Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:40](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:40])=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(N)=O)cc3F)ncc21
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
A mixture of 0.0703 g (0.161 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182), 4 mL of dimethylformamide, 0.0792 g (0.202 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.103 mg (0.804 mmole) of diisopropylethylamine was stirred for 20 minutes, then 0.0186 g (0.348 mmole) of ammonium chloride was added. The reaction mixture was stirred for 1.5 hours and then 150 mL of ethyl acetate and 25 mL of water was added. The organic layer was washed with 25 mL of ammonium chloride solution, 25 mL of water, 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0531 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzamide (I-231).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.S(O[CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[O:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:5]3[C:4]([NH2:3])=[N:9][CH:8]=[N:7][C:6]=3[N:10]([CH:37]3[CH2:41][CH2:40][O:39][CH2:38]3)[CH:11]=2)=[CH:18][CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOC1
Temperature: 95 °C

Procedure:
Sodium hydride (120 mg, of a 60% dispersion in mineral oil) was added to a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (906 mg) and dimethylformamide (30 ml) with stirring under nitrogen. The mixture was stirred for 30 minutes and then a solution of 3-(tosyloxy) tetrahydrofuran (750 mg) in dimethyl formamide (10 ml) was added with stirring. The mixture was stirred and heated at 95° C. for 18 hours and then evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried and evaporated to give a residual gummy solid which was triturated with ether and filtered to give 5-(4-phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine m.p. 196-196.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[O:2][CH3:1])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 125.2 %

Procedure:
2-(2-Methoxy-4-nitrophenoxy)ethanol (12.0 g) and triethylamine (8.9 g) were dissolved into chloroform (60 ml) and p-toluenesulfonyl chloride (12.3 g) was added into this solution. The solution was stirred for 9 hours at room temperature and allowed to stand for one night. The reaction mixture was washed with water (100 ml) two times and dehydrated with anhydrous sodium sulfate and then concentrated under vacuum to dryness to obtain 2-(2-methoxy-4-nitrophenoxy)ethyl p-toluenesulfonate (25.9 g) as yellowish solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1cccs1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Methyl N-cyano-2-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether-hexane to give the title compound (0.50 g, 1.97 mmol, yield: 98%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[Li:12]CCCC>CCCCCC>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([Li:12])[CH:4]=1
Reactant: COC1=CCc2ccccc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1C=C(OC)c2ccccc21
Yield: 97 %

Procedure:
3-Methoxy-1H-indene (9.65 g, 66.04 mmol) was dissolved in 150 mL of hexane. To this solution 50 mL of a 1.6 M solution of n-BuLi was added (80 mmol) within 10 minutes After 20 hours of stirring the off-white solid was collected on a medium-size frit, washed with hexane (3×30 mL) and dried under reduced pressure to give 9.72 g of product. Yield 97 percent.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[P:19](OC)([O:23][CH3:24])([O:21][CH3:22])=[O:20]>O>[CH3:22][O:21][P:19]([CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1)(=[O:20])[O:23][CH3:24]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: COP(=O)(OC)OC
Solvent: O
Product: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Temperature: 25 °C

Procedure:
A mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 30 from Example 9 (1.0 g) and trimethyl phosphate (5 mL) was heated at reflux for 3 h. After cooling to room temperature, water (20 mL) was added and the product filtered, washed with water and dried under vacuum to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-phosphonic acid dimethyl ester as a yellow solid (0.54 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:11][CH:10]=1
Reactant: Brc1nccs1
Reactant: COc1ccc(B(O)O)cc1
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
Product: COc1ccc(-c2nccs2)cc1
Yield: 47.1 %

Procedure:
A mixture of 2-bromothiazole (2.0 g, 12.2 mmol), (4-methoxyphenyl)boronic acid (1.9 g, 12.8 mmol), K2CO3 (5.0 g, 36.5 mmol) and (Ph3P)4Pd (0.7 g, 0.61 mmol) in dioxane (40 mL) was refluxed for 16 h. After the solids were filtered off, the filtrate was concentrated in vacuo. The residue was purified by a column chromatography on silica gel to yield the title compound (1.1 g, 50%). 1HNMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.25 (d, J=3.2 Hz, 1H), 7.81 (d, J=3.2 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), MS m/z 192 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 2-morpholin-4-yl-ethylamine (30 μL) by a procedure similar to Example 10 and was isolated as white powder (10 mg, 100%). 1H NMR (CDCl3): 7.42 (dd, J=8.7 and 1.2 Hz, 1H), 7.36 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.10-7.09 (m, 2H), 6.92-6.86 (m, 3H), 6.67 (ddd, J=8.1, 6.6 and 1.4 Hz, 1H), 3.82 (s, 3H), 3.75-3.62 (m, 6H), 3.52 (s, 3H), 2.55-2.44 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:16]=[C:13]([CH:14]=[O:15])[C:12]([C:25]2[CH:26]=[C:21]([CH:18]([CH3:20])[CH3:19])[CH:22]=[CH:23][C:24]=2[O:30][CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1C=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
5-Benzyloxy-2-bromo-benzaldehyde (1.0 g) is dissolved in 1,4-dioxane (30 ml) and thereto are added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane complex (280 mg), (5-isopropyl-2-methoxyphenyl)boronic acid (800 mg) and cesium carbonate (1.68 g) and the mixture is stirred under nitrogen atmosphere at 80° C. for 6 hours. The reaction mixture is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-carbaldehyde (1.19 g). MS (m/z): 361 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][C:21]=3[Cl:35])[C:15]2=[O:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)=[O:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:44]4[CH:45]=[CH:46][C:41]([C:39]([O:38][CH3:37])=[O:40])=[CH:42][CH:43]=4)=[CH:22][C:21]=3[Cl:35])[C:15]2=[O:36])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
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: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(Cl)c2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Treat a solution of 4-[3-(2,6-Dichloro-4-trifluoromethanesulfonyloxy-benzyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 15) (0.5 g, 0.9 mmol), 4-methoxycarbonylphenylboronic acid (0.31 g, 1.7 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.1 mmol) in DME (5 mL) with 2M aqueous K2CO3 (1.3 mL), heat the reaction to 80° C., and stir overnight. Cool the reaction and quench with 1N HCl. Extract the aqueous with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.43 g (88%) of desired product. MS (m/e): 583 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A suspension of 2-methyl-5-phenyl-3-furancarboxylic acid (5.0 g), ethyl iodide (4.7 g) and potassium carbonate (3.5 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.7 g, 100%) as an oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21](C#N)[CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: N#CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 91.8 %

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a suspension of the indazole (4.3 g, 0.012 moles) and triethylamine (3.5 ml, 0.025 moles) in toluene (50 ml) was added dimethylcarbamyl chloride (1.26 ml, 0.014 moles). The reaction was stirred at ambient temperature for 21 hours. The mixture was then poured into H2O, extracted (CHCl3), dried (MgSO4), and concentrated to yield 5.08 g of an oil. The product was purified by high pressure liquid chromatography (HPLC) [silica gel, 100% ethyl acetate] to yield 3.6 g of product as an oil which crystallized upon standing. The product was washed with hexane and dried to yield 3.2 g (62%) of N,N-dimethyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p. 117°-119° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.I[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17]N(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:15]2>>[C:15]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)#[C:14][CH2:13][CH2:12][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CCCCCCC#Cc1ccc2[nH]ccc2c1
Yield: 36 %

Procedure:
When 5-iodo-1H-indole was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the identical process afforded the title compound in 36% yield. 1H-NMR (CDCl3) 0.9 (tr, 3H, J=6.9 Hz); 1.31 (m, 6H); 1.46 (m, 2H); 1.6 (m, 2H); 2.41 (tr, 2H, J=7.1 Hz); 6.49 (m, 1H); 7.14-7.31 (m, 3H); 7.71 (s, 1H); 8.13 (broad s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](OCC)=[O:10].[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9](=[O:10])[N:17]([CH2:16][CH2:15][Cl:14])[C:18]1=[O:19]
Reactant: O=C=NCCCl
Reactant: CCOC(=O)c1ccccc1NC
Solvent: Cc1ccccc1
Product: Cn1c(=O)n(CCCl)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
N-Methyl-2-carboethoxyaniline (5.0 g, 28 mmol) was treated with 2-chloroethylisocyanate (2.86 mL, 28 mmol) at reflux in toluene for 18 hours. The reaction was cooled to 25° C., and the crystalline product was collected by filtration to yield the intermediate 1-methyl-3-(2-chloroethyl)-quinazoline-2-4-dione. The intermediate quinazolinedione (0.53 g, 2.2 mmol) and cis-6-methoxy-2,3,3a,4,5,9b-[1H]-benz[e]isoindole (0.38 g, 1.87 mmol) were combined in acetonitrile (3 mL) and diisopropylethylamine (0.8 mL) was added. The reaction mixture was heated at reflux for 18 hours. The resulting product was converted to its HCl salt and recrystallized from acetone:ether to yield the title compound (0.30 g, 40%) as a white solid. m.p. 215°-217° C. (dec). 1H NMR (300 MHz, CDCl3) of the free base δ 8.2 (dd, 1H), 7.7 (dt, 1H), 7.1- 7.32 (m, 3H), 6.75 (t, 2H), 4.48 (m, 3H), 4.1-4.3 (m, 2H), 3.81 (s, 3H), 3.68 (m, 1H), 3.6 (s, 3H), 3.35-3.5 (m, 2H), 2.87-4.3 (m, 2H), 2.72-2.87 (m, 2H), 2.52-2.65 (m, 1H), 1.88-2.0 (m, 1H), 1.55-1.7 (m, 1H). MS (DCI/NH3) m/e 406 (M+H)+. Anal calcd for C24H27N3O3.HCl. H2O: C, 62.67; H, 6.57; N, 9.14. Found: C, 62.52; H, 6.51; N, 9.03.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[CH:17](Br)([CH3:19])[CH3:18].[OH-].[K+]>COCCOC>[CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=1)=[O:6]
Reactant: CC(C)Br
Reactant: CC(C)COC(=O)c1n[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)COC(=O)c1nn(C(C)C)c2ccccc12
Yield: 36.8 %

Procedure:
To a solution of 2-methylpropyl-1H-3-indazolecarboxylate (50 g; 0.24 moles) in 1,2-dimethoxy-ethane (300 ml) a solution of isopropyl bromide (27.5 ml; 0.29 moles) in 1,2-dimethoxy-ethane (100 ml) and KOH (13.5 g; 0.24 moles) was added and the mixture was heated under reflux for 8 hours. After removal of the solvent, the residue was dissolved in toluene (300 ml), the thus obtained solution was washed with 1N NaOH (100 ml), H2O (2×100 ml) and then dried and concentrated in vacuum. The residue was purified from the isomer 2-methylpropyl-2-isopropyl-2H-3-indazolecarboxylate via flash chromatography (eluent, hexane:ethyl acetate=95:5) to give the title compound (23 g) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[O:13].[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH2:4][N:5]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: CNC
Reactant: O=Cc1ccccc1N(CCCCl)c1ncccc1[N+](=O)[O-]
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
The title compound is prepared by reacting [2-[[3-chloropropyl)(3-nitro-2-pyridinyl)amino]phenylmethanone with dimethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](=N)OCC>ClC(Cl)Cl>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]1[O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CCCCl
Reactant: CCOC(=O)c1ccc(O)c(N)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2oc(CCCCl)nc2c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A mixture of 9 parts of ethyl 3-amino-4-hydroxybenzoate, 10.2 parts of ethyl 4-chlorobutanimidate hydrochloride and 150 parts of trichloromethane was stirred for 24 hours at 20° C. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The eluent of the desired fraction was evaporated, yielding 10 parts (74.7%) of ethyl 2-(3-chloropropyl)-5-benzoxazolecarboxylate as a residue (interm. 25).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl>N1C=CC=CC=1>[C:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:12][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)(=[O:11])[CH3:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(OC(=O)c2ccc([N+](=O)[O-])cc2)c(C(C)=O)c1

Procedure:
5′-methoxy-2′-hydroxyacetophenone (1.5 g, 9.03 mmol) was added to a pyridine solution (20 ml) that contained 4-nitrobenzoyl chloride (1.72 g, 9.26 mmol) in an ice bath. The obtained mixture was reacted at room temperature for 30 minutes, and the reaction solution was then poured into 1 N hydrochloric acid under cooling on ice. The obtained mixture was intensively stirred. The obtained precipitate was collected by filtration, and the filtrate was then washed with purified water, so as to obtain a product of interest, 4-nitrobenzoic acid 2-acetyl-4-methoxyphenyl ester (compound 21). Yield: 2.49 g (yield constant: 87.4%)
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].O>CS(C)=O.OO.C(OCC)(=O)C>[NH2:2][C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27]
Reactant: N#Cc1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.6 %

Procedure:
To a solution of benzyl 4-cyano-3-(cyclohexylamino)benzoate (66.2 mg, 0.198 mmol) in DMSO (2 mL) was added potassium carbonate (27.4 mg, 0.198 mmol) followed by 30% aqueous hydrogen peroxide (5 drops). The mixture was stirred at room temperature for 45 min, and was then diluted with ethyl acetate. Water was added and then the layers were separated. The aqueous phase was then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (40% ethyl acetate in hexanes) to provide benzyl 4-(aminocarbonyl)-3-(cyclohexylamino)benzoate (45.0 mg, 0.128 mmol, 64% yield) as a yellow film. 1H NMR (400 MHz, CDCl3): 7.81 (d, 1H), 7.46-7.32 (m, 7H), 7.16 (dd, 1H), 5.77 (br s, 2H), 5.36 (s, 2H), 3.48-3.38 (m, 1H), 2.05-1.98 (m, 2H), 1.80-1.72 (m, 2H), 1.66-1.59 (m, 1H), 1.45-1.23 (m, 4H); MS (EI) for C21H24N2O3: 353 (MH+).