Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:34][C:33]([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:32][CH:31]=1)CCC.CN(C)C=O>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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:30]3[O:34][C:33]([Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[N:32][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine)palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17]>[OH-].[Na+]>[NH:1]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.7 g (30 mmol) of H-Phe(4-CN)—OH were dissolved in 100 ml of 1M NaOH with addition of 2M NaOH to pH=10 with ice cooling. With vigorous stirring, allyl chloroformate (7.5 ml) was slowly added (pH kept at 10 by 2M NaOH). The reaction mixture was stirred at 0° C. for 15 min and at RT for 30 min, acidified with HCI to pH=2, extracted with ethyl acetate (3 times), dried with MgSO4, and evaporated. The residue was recrystallized from ethyl acetate/hexane to give a white solid. Yield: 7.0 g (85%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C=O.[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>Cl>[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Reaction time: 1.25 h
Yield: 42.6 %

Procedure:
To a flask charged with anhydrous aluminum chloride (128.1 g, 0.961 mol) was added dropwise neat dimethylformamide (21 mL, 0.27 mol) at a rate such that the internal temperature remained below 70° C. The resulting mixture was thoroughly mixed. To the stirred thick mixture was added in ten portions a mixture of acetanilide (13.53 g, 0.100 mol) and succinic anhydride (10.01 g, 0.100 mol) that had been preground together with a mortar and pestle. The addition rate was controlled to keep the internal temperature at less than or equal to 72° C. The resulting mixture was stirred at 65° C. to 70° C. for 1.25 hours, then poured hot onto ice (1.0 kg). The mixture was acidified with concentrated hydrochloric acid (60 mL), and the resulting solids were filtered. The filtercake was washed with 0.05 M hydrocloric acid and allowed to air dry overnight. The filtercake was suspended in hot water (93 mL), methanol (120 mL) was added, and the hot cloudy solution was gravity filtered. The filtrate was boiled down to 100 mL volume and allowed to cool. The solids were filtered, washed with water-methanol, and dried in vacuo to give 10.03 g of 4-(4-acetylamino-phenyl)-4-oxo-butyric acid as a tan solid.
Reaction SMILES: O.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7].[OH-].[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]([NH:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)CC[C@H](NC(=O)CCl)C(=O)O
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixed solvent of 1750 ml of water and 497 ml of toluene was added 733.7 g (5 mol) of L-glutamine at room temperature. The solution was cooled to 0° to 5° C. and adjusted to pH 11 with 5N sodium hydroxide. To the solution was added dropwise a solution of 565.3 g (5 mol) of chloro-acetyl chloride in 497 ml of toluene while maintaining the pH of the reaction mixture at 11 with 5N sodium hydroxide. After stirring at 0° to 5° C. for 1 hour, toluene was removed from the reaction mixture by liquid-liquid separation. The aqueous layer separated was adjusted to pH 2 by addition of 410 ml of concentrated hydrochloric acid. After seeding, the reaction mixture was subjected to crystallization at room temperature for 1 hour and then at 0° to 5° C. for 3 hours. The resulting crystals were collected by filtration and dried under reduced pressure to give 992.6 g (89.2 mole percent (mol %) yield) of crude N-chloroacetyl-L-glutamine (sodium chloride content: 13.6 weight percent (wt %)). The crystals were analyzed by high performance liquid chromatography (HPLC) (column: Shim-pack CLC-ODS, 6 ×150 mm (manufactured by Shimadzu Corporation); eluent: 0.01M sodium 1-octanesulfonate/0.01M KH2PO4 buffer (pH 2.5)/1% methanol; detection: UV 210 nm). The purity of the crystals was found to be 99.0% as calculated from the HPLC relative area ratio.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1C(O)=O)=[O:7])(C)(C)C.C([N:45](CC)CC)C>C1C=CC=CC=1.O1CCOCC1>[NH2:45][CH:19]1[CH:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:6]([OH:5])=[O:7])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]1[C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1
Reactant: CCN(CC)CC
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(C(=O)O)C2c1ccc2c(c1)OCO2
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(N)C2c1ccc2c(c1)OCO2
Temperature: 75 °C
Yield: 45.2 %

Procedure:
(1RS,2SR,3RS)-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry benzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. The reaction mixture was then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4 anhyd.), filtered and evaporated to give the corresponding isocianate as a colorless oil. After purification by column chromatography (silica gel, ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained was dissolved in 1 M HC1 in dioxane (3 mL) and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give a colorless oil that was purified by HPLC (1:1 CNCH3 :H2O (containig 0.1% TFA)) to produce the desired product (40 mg, 42%) as an off-white solid, m.p. 181-182° C. (dec).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][CH2:22][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:29]([NH:33][C:17]([C:14]1[CH:15]=[C:16]2[C:11]3=[C:12]([CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][CH2:22][N:10]3[CH2:9][CH2:8][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)=[O:19])[CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCNC(=O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxylic acid (14), (189 mg, 0.512 mmol) in dicloromethane (10 mL) were added butyl amine (0.027 mL, 0.512 mmol), EDCI (196 mg, 1.02 mmol), followed DMAP (4-(Dimethylamino)pyridine) (70 mg, 1.02 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 25 to 30% EtOAc:Hexane to give N-butyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxamide (481), (113 mg 52%). 1H NMR (300 MHz, CDCl3) ppm 1H NMR (300 MHz, Solvent) ppm 0.87 (t, J=6.0 Hz, 3H) 1.17-1.38 (m, 2H) 1.36-1.52 (m, 2H) 2.03-2.17 (m, 2H) 2.18-2.36 (m, 2H) 3.06-3.37 (m, 6H) 4.21 (t, J=5.27 Hz, 2H) 5.61-5.75 (m, 1H) 7.03-7.16 (m, 4H) 7.17-7.37 (m, 8H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.CN([CH:17]=[O:18])C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:17][OH:18])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1ccc(F)cn1
Temperature: -78 °C
Yield: 90 %

Procedure:
At −78° C. under nitrogen, add n-butyllithium (2.5 M in hexane, 16.4 mL, 40.9 mmol) via syringe to a solution of 2-bromo-5-fluoro-pyridine (6.0 g, 34.1 mmol) in toluene (220 mL), while keeping the reaction temperature below −60° C. Stir the mixture at −78° C. and then add DMF (3.4 mL, 44.3 mmol) and stir for 1 h at this temperature. Warm to −10° C. and quench with methanol (10 mL). Concentrate the mixture to half of the volume in vacuo. Dilute with methanol (150 mL), cool the mixture to −78° C. and add sodium borohydride (3.2 g, 85.2 mmol) portion wise over 5 min. Warm the mixture to ambient temperature and stir for 2 h. Quench with water (10 mL) and remove the organic solvent in vacuo to obtain an oil/water mixture. Extract with diethyl ether (3×100 mL), dry the combined organic extracts, wash with brine, dry and concentrate in vacuo to obtain the desired intermediate as an oil (3.9 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24]>O.O1CCOCC1>[CH:38]1[C:39]2[CH:27]([CH2:26][O:25][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:24])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a stirred mixture of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) and Na2CO3 (0.90 g, 10.80 mmol) in water (10 mL) was added solution of FMOC-Cl (1.23 g, 4.77 mmol) in 1,4-dioxane (10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h then diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1N aqueous HCl (10 mL) to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (0.87 g) as an off-white solid. The crude product was used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:14][CH2:13][Br:12])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2ncccc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCOc1cccc2ncccc12
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A mixture of 5-hydroxyquinoline (0.3 g, 2.1 mmol), 1,2-dibromoethane (3.9 g, 21 mmol) and potassium carbonate (1.5 g, 11 mmol) in methyl ethyl ketone (15 mL) was allowed to stir at 85° C. for 24 h. The mixture was evaporated in vacuo and the residue was partitioned between ether (200 mL) and water (200 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound (0.53 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:11])[CH:12]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(c1ccc(Cl)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (0.6 g 1 eq) were dissolved in CH3CN (5 mL). Ca(OTf)2 (0.456 g, 0.5 eq) was added into the mixture. Reaction mixture was stirred at RT for overnight, then 80-85° C. for 8 h. After concentrating and adding EtOAc 20 mL to the residue, the organic phase was washed with H2O, dried over Na2SO4. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 1.01 g of desired product as a sticky oil (92% yield). * Note: During workup, the organic phase should be washed with H2O and Sat. NaCl solution. DO NOT was with saturated NaHCO3 solution!
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)CCO2
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorosulphonic acid (43.4 g, 0.366 mol) in DCM (10 mL) was added to a cold solution (5° C.) of 2,3-dihydrobenzofuran (20 g, 0.166 mol) in DCM (200 mL). After the addition the reaction was left with stirring at room temperature overnight. The reaction mixture was quenched with water (150 mL) keeping the temperature below 10° C. The organic phase was separated and washed with an aqueous solution of NaHCO3 (13.9 g dissolved in 150 mL of water). The organic solvents were evaporated to yield the title compound as a solid residue 3.3 g (23%). 1H NMR 270 MHz (CDCl3) δ ppm 3.32 (t, J=8.91 Hz, 2H) 4.75 (t, J=8.91 Hz, 2H) 6.90 (d, J=9.15 Hz, 1H) 7.78-7.90 (m, 2H)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Difluoro-1-nitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and DIPEA (2.2 mL, 12.57 mmol) added, followed by the dropwise addition of benzylamine (1.35 g, 12.57 mmol). The reaction mixture was stirred at RT, under an atmosphere of nitrogen overnight. The mixture was concentrated in vacuo to afford the title compound as a yellow oil, which solidified on standing (3.8 g, 100%). The crude material was used without purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 8.55 (1H, s), 8.25 (1H, dd, J=9.46, 6.08 Hz), 7.43-7.29 (5H, m), 6.47 (1H, dd, J=11.35, 2.60 Hz), 6.39 (1H, ddd, J=9.46, 7.28, 2.61 Hz), 4.51 (2H, d, J=5.60 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 2-amino-5-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 2-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O-].[Na+]>[Br-].C1([N+](C)(C)C)C=CC=CC=1.CN(C)C=O>[CH3:9][O:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1ncccc1O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1C
Yield: 16.8 %

Procedure:
A stirred solution of 3-hydroxy-2-methylpyridine (1.0 g, 9.2 mmol), phenyltrimethylammonium bromide (2.2 g, 11 mmol) and sodium methoxide (550 mg, 11 mmol) in dimethylformamide (10 ml) was heated under reflux for 3 hours, then the cool reaction mixture washed with water (40 ml) and extracted with ether (3×40 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure, then the residue purified by column chromatography on silica gel, using hexane:ethyl acetate (1:1) as eluant, to give the title compound (190 mg) as a solid. δ (CDCl3): 2.34 (3H, s), 3.68 (3H, s), 6.93 (2H, m), 7.94 (1H, d). LRMS: m/z 124 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl.Cl[CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(SCCN)cc1
Yield: 97 %

Procedure:
4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol.), K2CO3 (78.8 g, 0.57 mol) and diisopropyl ethylamine (32 mL, 0.178 mol) were mixed in 200 mL of THF. The mixture was degassed for 5 min. under reduced pressure and refluxed under argon overnight. The solvent was removed and water (300 mL) was added to the flask. The mixture was extracted with dichloromethane (3×200 mL). The organics were collected, dichloromethane was removed and 50 mL conc. HCl was added, followed by 200 mL of water. The solution was extracted with 1:1 EtOAc/hexane (3×200 mL). The aqueous layer was adjusted to pH 10 with 2 M NaOH, and was extracted with dichloromethane (3×200 mL). The combined organic solution was dried over anhydrous sodium sulfate. Removal of solvent provided 61 g of the target compound as a colorless liquid, with a yield of 97%.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:15].Cl>O.[Cu]Cl>[NH2:15][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: Cl[Cu]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid (5.00 g, 24.8 mmol), ammonium hydroxide (25.0 ml) and copper (1) chloride (50 mg) is heated hi a bomb at 125° for 20 hr and is then allowed to cool to 20°-25°. The solid residue is dissolved in water and the solution acidified with 3 N hydrochloric acid. The resultant mixture is filtered, washed, and dried to provide the 2-amino-3-nitrobenzoic acid, mp 201°-203; IR (mineral oil) 3478, 3345, 2954, 2925, 2855, 1692, 1677, 1571, 1559, 1520, 1512, 1442, 1271, 1259, 1130 cm-1 ; NMR (300 MHz, CDCl3 -MeOD) 8.38, 8.30, 6.66; MS (EI) m/e 182, 164.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:2]1)=[O:18]
Reactant: CN=C=O
Reactant: NC(=O)c1ccccc1OC1CNC1
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccccc2C(N)=O)C1
Reaction time: 24 h

Procedure:
To 8.0 g. (0.028 mole) of 2-(3-azetidinyloxy)benzamide stirring in 100 ml of dry benzene was added dropwise 1.6 g. (0.028 mole) of methylisocyanate with ice bath cooling. Stirring was continued at room temperature for 24 hours. The solid material was filtered and was recrystallized from 95% ethanol. The product (4.0 g., 57%) melted at 236°-240° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6′-bromo-1′-(1,1-dimethylethylsulfinamido)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (6) (62.8 mg, 0.129 mmol) in MeOH (5 mL) was added a 4 M HCl solution in dioxane (2 mL). The resulting mixture was stirred for 30 min. Solvent was removed under reduced pressure, and the residue 7 was used for next step without further purification. MS ESI+ve m/z 382 (M+H)+.