Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1c2ccccc2[nH]c2cc(O)cc(O)c12
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=c1c2ccccc2[nH]c2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
Trifluoromethanesulfonic anhydride (3.1 mL, 18.4 mmol) was slowly added to a solution of 1,3-dihydroxy-10H-acridin-9-one (4.0 g, 17.6 mmol), and 2,6-lutidine (65 mL) in CH2Cl2 (180 mL) at 0° C. See J. Reisch et al., Liebigs Ann. Chem., pp. 685-689 (1991). The reaction then was allowed to slowly warm to room temperature. After 16 h, the reaction was concentrated, redissolved in EtOAc (250 mL), and washed with 10% citric acid (5×50 mL) water (2×25 mL), and brine (2×25 mL). The organics then were dried (Na2SO4), filtered, and concentrated. The crude material then was purified via Biotage chromatography using 5% EtOAc/hexanes as eluent to yield 1.77 g (28%) of trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9,10-dihydro-acridin-3-yl ester as an orange solid. Rf=0.50 (50% EtOAc/hexanes). 1H NMR (DMSO-d6, 400 MHz) δ: 12.45 (s, 1H), 8.25 (d, 1H), 7.87 (dd, 1H), 7.59 (d, 1H), 7.40 (dd, 1H), 6.99 (s, 1H), 6.67 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[CH3:34][N:35]1C(=O)CCC1>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([C:34]#[N:35])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C#N)cc32)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (0.860 g, 1.60 mmol, intermediate 53), zinc cyanide (0.112 g, 0.96 mmol), Pd2(dba)3 (0.293 g, 0.320 mmol), and dppf (0.443 g, 0.80 mmol) in NMP (6.5 mL) under nitrogen was stirred at rt for 0.5 h and at 100° C. overnight. After cooling to rt, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×), brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting with mixtures of hexane and EtOAc, to provide the title compound. LC/MS: m/e 487.2 (M+H)+. NMR (500 MHz, CDCl3): δ 7.94 (1H, d, J=1.6 Hz), 7.66 (1H, d, J=7.5 Hz), 7.53 (1H, dd, J=8.4, 2.0 Hz), 7.19 (1H, d, J=7.3 Hz), 7.13 (2H, d, J=8.7 Hz), 7.04 (1H, s), 6.94 (2H, d, J=8.6 Hz), 6.83 (1H, d, J=8.5 Hz), 4.70-4.90 (2H, br), 1.26 (9H, s).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].N(OC(C)(C)C)=O.[I:18]I.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([I:18])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: II
Reactant: N#Cc1cc(Br)ccc1N
Agent: CC(C)(C)ON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(Br)ccc1I
Reaction time: 1 h
Yield: 65 %

Procedure:
2-amino-5-bromobenzonitrile (100 g, 0.5 mol) was added during 1 hour to tert-butyl nitrite (117 mL, 0.75 mol) and iodine (250 g, 1.1 mol) in dry acetonitrile (600 mL) under nitrogen while maintaining the temperature between 30° C. and 35° C. Stirring was continued for 60 minutes at 23° C. Subsequent addition of saturated aqueous Na2SO3 (2 L) gave precipitate which was collected by filtration, and washed with hexanes to obtain 100 g (65%) of 5-bromo-2-iodobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.64 (dd, J=2.4, 8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10](CC2C=CC(OC)=CC=2OC)[CH2:9][C:8]2[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][S:24][C:7]=2[C:6]1=[O:32])=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][S:24][C:7]=2[C:6]=1[OH:32])=[O:4]
Reactant: COC(=O)C1C(=O)c2scc(-c3ccc(F)cc3)c2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc2c(-c3ccc(F)cc3)csc2c1O
Reaction time: 5 h
Yield: 61.3 %

Procedure:
5-(2,4-dimethoxy-benzyl)-3-(4-fluoro-phenyl)-7-oxo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (0.39 g, 0.86 mmol), example 31-e, was dissolved in 6 mL of anhydrous dichloromethane. To the solution was added 93.7 μL of thionyl chloride, and the reaction mixture was stirred for 5 hours. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to produce 0.16 g of a white solid. MS: (+) m/z 304.0 (M+1)
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[CH:18]([C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)=O.O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[CH:18][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:39])[CH3:40])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)[CH3:3]
Reactant: CCCOc1c(-c2cccc3sc(C=O)cc23)cc(C(C)C)cc1C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(-c2cccc3sc(C=C(F)C(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl phosphonofluoroacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[C:5](/[N+:10]#[C-:11])=[CH:6]/[N:7]([CH3:9])C)[CH3:2].[CH:13]1(N)[CH2:16]C[CH2:14]1>>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[CH:11][N:7]([CH:9]2[CH2:16][CH2:13][CH2:14]2)[CH:6]=1)=[O:12])[CH3:2]
Reactant: NC1CCC1
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Product: CCOC(=O)c1cn(C2CCC2)cn1
Temperature: 70 °C

Procedure:
The stirred mixture of (Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester (17.0 g, 100 mmol) and cyclobutaneamine (21.79 g, 300 mmol) was heated for 2.5 h at 70° C. The reaction mixture was cooled to rt and concentrated. The residue was purified by flash chromatography (EtOAc/hexane, 5:1) to afford the title compound as an orange oil. tR: 0.70 min (LC-MS 2); ESI-MS: 195.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 8.03 (s, 1H), 7.83 (s, 1H), 4.73 (m, 1H), 4.18 (q, 2H), 2.36 (m, 4H), 1.74 (m, 2H), 1.24 (t, 3H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: Cc1cccc(O)c1NC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc12

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-6-methylphenyl)-2-fluoro-5-nitrobenzamide (667 mg, 2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) the subtitle compound was obtained (327 mg, 52%). 1H NMR (DMSO) δ 8.92(m, 1H), 8.50(m, 1H), 7.82–7.74(m, 2H), 7.70(s, 1H), 7.33(dd, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)C.CC(C[AlH]CC(C)C)C>>[O:9]1[CH2:10][CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH:4]=[O:3])[CH2:8]1
Reactant: CCOC(=O)CCC1CCCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: O=CCCC1CCCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of ethyl-3-(tetrahydro-2H-pyran-3-yl)propionate (3.0 g) was, at -78° C., added dropwise DIBAL (16 ml of 1.5 mole toluene solution) under a nitrogen atmosphere. Stirring was continued for one hour. The reaction was quenched by adding a methanol-water mixture. The resulting solution was allowed to warm up to room temperature. The solids which formed were removed. The filtrate was dried over magnesium sulfate and concentrated to yield a crude oil. The crude product was purified by distillation to yield 2.0 g of the title compound.
Reaction SMILES: CO.[C:3](=[O:6])(O)[O-].[Na+].[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10].C(=O)=O>O>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([O:6][CH3:3])[N:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)nc(Cl)n1
Yield: 58 %

Procedure:
To 200 ml. of methanol and 25 ml. of water were added 33.6 g. (0.4 mole) of sodium bicarbonate and 36.8 g. (0.2 mole) of cyanuric chloride. This mixture was stirred at 30°C. for 30 minutes until the evolution of carbon dioxide had nearly ceased, and water was then added. The crystalline solid which separated was filtered, washed with water, and dried in a vacuum desiccator. The yield of crude 2,4-dichloro-6-methoxy-s-triazine was 10.5 g. (58% yield), m.p. 87°-89°C. After recyrstallization of the product from heptane, the m.p. was 88°-90°C.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C1C(=O)N([I:31])C(=O)C1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[C:5]([F:23])=[C:6]([F:22])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:31])=[CH:17][C:16]=2[F:21])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-acetyl-2-(2-fluorophenylamino)-3,4-difluorobenzoate (0.47 mmol, 0.16 g) in DMF (10 ml) was added NIS (0.56 mmol, 0.13 g) and TFA (0.10 ml), and the reaction was stirred at room temp overnight. The crude was diluted with EtOAc and washed with H2O. The organic fraction was dried over MgSO4 and concentrated under reduced pressure to yield the desired product in 90% (0.23 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]([OH:12])=O)=[N:3][CH:2]=1.[C:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[NH:14][NH2:15]>>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]([NH:15][NH:14][C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[O:12])=[N:3][CH:2]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(O)c1ncnc2[nH]ccc12
Product: O=C(NNC(=O)c1ncnc2[nH]ccc12)OCc1ccccc1
Yield: 83 %

Procedure:
In the same manner as in Reference Example 1 and using 7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid instead of benzothiazole-6-carboxylic acid and benzyl carbazate instead of tert-butyl carbazate, the title compound (yield 83%) was obtained as colorless crystals.
Reaction SMILES: S(O)([O:4][CH2:5][CH2:6][NH2:7])(=O)=O.[OH-].[Na+].[CH2:11]([O:18][CH2:19][CH:20]1[CH2:22]O1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:18][CH2:19][CH:20]1[O:4][CH2:5][CH2:6][NH:7][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(COCC2CNCCO2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
199 g of 2-aminoethyl hydrogen sulfate are added to 164 ml of 70% sodium hydroxide solution, the solution is heated to 50° C. and added dropwise to a solution of (RS)-benzyloxymethyloxirane in 280 ml of methanol. After 1 hour at 50° C. a further 280 ml of 70% sodium hydroxide solution are added thereto and the solution is stirred overnight. Then, the reaction mixture is poured on to ice and extracted with toluene. The organic phase is washed with water, dried and evaporated. After distillation there are obtained 26.8 g of rac-2-benzyloxymethylmorpholine, MS: M+ -91=116 (benzyl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1.Cl[CH2:21][CH2:22][N:23]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[CH2:24][CH2:25]Cl>>[CH2:18]([O:17][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[CH2:25][CH2:24][N:23]([C:27]4[CH:36]=[CH:35][C:30]5[O:31][CH2:32][CH2:33][O:34][C:29]=5[CH:28]=4)[CH2:22][CH2:21]3)[CH:7]=[N:8][C:9]=2[CH:14]=1)=[O:16])[CH3:19]
Reactant: ClCCN(CCCl)c1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1ccc2c(c1)ncn2CCCCN
Product: CCOC(=O)c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1

Procedure:
Analogously to Example 3, reaction of 1-(4-aminobutyl)-5-ethoxycarbonylbenzimidazole with 6-(N,N-bis(2-chloroethyl)amino)-1,4-benzodioxane ("B") gives 6-[4(4-(5-ethoxycarbonylbenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>O1CCOCC1>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: C=Cc1ccccn1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Solvent: C1COCCO1
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccccn2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.0 g-see Preparation 8), 2-vinylpyridine (0.5 g) and 1,4-dioxane (10 ml) was heated under reflux for 20 hours. On cooling to room temperature the mixture was filtered and the filtrate was diluted with water (100 ml) then extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a brown oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.31 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1.[I-].[K+]>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][N:47]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (6.0 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.4 g), diisopropylethylamine (5.1 ml), 1-(3-chlorophenyl) piperazine (4.9 g) and potassium iodide (0.3 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 18 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine twice, and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel) afforded 3.4 g of 5-[3-(4-(3-chlorophenyl) -1-piperazinyl) propyl]-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The hydrochloride was prepared in methanol with ethereal HCl. The precipitate was filtered and washed with anhydrous ether, m.p. 104°-106° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:27][C:25](=[O:26])[CH2:24][CH2:23]1.CC(C)([O-])C.[K+]>[OH-].[Na+]>[OH:12][C:10]1[C:9]2[C:8](=[N:17][CH:16]=[CH:15][CH:14]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25](=[O:26])[C:24]=1[CH2:23][CH:22]([OH:27])[CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Reactant: CCCCC1CCC(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Product: CCCCC(O)Cc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 95 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-phenylaminonicotinate (5 g.), gamma-octanoic lactone (10 g.) and potassium t-butoxide (7.5 g.) was stirred in a nitrogen atmosphere and heated to 95° C. where it was held for 6 hrs. After cooling, the mixture was poured into 5% NaOH (200 ml.) and stirred overnight. Acidification to pH 4.6 yielded an oil, which was extracted with ether, washed with water, dried (Na2SO4), filtered, and evaporated to a small volume. Hexane was added until turbidity was noticed, and the mixture was allowed to stand for about 5 hrs. The solid was filtered off and recrystallized from CH2Cl2 /isopropanol/isopropyl ether to produce the desired product, m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].Cl.Cl.[NH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[N:38]([CH3:40])[CH3:39]>CCCCCCC.C(OCC)(=O)C>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([N:38]([CH3:40])[CH3:39])=[C:31]([NH:30][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:36]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: CN(C)c1ccc(Cl)cc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C)c1ccc(Cl)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate), (2-amino-4-chlorphenyl)dimethylamine dihydrochloride (commercially available, CAS RN 183251-88-9), using 5 mole equivalents of base and using a gradient of n-heptane:ethyl acetate (100:0 to 50:50) for the chromatographic purification. White solid (72%). MS (ESI): m/z=436.038 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCCCS(C)(=O)=O)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCCCS(C)(=O)=O)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 858.4 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[3-(methylsulfonyl)propoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (0.11 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.9 g, 80%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH:33][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:32])[CH2:27][CH2:26]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CN1CCC(C(N)=O)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)CC1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
A mixture of Example A1 (0.25 g, 0.994 mmol), Cs2CO3 (0.486 g, 1.490 mmol), 1-methylpiperidine-4-carboxamide (0.155 g, 1.093 mmol), and X-phos (0.024 g, 0.050 mmol) in dioxane (5 mL) was sparged with Ar, treated with Pd2(dba)3 (0.045 g, 0.050 mmol) and heated at 90° C. overnight. Additional X-phos (17 mg) and Pd2(dba)3 (30 mg) were added and the mixture heated at 90° C. for 7 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (200 mg, 56%). MS (ESI) m/z: 358.2 (M+H+).