Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[C:32](Cl)(=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:12]1[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=[C:8]([NH:7][C:32](=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=1
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Pyridine (0.014 mol) was added to a mixture of 4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile (0.0013 mol) in CH2Cl2. A solution of octanoyl chloride (1.5 equiv) in CH2Cl2 (0.5 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. More octanoyl chloride (3.5 equiv) in CH2Cl2 was added dropwise. The mixture was stirred. The solvent was then evaporated. The residue was treated with a saturated aqueous NaHCO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated to give the crude product. The residue was recrystallized from CHCl3 and hexane, yielding 0.443 g (68.6%) of N-[6-[(2,6-dichloro-phenyl)-methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]octanamide (mp. 135–137° C.).
Reaction SMILES: C([CH:3]([C:28]([OH:30])=[O:29])[N:4]([CH2:15][P:16]([S:23][CH2:24][CH2:25][CH2:26][CH3:27])([S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[C:32](O)(=O)C>>[CH2:5]([N:4]([CH2:15][P:16]([S:23][CH2:24][CH2:25][CH2:26][CH3:27])([S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[S:17])[CH2:3][C:28]([OH:30])=[O:29])[CH3:32]
Reactant: CC(=O)O
Reactant: CCCCSP(=S)(CN(C(=O)OCc1ccccc1)C(CC)C(=O)O)SCCCC
Agent: Br
Product: CCCCSP(=S)(CN(CC)CC(=O)O)SCCCC

Procedure:
Ethyl-N-[bis(n-butylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (3.1 g.) was dissolved in 15 ml. of 35% hydrobromic acid in acetic acid and stirred for two hours. The solvent was then removed under reduced pressure and the residue triturated four times with diethyl ether. The residue was then dissolved in benzene, treated with excess propylene oxide and concentrated to a viscous oil. The viscous oil was chromatographed on silica gel employing dichloromethane to yield ethyl-N-[bis(n-butylthio)phosphinothioylmethyl]glycine as an oil, ND25 =1.4835.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[NH:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:27][C:23]1[NH:22][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH3:21]
Reactant: O=Cc1ccc[nH]1
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc[nH]1
Temperature: 0 °C
Reaction time: 17 h
Yield: 54.6 %

Procedure:
0.492 g (1.71 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 9.8 ml of ethanol, and 0.325 g (3.42 mmol, 2.0 equivalents) of pyrrole-2-aldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.870 g (4.11 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 17 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=1:1), thereby obtaining 0.342 g of 4-{[(4-dipropylaminobutyl)-(1H-pyrrol-2-ylmethyl)amino]methyl}benzonitrile (18) as a light yellow oily substance (yield: 54.5%). [HPLC: 87.6% (HPLC measurement conditions B)]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:36]([O:37][CH3:38])=[CH:35][C:26]2[N:27]([CH2:33][CH3:34])[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=2[CH:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[C:36]([O:37][CH3:38])=[CH:35][C:26]3[N:27]([CH2:33][CH3:34])[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(C)S(C)(=O)=O)n3)c(OC)cc21
Yield: 26.4 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (79 mg, 0.22 mmol), 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (52 mg, 0.22 mmol), and 10-Camphorsulfonic acid (80 mg, 0.34 mmol) in Isopropyl alcohol (3 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. Chromatography (ISCO, 2×12 g silica gel, 0-85% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as a white foam (32 mg, 26%). LCMS: 551 (M+H), 1H-NMR (CDCl3): 8.20 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H), 6.70 (s, 1H), 5.61 (d, 1H, J=7.9 Hz), 4.11 (m, 2H), 3.90 (s, 3H), 3.78 (m, 1H), 2.84 (s, 3H), 2.75 (s, 3H), 2.59 (br s, 1H), 2.41 (m, 1H), 2.28 (m, 2H), 2.19 (br s, 1H), 1.90 (m, 3H), 1.71 (m, 1H), 1.2-1.5 (m, 6H), 1.14 (t, 3H, J=7.0 Hz).
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[CH:21]3OC)=[O:15])=[CH:11][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:21]3)=[O:15])=[CH:11][CH:10]=1
Reactant: COC1c2cccc(NC(=O)c3ccc(Cl)s3)c2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2)c1ccc(Cl)s1
Reaction time: 8 h

Procedure:
0.23 ml (1.4 mmol) of triethylsilane is added to a solution of 378 mg (0.704 mmol) of tert-butyl 4-[2-(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1-methoxy-3-oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl]-1-piperidine carboxylate in 12 ml of dichloromethane and 0.65 ml of trifluoroacetic acid. The mixture is stirred overnight, concentrated and taken up in dichloromethane. The solution is washed with 1N sodium hydroxide solution, dried and concentrated. The residue is crystallized using diethyl ether. The resulting solid is purified further by chromatography on silica gel (gradient from dichloromethane/methanol 95:5 to dichloromethane/methanol/triethylamine 9:1:0.1). Yield: 144 mg (50.5% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1)[CH:6]=[CH:5]2.[CH3:19][CH:20]([CH3:47])[CH:21]([C:23]1[N:24]=[CH:25][N:26](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)[OH:22]>>[CH3:17][C:15]1([CH3:18])[CH2:14][O:13][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:21]([C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)([OH:22])[CH:20]([CH3:47])[CH3:19])[CH:11]=[CH:10]3)=[N:16]1
Reactant: CC1(C)COC(c2ccc3cc(Br)ccc3c2)=N1
Reactant: CC(C)C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(C3=NC(C)(C)CO3)ccc2c1)c1c[nH]cn1
Yield: 157.5 %

Procedure:
2-(6-Bromo-2-naphthyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (1.0 g) and 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (835 mg) were used as the starting materials. By the same procedure described in Reference example 1, the titled compound (1.25 g) was obtained as a colorless amorphous powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[S:16])[CH3:13]
Reactant: CCN=C=S
Reactant: NCCNCc1cnccn1
Product: CCNC(=S)NCCNCc1cnccn1

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3 and chromatographing gives N-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3 gives N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]-guanidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1.[CH:17]([O-])=[O:18].[Na+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:14][C:13]=2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=2)[CH3:16]
Reactant: CCn1c2c(c3cc(Br)ccc31)CCCC2
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(C=O)ccc31)CCCC2
Temperature: 110 °C
Yield: 91.4 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 3-bromo-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole (2 g, 7.22 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), sodium formate (740 mg, 10.88 mmol, 1.50 equiv), Pd(PPh3)2Cl2 (500 mg, 0.72 mmol, 0.10 equiv) and CO (500 mL). The resulting solution was heated to 110° C. in an oil bath for 3 hours. The reaction progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the resulting solution was diluted with ethyl acetate (200 mL) and then quenched by the addition of brine (200 mL). The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbaldehyde as pale yellow solid (1.5 g, 70%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccccc3OC)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [1-(2-methoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6](=[O:28])[NH:5]1)([CH3:3])[CH3:2].CC([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41]C(C)=O)[C@@H:36]([O:45]C(C)=O)[C@@H:35]1[O:49]C(C)=O)=O.[OH-].[Na+]>ClCCl>[C@@H:38]1([O:28][C:6]2[C:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])=[C:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)[O:39][C@H:34]([CH2:33][OH:32])[C@@H:35]([OH:49])[C@H:36]([OH:45])[C@H:37]1[OH:41]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(=O)[nH]n2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a suspension of 1-isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one (0.090 g), acetobromo-α-D-glucose (0.48 g) and benzyl-(n-tributyl)ammonium chloride (0.037 g) in dichloromethane (2 mL) was added sodium hydroxide (5 mol/L, 0.47 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 1-isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethylphenyl)-methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.45 mL) was added to the solution. The mixture was stirred at room temperature overnight. The solvent of the reaction mixture was removed, and methanol (0.5 mL) and 10% citric acid aqueous solution (5 mL) were added to the residue. The mixture was purified by solid phase extraction on ODS (washing solvent: water, eluent: methanol). Further purification by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18 UG80, 5 μM, 20×50 mm, flow rate 30 mL/min linear gradient, water/methanol=90/10-10/90) gave the title compound (0.065 g).
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@@H:20]([S:41][CH2:42][CH2:43][CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([CH2:39][CH3:40])[C:30]([O:32]CC[Si](C)(C)C)=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>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@@H:20]([S:41][CH2:42][CH2:43][CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([CH2:39][CH3:40])[C:30]([OH:32])=[O:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)OCC[Si](C)(C)C)c1ccccc1CC[C@H](SCCCC(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)O)c1ccccc1CC[C@H](SCCCC(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a solution of the ester of Step 8 (4.25 g, 60 mmol) in THF (43 mL) at r.t. was added the 1M nBu4NF solution (18 mL, 180 mmol). The solution was stirred at 50° C. for 1 h, and was then concentrated under vacuum to give a brown residue which was purified directly by flash chromatography. Elution was effected with 1:10 EtOAc:toluene containing 1% HOAc, followed by 1:5 EtOAc:toluene containing 1% HOAc to give the title compound as a yellow foam (3.6 g).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=O.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:3](=[O:5])[C:2]([CH3:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:6])[N+:20]([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)NCCO[N+](=O)[O-]
Yield: 19.6 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.91 g of 2-methyl-2-(4-chlorophenoxy)propionic acid and 0.60 g of nitroxyethylamine nitrate, 0.21 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[C:7]([CH2:9]Br)[CH:6]=[CH:5][C:4]=1[F:11].II.C[O:15][C:16]([C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O>C(OCC)C.O1CCCC1>[Br:2][C:3]1[CH:8]=[C:7]([CH2:9][C:16]([C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:15])[CH:6]=[CH:5][C:4]=1[F:11]
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: Fc1ccc(CBr)cc1Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1C(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of magnesium turnings (880 mg, 37 mmol) and 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.0 g, 3.7 mmol) in anhydrous diethyl ether (15 ml) was treated with a piece of iodine. The mixture was then heated to gentle reflux until the color of the mixture disappeared, after which the heating continued for additional hour. The suspension was cooled to room temperature, and cannulated into a solution of dimethylpyridine-2,3-dicarboxylate (1.0 g, 5.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction mixture was maintained at the same temperature for 30 minutes, and was quenched with addition of water. After warming up to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13]Br>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: N#CCc1ccc(Cl)nc1
Product: N#CC1(c2ccc(Cl)nc2)CC1
Yield: 43 %

Procedure:
The title compound was prepared from (6-chloro-pyridin-3-yl)-acetonitrile and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 43% of theory; LC (method 3): tR=2.71 min; Mass spectrum (ESI+): m/z=179/181 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>C1COCC1>[CH2:1]([O:5][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH:3]=[CH2:4]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 3-butene-ol (1.08 mL, 12.53 mmol) in THF (30 mL) at 0° C. was added NaH (60%, 592 mg, 14.81 mmol). The mixture was stirred for 30 minutes, and 4-chloro-1-fluoro-2-nitrobenzene (2 g, 11.39 mmol) in THF (5 mL) was added dropwise. The reaction mixture was further stirred at 0° C. for 2 hours, poured into ice-water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the desired product (2.5 g, 97%). MS (DCI/NH3) m/z: 244.95 (M+H)+; 1H NMR (400 MHz, DMSO-D6) δ ppm 2.47 (q, J=6.55 Hz, 2 H) 4.22 (t, J=6.60 Hz, 2 H) 5.08 (d, J=10.13 Hz, 1 H) 5.15 (dd, J=17.18, 1.84 Hz, 1 H) 5.80–5.91 (m, 1 H) 7.42 (d, J=9.21 Hz, 1 H) 7.70 (dd, J=9.21, 2.76 Hz, 1 H) 8.00 (d, J=2.76 Hz, 1 H)
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:17]=[C:18]([C:28](=[O:30])[CH3:29])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([N:25]1[CH2:24][CH2:23][N:22]([C:21]2[CH:20]=[CH:19][C:18]([C:28](=[O:30])[CH3:29])=[CH:17][C:16]=2[F:15])[CH2:27][CH2:26]1)=[O:6]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Product: CC(=O)c1ccc(N2CCN(C(=O)c3c(Cl)ccc([N+](=O)[O-])c3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2,6-dichloro-3-nitro-benzoic acid (CAS: 55775-97-8; commercial) and 1-(3-fluoro-4-piperazin-1-yl-phenyl)-ethanone: colourless solid, m.p. 209-211° C., MS (ISP): 440.1 MH+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:37]1([C:42](=[S:44])[NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:44][C:42]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[N:43][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: NC(=S)N1CCCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a stirring suspension of N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.0 g, 2.36 mmol, 1.0 eq) in DCM (˜5 mL) was added NBS (0.44 g, 2.48 mmol, 1.05 eq). Upon formation of a red solution (˜10 minutes) the reaction mixture was concentrated to a solid and taken up in dioxane (10 mL). To this solution was added MgCO3 (0.38 g) followed by 1-pyrrolidinecarbothioamide (0.384 g, 2.95 mmol, 1.25 eq). After stirring 3 h, the mixture was quenched with water (50 mL) and 1N HCl (10 mL) and stirred 0.25 h. The mixture was filtered and the resultant solid triturated with EtOAc/Hexanes to give 0.52 g (41%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.11 (s, 1H), 8.14 (d, J=5.7 Hz, 1H), 7.65-7.74 (m, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.18-7.29 (m, 5H), 6.44 (d, J=5.5 Hz, 1H), 3.45-3.52 (m, 4H), and 1.98-2.05 (m, 4H).
Reaction SMILES: C[Si]([CH2:5][C:6]([O:8]CC)=[O:7])(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:35](=O)[CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=1>C1COCC1>[CH3:21][O:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)/[C:35](=[CH:5]/[C:6]([OH:8])=[O:7])/[CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2ccc3c(c2)CCCC3=O)cc1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc3c(c2)CCC/C3=C\C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl (trimethylsilyl)acetate (12.07 g, 75 mmol) in anhydrous THF (60 mL) at −78° C. was treated dropwise with LiHMDS (1M in THF, 66 mL). The resulting mixture was stirred at −78° C. for 30 minutes. A solution of 52.3 (14.0 g, 50 mmol) in THF (10 mL) was added to the mixture over 20 minutes. The resulting mixture was stirred at −78° C. for 2 hours before warming to 0° C. The reaction mixture was quenched with NH4Cl (sat. 200 mL) and extracted with ethyl acetate (70 mL×4). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate in Hexane). [6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-acetic acid (52.4) was obtained as a light yellow oil (12.2 g, 69% yield). MS ESI (pos.) m/e: 353 (M+1)+.