Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:14](O)[CH3:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: CCO
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
A mixture of 4-oxo-4-phenylbutanoic acid (5.00 g), ethanol (2.59 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.46 g), and 4-(dimethylamino)pyridine (171 mg) in N,N-dimethylformamide (25 mL) was stirred for 1.5 hours at room temperature. The mixture was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (75 mL), and the organic layer was washed with water (75×3 mL), saturated sodium bicarbonate (75 mL), and brine (75 mL), dried over magnesium sulfate, and evaporated to give ethyl 4-oxo-4-phenylbutanoate as a colorless oil (4.19 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19].N1CCCCC1>C(O)C>[C:18]([C:17]1[C:16](=[NH:20])[O:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:19]
Reactant: N#CCC#N
Reactant: O=C(c1ccccc1)c1ccccc1O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a mixture of 2-hydroxybenzophenone (2.0 g, 10 mmol) and malononitrile (661 mg, 10 mmol) in ethanol (15 mL) was added piperidine (0.5 mL, 5.0 mmol). The mixture was stirred under 0-5° C. for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 1.2 g (48%) of the title compound. 1H NMR (CDCl3): 7.74-7.29 (m, 7H), 7.20-7.13 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:12][C:13]([C:15]1[C:16](=[O:30])[N:17]([CH3:29])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([N:26]([CH3:28])[CH3:27])[CH:21]=[CH:20][CH:19]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([C:15]1[C:16](=[O:30])[N:17]([CH3:29])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([N:26]([CH3:27])[CH3:28])[CH:21]=[CH:20][CH:19]=2)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2c(N(C)C)cccc2n(C)c1=O
Reactant: CCNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=O)c1c(O)c2c(N(C)C)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
N-Ethylaniline (4.4 g, 0.036 mol) was dissolved in 80 ml of toluene. About 30 ml of the solvent was distilled off in order to obtain a dry solution. 1,2-Dihydro-4-hydroxy-5-dimethylamino-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (3.5 g, 0.012 mol) was added to the boiling solution. The ethanol formed during the reaction was distilled off together with some toluene for about 10 hours. The mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (3.1 g), yield 71%.
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:23])[C:13](=[CH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:12]=1.CI>CN(C)C=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[N:15]([CH3:1])[C:14](=[O:23])[C:13](=[CH:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:12]=1
Reactant: C[O-]
Reactant: O=C1Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1=CN1CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(=CN2CCOCC2)N=C(c2ccccc2Cl)c2cc(F)ccc21
Temperature: 0 °C

Procedure:
1.6 gm of a methanolic 30% sodium methylate solution were added to a suspension of 2 gm of 5-(2'-chloro-phenyl)-1,3-dihydro-7-fluoro-3-(morpholino-methylene)-2H-1,4-benzodiazepin-2-one in 50 ml of dimethylformamide at room temperature, whereby a reddish-brown solution was immediately formed. The resulting solution was cooled to 0°C, and then 2.1 gm of methyl iodide were added dropwise thereto. After one hour the mixture was poured into ice water, and the precipitate formed thereby was collected by vacuum filtration and dried over phosphorus pentoxide, yielding the compound named in the heading, which had a melting point of 110°-115°C.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][C:8]([CH3:14])([CH2:10][N:11]=C=O)[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5]1)=C=O.CP1(=O)CCC=C1.CP1(=O)CC=CC1.C(=O)=O.C(O)(=O)C(C)=C>CN(C)C=O>[NH2:1][CH:4]1[CH2:9][C:8]([CH3:14])([CH2:10][NH2:11])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5]1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: C=C(C)C(=O)O
Agent: CP1(=O)C=CCC1
Agent: CP1(=O)CC=CC1
Solvent: CN(C)C=O
Product: CC1(C)CC(N)CC(C)(CN)C1
Temperature: 50 °C
Yield: 140 %

Procedure:
After the prepolymer has been cooled to 50° C., 695 parts by weight of dimethyl formamide and 44.4 parts by weight (0.2 mol) of 1-isocyanato-3,3,5-trimethyl-5-isocyanato methyl cyclohexane are added. 34.8 parts by weight (0.2 mol) of a mixture of 2,4- and 2,6-tolylene diisocyanate in a ratio of 8:2, and 2.4 parts by weight (0.02 mol) of a mixture of 1-methyl-1-phospha -2-cyclopenten-1-oxide and 1-methyl-1-phospha -3-cyclopenten-1-oxide, are added to the resulting solution. When the evolution of carbon dioxide has virtually stopped, 17.2 parts by weight (0.2 mol) of methacrylic acid in 17.2 parts by weight of dimethyl formamide are added, followed by stirring at 80° C. until a clear solution is formed. Chain extension with 48 parts by weight (0.28 mol) of 1-amino-3,3,5-trimethyl-5-aminomethyl cyclohexane in 100 parts by weight of dimethyl formamide at 25° C. gives a solution of a polyurethane acyl urea having a viscosity of 1650 cP at 24° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([N:39]([CH3:41])[CH3:40])=[O:38])=[CH:35][C:34]=1[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:41][N:39]([CH3:40])[C:37](=[O:38])[C:36]1[CH:42]=[CH:43][C:33]([NH:32][C:2]2[N:3]=[C:4]([NH:25][CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:24])[CH3:22])[C:6]=3[N:7]=2)=[C:34]([CH3:44])[CH:35]=1
Reactant: Cc1cc(C(=O)N(C)C)ccc1N
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(NC3CCOCC3)nc(Cl)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N(C)C)ccc1Nc1nc(NC2CCOCC2)c2c(-c3ccncc3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a degassed mixture of 2-chloro-5-(pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 equiv), 4-amino-N,N,3-trimethylbenzamide (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.2 M) was added palladium acetate (0.3 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.6 equiv). The reaction was stirred at 110° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-2% DCM in MeOH) to afford the desired product (35% yield) as a yellow solid. MS (ESI) m/z 602.3 [M+1]+.
Reaction SMILES: C([O-])=O.[NH4+:4].C[O:6][C:7]([C:9]1[S:10][CH:11]=[C:12]([CH3:17])[C:13]=1[NH:14][CH:15]=O)=O>C(N)=O>[CH3:17][C:12]1[C:13]2[N:14]=[CH:15][NH:4][C:7](=[O:6])[C:9]=2[S:10][CH:11]=1
Reactant: COC(=O)c1scc(C)c1NC=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: NC=O
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 150 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
To a solution of ammonium formate (5.1 g, 81 mmol) in formamide (25 mL) at 150° C. was added 3-(formylamino)-4-methyl-2-thiophenecarboxylic acid methyl ester (2, 5.0 g, 25 mmol) as a solid in small portions. The resulting solution was heated at 150° C. for 5 hours and then allowed to stand at room temperature for 12 hours. The precipitate that formed was collected by vacuum filtration to give 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3.4 g, 84% yield) as white needles.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(C(C(=O)C(N(C)C)=O)=CN2)=CC=1F)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:14]2[C:15]([C:11]([CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:12][NH:13]2)=[CH:16][C:17]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Agent: CN(C)C(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)c(F)cc12
Product: CN(C)CCc1c[nH]c2cc(OCc3ccccc3)c(F)cc12
Yield: 77 %

Procedure:
Following the procedure used to prepare compound 1-7a (step 6 scheme 1), compound 4-4 gave compound 4-5 in 77% yield as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[Cl:32])=[CH:9][C:8]=1[CH3:33])[CH3:2].[CH2:35](OC(=O)COC1C=C(C)C(SC2C=CC(CO)=CC=2Cl)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:35])[C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[Cl:32])=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(CO)cc2Cl)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.6, using compound 24.2 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.54 (2H, d, J=8.8 Hz); 7.42 (1H, d, J=1.6 Hz); 7.34 (1H, s); 7.06 (1H, dd, J=1.8, 8.2 Hz); 6.99 (2H, d, J=8.7 Hz); 6.67 (1H, s); 6.51 (1H, d, J=8.2 Hz); 4.99 (2H, s); 4.68 (2H, s); 4.30 (2H, q, J=7.1 Hz); 2.31 (3H, s); 2.25 (3H, s); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][CH2:8][C:9]([OH:11])=[O:10].[N+](=[CH2:18])=[N-].CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+]>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][CH2:8][C:9]([O:11][CH3:18])=[O:10]
Reactant: C=[N+]=[N-]
Reactant: CCCCC(OCC(=O)O)c1ccco1
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCC(OCC(=O)OC)c1ccco1

Procedure:
Crude acid from example 84 (25 g, 118 mmol) was dissolved in ether and treated with excess diazomethane (generated by adding 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) to a mixture of 40% KOH (aq) and ether at 0° C.). Excess diazomethane was quenched with acetic acid after 30 m. Vacuum distillation gave 18.8 g (70%): [α]25D -100°; bp 100°-109° C. (0.5 mmHg); 1H NMR (300 MHz, CDCl3) δ 7.40 (1H, dd, J=1 Hz), 6.34 (1H, dd, J=1 Hz), 6.29 (1H, dd, J=1 Hz), 4.43 (1H, t, J=7 Hz), 4.00 (2H, q, J=16 Hz), 3.72 (3H, s), 1.92 (2H, m), 1.33 (4H, m), 0.89 (3H, t, J=7 Hz); mass spectrum (FAB): 244 (M+NH4).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:42]=[O:43])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[C:25]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:42][OH:43])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[CH:36][CH:37]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(C)(C)O)cc5)n4)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(C)(C)O)cc5)n4)c3CO)ncc2c1
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide (34 mg, 0.06 mmol) was dissolved in a solution of 1:1 methanol and dichloromethane (15 ml). To this was added a solution of sodium borohydride (11 mg, 0.29 mmol) dissolved in water (0.25 ml), via drop-wise addition. After 10 minutes stirring the volatiles were stripped (rotary evaporator) and the remainder was taken up in dichloromethane (30 ml) and water (30 ml) and shaken in a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with dichloromethane (2×25 ml). The organic extracts were combined, dried from magnesium sulfate, filtered and stripped. The crude was purified by silica gel chromatography (1 g, eluting with 7.5% methanol in dichloromethane) providing the desired product 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as an off-white powder (32 mg). LC/MS calcd for C32H33FN6O4 (m/e) 584.66, obsd 583 (M−H, ES−).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:9]=2[O:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:27]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:26][C:24]1[CH:23]=[CH:22][C:9]([O:10][CH:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][CH3:15])=[O:13])=[C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:25]=1
Reactant: COC(=O)C(Oc1ccc(C)cc1C1(C)CCCCC1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C1(C)CCCCC1)c1ccccc1
Yield: 21.3 %

Procedure:
To a solution of 0.780 g (2.21 mmol) of the product of Step A dissolved in 12 mL of CCl4 was added 0.394 g (2.21 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture was stirred and refluxed under a N2 atmosphere for 6 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 7% ethyl acetate/hexane to afford 0.203 g (21%) of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:14]=2[CH3:23])[C:6]2[CH:5]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:3]=[C:2]([CH3:30])[C:10]=2[N:9]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
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: C1COCCO1
Solvent: O
Product: Cc1c(Cn2c(C)nc3c(C)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (200 mg, 0.427 mmol), trimethylboroxine (0.239 mL, 1.708 mmol), Pd(Ph3P)4 (49.4 mg, 0.043 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-Dioxane (2.5 mL)/Water (0.25 mL) was irradiated at 120° C. in a microwave synthesizer for 40 min, then cooled and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by RP-HPLC (25-45% AcCN in water plus 0.1% TFA) to give the desired compound (77 mg, 0.181 mmol, 42.5% yield) as a white solid (contains 3-5% of the 4-H compound). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.08 Hz, 1H), 7.12 (t, J=7.83 Hz, 1H), 6.80 (d, J=1.01 Hz, 1H), 6.51 (d, J=7.83 Hz, 1H), 6.40 (d, J=1.77 Hz, 1H), 5.26 (s, 2H), 3.78-3.91 (m, 4H), 3.01-3.15 (m, 4H), 2.67 (s, 3H), 2.56 (s, 3H), 2.50 (s, 3H). MS(ES+) m/e 404.1 [M+H]+. (NOTE: The reaction was repeated using PdCl2(dppf) as catalyst. Less (to negligible) reduction was observed).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:32][CH2:33][N:34]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:16][CH:15]=3)[CH2:35][CH2:36]1)(=[O:29])=[O:30])[CH:22]=[CH:21]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)ccn1
Yield: 68 %

Procedure:
4-(2-Methyl-4-pyridyl)benzoic acid (62 mg), 1-(6-bromonaphth-2-ylsulphonyl) piperazine (94 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg) were dissolved in DMF (2.5 ml) and the resultant solution stirred at ambient temperature for 16 hours. Excess DMF was removed in vacuo, water (10 ml) was added and the precipitate that formed was filtered, washed thoroughly with cold water and dried over P2O5. The solid thus obtained was purified by flash chromatography at 3 psi on silica (Merck ART 9385) eluting with 2.5% v/v methanol in dichloromethane. There was thus obtained the 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-methyl-4-pyridyl)benzoyl]piperazine (99 mg); mp 204-205° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.48 (s,3H), 3.03 (s,4H), 3.57 (broad s, 4H), 7.46 (t,3H), 7.56 (s,1H), 7.77(d,2H), 7.83(d,2H), 8.17(q,2H), 8.42 (s,1H), 8.48 (d,2H) ppm; MS: m/z 550/552 (M+H)+ (1 Br pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][C:12]=3[C:13](=[O:15])[CH:14]=2)=[CH:5][CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:12]=3[C:13](=[O:15])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)c3cc(NC(C)=O)ccc3o2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(=O)c3cc(N)ccc3o2)cc1
Yield: 97 %

Procedure:
To a suspension of 2-(4-methoxyphenyl)-6-acetamido-4H-1-benzopyran-4-one, 5 g (0.016 mol) in ethanol (solution 80% in water) (70 mL) was added H2SO4 30% (25 mL) and the mixture was stirred under reflux for 4 hours. After cooling, aqueous NaOH was added until pH 10, and the mixture was extracted with dichloromethane, washed with water, dried and evaporated. Yield: 97%; TLC (85/25/2/1 Chloroform/Methanol/Water/Ammonia) Rf: 0.82.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Agent: CC=O
Solvent: C1CCOC1
Product: C[C@H](O)c1cc(F)cc(F)c1
Reaction time: 7 h
Yield: 39.5 %

Procedure:
To a stirred solution of (−)-DIP-Cl ((−)-diisopinocampheylboron chloride) (2.67 g, 8.33 mmol, 1.3 eq) in THF (20 mL) kept under inert atmosphere (Ar) and cooled to −27° C. to −25° C., 3′,5′-difluoroacetophenone (1.00 g, 6.40 mmol) was added drop wise over 2 min. The reaction was maintained at this temperature for 17 h. The reaction mixture was then treated with acetaldehyde (0.44 mL, 7.69 mmol, 1.2 eq). Thereafter, the temperature was allowed to reach room temperature and the reaction mixture was stirred at for 7 h. The solvent was then removed in vacuo and the resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL). The aqueous phase was extracted again with TBME (20 mL). The organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a residue, which was purified by two subsequent column chromatographic steps: First by normal phase chromatography (silica gel, heptane/ethyl acetate, v/v=1/0-9/1) followed by a reversed phase chromatography (90 C18-silica gel, acetonitrile for the second one). This gave the title compound (0.40 g, 40%) as a colorless oil with a specific rotation of [α]25D=−26.66 (c=1.054 g/100 mL, CH2Cl2, 589 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O.[N+:29]([C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34])([O-:31])=[O:30]>C(Cl)Cl.O.N1C=CC=CC=1>[N+:29]([C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:18][CH3:19])[CH:11]=1)([O-:31])=[O:30]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(C(=O)O)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Nc2ccccc2[N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
In 20 ml of methylene chloride was suspended 2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxy benzoic acid. DMF (0.05 g) and thionyl chloride (0.68 ml) were added to this suspension. The mixture was stirred at 50° C. for 2 hours. At a temperature of 0° C., 20 ml of pyridine wherein 1.1 g (8.0 mmol) of 2-nitroaniline had been dissolved at room temperature was added dropwise to the mixture. The mixture was stirred for 2 hours at room temperature, and water was added thereto to extract the methylene chloride phase. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The crystals thus obtained were recrystallized using methylene chloride-hexane, thereby yielding 1.5 g of N-(2-nitrophenyl)-4-benzyloxy-3-methoxybenzamide crystals.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.O1CCCC1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(COc2ccccc2)cn1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccc(COc2ccccc2)cn1
Yield: 51 %

Procedure:
2-(5-Phenoxymethyl-pyridin-2-ylmethyl)-isoindol-1,3-dione described in Preparation Example 188 (383 mg, 1.11 mmol) was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL). Hydrazine monohydrate (538 μL, 11.1 mmol) was added to this solution at room temperature, and the solution was stirred under reflux for 1 hour. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=10/1), and the title compound (122 mg, 51%) was obtained as a colorless oil.