Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][C:10]=1[S:20]([CH2:22][CH2:23][CH2:24][CH3:25])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S(CCCC)=O)CCC.S(C1C=CC([N+]([O-])=O)=CC=1)(OC[C@H]1OC1)(=O)=O.Cl.[NH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([C:61]2[CH:75]=[CH:74][C:64]([O:65][C:66]([CH3:73])([CH3:72])[C:67]([O:69][CH2:70][CH3:71])=[O:68])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1>C(O)C.CO>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]([OH:16])[CH2:17][NH:54][C@H:55]2[CH2:60][CH2:59][C@H:58]([C:61]3[CH:62]=[CH:63][C:64]([O:65][C:66]([CH3:72])([CH3:73])[C:67]([O:69][CH2:70][CH3:71])=[O:68])=[CH:74][CH:75]=3)[CH2:57][CH2:56]2)=[CH:11][C:10]=1[S:20]([CH2:22][CH2:23][CH2:24][CH3:25])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCS(=O)c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)cc1
Agent: CCCCS(=O)CCCC
Agent: Cl
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Solvent: CO
Solvent: CCO
Product: CCCCS(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(OC(C)(C)C(=O)OCC)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A mixture of 0.742 g of (2S)-2-{[4-(benzyloxy)-3-(butylsulfinyl)phenoxy]methyl}oxirane (obtained by analogy with the method disclosed in WO 99/65895 but starting from the butyl sulfoxide instead of the methyl sulfoxide and using (S)-(+)-glycidyl nosylate; [α]D=+1.9 (c=1%, MeOH)) (2.06 mmol) and of 0.666 g of ethyl trans-2-[4-(4-aminocyclohexyl)phenoxy]-2,2-dimethylacetate hydrochloride (2.18 mmol) in ethanol (25 ml) is heated to reflux overnight. The solvent is evaporated under reduced pressure and the product obtained is purified by flash chromatography, elution being carried out with a methylene chloride/methanol/aqueous ammonia (95/5/0.5) mixture. The title product is obtained in the form of a yellow oil (0.730 g, 53%).
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].[CH3:6][O:7][C:8]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)=[O:9]>C(Cl)Cl>[CH3:6][O:7][C:8]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[CH2:13][N:12]([C:1]([O:2][C:10]([CH3:14])([CH3:11])[CH3:8])=[O:4])[CH2:11]1)=[O:9]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1cccc(Br)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Add a saturated aqueous solution of sodium bicarbonate (350 mL) to a solution of trans-4-(3-bromo-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (11 g, 38 mmol) in methylene chloride (350 mL). Cool the mixture to 0° C. and add BOC-anhydride (8.9 g, 41 mmol) dropwise. Slowly warm the mixture to room temperature and stir for 12 h. Extract the reaction mixture with methylene chloride, dry the combined organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by silica gel chromatography to provide 13 g of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[CH:10]3[O:12][CH:11]3[C:6]=2[CH:5]=1)(=[S:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[H-].[Na+]>CS(C)=O>[C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C@@H:10]([OH:12])[C@H:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[C:6]=2[CH:5]=1)(=[S:3])[CH3:2]
Reactant: CC(=S)c1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=S)c1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2

Procedure:
The title compound is prepared by reaction between 6-thioacetyl-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran and 2-pyrrolidone in dimethylsulphoxide in the presence of sodium hydride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[C:30]#[N:31])=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:16]1[CH:17]=[C:18]([S:21]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[N:7][C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=2)=[CH:3][CH:4]=1)#[N:31]
Reactant: Cn1cc(-c2nc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)cn1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2nc(-c3cccc(F)c3)ccc2Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)cn1
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.4 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.63 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].[NH2:22][C:23]1[C:27]([NH2:28])=[N:26][O:25][N:24]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:28][C:27]1[C:23]([NH:22][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:18])[F:19])=[N:16][C:8]=2[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][S:2]2(=[O:1])=[O:21])=[N:24][O:25][N:26]=1
Reactant: Nc1nonc1N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1CN1CCCS1(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nonc1NC(=O)c1ccc(C(F)(F)F)nc1CN1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
150 mg (0.46 mmol) of 2-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-6-(trifluoromethyl)nicotinic acid and 46 mg (0.46 mmol) of 3,4-diamino-1,2,5-oxadiazole are dissolved at RT in 10 ml of CH2Cl2, and 0.32 ml (2.31 mmol) of triethylamine, 11 mg (0.09 mmol) of DMAP and 442 mg (0.69 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 5 ml each time of water. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield: 42 mg (22%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[CH:16]=[O:17].Cl>O1CCCC1.O>[OH:17][CH:16]([CH:10]1[CH2:11][CH:12]2[CH2:15][CH:9]1[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7]
Reactant: O=CC1CC2C=CC1C2
Reactant: COCCCCCl
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COCCCCC(O)C1CC2C=CC1C2
Reaction time: 2 h
Yield: 75.4 %

Procedure:
In 300 g of tetrahydrofuran was dissolved 122.6 g of 1-chloro-4-methoxybutane. The solution was added dropwise to 24.3 g of metallic magnesium over 2 hours and below 60° C. Agitation was continued for 2 hours at room temperature. To the solution, 122.2 g of 5-norbornene-2-carbaldehyde was added dropwise over one hour and below 50° C. Agitation was continued for one hour at room temperature to drive the reaction to completion. Then 300 g of water and 44 g of 20% HCl were added to the solution, which was agitated. Extraction with 500 g of hexane gave the organic layer, which was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The oily matter thus obtained was distilled in vacuum, obtaining 158.6 g of 5-(1-hydroxy-5-methoxypentyl)-2-norbornene. The yield was 75.4%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.75 h
Yield: 101.3 %

Procedure:
A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was added with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1)#[N:14].Cl>CN(C=O)C>[C:25]1([C:17]2[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]([C:13]3[NH:14][N:3]=[N:2][N:1]=3)[N:16]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)nc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodium azide (1.7 g) and triethylamine hydrochloride (3.5 g) were added to a DMF (80 mL) solution of methyl 2-cyano-6-phenylpyridine-4-carboxylate (2 g), and stirred overnight at 100° C. With cooling with ice, diluted hydrochloric acid was added to it, and extracted with a mixed solution of chloroform/methanol=10/1. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away to obtain the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:20]=[CH:21][C:22]3[N:26]=[C:25]([CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[O:29])[NH:24][C:23]=3[CH:35]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(#N)C>[OH:1][C:2]1([C:19]2[CH:20]=[CH:21][C:22]3[N:26]=[C:25]([CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[O:29])[NH:24][C:23]=3[CH:35]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cc1nc2ccc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)cc2[nH]1)OCCCCl
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(CCCOC(=O)Cc2nc3ccc(C4(O)c5ccccc5C(=O)N4Cc4ccccc4)cc3[nH]2)CC1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of 3-chloropropyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}acetate (0.25 g, 0.51 mmol) and 1-methyl-piperazine (0.46 mL, 5.10 mmol) in acetonitrile (5.0 mL) was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The aqueous residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave a pale yellow residue, which was freeze-dried from a mixture of acetonitrile-water (1:1, 3.0 mL) to give 3-(4-methylpiperazin-1-yl)propyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}acetate (0.12 g, 43%). 1H NMR (400 MHz, DMSO-d6): 11.50 (br.s, 1H), 7.70 (d, 1H), 7.49 (m, 3H), 7.23 (t, 1H), 7.15 (m, 6H), 6.84 (d, 1H), 4.49 (d, 1H), 4.16 (t, 4H), 4.10 (d, 1H), 3.34 (s, 6H), 2.36 (m, 3H), 2.18 (s, 3H) open, 2.16 (s, 3H) closed, 1.78 (m, 1H); MS (EI) for C31H34N6O4: 555 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].[I-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:12][C:5]1[N:4]([CH2:3][CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)c2ccccc2C1=O
Reaction time: 16 h

Procedure:
A mixture of 17.0 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole, 18.0 parts of potassium phthalimide, and 2.0 parts of potassium iodide in 240 parts of dimethylformamide is heated in a boiling water bath for 3 hours with stirring. Stirring is then continued for 16 hours at room temperature. The resulting brown mixture is diluted with 870 parts of toluene and the toluene solution is washed with several portions of water. The toluene solution is dried over sodium sulfate and the solvent is evaporated to leave a residue which is digested with cold alcohol. The alcohol solution is then cooled and the precipitate which forms is separated by filtration and recrystallized from ethanol to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]phthalimide melting at about 177° C. This compound has the following formula ##STR6##
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[N+:9]([O-])([OH:11])=[O:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:9]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccn([N+](=O)[O-])n1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a stirred mixture of 3-nitro-1H-pyrazole (3.16 g, 27.9 mmol) in glacial acetic acid (20 mL) at 0° C. was added fuming nitric acid (2.6 mL, 58.69 mmol) dropwise, followed by acetic anhydride (6.6 mL, 69.87 mmol). The mixture was stirred and allowed to warm to rt over 3 h, then poured into ice water (50 mL) and stirred for 20 h. The mixture was extracted with EtOAc combined organic layers were dried over MgSO4, filtered and concentrated to dryness to afford 1,3-dinitro-1H-pyrazole (4.3 g, 97%). 1H NMR (300 MHz, DMSO-d6) δ 8.00 (br s, 1H), 6.44 (br s, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH2:22])[CH2:17]2)[CH:13]=[CH:14][CH:15]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:22][CH:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=2)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc([C@H]2CCC[C@H](N)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(C2CCCC(NC(C)=O)C2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
Acetic anhydride (1 ml) and pyridine (0.5 ml) were added to (trans)-3-(3-methoxyphenyl) cyclohexylamine (10 mg) and the mixture was stirred at 50° C. for 2 hours. The reaction solution was poured into glacial sodium bicarbonate water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate water and saturated saline and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 8 mg of N-acetyl-N-[3-(3-methoxyphenyl)cyclohexyl]amine (53.3%).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C1(C)C=CC(S(O[CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])(=O)=O)=CC=1>O>[N+:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH:15]=[CH:16][C:17]=1[OH:23])([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCO[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)OCCCCO[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a mixture comprising DMF (200 ml), 5-t-butoxycarbonylaminosalicylic acid (4.37 g, 17.3 mmol) and 4-nitrooxybutyl p-toluenesulfonate (5 g, 17.3 mmol), at room temperature and under stirring triethylamine was added (2,6 ml; 19 mmol). The reaction mixture was maintained 3 days under stirring at room temperature. It was then poured in water and extracted with ethyl ether. The combined organic phases were washed with a sodium carbonate solution and then with water. After drying on sodium sulfate, the evaporation of the solvent yields a raw product that purified by silica gel chromatography gives the title compounds with a yield of 65%.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH3:34])[CH3:33])[CH:26]=1>>[CH3:33][N:32]([CH3:34])[C:27]1[N:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3][CH:4]3[CH2:8]2)[CH:26]=1
Reactant: Cc1nc(Cl)cc(N(C)C)n1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cc(N(C)C)nc(C)n4)CC3C2)c(-n2nccn2)c1

Procedure:
The title compound was prepared utilizing (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288, product from Step B) and 6-chloro-N,N,2-trimethylpyrimidin-4-amine. MS (ESI) mass calcd. C23H28N8O2, 448.52; m/z found 449.2 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:7]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccccc2)cc1C#N
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture is prepared by adding 104 grams (1.1 moles) of phenol, 173 grams (1 mole of 4-nitrophthalonitrile, and 207 grams of potassium carbonate in 1667 ml of dimethylformamide. The mixture is heated to 70° C. and mechanically stirred. Samples are taken of this reaction mixture periodically and analyzed by GLC. After five hours, the reaction is complete. The 4-phenoxyphthalonitrile is isolated by quenching the crude reaction mixture in ice water. The product is further purified by washing the crude precipitate with dilute sodium carbonate and then water. Finally the 4-phenoxyphthalonitrile is vacuum dried at 60° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9]([NH:16][CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCC(C(=O)O)c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(C(=O)NC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
2-(4-Fluorophenyl)pent-4-enoic acid (Bioorg. Med. Chem. Lett. 2000, 1893; 4.20 g, 21.6 mmol) was dissolved in CH2Cl2 (75 mL) and to the resultant solution was added TBTU (7.29 g, 22.7 mmol). The mixture was stirred at RT for 15 min and then methylamine (11.9 mL of 2M THF solution, 23.8 mmol) and DIPEA (11.2 g, 86.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, subsequently diluted with CH2Cl2 (50 mL) and then washed several times with water. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (heptane-ethyl acetate, 1:1). There was obtained 3.5 g (78%) of 2-(4-fluorophenyl)-N-methylpent-4-enamide as an oil, which shortly after crystallized. 1H NMR (400 MHz, CDCl3): 2.5 (qn, 1H), 2.7 (d, 3H), 2.9 (qn, 1H), 3.4 (t, 1H), 4.9-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.0-6.2 (b, 1H), 7.0 (m, 2H), 7.3 (m, 2H).
Reaction SMILES: C([C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:11]=[C:10]2[C:6]=1[C:7]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[C:8]([Br:24])[C:9]2=[O:23])(C)(C)C.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Br:24][C:8]1[C:9](=[O:23])[C:10]2[C:6]([C:7]=1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[CH:5][CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:19][CH2:18]1)[CH:11]=2
Reactant: CC(C)(C)c1cc(OCCC2CCNCC2)cc2c1C(c1cc(F)cc(F)c1)=C(Br)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of t-butyl 6-(2-(piperidin-4-yl)ethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one (211 mg, 1.2 eq, 1.03 mmol) obtaind in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[NH2:17]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzenesulphonamide (3.35 g, 14.2 mmole) was dissolved in ethanol (75 ml) with heating and hydrazine hydrate (5 ml. 100 mmole) added. The mixture was refluxed for 45 minutes and then allowed to cool to room temperature. The product cystallised in long needles, 2.4 g. A second crop was obtained on cooling the filtrate in an ice bath, 0.5 g. The combined crops were recrystallised from water (120 ml) to afford pure 2-hydrazino-5-nitrobenzenesulphonamide, m.p. 209°-210° C., 1.85 gm, 60% as orange-yellow needles. TLC analysis (EtOAc:petrol, 1:1) showed one spot (Rf =0.3). Spectroscopic data was consistent with the product.