Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3cccnc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3cccnc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(pyridin-3-yl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25](=[O:26])[CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: COc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)c2c(F)cc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
In a 100 mL 3-neck round-bottomed flask fitted with condenser and magnetic stirrer were placed dry THF (20 mL) and p-methoxy acetophenone (0.386 g, 2.57 mmol) under nitrogen. To this solution, LHMDS (2.69 mL as a 1M solution in THF, 2.57 mmol) was added drop wise at 25° C. After completion of addition, the mixture was stirred for 30 min at rt, then 2,4,6-trifluoro-benzoyl chloride (0.5 g, 2.57 mmol) in THF (5 mL) was added slowly at rt via syringe. The reaction mixture was stirred overnight at rt. The reaction was quenched with saturated NH4Cl solution (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was dries over Na2SO4, concentrated to give crude product, which was purified by column chromatography using 20% EtOAc in hexane, to give 215 mg of 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (27%). 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (100 mg) in DMSO (2 mL) was heated at 100-110° C. for 1 h. Then the reaction mixture was cooled to rt and diluted with water. The product was filtered and dried to give 62 mg of 5,7-difluoro-2-(4-methoxy-phenyl)-chromen-4-one (68%). MS (ES) m/z: 289.07 (M+1); 19F-NMR (DMSO-d6): δ −101.9, −109.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([Cl:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=2[Cl:14])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[C:25](=[CH:30]\[O:31][CH3:32])/[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.O>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([Cl:14])=[CH:8][C:9]([O:13][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3/[C:25](=[CH:30]\[O:31][CH3:32])/[C:26]([O:28][CH3:29])=[O:27])=[CH:10][C:11]=2[Cl:12])[CH2:2][CH2:3]1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: Oc1cc(Cl)c(OCC2CC2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(Cl)c(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 4-cyclopropylmethoxy-3,5-dichlorophenol (1.54 g; 6.6 mmoles) in DMF (5 ml) is added dropwise, at 0° C., to a suspension of sodium hydride (0.16 g; 6.6 mmoles) in N,N-dimethyl formamide (DMF; 5 ml). The mixture is kept under stirring at room temperature for 30 minutes and a solution of methyl (E)-2-(2bromomethylphenyl)-3-methoxyacrylate (1.9 g; 6.6 mmoles) in DMF (5 ml) is then added. The mixture is kept under stirring for 4 hours; the mixture is diluted with water (40 ml) and an extraction is effected with ethyl acetate (3×25 ml). The organic phases are joined, washed with water (2×20 ml), dried with sodium sulfate, filtered and concentrated at reduced pressure. The raw product obtained is purified by means of silica gel chromatography, eluting with hexane/ethyl acetate 9:1. 1.9 g of the desired product (thick oil) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[N-:46]=[C:47]=[O:48].[K+]>O.C(O)(=O)C>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:47]([NH2:46])=[O:48])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: [N-]=C=O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NC(N)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 35 °C
Yield: 33.8 %

Procedure:
To a suspension of (S)-2-(1-((5-(3-amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (10 mg, 0.12 mmol) The mixture was heated 35° C. overnight. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 18 mg (33% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(C)C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:18]1([S:24]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
A mixture of 5-bromoindole (5 g, 25.5 mmol) and tetra-n-butylammonium hydrogen sulfate (866 mg, 2.55 mmol) in 50% NaOE (50 mL) and toluene (200 mL) is stirred at room temperature for 5 min. Benzenesulfonyl chloride (3.57 mL, 28 mmol) is added and the mixture stirred for 1 hr. The mixture is diluted with water (500 mL) and extracted with EtOAc (3×100 mL). The extracts are washed with brine (250 mL), dried over MgSO4, filtered and evaporated to a yellow oil. The oil is purified by medium-pressure column chromatography on silica gel eluting with 10% EtOAc/hexanes to give the title compound as a white solid (7.81 g).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(N(CC)CC)C>CN(C=O)C>[C:3]1(=[O:12])[N:2]([O:1][CH2:16][CH2:15][CH2:14][Br:13])[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: BrCCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Temperature: 47.5 °C
Reaction time: 5.5 h

Procedure:
A mixture of N-hydroxyphthalimide (16.3 g, 100 mmol) and 1,3-dibromopropane (20.19 g, 100 mmol) in dry DMF (150 mL) and triethyl amine (15.33 mL, 110 mmol) is stirred at 20 to 75° C. for 1 to 10 hours. After filtration, the mixture is evaporated to dryness in vacuo. The residue is purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:22]([CH:26]1[CH2:31]CC(O)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+].C(O)C>CO>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:28][CH2:27][CH:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:31][CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)C1CCC(OC(=O)C(C#N)=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 67 %

Procedure:
139 g (0.5 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 200 ml of 4-tert-butylcyclohexanol and 10 g of Na2CO3 were reacted together at 182° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 4 h, the reaction mixture was diluted with 300 ml of methanol and filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 130 g (67%) of 4-tert-butyl-cyclohexyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 302 nm; E11 (MeOH) 324]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2ccc3ccccc32)cc1
Temperature: 120 °C
Yield: 21.1 %

Procedure:
Ethyl-4-fluorobenzoate (4 mL, 27.3 mmol) and indole (3.51 g, 30 mmol) were dissolved in 50 mL of dimethylsulfoxide (DMSO). Potassium fluoride (37% on basic alumina, 12.8 g) and 18-crown-6 (720 mg, 2.73 mmol) were added and the mixture was heated to 120° C. for 24 hours. The reaction was diluted with ethyl acetate and washed with hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). The organic layer was dried over magnesium sulfate, filtered and the solvent removed. Purification by flash chromatography on silica gel eluted with 5% ethyl acetate, hexane provided 1.45 g (20%) of a white solid
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[Ag:13]=O>COC(C)(C)C>[Ag:13].[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Ag]
Agent: O=C(O)c1ccccc1
Solvent: CC#N
Solvent: COC(C)(C)C
Product: [Ag]
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.54 parts of benzoic acid and 12.00 parts of acetonitrile was stirred at 23° C. for 30 minutes. To the resultant mixture, 2.32 parts of silver oxide was added and then, the resultant mixture was stirred at 23° C. for 4 hours followed by filtration. The solid obtained was mixed with 10 parts of tert-butyl methyl ether and the resultant mixture was stirred at 23° C. for 30 minutes followed by filtration. The solid obtained was dried to obtain 3.19 parts of silver salt of benzoic acid.
Reaction SMILES: [C:1]([N:6]=[C:7]=[N:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].C([N:19]=[C:20]=[N:21]C1C=NC=CC=1)(C)(C)C>>[C:20]([N:21]=[C:7]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH:6][C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])#[N:19]
Reactant: CCC(C)(C)N=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCC(C)(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-tert-pentyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-tert-pentyl-N'-3-pyridylguanidine was obtained with a melting point of 187.0°-187.5° C.
Reaction SMILES: Cl[S:2][N:3]([CH3:10])[C:4](=[O:9])[O:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:13]=1[NH2:14].C(N(CC)CC)C>C(OCC)C>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][S:2][N:3]([CH3:10])[C:4](=[O:9])[O:5][CH2:6][CH2:7][CH3:8])=[C:12]([F:11])[CH:18]=1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: CCCOC(=O)N(C)SCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCOC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Yield: 97.7 %

Procedure:
A solution of propyl N-chlorosulphenyl-N-methylcarbamate (12.1g) in diethyl ether (20 ml) was added to a stirred solution of the compound of Example 1 (18.3 g) and triethylamine (7 g) in the same solvent (70 ml) over 20 minutes, the temperature being maintained at 15°-20° C. with cooling. Stirring was continued at room temperature for a further 11/2 hours. The reaction mixture was then diluted with diethyl ether (200 ml), washed with water, dried and stripped of solvent. The residue was added to 100 mls toluene, and the toluene was removed under reduced pressure to leave 26.5 g of the desired product in crude form as a brown oil.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=1.[CH2:53]([O:55][C:56](=[O:69])[C@@H:57]([O:66][CH2:67][CH3:68])[CH2:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1)[CH3:54]>ClCCl>[CH2:53]([O:55][C:56](=[O:69])[C@@H:57]([O:66][CH2:67][CH3:68])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[CH:49]([CH3:50])[CH3:51])=[CH:43][CH:42]=2)=[CH:61][CH:60]=1)[CH3:54]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1)OCC
Reaction time: 24 h
Yield: 87.3 %

Procedure:
Azodicarbonyl dipiperidine (0.99 g; 3.93 mmole) and triphenylphosphine (1.03 g; 3.93 mmole) were added to a solution of N-[4-(2-hydroxyethyl)phenyl]isobutyramide (described in Example 68a) (0.79 g; 3.93 mmole) and (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 40h) (0.78 g; 3.27 mmole) in dry dichloromethane (25 ml). After stirring at room temperature over night more N-[4-(2-hydroxyethyl)phenyl]isobutyramide, azodicarbonyl dipiperidine (0.16 g; 0.65 mmole) and triphenylphosphine (0.17 g; 0.65 mmole) were added. After stirring for 24 hours the reaction mixture was filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (2:1) as eluant gave 1.22 g (yield 87%) of (S)-2-ethoxy-3-{4-[2-(4-isobutyrylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3]([Cl:6])(Cl)Cl.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:3]([Cl:6])=[O:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 282.7 %

Procedure:
A solution of 1.47 g of bis(trichloromethyl) carbonate in 10 ml of methylene chloride was added dropwise within 20 min. to a solution of 2 g of 1,2,3,4-tetrahydro-isoquinoline in 30 ml of methylene chloride and 2.5 ml of triethylamine under argon at 0° C. The reaction mixture was stirred at room temperature for 2 h., then diluted with 50 ml of methylene chloride and washed with 50 ml of water, 50 ml of a 5% hydrochloric acid solution, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium chloride solution. The organic phases were dried over magnesium sulfate, concentrated, and the residue was dried at room temperature and about 12 mbar. 2.74 g (94%) of 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride were obtained as a pale orange oil. MS (EI): 195M30 .
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11]C)(=[O:4])=[O:3].[BrH:22]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])=[O:4].[BrH:22]
Reactant: CCCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1
Agent: Br
Product: CCCN1CCN(c2ccc(O)c(S(C)(=O)=O)c2)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1-(3-Methanesulfonyl-4-methoxy-phenyl)-4-propyl-piperazine (30 mg) was dissolved in 48-% HBr (2 ml) and stirred at 120° C. under an Argon-atmosphere for 3 h. The excess of HBr was then evaporated and absolute ethanol added and evaporated. This procedure was repeated several times to yield an residue of 2-Methanesulfonyl-4-(4-propyl-piperazin-1-yl)-phenol×HBr. MS m/z (relative intensity, 70 eV) 298 (M+, 35), 269 (bp), 226 (15), 199 (12), 70 (62).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:17](OC(=O)CC)(=O)[CH2:18][CH3:19].C(=O)(O)[O-].[Na+]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH2:18][CH3:19])=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Reactant: CCC(=O)OC(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc2cnccc2n1-c1ccc(C#N)cc1
Yield: 21.6 %

Procedure:
A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (Preparation 26(b)) (2.00 g, 9.5 mmol) and propionic anhydride (12.2 ml, 95 mmol) were heated together under nitrogen at reflux for 17 hours. The resulting solution was treated with excess aqueous sodium bicarbonate and the product was extracted into dichloromethane (3×150 ml). The combined extracts were dried (MgSO4), concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution with ethyl acetate/methanol) to give the title compound as a brown solid (510 mg, 22%).
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])N>>[Br:11][C:12]1[CH:13]=[C:14]([N:1]([C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Reactant: Nc1ccc(F)c(Br)c1
Product: O=C1CCCC(O)=C1N(C1=C(O)CCCC1=O)c1ccc(F)c(Br)c1

Procedure:
Following the procedure described in the Example 1, using 2-diazo-cyclohexane-1,3-dione and 3-bromo-4-fluoroaniline as starting materials to yield the title compound as a white solid.
Reaction SMILES: [CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11](O)=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11]([Cl:18])=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1C2C3CC(C4CCCC43)C12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1C2C3CC(C4CCCC43)C12
Reaction time: 2 h

Procedure:
To a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carboxylic acid (0.43 g, 2.2 mmol, Bennani, Y. L., et al., US2004077617) in dichloromethane (11 mL) was added oxalyl chloride 0.21 mL, 2.4 mmol) and a catalytic amount of dimethylformamide (2 drops). The mixture was stirred for 2 hours and then concentrated under reduced pressure to afford tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride. To a suspension of the product of Example 46A (0.30 g, 1.1 mmol) and triethylamine (0.46 mL, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride (0.23 g, 1.2 mmol) in tetrahydrofuran (1 mL). The mixture was heated at reflux for 14 hours, then cooled to room temperature and diluted with water and CH2Cl2. The layers were separated and the organic extract was washed with water and brine, dried (Na2SO4), and concentrated. Purification by column chromatography (SiO2, 10-35% ethyl acetate/hexanes gradient) afforded the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.94 (d, J=10.5 Hz, 1H), 1.22 (d, J=11.9 Hz, 1H), 1.45-1.76 (m, 6H), 1.87-1.98 (m, 2H), 2.17 (s, 3H), 2.20 (s, 3H), 2.32 (s, 2H), 2.35-2.43 (m, 3H), 3.30 (s, 3H), 3.70 (t, J=5.3 Hz, 2H), 4.20-4.33 (m, 2H); MS (DCI/NH3) m/z 361 (M+H)+. Anal. Calculated for C20H28N2O2S: C, 66.63; H, 7.83; N, 7.77. Found: C, 66.49; H, 7.91; N, 7.53.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20]=O)[CH:18]=3)[S:13][C:6]=12.CC(O)=O.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[CH:18]=3)[S:13][C:6]=12
Reactant: CN1CCNCC1
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cn2)CC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of 146 (450 mg, 1.13 mmol, Scheme 36) in NMP (10 mL) was added AcOH (0.129 mL, 2.259 mmol) and 1-methylpiperazine (113 mg, 2.259 mmol) and the reaction mixture was stirred at RT for an hour. Sodium triacetoxyborohydride (718 mg, 6.10 mmol) was added and the mixture was stirred at RT overnight. The mixture was diluted with saturated NaHCO3 solution then solid NaHCO3 was added to neutralize the acid. The mixture was extracted with DCM and the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent 10% MeOH to 50% MeOH in EtOAc) to afford title compound 152 (250 mg, 27% yield) as a brown oil. MS (m/z)=483.53 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O>[O:7]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=CCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccccc1
Reaction time: 4 h
Yield: 7.4 %

Procedure:
A mixture of phenol (18.8 g) and sodium hydroxide (8 g) was stirred at 60°-70° in dimethylformamide (162 ml) and water (18 ml) while 1-bromo-3-methylbut-2-ene (VII, R1 =R2 =CH3, Hal=Br) (29.8 g) was added dropwise over 11/2 h. The mixture was stirred at 60° for 4 h after the addition was complete. It was then poured into water (800 ml) and extracted with ether (3×300 ml). The ether extract was washed with 10% sodium hydroxide (200 ml) and then with water (3×200 ml) before drying over anhydrous sodium sulphate. The solvent was removed in vacuo, and the residue distilled to give 1-phenoxy-3-methylbut-2-ene (2.4 g, yield 75%) as a clear liquid b.p. 116°-118°/18 mm. Hg.