Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Reactant: O=C(CCI)CCc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccc(Cl)cc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
To a solution of 48.5 g (0.23 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 400 ml of dry tetrahydrofuran was added 96.0 g (0.23 mole) of 40% Triton B. The solution was stirred at room temperature for 10 min. 70.3 g (0.23 mole) of 5-iodo-1-(4'-chlorophenyl)-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was heated at 50° C. for 3 hr., then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh MgSO4, filtered and concentrated at reduced pressure. The crude concentrate was passed through HPLC to give 65 g of purified material.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CS(C)=O>[CH3:13][C:11]1[N:12]=[C:5]2[C:4]([O:3][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)=[CH:9][CH:8]=[CH:7][N:6]2[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1cn2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn2cccc(OCc3ccc([N+](=O)[O-])cc3)c2n1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.3 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (1.0 g) in dimethyl sulfoxide (10 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 4-nitrobenzyl bromide (1.6 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-methyl-8-(4-nitrobenzyloxy)imidazo[1,2-a]pyridine (0.77 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[N:15]=[C:14](Cl)[C:13]=2[CH2:12][CH2:11]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[N:15]=[C:14]([NH:15][CH2:16][CH2:17][OH:23])[C:13]=2[CH2:12][CH2:11]1
Reactant: COc1ccc(N2CCc3c(Cl)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Solvent: NCCO
Product: COc1ccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Temperature: 190 °C
Yield: 181 %

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(550 mg, 1.3 mmol) was dissolved in ethanolamine(10 ml) in the pressure tube. The reaction mixture was refluxed at 190° C. for 3 hours. After removing the reaction solvent under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 510 mg of desired compound as solid in 91% of yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cccc(F)c1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(2,3-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.15 (1H, d, J=2.6 Hz), 7.96 (2H, d, J=8.4 Hz), 7.62 (1H, d, J=7.4 Hz), 7.44–7.31 (3H, m), 7.14–7.00 (2H, m), 6.85 (1H, d, J=8.7 Hz), 6.81–6.68 (1H, m), 5.33 (1H, dq, J=7.4, 7.1 Hz), 3.90 (3H, s), 1.51 (3H, d, J=7.1 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)(=O)[CH3:2].N>S(=O)(=O)(O)O>[CH3:2][C:1]1[O:13][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][CH:4]=1
Reactant: CC(=O)CNC(=O)c1cccnc1
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1cnc(-c2cccnc2)o1
Temperature: 120 °C

Procedure:
A mixture of 20 g (0.110 mol) of 73 and 100 ml of conc. sulphuric acid was heated to 120° C. for 4 h. After cooling the mixture was poured over ice followed by basification with ammonia. Extraction with 3×400 ml of dichloromethane, drying of the combined organic phases over magnesium sulphate, and removal of the solvent in vacuo gave crude 74 as a red oil, which was sufficiently pure. Yield: 17 g (0.100 mol, 97%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:37]=[CH:36][C:31]([C:32](OC)=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:37]=[CH:36][C:31]([CH2:32][OH:33])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc(CO)cc2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (395 mg), methyl 4-hydroxybenzoate (225 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 90° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained yellow oily substance was dissolved in tetrahydrofuran (30 ml), lithium aluminum hydride (80 mg) was added little by little at 0° C., and stirring was carried out at 0° C. for 1 hour. To the reaction mixture, sodium sulfate decahydrate (1.0 g) was added, and stirring was carried out at room temperature for 30 minutes, after which filtration was carried out. The filtrate was concentrated and the residue was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate, 4-({3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl}oxy)benzyl alcohol (304 mg, yield 72%) was obtained as a colorless oily substance.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][N:7]([CH2:9][C:10]1[N:15]=[C:14]([CH2:16]O)[CH:13]=[CH:12][CH:11]=1)[CH3:8]>Br>[CH3:6][N:7]([CH2:9][C:10]1[N:15]=[C:14]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])[CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: CN(C)Cc1cccc(CO)n1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: CN(C)Cc1cccc(CSCCN)n1
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Cysteamine hydrochloride (3.58 g; 31.5 mmoles) and 6-dimethylaminomethyl-2-hydroxymethylpyridine (5.0 g; 30.1 mmole) [prepared in Step B] were dissolved in 50 ml of 48% hydrobromic acid and the solution heated at reflux temperature for 12 hours and then allowed to stand at ambient temperature for 8 hours. The reaction mixture was evaporated under reduced pressure to half volume, made basic with 40% aqueous NaOH and extracted with several portions of methylene chloride. The combined organic phase was washed with a small amount of water and saturated brine solution then dried and evaporated under reduced pressure to yield 3.14 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][C:27]([OH:30])([CH3:29])[CH3:28])C>>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([C:27]([OH:30])([CH3:29])[CH3:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CC(C)(C)O
Product: CC(C)(O)c1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester employing the procedure described in Example 105.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[F:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+]>C(O)CCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:2][C:3]2[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=2[F:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCCCO
Product: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1

Procedure:
Process 3: After addition of 2-bromomethyl-1,4-difluorobenzene (12.3 ml, 95.5 mmol) to a suspension of sodium 4-chlorobenzenesulfinate (19.0 g, 95.5 mmol) in butanol (200 ml), the mixture was heated under reflux for 5 hours. The solid thus precipitated was collected by filtration and dissolved in methylene chloride. The resulting solution was washed with brine, dried over MgSO4, and concentrated. The solid thus obtained was recrystallized from hexane, whereby the title compound (12.3 g, 43%) was obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2/[CH:22]=[CH:23]/[C:24](Cl)=[O:25])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:20])[CH3:21])[C:9]=2/[CH:22]=[CH:23]/[CH:24]=[O:25])=[CH:6][CH:7]=1
Reactant: CC(C)n1c(/C=C/C(=O)Cl)c(-c2ccc(F)cc2)c2ccccc2c1=O
Solvent: Cc1ccccc1
Product: CC(C)n1c(/C=C/C=O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The (E)-3-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]prop-2-enoyl chloride, prepared as described in section (i), was dissolved in dry toluene (10 ml). The solution was flushed with nitrogen, and then it was treated with tetrakis(triphenylphosphine)palladium(0) (58 mg). The mixture was then treated with tributyltin hydride (0.27 ml), dropwise, during 5 minutes and the resulting mixture was stirred at room temperature for 90 minutes. The solvent was then evaporated off and the residue was subjected to flash chromatography on silica gel, using ethyl acetate as eluent. The product was triturated with petroleum ether (b.p. 60°-80° C.), to give (E)-3-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]prop-2-enal (100 mg) in the form of a yellow solid, m.p. 159°-161° C. [Elemental analysis: C, 75.0; H, 5.44; N, 4.13; F, 5.86%; calculated: C, 75.21; H, 5.41; N, 4.18; F, 5.67%].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])#[CH:2]
Reactant: CN(C)CCCl
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#Cc1cccc(OCCN(C)C)c1
Temperature: 65 °C
Yield: 31.7 %

Procedure:
3-Ethynylphenol (1.18 g, 10 mmol), 2-chloro-N,N-dimethylethanamine (1.44 g, 10 mmol), Cesium carbonate (7.0 g, 21 mmol) was dissolved in dimethyl formamide (20 mL) and the mixture was heated to 65° C. for 1 h. The mixture was cooled to RT and the partitioned between water and dichloromethane. The organic layer was separated, washed with 2N NaOH and then extracted with 1N HCl. The HCl solution was then neutralized with aqueous NaOH and extracted with dichloromethane. The organic layer was dried and concentrated to afford 2-(3-ethynylphenoxy)-N,N-dimethylethanamine (0.6 g) as an oil. LC/MS; (M+H)+=190.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]([OH:12])[CH2:15][CH:14]=[CH2:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[Mg]Br
Reactant: O=CC#Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)prop-2-yn-1-al (6.46 g; 32.4 mmol; 1 eq) in THF was added to a solution of allylmagnesium bromide (48.5 mL; 1M in Et20, 1.5 eq) at 0° C. over 25 minutes. Stirring was continued for an additional 2 h, and the reaction was carefully quenched with water (50 mL) at 0° C. MTBE (100 mL) was added, and the layers were stirred and allowed to separate. The aqueous phase was re-extracted with MTBE (50 mL) and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated using a rotary evaporator, and purification of the residue by flash chromatography (4:1→1:1 heptane/EtOAc) afforded the desired homoallylic alcohol (5.86 g; 24.3 mmol; 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (t, 2 H) 4.63 (t, 1H) 5.21-5.29 (m, 2H) 5.85-5.97 (m, 1H) 7.21 (d, 1H) 7.37 (d, 1H) 7.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:31][CH2:32][CH3:33].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:31][CH2:32][CH3:33]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1c(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-chloro-3-ethoxy 8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-166, 0.14 g, 0.30 mmol) was hydrolyzed with 1 N NaOH to produce the title compound as a yellow solid after recrystallization from acetonitrile.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH3:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(O[Si](C)(C)C(C)(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a 5.0 L round bottom flask containing 4-(tert-butyldimethylsilyloxy)cyclohexanone (7.03 g, 30.8 mmol) (Aldrich) was added THF (100 mL) and the reaction was cooled to −78° C. To the reaction mixture was added lithium bis(trimethylsilyl)amide (33.9 ml, 33.9 mmol) (Aldrich) and the reaction mixture was stirred for 30 minutes followed by the addition of iodomethane (2.309 ml, 36.9 mmol). The reaction mixture was stirred for 30 minutes at −78° C. and 2 hours at room temperature, quenched with saturated NH4Cl, extracted with EtOAc (200 mL), dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified on SiO2 and eluted with 0-20% ethyl acetate/hexane to give a white solid (6.40 g) in 86% yield. 1H NMR (300 MHz, CDCl3) δ ppm 4.19-4.07 (m, 1H), 2.98-2.72 (m, 1H), 2.50-1.99 (m, 2H), 1.91-1.64 (m, 2H), 1.62-1.44 (m, 1H), 1.15 (dt, J=4.4, 6.8, 1H), 1.07-0.99 (m, 3H), 0.95-0.85 (m, 9H), 0.11 (d, J=1.6, 6H). MS (DCI+) M/Z 243.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.CCOC([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[K+]>C(O)C.C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Clc1ccc(CN2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 39.0 g (0.2 moles) of 3,4-dichlorobenzyl chloride, 31.6 g (0.2 moles) of ethyl N-piperazinocarboxylate, 22.0 g (0.21 moles) of anhydrous sodium carbonate and 200 ml of xylene was refluxed for 3 hours using a Dean-Stark trap. Then the mixture was stirred at room temperature for 16 hours, filtered and washed with xylene. The filtrate was evaporated in vacuo to give a syrup. A 750 ml amount of 4N potassium hydroxide in 95% ethanol was added to the syrup and the mixture was refluxed for 18 hours. The reaction mixture was evaporated to a paste and 250 ml of water was added. The solution was extracted twice with 250 ml of chloroform. The extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a syrup. The syrup was distilled, bp 132°-135° C./0.05 mm of mercury and gave 9.3 g of 1-(3,4-dichlorobenzyl)piperazine as a colorless liquid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:11]=[C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:13]3[S:17][C:16]([N:18]4CN(C)C[N:20]([CH2:25][CH3:26])[C:19]4=[O:27])=[N:15][C:14]=3[CH:28]=2)[CH:9]=1)C>Cl>[CH2:25]([NH:20][C:19]([NH:18][C:16]1[S:17][C:13]2[C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:11][C:10]([N:8]3[CH:9]=[C:5]([CH:4]=[O:3])[N:6]=[N:7]3)=[CH:28][C:14]=2[N:15]=1)=[O:27])[CH3:26]
Reactant: CCOC(OCC)c1cn(-c2cc(-c3ccccn3)c3sc(N4CN(C)CN(CC)C4=O)nc3c2)nn1
Agent: Cl
Product: CCNC(=O)Nc1nc2cc(-n3cc(C=O)nn3)cc(-c3ccccn3)c2s1
Temperature: 70 °C
Yield: 112.8 %

Procedure:
Compound iii (250 mg, 0.48 mmol) was suspended in 1M HCl solution (9 mL) and the mixture heated at 70° C. overnight. The mixture was concentrated in vacuo to give iv (213 mg, quantitative). MS: 394.0 [M+H]+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]2[CH:14]=[N:15][S:16][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]2[CH:14]=[N:15][S:16][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (95 mg, 0.21 mmol) in MeOH (4 mL) was added a 1.0M aqueous solution of hydrochloric acid (0.42 mL). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The resultant residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, ethyl acetate in DCM) to afford the title compound as a yellow solid (62 mg, 70%). LCMS (method A): RT=9.51 min, [M+H]+=426/428. 1H NMR (CDCl3, 400 MHz) 9.37 (1 H, s), 8.85 (1 H, s), 8.76 (1 H, s), 7.51 (1 H, d, J=8.40 Hz), 7.43 (1 H, d, J=8.40 Hz), 7.34-7.29 (1 H, m), 7.28 (1 H, d, J=8.75 Hz), 7.02 (1 H, t, J=8.46 Hz), 4.10 (2 H, t, J=4.09 Hz), 3.91 (1 H, s), 3.80 (2 H, s).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].NC(N)=O.[N+:15]([O-])([OH:17])=[O:16].[N+]([O-])=O>C(OC(=O)C)(=O)C>[OH:1][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C#N)c(O)n1
Agent: NC(N)=O
Agent: O=[N+][O-]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(O)c(C#N)cc1[N+](=O)[O-]
Temperature: 2 °C
Reaction time: 3 h

Procedure:
A suspension of 2-hydroxy-6-methylnicotinonitrile (16.5 g) in acetic anhydride (60 mL) was stirred and cooled in an ice-salt bath. Separately, acetic anhydride (16 mL) containing a crystal of urea (21 mg) was cooled in an ice-salt bath to 2° C. To the latter mixture was added fuming nitric acid (8.6 mL). The mixture evolved nitrogen dioxide gas and became hot. Cooling in the bath was continued until the temperature reached 8° C. This solution was then added to the nitrile suspension, which was at −2° C. The temperature rose to 0° C., and the cooling bath was removed. The temperature rose slowly as the mixture was stirred, and the rate of temperature rise increased as the temperature rose. When the temperature reached 35° C., the flask was cooled in the bath until the temperature fell to 25° C. The bath was again removed. The temperature rose more slowly this time, and reached a maximum of 34° C. The reaction was allowed to cool on its own, and did not reach ambient temperature for about 3 hours. The resulting mixture was allowed to stir at ambient temperature overnight. The mixture was poured into a beaker containing crushed ice (300 g). The mixture was stirred until the ice melted, and the resulting precipitate was collected by filtration, washed with ice water, and air-dried to give about 13 g of light yellow solid. This material was recrystallized from boiling glacial acetic acid (130 mL). The resulting mixture was allowed to cool to ambient temperature and stirred overnight. The precipitate was collected by filtration, washed with a small amount of glacial acetic acid, and dried under vacuum to provide the title compound (8.2 g) with the following physical data.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[N:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:17]2[N:16]=[C:15]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH2:12][CH2:11]3)[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=2)=[CH:27][CH:28]=1
Reactant: Cc1nnc(N2CCC(N)CC2)o1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)o1

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-ylamine (50 mg, 0.27 mmol), 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (81.5 mg, 0.27 mmol)) and N,N-diisopropylethylamine (71 L, 0.41 mmol) in dioxane (2.8 mL) was heated at 160° C. in a microwave oven for 6 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless foam (31 mg, 26%).