Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].[CH3:9]C(C)([O-])C.[K+].[F:15][C:16]([F:23])([F:22])S(OC)(=O)=O.Cl>O1CCCC1>[CH3:9][N:1]1[C:6]([C:16]([F:23])([F:22])[F:15])=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of pyrimidine-2,4-dione (158 mg, 0.88 mmol) in anhydrous tetrahydrofuran (1 ml) was added dropwise to a suspension of potassium tert-butoxide (99 mg, 0.88 mmol) in tetrahydrofaran (2 ml) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Methyl trifloromethanesulfonate (100 μl, 0.88 mmol) was added dropwise to the reaction mixture with ice-cooling. This mixture was stirred at the same temperature for 12 hours. The reaction mixture was poured into 1N hydrochloric acid, and then this was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=8/2 as the eluant to give the title compound (105 mg, yield 62%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]([CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>CO.O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Yield: 54.4 %

Procedure:
Diethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidenemalonate (9.55 g, 21.3 mmol) obtained in Example 54 was dissolved in methanol (48 ml) and tetrahydrofuran (32 ml). 5% Palladium carbon (1 g) was added and the mixture was vigorously stirred at normal temperature under a hydrogen atmosphere (3.1 kgf/cm2). One and a half hours later, the catalyst was filtered off. The solvent was evaporated to give a crude solid. Recrystallization from ethyl acetate-hexane gave the title compound (5.23 g, yield 55%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[O:29].CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:34]=[C:33]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[O:29]
Reactant: CN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ccc(-c4ccc(C(N)=O)c(F)c4)n4ncnc34)cc2)CC1
Temperature: 110 °C
Yield: 18.4 %

Procedure:
A suspension of (5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (50 mg, 146 μmol), 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (97 mg, 360 μmol), Pd(PPh3)4 (51 mg, 40 μmol) and NaOtBu (56 mg, 580 μmol) in 1.2 mL of DMF/water (5:1, degassed) is degassed for 1 min in a sealed tube. The tube is sealed and the reaction mixture heated at 110° C. for forty minutes in the microwave (CEM explorer) and then at the same temperature for thirty minutes in an oil bath. After evaporation of the solvents the residue is taken up in dichloromethane, filtered and evaporated. The crude product is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 97:3 to 90:10) and triturated (3× with ethyl acetate) affording the title compound (12 mg) as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:33])[CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:20][N:21]([CH3:33])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:32]=1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CN(C)CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(2-dimethylaminoethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-2-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]ethanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:18])[CH3:16])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:18])[CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(C)[C@@H]2CCNC[C@H]2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 199.4 %

Procedure:
To a solution of tert-butyl (3R,4R)-3-(3,4-dichlorophenyl)-4-{[(4-methoxyphenyl)carbonyl](methyl)amino}piperidine-1-carboxylate (700 mg) obtained in Example 169 in ethyl acetate (5 mL) was added 4N hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure to give (3R,4R)-3-(3,4-dichlorophenyl)-4-{[(4-methoxyphenyl)carbonyl](methyl)amino}piperidine monohydrochloride (608 mg, 99%) as a white powder.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:17]=[CH:16][C:10]2[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=2[CH:8]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([Cl:6])[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1cc2c(Cl)ncnc2cn1
Reaction time: 1 h

Procedure:
DMF (0.1 ml) was added to 6chloro-3H-pyrido[3,4-d]pyrimidin-4-one (1.82 g, 10 mmol) followed by dropwise addition of thionyl chloride (10 ml). The flask was fitted with a condenser and a drylng tube and the contents heated to reflux for ˜20 minutes whereupon the solids dissolved. The heating was continued for a further 1 h and then cooled. Toluene was added to wash the sides of the flask and the solvents were evaporated in vacuo. Azeotroping with toluene was repeated twice and the crude so obtained was taken through to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH:11]1([C:14]2([F:18])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][C:14]([CH:11]3[CH2:13][CH2:12]3)([F:18])[CH2:15]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC1(C2CC2)CN(c2cc(Cl)nc(Cl)c2)C1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A solution of 2,4,6-trichloropyridine (3.0 g, 16.4 mmol), 3-cyclopropyl-3-fluoroazetidine hydrogen chloride (2.49 g, 16.4 mmol) and DIPEA (7.09 ml, 41.0 mmol) in ethanol (40 ml) was heated under reflux for 1 h. Reaction mixture cooled to room temperature then concentrated to dryness in vacuo. Crude product purified by flash chromatography on silica (0 to 100% EtOAc:petrol) to give title compound as a white solid (1.56 g, 36%). 1H NMR (CDCl3) 0.52-0.48 (2H, m), 0.72-0.67 (2H, m), 1.42-1.31 (1H, m), 3.91 (2H, ddd), 4.05 (2H, ddd), 6.20 (2H, s). ES+ 261.30.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C.CN(C=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]2)=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)CCNC(=O)C1CCCNC1
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)C1CCCN(C(=O)c2sc(NC(=N)N)nc2C)C1
Yield: 65.7 %

Procedure:
220 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 265 mg of ethyl (RS)-3-[(piperidine-3-carbonyl)-amino]-propionate hydrochloride, 3 ml of DMF, 0.34 ml of N-methylmorpholine (N-MM) and 569 mg of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) are stirred at RT for 22 hours. The reaction mixture is diluted with ethyl acetate and washed firstly with a dilute aqueous solution of sodium carbonate and sodium chloride, then with dilute sodium chloride solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated in a vacuum. Chromatography on silica gel with ethyl acetate: ethanol 5:1 gives 270 mg of ethyl (RS)-3-[[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-piperidine-3-carbonyl]-amino]-propionate as a pale yellow foam. MS: 411 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH2:37]([NH:39][CH3:40])[CH3:38]>ClCCCl>[CH3:36][N:34]([CH3:35])[CH2:33][CH2:32][N:17]1[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=2)[N:20]=[C:16]1[CH:13]1[CH2:12][CH2:11][N:10]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[CH2:8][N:39]([CH2:37][CH3:38])[CH3:40])[CH2:15][CH2:14]1
Reactant: CCNC
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Solvent: ClCCCl
Product: CCN(C)Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde (90.00 mg; 0.18 mmol; 1.00 eq.) in 1 ml DCE added ethyl-methyl-amine (0.02 ml; 0.19 mmol; 1.05 eq.) and sodium p-triacetoxyborohydride (113.20 mg; 0.53 mmol; 3.00 eq.), stirred for overnight at RT, lc-ms showed desired (<30%, major ms 618/619), purified by prep HPLC, collected title compound. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: [O:1]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1>[OH-].[Na+]>[O:1]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccc(NC(=O)C(=O)OCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)Nc1ccc(Oc2ccc(NC(=O)C(=O)O)cc2)cc1

Procedure:
Diethyl N,N'-(oxydi-p-phenylene)dioxamate (2.0 gm.) is stirred at room temperature for three hours in 1.0 N sodium hydroxide (50 ml.). The solid is collected by filtration and dissolved in water. The pH is adjusted to pH=3 with concentrated hydrochloric acid and the desired product collected by filtration (1.6 gm., mp >320°).
Reaction SMILES: [Cl:1][C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[C:9]([C:17]1[CH:18]=[CH:19][C:20]([N+:27]([O-:29])=[O:28])=[C:21]([CH:23](C)[CH2:24]O)[CH:22]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[C:9]([C:17]1[CH:18]=[CH:19][C:20]([N+:27]([O-:29])=[O:28])=[C:21]([CH:23]([CH3:24])[CH2:5][O:4][C:2]([Cl:1])=[O:3])[CH:22]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(CO)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COC(=O)Cl)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trichloromethyl chloroformate (15.83 g, 80 mmol, 0.8 equivalents) in dry tetrahydrofuran (150 mL), which has been pre-cooled to 0° C., was added over a period of approximately 2 hours a solution of 2-(5-benzoyl-2-nitrophenyl)-1-propanol (41) (28.53 g, 100 mmol) and triethylamine (10.12 g, 100 mmol) in tetrahydrofuran (250 mL) with continued cooling. After stirring for 1 hour at ambient temperature the resulting suspension was filtered, the filter cake was washed with a little tetrahydrofuran, and the combined organic phases were concentrated in vacuo to give 19f as yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24](O)=[O:25])=[CH:18]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.O1CCCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:2][C@@H:3]1[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]1=[O:13])=[O:25])=[CH:18]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H]1Cc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Alternatively, (R)-3-amino-3,4-dihydrocarbostyril hydrochloride (95 mg) was added to a mixture of tetrahydrofuran (10 mL), 5-chloroindole-2-carboxylic acid (103 mg), 1-hydroxy-7-azabenzotriazole (85 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (120 mg) at room temperature. Diisopropylethylamine (186 mg) was added, and the resulting yellow suspension was stirred for 2 h, during which a solution formed. The solution was diluted with ethyl acetate (50 mL) and washed sequentially with 1.0 M aqueous hydrochloric acid (25 mL), 1.0 M aqueous sodium hydroxide (25 mL), and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with diethyl ether (5 mL twice), then 50% methanol in diethyl ether (5 mL twice). Drying under vacuum provided pure title compound (132 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[C:2]1([C:1]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[C:26]=2[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)OC(C)(C)C)c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 16 h
Yield: 115.3 %

Procedure:
To a stirred solution of 2.30 g of compound I in 175 cc of methanol was added 0.39 g of sodium methoxide at room temperature and the mixture was stirred for 16 hours. The methanol was distilled off and to the residue was added water, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and distilled to remove the solvent. The resulting crude product was dissolved in 50 cc of benzene, followed by adding dropwise thereto 1.41 cc of pyridine and then 0.52 g of thionyl chloride at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was dried over magnesium sulfate and distilled to remove the solvent the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to obtain 2.55 g of compound J. Yield: 80.2%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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.CN(C)C(=O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(F)cc1-c1ccccc1F
Temperature: 110 °C
Reaction time: 6 h
Yield: 93.8 %

Procedure:
To a solution of 2-bromo-4-fluoronitrobenzene (1.500 g, 6.8 mmol), 2-fluorophenylboronic acid (1.145 g, 8.2 mmol), N,N-dimethylacetamide (50 mL), and 2.0 M aqueous potassium carbonate (10 mL) under argon was added tetrakis(triphenylphosphine)palladium (0) (0.394 g, 0.3 mmol). The mixture was stirred at 110° C. for 6 hrs. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100 mL) and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% methylene chloride/hexanes) to afford a light yellow oil (1.5 g, 94%). 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, 1H, J=9.0, 5.1 Hz), 7.44 (m, 1H), 7.34 (td, 1H, J=7.5, 2.1 Hz), 7.31-7.10 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][C:13]([Cl:30])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:13]([Cl:12])([Cl:29])[C:14]([N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:25]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)(=[O:27])=[O:26])[CH:22]=2)[CH2:17]1)=[O:15]
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(N1Cc2ccc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)cc2C1)C(Cl)(Cl)Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
To a solution of 4-trifluoromethyl aniline (213 μL, 1.70 mmol) in pyridine (270 μL) was added 2-(trichloroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride (617 mg, 1.70 mmol) at room temperature, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with 1 mol/L hydrochloric acid, brine and water. The organic layer was dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a colorless powder (586 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[Cl-].[NH4+]>O1CCCC1>[CH3:2][C:3]1[CH:5]=[CH:7][S:8][C:4]=1[C:5]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2][O:6]1
Reactant: O=C(CCCCl)c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccsc1C1(c2cccs2)CCCO1
Temperature: 25 °C
Yield: 138.4 %

Procedure:
The reaction mixture was kept under reflux for 1 h after the exotherm had subsided and cooled to ambient temperature. To the reaction mixture was added 27.85 g of 4-chloro-1-(2-thienyl)-butan-1-on in 75 ml of anhydrous tetrahydrofuran. The reaction mixture was heated at reflux for 0.5 h, cooled and 175 ml of saturated ammonium chloride solution was introduced, and the mixture was extracted with 3×200 ml of ethyl acetate. The combined extracts were dried (MgSO4) and evaporated to an oil. Flash chromatography on silica gel (Art. 9385) eluting with heptane/ethyl acetate (40:1) provided 2-(3-methylthien-2-yl)-2-(thien-2-yl)tetrahydrofuran (25.58 g, 69%) as an oil.
Reaction SMILES: [CH3:1][CH:2]([N:12]([CH3:14])[CH3:13])[CH2:3][CH2:4]OC1C=CC=CC=1.[BrH:15]>C(Cl)(Cl)Cl>[BrH:15].[CH3:1][CH:2]([N:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Br:15]
Reactant: CC(CCOc1ccccc1)N(C)C
Agent: Br
Solvent: ClC(Cl)Cl
Product: CC(CCBr)N(C)C
Yield: 79 %

Procedure:
5 g of the 1-methyl-3-phenoxypropyldimethylamine thus obtained was reacted with 30 ml of 40% hydrobromic acid at 150° C. for 7 hours with stirring. The reaction solution was cooled and added with 20 ml of chloroform, and then the hydrobromic acid layer was separated from the chloroform layer. The hydrobromic acid was removed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 4.46 g of 1-methyl-3-bromopropyldimethylamine hydrobromide in a yield of 79%.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([Br:60])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([Br:60])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-bromo-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (29 mg, 81%). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.46 (s, 1H), 7.44-7.31 (m, 7H), 7.14-7.10 (m, 2H), 4.02 (s, 3H), 2.40-2.32 (m, 2H), 2.13-2.03 (m, 2H), 2.03-1.94 (m, 1H), 1.70-1.60 (m, 1H). LCMS (Method E): RT=3.87 min, [M+H]+=476/478.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccccc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2-chloroaniline to yield 2-[(2-chlorophenyl)amino]phenylacetic acid.