Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C@@H:30]([CH2:32][OH:33])[CH3:31]>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:29][C@H:30]([CH3:31])[CH2:32][OH:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(C)(=O)=O
Reactant: C[C@@H](N)CO
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(SCc2ccccc2)n1
Temperature: 80 °C

Procedure:
To a solution of the product of step i) (21.2 g) in NMP (40 ml) was added (R)-alaninol (10 g) and the whole heated at 80° C. for 4 h. The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was collected, dried (MgSO4) and the solvent removed to leave a pale yellow oil. This was purified by silica gel chromatography (60:40 iso-hexane EtOAc) to afford the subtitle compound as a colourless oil. Yield: 13.9 g.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[CH2:6][C:7]#[N:8]>C(O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[C:7]([NH2:8])[NH:3][N:2]=2)[CH2:14][CH2:13]1
Reactant: NN
Reactant: N#CCC(=O)C1CCN(c2ccccn2)CC1
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CCN(c3ccccn3)CC2)n[nH]1
Reaction time: 5 h
Yield: 89.1 %

Procedure:
Hydrazine monohydrate (0.20 mL, 4.12 mmol) was added to a solution of 3-oxo-3-[1-(pyridin-2-yl)piperidin-4-yl]propanenitrile (138 mg, 0.60 mmol) produced in Reference Example 1 in ethanol (20 mL), and the mixture was stirred for 5 hours under heating to reflux. The reaction solution was left until reaching room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: ethyl acetate/methanol=100/0-94/6 (gradient)] to obtain the title compound (130 mg, yield: 89%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CN(C1C=CC=CN=1)C.C(OCC)(=O)C>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Yield: 81 %

Procedure:
Dissolve (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (292 mg, 1.59 mmol, prepared in example 11) in pyridine (2.8 mL) and treat with acetic anhydride (0.39 mL) and dimethylaminopyridine (16 mg). Stir the reaction overnight. Concentrate the reaction under vacuum, dissolve the residue with ethyl acetate (10 mL). Wash with 0.5M hydrochloric acid that is 1/2 saturated with brine (2×10 mL), saturated sodium bicarbonate (10 mL), brine (10 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by chromatography (silica gel, 10 g, 1.5×4 cm columnar 20% ethyl acetate/hexane) to provide the title compound (290 mg, 81%).
Reaction SMILES: B(F)(F)F.CCOCC.N[C:11]1[C:12]([CH3:18])=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1.N(OC(C)(C)C)=O.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>COCCOC.CCCCCC>[Cl:17][C:14]1[N:13]=[C:12]([CH3:18])[C:11]([O:29][C:26](=[O:28])[CH3:27])=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)ccc1N
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: CC(=O)Oc1ccc(Cl)nc1C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A mixture of boron trifluoride etherate (667 μL, 5.3 mmol) and 1,2-dimethoxyethane (2 mL) was cooled to −15° C. in an ice/acetonitrile bath and stirred at this temperature for 15 min under nitrogen. A solution of 3-amino-6-chloro-2-picoline (Oakwood Products, Inc., West Columbia, S.C., USA; 500 mg, 3.5 mmol) in 1,2-dimethoxyethane (16 mL) was added dropwise at −15° C. and the mixture was stirred at this temperature for 15 min. tert-Butyl nitrite (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1.15 mL, 4.2 mmol) was added dropwise and the mixture was stirred at −15° C. for 15 min and then at 0° C. (ice/water bath) for 1 h. Hexane (20 mL) was added and the precipitate was filtered off and washed with hexane. This solid was added to acetic anhydride (5.00 g, 49 mmol) and the mixture was heated at 100° C. for 2 h. The acetic anhydride was evaporated under high vacuum and then 1 M aqueous sodium carbonate was added to pH 9. The mixture was stirred, and then extracted three times with dichloromethane. The solvent was evaporated and the residue purified using a silica gel column, eluting with 0-10% ethyl acetate) to give acetic acid 6-chloro-2-methyl-pyridin-3-yl ester (316 mg, 49%) as an oil.
Reaction SMILES: Br[CH:2]1[CH2:11][CH:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:15]1[CH:19]=[C:18]([CH2:20][C:21]([NH2:23])=[S:22])[N:17]=[CH:16]1>>[NH:15]1[CH:19]=[C:18]([CH2:20][C:21]2[S:22][C:2]3[CH2:11][CH:10]([CH3:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[N:23]=2)[N:17]=[CH:16]1
Reactant: CC1CC(Br)C(=O)c2ccccc21
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: CC1Cc2sc(Cc3c[nH]cn3)nc2-c2ccccc21

Procedure:
Starting compounds: 2-bromo-4-methyl-1-tetralone, 4-imidazolyl thioacetamide hydrochloride
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:6]=1[C:7]([OH:9])=O.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([NH:14][CH3:15])=[CH:13][C:5]=2[O:4][CH2:3][CH:2]([F:1])[F:19])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CNc1cc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared in accordance with Example 72, step (c) using 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoic acid (800 mg; 2.90 mmol), 4-bromoaniline (499 mg; 2.90 mmol), HBTU (1.10 g; 2.90 mmol), TEA (587 mg; 5.80 mmol) and DMF (15 mL). Yield: 1.01 g (81%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]2=[O:20])[CH:10]=1)=[O:4].O.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:7]2[CH:8]=[C:9]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C:12]3=[O:20])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(N2C(=O)Cc3ccccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(N3C(=O)Cc4ccccc43)c2)cc1
Reaction time: 2.5 h

Procedure:
The crude 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid methyl ester from step 2 was in a mixture of methanol (3 mL), water (1 mL) and THF (1 mL), and 2M aqueous NaOH (0.4 mL) was added. The mixture was stirred for 2.5 hours, then neutralized by addition of 1N aqueous HCl. The mixture was concentrated under reduced pressure and co-evaporated with toluene three times to afford crude 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: OCc1ccc(O)cc1Cl
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-(hydroxymethyl)phenol (for a preparation see Intermediate 16)(3 g, 18.9 mmol) in ethanol (80 ml) was added benzyl bromide (2.25 ml, 18.9 mmol, Aldrich) and then 2 M aqueous sodium hydroxide (10.4 ml, 20.8 mmol). The mixture was stirred at ambient temperature overnight under nitrogen. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give {2-chloro-4-[(phenylmethyl)oxy]phenyl}methanol as a white solid (2.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]=[N:11][N:12]([CH3:18])[N:13]=2)=[CH:14][CH:15]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(CSc2nnn[nH]2)cc1
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(CSc2nnn(C)n2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-p-methoxybenzylthiotetrazole (7.00 g : 31.5 mMol.) in methanol (150 ml) is added under ice cooling a solution of diazomethane in ether (produced from 14 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour and then concentrated. The residue is purified by Lobar column chromatography (toluene : ethyl acetate=5: 1) to give 5-p-methoxybenzylthio-2-methyltetrazole 4.86 g :
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][NH:10][CH2:9]1.CN(C)C=O.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:10]1[CH2:11][C@@H:12]([CH3:14])[CH2:13][C@H:8]([CH3:7])[CH2:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CC1CNCC(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@H](C)CN(Cc2ccccc2)C1
Reaction time: 15 h
Yield: 14.8 %

Procedure:
A suspension of potassium carbonate (83 g) in a mixture of benzyl chloride (37 g), 3,5-dimethylpiperidine (30 g of acommercial mixture of cis and trans isomers) and N,N-dimethylformamide (200 mL) is stirred for 15 h at a temperature close to 60° C. The mixture is filtered, concentrated under reduced pressure and diluted in ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a mixture diethyl oxide/ligroin/triethylamine 20/80/1 as eluent to give 8 g of trans-1-benzyl-3,5-dimethylpiperidine as a colourless oil used without further purification.
Reaction SMILES: [N:1]1([N:6]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH2:7][N:6]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:9][S:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(CN(c3ccc(C#N)cc3)n3ccnc3)csc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(N(Cc2csc3cc(O)ccc23)n2ccnc2)cc1
Yield: 62.3 %

Procedure:
A solution of 4-{N-[1H-imidazol-1-yl]-N-[(6-methoxy-benzothien-3-yl)methyl]amino}benzonitrile (0.50 g, 1.39 mmol) in 10 ml of methylene chloride is added at room temperature to a solution 1M of boron tribromide in methylene chloride (1.50 ml, 1.52 mmol). After 2 h at room temperature the mixture was hydrolysed with saturated aqueous NaHCO3, extracted with dichloromethane, dried over Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel (toluene/dioxan:6/4) to give the expected product (0.30 g, 62%, powder). Crystallization with ethanol yielded white crystalsl (0.10 g, mp: 169° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)[CH:17]=[CH:16][C:15]=3[N+:29]([O-])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:34]1(=[O:44])[C@@H:42]2[C@@H:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[C:36](=O)[O:35]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.C([O-])(O)=O.[Na+]>O.C(Cl)Cl.CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:33]=[CH:32][C:11]([CH2:12][N:13]3[C:14]4[CH:19]=[C:18]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=5)[CH:17]=[CH:16][C:15]=4[N:29]=[C:36]3[C@H:37]3[CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]3[C:34]([OH:44])=[O:35])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(-c4ncc(Cl)cn4)cc3)c2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(-c5ncc(Cl)cn5)cc4)c3c2)nc1
Temperature: 50 °C
Yield: 28 %

Procedure:
In a 5 mL microwave vial were added N-(4-(5-chloropyrimidin-2-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-2-nitroaniline (59 mg, 0.13 mmol), cis-hexahydroisobenzofuran-1,3-dione (33 mg, 0.21 mmol), sodium dithionite (69 mg, 0.39 mmol), DMA (1 mL) and water (0.2 mL). The resulting mixture was heated to 50° Celsius for 16 h. The mixture was cooled to RT, diluted with water (10 mL) and pH adjusted to ˜1 with HCl (1M). To the mixture was added DCM (1 mL) and the pH was adjusted to ˜3 with saturated NaHCO3 (10 mL). The organic layer was separated, concentrated to dryness and the residue was purified using FCC to provide 20.7 mg of the title compound. MS (ESI): mass calcd. for C32H30ClN5O3, 567.20; m/z found, 569.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.76-8.71 (s, 2H), 8.39-8.31 (m, 3H), 7.66-7.59 (d, J=8.9, 1H), 7.50-7.43 (dd, J=8.0, 1.7, 1H), 7.39-7.32 (d, J=8.0, 1H), 7.15-7.08 (m, 2H), 7.07-7.00 (dd, J=8.9, 2.3, 1H), 6.85-6.79 (d, J=2.3, 1H), 5.41-5.27 (m, 2H), 5.18-5.13 (s, 2H), 3.22-3.14 (m, 1H), 3.07-3.03 (m, 1H), 2.61-2.51 (m, 1H), 2.30-2.25 (s, 3H), 1.89-1.55 (m, 5H), 1.49-1.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][C:54]=1[NH:63][C:64](=[O:75])[C:65]1[CH:70]=[CH:69][C:68]([NH:71][CH2:72][CH2:73][NH2:74])=[N:67][CH:66]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][C:54]=1[NH:63][C:64](=[O:75])[C:65]1[CH:70]=[CH:69][C:68]([NH:71][CH2:72][CH2:73][NH:74][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:67][CH:66]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCCNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.9 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-trifluoromethylphenyl)-6-(2-aminoethylamino)nicotinamide (356 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (422 mg, 68%) as a yellow solid. LC-MS (m/z) 622 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](OC)=[O:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][OH:38])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M, 15 ml, 22.5 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-(4-methoxycarbonylphenyl)piperazine (2.90 g, 9.05 mmol) in THF (116 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours then allowed to warm to room temperature. The solution was recooled to -4° C. and the reaction quenched by the addition of methanol (6 ml), water 3 ml) and finally 2M sodium hydroxide (3 ml). The mixture was allowed to warm to room temperature, the precipitated aluminium salts collected under suction and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate, to give the title compound (2.30 g, 74%); δH (CDCl3) 1.48 (9H, s, C(CH3)3), 1.60 (1H, v br, CH2OH), 3.13 (4H, m, 2×piperazinyl CH3), 3.58 (4H, m, 2×piperazinyl CH2), 4.61 (2H, s, CH2OH), 6.92 (2H, m, ArH), and 7.29 (2H, m, ArH).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][C:15]1=[O:24].Cl>CN(C)C=O>[C:5]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[NH:14][C:15](=[O:24])[NH:16][CH2:17]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NCc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1NCc2cc(C(=O)c3ccccc3)ccc2N1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
To a vigorously stirred amount of 45 parts of aluminum chloride were added dropwise 7.05 parts of N,N-dimethylformamide. After stirring for 5 min. at 70° C., there were added 5 parts of benzoyl chloride and, dropwise, 4.7 parts of 3,4-dihydro-2(1H)-quinazolinone. Stirring was continued for 2 hours at 70° C. The reaction mixture was poured into ice-water and there were added 63.5 parts of HCl. The precipitate was filtered off and recrystallized from 2-methoxyethanol, yielding 6.5 parts (76.4%) of 6-benzoyl-3,4-dihydro-2(1H)-quinazolinone; mp. 264.8° C. (interm. 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]1[C:10]([C:11](=[O:35])[CH2:12][C:13]2[C:18]([CH2:19][CH2:20][NH:21][CH2:22]CC3C=CC=CC=3)=[CH:17][C:16]3[O:30][CH2:31][O:32][C:15]=3[C:14]=2[O:33][CH3:34])=[CH:9][CH:8]=[C:7]([O:36][CH3:37])[C:6]=1[O:38][CH3:39])[CH3:2].[ClH:41]>[Pd].C(O)C>[ClH:41].[CH2:1]([O:3][C:4](=[O:40])[C:5]1[C:10]([C:11](=[O:35])[CH2:12][C:13]2[C:18]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:17][C:16]3[O:30][CH2:31][O:32][C:15]=3[C:14]=2[O:33][CH3:34])=[CH:9][CH:8]=[C:7]([O:36][CH3:37])[C:6]=1[O:38][CH3:39])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)Cc2c(CCNCCc3ccccc3)cc3c(c2OC)OCO3)ccc(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)Cc2c(CCNC)cc3c(c2OC)OCO3)ccc(OC)c1OC

Procedure:
73.7 g of 2,3-dimethoxy-6-(2-methoxy-3,4-methylenedioxy-6-benzylmethylaminoethylphenylacetyl)benzoic acid ethyl ester as the HCl salt (mp 160°-161°C) was dissolved in 1.8 l. of ethanol. The resulting mixture was hydrogenated in the presence of 11.5 g of 10% Pd/C at 3 atm for 20 hr. After removal of the catalyst, the solution was concentrated to a small volume. After cooling, 2,3-dimethoxy-6-(2-methoxy-3,4-methylenedioxy-6-methylaminoethylphenylacetyl)benzoic acid ethyl ester hydrochloride of mp 199°-200° was isolated.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=2)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-trifluoromethylpyridin-3-ylamine (1.0 g, 6.17 mmol) and 4-amino-3-nitrobenzoic acid (1.12 g, 6.17 mmol) in DMF (25 mL) was added HATU (3.5 g, 9.23 mmol) followed by NEt3 (1.77 ml, 9.23 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a heptane/EtOAc (1:1 then followed by 100% EtOAc) to give 4-amino-3-nitro-N-(6-trifluoromethylpyridin-3-yl)-benzamide as a red solid.
Reaction SMILES: [Br:1][CH2:2][C:3](C1C=CC=CC=1NS(C)(=O)=O)=[O:4].C([C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])(=O)C>>[Br:1][CH2:2][C:3]([C:27]1[CH:26]=[C:20]([CH:19]=[CH:29][CH:28]=1)[NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[O:4]
Reactant: CC(=O)c1ccccc1NS(C)(=O)=O
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)CBr
Product: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1

Procedure:
2'-(Bromoacetyl)methanesulfonanilide can be derived from 2'-acetylmethanesulfonanilide (Preparation 1) following the bromination procedure described in Example 10, Step X. In a like manner, 3'-(2-bromoacetyl)methanesulfonanilide can be obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:33][CH2:34][S:35][C:36](Cl)=[O:37].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[O:23][C:36]([S:35][CH2:34][CH3:33])=[O:37])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CCSC(=O)Cl
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 5-hydroxy-1-methylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone obtained in the same manner as the above step (3) was dissolved in anhydrous THF (10 mL), and triethylamine (190 mg) and 96% S-ethyl chlorothiolformate (151 mg) were added, followed by stirring for 1 hour at room temperature. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (250 mg).