Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4Br)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccn1
Yield: 46.6 %

Procedure:
A mixture of 1.94 g of N-[4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-bromobenzamide, 2.95 g of 2-pyridyl tri-n-butyl tin and 400 mg of tetrakis(triphenylphosphine)palladium(O) is refluxed for 24 hours in degassed toluene for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 70% ethyl acetate:hexane to give 900 mg of the desired product as a pale yellow solid:M+1=485.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.CC(C)([O-])C.[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:21]=1[N+:27]([O-:29])=[O:28]>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[C:21]=2[N+:27]([O-:29])=[O:28])[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-fluoro-2-hydroxybenzoate (3.0 g) in tetrahydrofuran (65 mL) was added potassium t-butoxide (1.979 g) portion wise. The resulting solution was stirred at ambient temperature for 30 minutes and a solution of 1,3-difluoro-2-nitrobenzene (2.338 g) in tetrahydrofuran (15 mL) was added dropwise. After 1 hour, the reaction was heated at reflux for 18 hours. The reaction was quenched with water (10 mL), diluted with brine (75 mL) and extracted with methylene chloride (2×75 mL). The crude product was isolated by concentration and purified on silica gel, eluted with a 10, 20, 50% ethyl acetate in hexane step gradient to provide the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.CO.ClCCl>C1COCC1.[Ni]>[CH2:16]([C:5]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[CH2:14][NH:15][C:3](=[O:2])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(C2(Cc3ccccc3)CNC(=O)C2)c1
Reaction time: 13 h
Yield: 90.6 %

Procedure:
To a solution of 3-benzyl-3-cyano-3-(3-methoxy-phenyl)-propionic acid methyl ester (200 mg, 0.6 mmol) in THF (20 ml) was added Raney-Nickel (3×300 mg at 0/5/10 h). Hydrogenation occurred at 50° C. over 13 h. Methanol (15 ml) and dichloromethane (15 ml) was added, stirred for 15 min, then the mixture was filtered and the solvent evaporated. The oil was dissolved in dichloromethane, washed with HCl (1M) and brine. The organic layer was dried, filtered and the solvent evaporated. The residue was suspended in pentane, stirred over night, filtered and dried to obtain 153 mg of product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2].O.O[Li].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 40 °C
Yield: 25 %

Procedure:
Ethyl 2-[3-[[3-cyano-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (300 mg, 0.68 mmol, 1.0 eq) was dissolved in THF (20 mL). Water (10 mL) and LiOH.H2O (110 mg, 2.7 mmol, 4 eq) were added and the solution heated at 40° C. overnight. The THF was removed in vacuo and the aqueous phase acidified to pH 6 by addition of diluted HCl. The precipitate that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (70 mg, 25%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:43][O:44][CH2:45][CH2:46][OH:47]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][OH:23])=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:43][O:44][CH2:45][CH2:46][OH:47])=[O:7].[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:43][O:44][CH2:45][CH2:46][OH:47])=[O:6]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCCO)cc1F
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F

Procedure:
The title compound was prepared by reaction of 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino}benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by column chromatography on silica gel (50% EtOAc/PE as eluant) to give 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino}-N-(2-hydroxyethoxy)benzamide as a viscous transparent oil which was immediately dissolved in EtOH and treated with 1 M HCl according to the general procedure of Example 10, Step D. Purification of the resulting oil was carried out by filtration through a plug of silica gel (EtOAc as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(4-hydroxy-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide as a pale yellow crystalline solid (51%); m.p. (EtOAc/Et2O) 126–129° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.82 (br s, 1 H), 8.85 (br s, 1 H), 7.45–7.39 (m, 1 H), 7.25–7.17 (m, 2H), 7.07 (dd, J=8.3, 1.4 Hz, 1 H), 6.78 (dd, J=8.8, 8.8, 4.7 Hz, 1 H), 4.88 (t, J=5.6 Hz, 1 H), 4.73 (br s, 1 H), 3.85 (t, J=4.8 Hz, 2 H), 3.59–3.53 (m, 4 H), 2.53 (t, J=6.9 Hz, 1 H). Anal. calcd. for C19H17F3N2O4.0.25Et2O: C, 58.2; H, 4.8; N, 6.8. Found C, 58.1; H, 4.8; N, 7.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]([N+:31]([O-:33])=[O:32])=[C:21](Cl)[N:20]=1.C(O)(=O)C>C1COCC1.O>[Cl:18][C:19]1[N:20]=[C:21]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[C:22]([N+:31]([O-:33])=[O:32])=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:24]=1
Reactant: Nc1cncnc1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(Nc2cncnc2)nc(Cl)nc1N1CCOCC1
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
To 0.482 g (5.06 mmol) of 5-aminopyrimidine in THF (10 mL) was added 2.90 mL of NaHMDS (2 M solution in THF) at 0° C., and the mixture was stirred for 10 min. A solution of 0.5924 g (2.12 mmol) of 4-(2,6-dichloro-5-nitro-4-pyrimidinyl)morpholine (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) in THF (5 mL) was added, and the resulting mixture was stirred for 15 min. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, dried, and concentrated. Chromatography on silica, eluting with hexanes/EtOAc (8:2), gave 0.465 g (65% yield) of 2-chloro-6-(4-morpholinyl)-5-nitro-N-(5-pyrimidinyl)-4-pyrimidinamine as a white powder: 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 8.98 (s, 1H), 8.92 (s, 2H), 3.70 (t, J=4.8 Hz, 4H), 3.50 (t, J=4.8 Hz, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)CC2
Reactant: BrCC1CO1
Product: CCCc1c(OCC2CO2)ccc2c1OC(CCC(=O)OCC)CC2

Procedure:
The title compound was prepared by the method of Example 11 using 3.0 g (10.3 mmole) of the product of Example 27 and 1.3 ml (15 mmole) of epibromohydrin as starting materials. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([C:29](O)=[O:30])[CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:29]([C@@H:25]3[CH2:26][CH2:27][CH2:28][C@H:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:24]3)=[O:30])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of 4-(3,4-dichlorophenyl)piperazine (350 mg, 1.51 mmol), cis-3-(N-Boc-amino)cyclohexane carboxylic acid (368 mg, 1.51 mmol), HOBt (209 mg, 1.51 mmol) and EDC (291 mg, 1.51 mmol) was added dichloromethane followed by TEA (153 mg, 1.51 mmoL). Upon completion of addition, the resulting solution was allowed to stir overnight. At the conclusion of this period, the reaction mixture was concentrated and then purified via silica gel chromatography (20% to 50% EtOAc/hexanes) to provide the title compound (640 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:12])[CH3:2].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[CH3:12])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccc2)cc1C

Procedure:
27.5 g of 4-bromo-2-methyl-benzoic acid ethyl ester was dissolved in 120 mL of anhydrous toluene. To the solution was added 21.3 g of phenol, 73.6 g of Cs2CO3, 551 μL of ethyl acetate, 22 g of activated 4 A molecular sieves, and 5.68 g of 90% copper(I) trifluoromethanesulfonate benzene complex. The reaction was placed under a nitrogen atmosphere and heated at reflux temperature for 48 h. The resultant mixture was partitioned between water and ethyl acetate, and the mixture filtered through a fine sintered glass filter to remove insoluble material. The organic fraction was washed three times with 1.0 N NaOH, once with brine, dried over anhydrous sodium sulfate, and concentrated to 18.2 g of a pale tan liquid: 1H NMR (200 MHz, CDCl3) δ 7.93-7.88 (dd, J=1.3, 7.8 Hz, 1H) 7.39-7.30 (m, 2H), 7.19-7.10 (tt, J=1.2, 7.4 Hz, 1H), 7.06-7.7.0 (m, 2H), 6.80-6.75 (m, 2H), 4.37-4.26 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.40-1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(OCC)C>[C:22]1([CH2:28][CH2:29][C:30]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cccc(C2CCCNC2)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc(C2CCCN(C(=O)CCc3ccccc3)C2)c1
Temperature: 25 °C
Yield: 148.9 %

Procedure:
To a stirred solution of 9.4 g (49.2 mmole) of 3-(3-methoxyphenyl)piperidine and 10.2 ml (73.8 mmole) of triethylamine in 120 ml of toluene, at 0° C., under nitrogen, was added dropwise, a solution of 12.4 g (73.8 mmole) of 3-phenylpropionyl chloride in 45 ml of toluene. The mixture was allowed to warm to room temperature, and then it was diluted with an equal volume of diethyl ether. The solid was removed by filtration and the filtrate was evaporated in vacuo to give 23.7 g of 1-(3-phenylpropionyl)-3-(3-methoxyphenyl)piperidine.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[NH2:13][NH2:14].[ClH:15]>CN1CCCC1=O>[ClH:15].[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:13][NH2:14])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Reactant: NN
Agent: Cl
Solvent: CN1CCCC1=O
Product: NNc1cc(Br)c(F)cc1C(=O)O
Temperature: 95 °C
Yield: 44 %

Procedure:
A mixture of 4-bromo-2,5-difluorobenzoic acid (2.50 g, 10.6 mmol) and hydrazine (3.81 mL, 121 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 95° C. for 4 h. The cooled mixture was poured into vigorously stirred 6 M aqueous HCl (400 mL) which was cooled in an NaCl-ice bath. The resulting precipitate was collected by filtration, washed with 6 M aqueous HCl (200 mL) and dried under vacuum to give 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride as a yellow solid (1.88 g, 71% purity, 44% yield), used without further purification.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O.C(O)(=O)C=O.[CH3:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([CH3:24])=[O:23])=[CH:17][C:16]=1[Cl:25].C(OC(C)C)(C)C>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:21][C:20]1[CH:19]=[C:18]([C:22](=[O:23])[CH:24]=[CH:6][C:5]([OH:4])=[O:7])[CH:17]=[C:16]([Cl:25])[C:15]=1[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc(Cl)c(C)c(Cl)c1
Agent: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
10.2 g (0.1 mole) of acetic anhydride were added to 9.3 g (0.1 mole) of glyoxylic acid monohydrate and the mixture was heated, with stirring, on an oil bath at 60° C. for 10 minutes to obtain a homogeneous solution. To this solution were added, in turn, 20.3 g (0.1 mole) of 3,5-dichloro-4-methylacetophenone, prepared as described in step (a) above, 28.8 g of acetic acid and a catalytic amount (300 mg) of concentrated sulphuric acid, whilst ice-cooling. The mixture was then heated, with stirring, on an oil bath at 105°-110° C. for 2 hours, after which it was cooled and 100 ml of diisopropyl ether were added. The mixture was stirred and the resulting crystals were collected by filtration and washed first with water and then with a small amount of diisopropyl ether, after which they were dried to give 20.8 g (yield 80.3%) of the desired 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, melting at 206°-216° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7]O)=[CH:5][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2([C:27]3=[CH:28][C:29]4[O:33][CH2:32][O:31][C:30]=4[CH:34]=[C:26]3[O:25][CH2:24]2)[C:16]1=[O:35].S(Cl)([Cl:38])=O>>[Cl:38][C:2]1[S:3][C:4]([CH2:7][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3([C:27]4=[CH:28][C:29]5[O:33][CH2:32][O:31][C:30]=5[CH:34]=[C:26]4[O:25][CH2:24]3)[C:16]2=[O:35])=[CH:5][N:6]=1
Reactant: OCc1cnc(Br)s1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1N(Cc2cnc(Cl)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 38 %

Procedure:
A mixture of 2-bromothiazole-5-methanol (0.80 g, 4.12 mmol) in thionyl chloride (10 mL) was refluxed for 3 h, and the mixture was evaporated to dryness and dried in vacuo. The residue was re-dissolved in 2-butanone (15 mL), followed by addition of cesium carbonate (2.61 g, 8.0 mmol) and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.12 g, 4.0 mmol). The reaction mixture was refluxed for 16 h, then concentrated to dryness in vacuo. The residue was taken up in ethyl acetate (200 mL), washed by water (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography with 25% ethyl acetate in hexanes to afford 1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.70 g, 38%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.30 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.22-7.17 (m, 1H), 7.09 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.09 (s, 1H), 5.90-5.86 (m, 2H), 5.16-5.08 (m, 1H), 4.97 (d, J=15.9 Hz, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H); MS (ES+) m/z 413.0 (M+1), 415.0 (M+1).
Reaction SMILES: [NH2:1]N.C[N:4](C)[C:5]([CH3:31])=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[CH:28]=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O>C(O)(=O)C>[CH3:31][C:5]1[NH:4][N:1]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[CH:28]=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: NN
Reactant: CC(=CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n[nH]1
Yield: 71.6 %

Procedure:
Anhydrous hydrazine (0.10 g) was added to a solution of 3-Dimethylamino-1-[4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-2-buten-1-one (0.50 g) in glacial acetic acid (25 ml). The reaction mixture was refluxed for 18 hours and then concentrated under vacuum. The solid was extracted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane to give an opaque solution. After cooling the amorphous solid was recovered by filtration to yield the product (0.33 g), MS, m/z: 368 (M)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9](N)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:15].N([O-])=O.[Na+].[S:20](=[O:22])=[O:21]>>[F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([S:20]([Cl:15])(=[O:22])=[O:21])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: O=S=O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 5 °C
Yield: 84 %

Procedure:
Under ice-cooling, thionyl chloride (2.7 mL) was added dropwise to water (16 mL) over 30 min. The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Under ice-cooling, {4-[(trifluoromethyl)sulfonyl]phenyl}amine (2.0 g) was added to concentrated hydrochloric acid (9 mL) and the mixture was stirred. An aqueous solution (3 mL) of sodium nitrite (0.67 g) was added dropwise while maintaining the inside temperature at not higher than 5° C. and the mixture was further stirred for 15 min. The mixture was gradually added at 5° C. to a mixture of the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (10 mg). Under ice-cooling, the mixture was further stirred for 30 min. After stirring, the precipitated product was collected by filtration, washed with water, and dried in the presence of phosphorus pentoxide under reduced pressure at 50° C. to give the title compound (yield 2.3 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:3]2[C:2]([NH:1][C:29]([O:31][CH3:32])=[O:30])=[CH:11][CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-2-[(2′-cyanobiphenyl-4-yl)methylamino]benzoate (10 g) in pyridine (50 ml) was added dropwise methyl chloroformate (9.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to afford pale yellow needles (10.5 g, 90%), m.p. 113-115° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].[CH2:6](Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>O>[O:4]=[C:3]1[C:6]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:7]=2[CH2:9][CH2:10][CH2:11]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CN(C)C=O
Solvent: O
Product: O=C1CCCc2oc(-c3ccccc3)cc21
Temperature: 80 °C
Reaction time: 47 h

Procedure:
A solution of 5.0 g. of 3-(1-pyrrolodinyl)-2-cyclohexan-1-one in 30 ml. of anhydrous dimethylformamide is treated dropwise over twenty minutes under nitrogen with a solution of 6.0 g. of phenacyl bromide in 10 ml. of anhydrous dimethylformamide. The mixture is stirred for 47 hours at 80°C., allowed to cool to ambient temperature, and then poured into water and stirred for 30 minutes. The resulting suspension is extracted with chloroform, the chloroform extracts are combined, washed with water and dried. The solvent is removed and the residue is dried under high vacuum and crystallized from ethanol to yield 4-oxo-2-phenyl-4,5,6,7-tetrahydrobenzo[b]furan, m.p. 132°-134°C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH2:35]([O:34][C:32]([N:30]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)[CH:26]1[CH2:29][CH2:28][CH2:27]1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OCc1ccccc1)C1CCC1

Procedure:
{2′-[(Benzyloxycarbonyl-cyclobutyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-34) was prepared by following the procedures of Example 1 and using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, cyclobutylamine, and benzyl chloroformate.