzoic acid (343 mg, 2 eqts). The reaction mixture was stirred at room temperature under nitrogen for one hour. An additional 20 mg of m-CPBA was added and stirring was continued for one hour. Calcium hydroxide (400 mg) was added to the reaction mixture and stirring was continued for ten minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with ether to afford the title compound, m.p. 138°-140°.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1.[Cl-].[CH3:19][O:20]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:19]([C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1)=[O:20]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(COc2cccc(F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Yield: 78.7 %

Procedure:
13.8 g of 1-((4-oxocyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 23.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 7.7 g of potassium-t-butoxide was added dropwise at an internal temperature of 10 to 25° C., and the solution was stirred for 30 nm. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 mL of THF, and 100 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 3 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline, saturated sodium hydrogencarbonate, and saturated saline in this order, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. To the residue, 30 mL of methanol and 20% sodium hydroxide aqueous solution were added, and the solution was stirred with ice-cooling for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 11.5 g of 1-((trans-4-formylcyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][OH:15].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCC(N)CO
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCC(CO)Nc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-aminobutan-1-ol according to general procedure 1 providing the amino compound (70 mg, 18%) as yellow solid: Rf=0.53 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J=9.5 Hz, 1H), 7.48 (s, 1H), 6.45 (d, J=9.5 Hz, 1H), 4.51 (d, J=6.3 Hz, 1H), 3.97-3.90 (m, 2H), 3.75-3.72 (m, 1H), 2.65 (br, 1H), 1.76-1.64 (m, 2H), 1.04 (t, 3H); ES-MS: (M+H)=285, 287 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:19])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][C:20](=[O:22])[CH3:21])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCC(N)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC(Cn1cncn1)(NC(C)=O)c1ccc(Cl)cc1
Yield: 32 %

Procedure:
To a stirred, cooled (0° C.) solution of 0.54 g (1.94 mmols) of [2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexylamine and 0.02 g (0.15 mmols) of N,N-dimethylaminopyridine in 10 mL of methylene chloride under nitrogen was added dropwise 0.50 mL (5.28 mmols) of acetic anhydride. After 5 days the reaction was quenched with the addition of methanol and the solvents were removed to give a white solid. The solid was dissolved in toluene which was removed under reduced pressure to remove any acetic acid. The resultant solid was recrystaltized from chloroform to give 0.2 g (32%) of white crystals, melting point 178.5°-179° C. 1H-NMR 200 MHz (CDCl3, Me4Si) 0.85 (t, J=7.5 Hz, CH2 -CH3), 1.0-1.4 (m, 4H), 1.8-2.2 (m, 2H), 2.05 (s, COCH3), 4.85 (ABq, J=35.3 Hz, JAB =12.5 Hz, CH2 -N), 5.95 (s, NH), 7.05-7.4 (q, aromatic H), 7.8 (s, CH=N), 7.95 ppm (s, CH=N).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.I[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CN1CCCN(C)C1=O.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH2:21][CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CI
Reactant: CC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -60 °C
Yield: 53.8 %

Procedure:
To a suspension of the ketone (10.0 g, 32.6 mmol) of Step 1 and the iodide (2.7 g, 47.7 mmol) of Step 2 in THF was added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The ketone was dissolved by heating and the resulting solution was cooled to -60° C. A solution of 0.35M lithium diisopropylamide (89.7 mL, 30.9 mmol) was then added dropwise. After the addition was completed, the dry ice bath was removed and the reaction was allowed to warm to +10° C. The reaction was quenched by the addition of 25% aq. NH4OAc and the desired product was extracted with EtOAc, dried over Na2SO4 and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (toluene to 5% EtOAc in toluene) to yield 8 g (55%) of the title product.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:27])([F:26])[C:16]([NH:18][C@@H:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17]>>[CH:8]1([CH2:7][N:6]2[C:2]([N:22]3[CH2:23][CH2:24][CH2:25][C@@H:19]([NH:18][C:16](=[O:17])[C:15]([F:26])([F:14])[F:27])[CH2:20][CH2:21]3)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(CC2CC2)c1Cl
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1)C(F)(F)F
Yield: 55 %

Procedure:
Following the procedure for Intermediate 28 starting with 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.98 g, 55%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 6.42-6.39 (m, 1H), 4.22-4.14 (m, 1H), 4.00-3.85 (m, 2H), 3.44-3.32 (m, 1H), 3.30-3.15 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.30-1.20 (m, 1H), 0.70-0.62 (m, 2H), 0.50-0.35 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C1N=[CH:36][N:35](C(N2C=NC=C2)=O)[CH:34]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:35]([CH3:36])[CH3:34])=[O:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.8 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.1 g, 0.22 mmol), CDI (0.05 g, 0.33 mmol) and dimethylamine (0.33 ml, 0.66 mmol) in THF (10 ml) to give as 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide white solid (0.05 g, 50% yield): mp 141-143° C.; 1HNMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CH2), 3.10 (s, 3H, NCH3), 3.60 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 4.33 (d, J=18 Hz, 1H, CH2N), 4.44 (d, J=18 Hz, 1H, CH2N), 5.59 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.04 (m, 4H, Ar), 7.45 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.5, 24.8, 35.5, 35.9, 37.2, 49.0, 53.8, 64.7, 111.9, 113.4, 113.5, 116.0, 116.8, 117.5, 117.8, 119.1, 119.1, 120.1, 122.6, 133.0, 137.7, 138.2, 139.7, 138.2, 139.6, 139.7, 141.5, 150.6, 168.9, 169.2, 169.5; Anal. Calcd. for C24H27F2N3O5: C, 60.62; H, 5.72; N, 8.84. Found: C, 59.90; H, 5.46; N, 8.66.