Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:11][C:4]1[NH:3][C:2](=[O:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(=O)[nH]1

Procedure:
A solution of 24 g. of 2-amino-6-methyl-3-nitro-pyridine in 25 ml. of concentrated sulfuric acid and 380 ml. of water was cooled to 0° C. and treated with 11 g. of sodium nitrite in 25 ml. of water. The temperature spontaneously rose to 45° C. After cooling, the precipitate of 6-methyl-3-nitro-2-pyridone was collected (m.p. 222°-223° C.) and used directly in the next step.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.CN(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (1.0 g) was added to a mixture of 10 ml of DMF and 0.85 ml of trimethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 440 mg of methanesulfonyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature as above for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.17 g of 6-(4-methanesulfonyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 241.5°-243° C., colorless granules.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[NH:18][CH:17]=2)=[CH:10][CH:9]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=O.C(N(CC)CC)C>ClCCCl>[Br:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:15][N:14]([C:27]1[CH2:28][CH2:29][CH2:30][N:26]=1)[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=1
Reactant: COc1ccc(NCc2c[nH]c3ccc(Br)cc23)cc1
Reactant: O=C1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(N(Cc2c[nH]c3ccc(Br)cc23)C2=NCCC2)cc1

Procedure:
Reaction of equimolar amounts of phosphorus oxychloride, 3-(p-anisidinomethyl)-5-bromoindole, 2-pyrrolidinone and triethylamine in 1,2-dichloroethane according to the procedure of Example 35 provides 5-bromo-3-[(N-[1-pyrrolin-2-yl]-p-anisidino)methyl]indole. Acidification of the free base with ethanolic hydrogen chloride provides 5-bromo-3-[(N-[1-pyrrolin-2-yl]-p-anisidino)methyl]indole hydrochloride, m.p. 205.5°-207.5° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.C([Li])CCC.[S].[S:27](=O)(=O)(O)O>CCCCCC.O1CCCC1>[Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[C:19]([SH:27])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:3][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: OC(Cc1ccccc1Cl)(Cn1cncn1)C1(Cl)CC1
Agent: [Li]CCCC
Agent: [S]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
At -20° C., a mixture of 3.12 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol and 45 ml of absolute tetrahydrofuran is admixed with 8.4 ml (21 mmol) of n-butyl-lithium in hexane and stirred at 0° C. for 30 minutes. The reaction mixture is subsequently cooled to -70° C., admixed with 0.32 g (10 mmol) of sulphur powder and stirred at -70° C. for 30 minutes. The mixture is warmed to -10° C., admixed with ice-water and adjusted to pH 5 by addition of dilute sulphuric acid. The mixture is extracted repeatedly with ethyl acetate and the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.2 g (93% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid substance which, after recrystallization, melts at 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.CCCCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(COCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
To a solution of the product of Example 8A (500 mg, 2.334 mmol) in DMF (23 mL) was added tert-butyldimethylsilyl chloride (528 mg, 3.501 mmol) and imidazole (238 mg, 3.501). The reaction was stirred at room temperature for 5 hours under nitrogen atmosphere, monitoring by TLC (3:1 pentane:ethyl acetate). Another 0.5 eq. portion of tert-butyldimethylsilyl chloride (176 mg) and imidazole (79 mg) were added and the resultant mixture stirred at room temperature overnight. The majority of the starting material was consumed in 16 hours, as indicated by thin layer chromatography. The reaction was diluted with water and extracted with ethyl acetate (2 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude oil which was purified by passage through thick pad of silica gel (3:1 pentane:ethyl acetate) to obtain the product as a clear oil (602 mg). 1H NMR (600 MHz, CDCl3): 8.00 (d, 2H, J=8.3 Hz), 7.40 (d, 2H, J=8.5 Hz), 4.62 (s, 2H), 3.90 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:16]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[N:17][CH:18]=[CH:19][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:22](=[O:23])[C:21]([C:16]2[C:15]([Cl:14])=[N:20][CH:19]=[CH:18][N:17]=2)([CH3:26])[CH3:25])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](NC(=O)C(C)(C)c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottomed flask was added tert-butyl(trans-3-aminocyclobutyl)carbamate (1.847 g, 9.92 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (1.99 g, 9.92 mmol), HATU (4.90 g, 12.89 mmol), and triethylamine (5.52 ml, 39.7 mmol) in DCM (25 ml) to stir at room temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 70% EtOAc in hexane, to provide the title compound (2.73 g, 7.40 mmol, 74.6% yield) as off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8](Cl)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH3:2].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([NH:20][C:21]2[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][CH:22]=2)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH3:2]
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(N)(=O)=O)c1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Nc2cccc(C)n2)c(S(N)(=O)=O)c1
Reaction time: 2 h

Procedure:
A mixture of ethyl-4-chloro-3-nitro-5-sulphamyl-benzoate (3.08 g) and 6-amino-2-methyl-pyridine (3.24 g) was melted on an oil bath at 140° C and kept at this temperature for 2 hours, while stirring. The still warm reaction mixture was triturated with ethanol (35 ml) and after cooling, the ethyl-4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoate was collected by suction and washed with ethanol. After recrystallization from acetonitrile, the compound had a melting point of 203°-204° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(F)cc2)c1C

Procedure:
4-[2-(4-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 94%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.35 (q, 2H), 7.01 (m, 2H), 7.22 (m, 2H), 7.50 (d, 1H), 9.70 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □□□ 11.79, 14.38, 46.36, 60.89, 115.51, 127.27, 129.93, 130.77, 162.04, 193.62 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.79, 14.38; CH2 carbons: 46.36, 60.89; CH carbons: 115.51, 127.27, 129.93, 130.77 ppm. LC/MS: 77.48%, m/z=289.
Reaction SMILES: [H-].[Na+].C(O/[N:7]=[C:8](\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])/[C:9]1[C:14]([OH:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=1[Cl:18])(=O)C>CN(C=O)C>[Cl:18][C:10]1[C:9]2[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:7][O:15][C:14]=2[CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: COc1cc(O)c(/C(=N/OC(C)=O)c2ccccc2F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (2.4 g) in 20 ml DMF, is added a solution of E-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone O-acetyl oxime (15 g) in 50 ml DMF. After stirring at ambient temperature for two hours, the mixture is poured into one l ice-water, stirred for 30 minutes and a precipitate is collected. The precipitate is washed with water then dried to yield 4-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 113°-115° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:24].O1CCCC1>O.C(#N)C>[Li+:24].[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][C:3]([O-:22])=[O:2])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CCC1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2CCC(CCC(=O)[O-])CC2)cc1

Procedure:
To 3-[1-(4-tert-butyl-phenyl)-piperidin-4-yl]-propionic acid methyl ester (295 mg; 0.97 mmol, prepared in accordance with Example 145) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to deliver the desired product (468 mg) which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2.C(N(CC)CC)C>C(Cl)Cl.O>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=3)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To 4-chloro-3-nitrobenzenesulfonyl chloride (2.56 g, 10 mmol) in dry DCM (20 mL) was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.54 g, 10.5 mmol) and triethylamine (3.3 mL, 25 mmol). The mixture was stirred at ambient temperature for 16 hrs. The mixture was then diluted with 40 mL of DCM and 30 mL of water. The organic layer was separated, washed with brine (2×20 mL), dried over MgSO4, and evaporated to afford 1-(3-nitro-4-chloro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a yellow solid (3.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:36](=[O:38])[CH3:37])=[CH:17][CH:18]=3)=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(CN)cc3)c3cc(Br)cnc32)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzylamine (Intermediate CB, 45 mg, 0.1 mmol) was combined with triethylamine (45 μl, 0.3 mmol) and acetic anhydride (11 μl, 0.11 mmol) in anh. DCM (2 ml). The mixture was stirred for 2 hrs, EtOAc, was added and washed with 0.5 N HCl, saturated NaHCO3, water and brine. Evaporation yielded the title compound (48 mg, 96%). MS ESI (m/z): 498.1/500.1 (M+1)+, calc. 497/499.
Reaction SMILES: [CH2:1]=[O:2].[C:3](=[O:6])(O)[O-].[Na+].[Br:8][CH2:9][N+:10]([O-:12])=[O:11]>>[Br:8][C:9]([N+:10]([O-:12])=[O:11])([CH2:3][OH:6])[CH2:1][OH:2]
Reactant: O=C([O-])O
Reactant: C=O
Reactant: O=[N+]([O-])CBr
Agent: [Na+]
Product: O=[N+]([O-])C(Br)(CO)CO
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
An aqueous formaldehyde solution, 37% by weight H2CO, containing 75.81 g. aldehyde (0.934 mole) was adjusted to pH 6.5 with 0.5M aqueous sodium bicarbonate. The entire reactor was placed in a room temperature water bath, and 65.29 g. bromonitromethane (0.467 mole) was added, with vigorous stirring, at such a rate that the reagent was immediately consumed. Aqueous sodium bicarbonate was added to the mixture by a pH-controlled feed pump so that the reaction zone pH was constantly maintained at a level between 6.0 and 6.4. When the bromonitromethane charge was complete, the temperature of the reaction mixture was elevated to 45° C. and held there for 1-12 hours, with constant stirring. The pH of the mixture was maintained in the preset range of 6.0 to 6.5 by the pH-controlled base feed. At the end of the heated stir time, the solution was allowed to cool to room temperature, whereupon the desired product precipitated as a crystalline solid, which was isolated by vacuum filtration. The yield of product was 86.8 g. (93%), with a purity assay of 99.8% (by GC of a derivatized sample).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C([Li])CCC.CCCCCC.[Cl:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1>O1CCCC1.O>[Cl:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=2)=[C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1
Reactant: Ic1cccc(I)c1
Reactant: CCC(=Cc1ccc(OCCCl)cc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(=C(c1ccc(OCCCl)cc1)c1cccc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1,3-diiodobenzene (5.45 g, 16.5 mmol) in dry tetrahydrofuran (25 ml) at -78° C. under nitrogen was treated with a solution of n-butyl lithium in hexane (1.6M; 10.3 ml, 16.5 mmol). After 5 min, a solution of 1-[4-(2-chloroethoxy)-phenyl]-2-phenyl-1-butene (5.0 g, 16.5 mmol) in dry tetra-hydrofuran (15 ml) was added and the mixture allowed to warm to room temperature. After 20 h, the mixture was poured into water (100 ml) and the products extracted with ether (2×50 ml). The extracts were concentrated under vacuum and the residue dissolved in ethanol (80 ml). Concentrated hydrochloric acid (30 ml) was added and the mixture heated under reflux. After 4 h, the mixture was cooled and partitioned between water (100 ml) and ether (2×60 ml). The ether layers were dried with sodium sulphate, concentrated, and the residue chromatographed on silica gel (Merck 15111, 60 g). Elution with 1:20 l dichloromethane-light petroleum (b.p. 60°-80° C.) gave 1-[4-(chloroethoxy) phenyl]-1-(3-iodophenyl)-2-phenyl-1-butene as a ca. 1.5:1 mixture of E (trans) and Z (cis) isomers (determined by n.m.r. spectroscopy) and as an oil (6.46 g, 80% yield). This mixture (3.63 g) was dissolved in a solution of methylamine (30% w/v) in ethanol, and the resulting solution heated in a sealed vessel at 100° C. for 4 h, then cooled and concentrated to dryness. The residue was partitioned between aqueous sodium hydroxide (100 ml) and ether (100 ml). The ether solution was washed with water (50 ml), dried with sodium sulphate and the residual oil dissolved in cyclohexane (10 ml). Eventually 3-iodotamoxifen crystallised (1.51 g, 41%), m.p. 55°-57° C. NMR: δH (CDCl3, 250 MHz) 0.91 (3H, t, J 7.4 Hz, CH3CH2), 2.29 (3H, s, NMe2), 2.43 (2H, q, J 7.4 Hz, CH3CH2), 2.65 (2H, t, J 5.8 Hz, OCH2CH2N), 3.93 (2H, t, J 5.8. Hz, OCH2CH2N), 6.57 (2H, d, J 8.8 Hz, ArH ortho to side chain), 6.74 (2H, d, J 8.8 Hz, ArH meta to side chain), 7.05-7.26 (7H, m, ArH), 7.58- 7.63 (2H, m, ArH ortho to I).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C.[CH3:23][CH:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>C(Cl)Cl>[CH3:23][CH:24]([S:26]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-BOC-piperazine (0.617 mmol) and diisopropylethylamine (0.679 mmol) in 0.5 mL of methylene chloride was added to a 4 mL vial. Propane-2-sulfonyl chloride (0.679 mmol) was added to the vial, and the reaction mixture was shaken overnight at room temperature. When the reaction was complete, it was diluted with 1.5 mL of methylene chloride and extracted with 1 mL of 1N solution of hydrogen chloride followed by 1 mL of 10% potassium carbonate solution. The organic layer was concentrated in vacuo. The residue was dissolved in 0.5 mL of tetrahydrofuran and 4M solution of hydrogen chloride in dioxane (0.5 mL). The solution was shaken overnight at room temperature then concentrated in vacuo to give 1-(propane-2-sulfonyl)-piperazine.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10](=[O:23])[O:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=3)=[N:13][C:8]=2[CH:7]=1)(=[O:4])[CH2:2][CH3:3].[CH2:26]([OH:29])[CH2:27][CH3:28].O1CCOCC1.[OH2:36]>>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]([NH:13][C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][C:9]=2[C:10]([O:29][CH2:26][CH2:27][CH3:28])=[O:23])=[O:11])=[CH:19][CH:18]=1)([OH:22])=[O:36]
Reactant: CCCO
Reactant: CCC(=O)Nc1ccc2c(=O)oc(-c3ccc(C(=O)O)cc3)nc2c1
Reactant: O
Solvent: C1COCCO1
Product: CCCOC(=O)c1ccc(NC(=O)CC)cc1NC(=O)c1ccc(C(=O)O)cc1
Yield: 80 %

Procedure:
The procedure of Example 1 was repeated for reacting 7-(propionamido)-2-(4-carboxyphenyl)-4H-3,1-benzoxazine-4-one with n-propanol, and the reaction product was treated as in Example 1 except that the solvent for recrystallization was a mixture of dioxane and water. The product obtained was a 80% yield of propyl 2-(4-carboxybenzamido)-4-propionamidobenzoate having a melting point in the range of from 233° to 235° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=O.[K+].[K+]>[Cu]>[OH:12][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[O:8])=[N:7][CH:2]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Product: Cc1cccc(=O)n1-c1ccc(CO)cn1
Reaction time: 8 h

Procedure:
2-bromo(5-hydroxymethyl)pyridine (3.00 g, 15.95 mmol), 6-methylpyridone (2.08 g, 19.14 mmol), Copper (2.64, 19.14 mmol) and K2CO3 (0.635 g, 10.0 mmol) were heated at 140° C. for 3 hrs. Added CHC13 to reaction when still warm and let stirred overnight. Filtered the mixture through a frit, concentrated in vacuo and the residue was chromatographed (silica gel, 0-4% MeOH-EtOAc solution). Obtained the title compound as a brown oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:38]=[N:37][C:36](Cl)=[CH:35][N:34]=1.O>CN1C(=O)CCC1>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[N:37][CH:38]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(Cl)cn2)c1
Temperature: 180 °C

Procedure:
To a solution of N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 100 mg, 0.31 mmol) in NMP (1.0 ml) was added DIPEA (160 mg, 1.24 mmol) and 2,5-dichloropyrazine (CAS number 19745-07-4; 92 mg, 0.62 mmol). The resulting reaction mixture was stirred and heated under microwave irradiation at 180° C. for 15 minutes. Upon completion, the reaction mixture was poured into water (3 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1Cl)(=[O:3])[CH3:2].[BH4-].[Na+].[OH:12]C(C1OC=CC=1Cl)C.BrBr>CO.O>[CH3:8][C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:12])[C:1]=1[OH:3]
Reactant: CC(O)c1occc1Cl
Reactant: CC(=O)c1occc1Cl
Agent: BrBr
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Acetyl-3-chloro-furan (1.0 g, 7 mmoles) in 30 ml methanol was cooled to 10° C. and 0.065 g, (1.7 mmoles) of NaBH4 added in one portion. After stirring for 30 minutes at 25° C., the solution was treated with 15 ml of water and cooled to 5° C. To the formed 2-(1-hydroxyethyl)-3-chloro-furan was then added 1.1 g (7 mmoles) of bromine, dropwise and with cooling. After the addition was complete the reaction was heated to 95° C. for 2 hours, distilling off a portion of the methanol. The reaction was then cooled and maltol isolated by the method of Example 1.