Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:29]1([CH:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1]3)=[CH:16][CH:17]=2)[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=c1[nH][nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2[nH]c3ccccc3c2=O)cc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
At 0° C., 170.9 mg (1.27 mmol) of 1,2-dihydro-3H-indazol-3-one were added to 50.9 mg (1.27 mmol, 60% pure) of sodium hydride in 1.8 ml of DMF. The mixture was stirred for 30 min, and 500 mg (1.06 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. The reaction mixture was stirred for a further 30 min, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 217 mg (50.3% of theory) of the target compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C([C:15]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:16]=1[O:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])(=O)C.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:35][C:32]1[CH:33]=[CH:34][C:15]([OH:9])=[C:16]([CH:31]=1)[O:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]
Reactant: CC(=O)c1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A solution of 26 g of metachloroperbenzoic acid (at 55%, 82.9 mmol) in 220 ml of dichloromethane is stirred for one hour and then transferred into a separating funnel. The aqueous phase is separated out and the organic phase is placed in a round-bottomed flask and cooled to 0° C. 18 g of 2-[2-(2-acetyl-5-fluorophenoxy)ethyl]isoindole-1,3-dione (55 mmol) are added portionwise and the mixture is stirred at room temperature for 16 hours. 6.9 g of sodium bicarbonate (82 mmol) are then introduced portionwise and the mixture is stirred for one hour. The mixture is then concentrated under vacuum and 200 ml of methanol are added, followed by 15.2 g of potassium carbonate (110 mmol). The mixture is stirred for 4 hours at room temperature, the solvent is then evaporated off and replaced with 200 ml of dichloromethane, and the mixture is washed with water and with saturated aqueous sodium chloride solution. The aqueous phase is dried over sodium sulfate and filtered, and the solvent is evaporated off. The product is crystallized from dichloromethane. 14 g of the title product are obtained in the form of a white solid:
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.CS(C)=O>O>[C:11]([O:10][C:8]([N:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:16]3[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:5]2)[CH2:1]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 90 °C
Reaction time: 40 h

Procedure:
In a 25 mL pear-shaped flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.81 g, 14.2 mmol), 5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml, 15.6 mmol) were combined with DMSO (12 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 40 h. Cooled to 25° C. and the reaction mixture was diluted with 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The purple oil was used crude in the subsequent reduction. (M+H)+=321 m/e.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([NH:19]N)=[C:8]3[C:16](=[O:17])[NH:15][NH:14][C:13](=[O:18])[C:9]3=[N:10][C:11]=2[CH:12]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27]N)[CH3:23]>N1C=CC=CC=1.O>[CH2:22]([O:24][C:25]([CH2:26][CH2:27][NH:19][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:12][C:11]=2[N:10]=[C:9]2[C:13](=[O:18])[NH:14][NH:15][C:16](=[O:17])[C:8]=12)=[O:29])[CH3:23]
Reactant: NNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Yield: 11.3 %

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydrazinopyridazino[4,5-b]quinoline-1,4-dione hydrochloride (1.0 g, 2.9 mM, as prepared in Example 44) and beta alanine ethyl ester hydrochloride (49.0 g, 320 mM) in pyridine (52 mL) was refluxed for 23 hr. After cooling, the vigorously stirred reaction mixture was diluted slowly with water (100mL) and then filtered to separate a fine red solid. The collected solids were washed with water and chromatographed (eluant: methanol/methylene chloride; 5/95) over silica gel to provide the title ester (0.13 g, 13%) as a red powder, mp 258°-260° C.; MS(CI): 363 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](OCC)=[O:26])[C:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Lithium aluminium hydride (1.33 g) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (15.1 g) in tetrahydrofuran (300 ml) at 0° C., which was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (12.26 g) and hexane (100 ml) was added to the reaction mixture, which was stirred at room temperature for 1 hour. After the precipitate was removed by filtration, the filtrate was concentrated to obtain 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-ylmethanol (12.9 g, yield 95%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 112–113° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CN(C)[CH:20]=[O:21].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:21]
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)-indane was dissolved in 100 ml of anhdyrous tetra-hydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithium-hexane solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformamide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy) indane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C([N+]([O-])=O)=CC=CC=3S([O-])(=O)=O)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.C(O)(=O)C.[BrH:48].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:48])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: Br
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2c([N+](=O)[O-])cccc2S(=O)(=O)[O-])=NN1c1ncccc1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1.5 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl3-nitrobenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 1.5 hours. After completion of the reaction, ethyl acetate, water and 1.8 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 320 mg of the desired product in a paste form.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][N+](C)(C)C)=[C:27]2[C:23]=1[C:24]([CH3:38])=[C:25]([CH3:37])[N:26]2[CH3:36].[I-].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:28]2[CH:29]=[CH:30][C:22]([Cl:21])=[C:23]3[C:27]=2[N:26]([CH3:36])[C:25]([CH3:37])=[C:24]3[CH3:38])[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1c(C)n(C)c2c(C[N+](C)(C)C)ccc(Cl)c12
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2ccc(Cl)c3c(C)c(C)n(C)c23)c2ccccc21
Temperature: 100 °C
Yield: 15 %

Procedure:
To a stirred solution of 3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (93 mg, 0.34 mmol) in DMF (10 ml) was added (4-chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-trimethyl-ammonium; iodide (132 mg, 0.34 mmol) followed by potassium carbonate (140 mg, 1.01 mmol). The resulting mixture was warmed at 100° C. over night and cooled to ambient temperature. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic phase was dried (MgSO4), filtered and concentrated to give the crude product. Purification via preparative TLC (1 mm silica gel, 20% EtOAc/hexanes) gave 25 mg (15%) of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][N:6]=[CH:5][CH:4]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[S:7][N:6]=[CH:5][CH:4]=1)[CH3:9]
Reactant: ClCc1ccns1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ccns1

Procedure:
prepared by reaction of 5-chloromethyl-isothiazole with 2M ethylamine in THF.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:15][C:14]([O:13][CH3:12])=[O:35])=[CH:4][CH:5]=1)([OH:9])=[O:8]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a suspension of 4-formylbenzoic acid (1.00 g) in dry tetrahydrofuran (15 ml) was added methyl(triphenylphosphoranylidene)acetate (2.50 g) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 hour at the same temperature, poured into aqueous sodium bicarbonate solution, and washed with ethyl acetate. 1N-Hydrochloric acid was added to the aqueous layer until the layer was adjusted to pH 2. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give methyl 4-carboxycinnamate (1.21 g) as colorless powder. mp :243° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].F[B-](F)(F)F.[C:14]([CH:22]([S+:27]([CH3:29])[CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC>C(Cl)(Cl)Cl>[CH3:28][S:27]([CH3:29])=[C:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: CCCCC(C(=O)c1ccccc1)[S+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCC(C(=O)c1ccccc1)=S(C)C
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
A mixture of a saturated aqueous solution (72 ml.) of potassium carbonate and a 12.5 M aqueous solution (10 ml.) of sodium hydroxide is added to an ice-cooled, vigorously stirred solution of 1-benzoylpentyl dimethylsulphonium tetrafluoroborate (36.0 g.) in chloroform (100 ml.) at such a rate that the temperature does not exceed 10° C. After the addition is complete, the mixture is allowed to warm up to 20° C. and is stirred at this temperature for 15 minutes. The mixture is then separated by filtration and the chloroform layer of the filtrate is dried (sodium sulphate) and evaporated to give an oily residue. Trituration of this residue with ether (5 ml.) gives crystalline α-dimethylsulphuranylidene-n-hexanophenone (4.0 g.), which is used as starting material immediately.
Reaction SMILES: Cl.Cl.[CH:3]1([C@H:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[NH2:7])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Br[C:28]1[C:29]2[CH2:37][N:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[CH2:35][CH2:34][C:30]=2[N:31]=[CH:32][N:33]=1.O>C(#N)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([N:36]2[CH2:35][CH2:34][C:30]3[N:31]=[CH:32][N:33]=[C:28]([NH:7][C@H:6]([CH:3]4[CH2:5][CH2:4]4)[C:8]4[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=4)[C:29]=3[CH2:37]2)=[N:39][CH:40]=1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Reactant: N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc([C@H](Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)C2CC2)cn1
Temperature: 180 °C
Yield: 30.7 %

Procedure:
To a stirred solution of (R)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (53 mg, 0.184 mmol) and N,N-diisopropylethylamine (60 uL, 0.4 mmol) in acetonitrile (1.2 mL) was added 4-bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (30 mg, 0.092 mmol). The reaction mixture was heated in microwave reactor at 180° C. for 8 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to obtain a brown oil which was purified using HPLC (semi-prep 30-80% water/acetonitrile) to give a light brown solid (13 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:44])[NH:15][C:16]2[N:25]3[CH2:26][CH2:27][N:28]=[C:24]3[C:23]3[CH:22]=[CH:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][S:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)(=[O:35])=[O:34])=[C:19]([O:42][CH3:43])[C:18]=3[N:17]=2)=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCN(CC)CC>[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([NH:15][C:16]2[N:25]3[CH2:26][CH2:27][N:28]=[C:24]3[C:23]3[CH:22]=[CH:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][S:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)(=[O:35])=[O:34])=[C:19]([O:42][CH3:43])[C:18]=3[N:17]=2)=[O:44])=[CH:10][N:9]=1
Reactant: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(NC(=O)OC(C)(C)C)nc1)N1CCN=C21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 48 h
Yield: 121.5 %

Procedure:
tert-Butyl[5-({7-methoxy-8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}carbamoyl)pyrimidin-2-yl]carbamate (Step 1, 150 mg 0.26 mmol) was dissolved in CH2Cl2 (15 mL) and TFA (0.16 mL, 2.1 mmol) was added dropwise. The mixture was stirred at rt over 2 d, after which 5 drops of Et3N were added causing a solid to precipitate. The mixture was stirred overnight, then the solvents removed under reduced pressure. The resulting residue was triturated in EtOAc (15 mL), collected by vacuum filtration and washed further with EtOAc (10 mL). This solid was then triturated in water (5 mL) collected by vacuum filtration and washed further with water (10 mL). High vacuum drying gave the title compound (172 mg, 92%): HPLC MS RT=0.87 min, MH+=545.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.21-2.26 (2H, m), 3.15-3.18 (4H, m), 3.24-3.29 (2H, m), 3.61-3.65 (4H, m), 3.99 (3H, s), 4.18-4.25 (2H, m), 4.37 (2H, t), 4.48-4.55 (2H, m), 7.44 (1H, d), 8.02 (1H, d), 9.06 (2H, s).
Reaction SMILES: [CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[CH3:32])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[CH:1]1([O:10][C:14]2[C:15]3[CH:24]=[CH:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[N:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: OC1CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2ccc3c(OC4CCc5ccccc54)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 1-indanol (60 mg, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 3 hours, then diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 28 mg (48%) of the title compounds as an oil.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]I>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(Br)cc2c1Cc1ccccc1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(Br)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-methyl-1H-indole (1.530 g, 5.097 mmol) was reacted with k-t-butoxide (0.601 g, 5.352 mmol) and methyl iodide (0.760 g, 5.352 mmol) in DMF (15 ml) to give the product (1.453 g, 4.624 mmol, 91%) as a yellow solid, mp 104-106° C. 1H NMR (DMSO-d6) δ 2.39 (s, 3H), 3.65 (s, 3H), 3.99 (s, 2H), 7.10-7.14 (m, 2H), 7.18 (d, J=6.7 Hz, 2H), 7.22 (t, J=7.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 314/316 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]B(O)O)=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[CH3:6].O.OO.S([O-])(O)=O.[Na+]>C1COCC1>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:9]=1)[CH3:6]
Reactant: CCOc1ccc(OB(O)O)c(C(F)(F)F)c1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(O)c(C(F)(F)F)c1
Temperature: 0 °C
Yield: 97.7 %

Procedure:
Acetic acid (21.3 g) was added to a mixture of THF (200 mL) and Compound (d) (8.28 g) at room temperature, and the mixture was stirred at 0° C. under a nitrogen atmosphere. After adding 30% hydrogen peroxide water (40.1 g) dropwise, the resulting reaction mixture was carefully heated and stirred at 50° C. for 4 hours. Saturated aqueous sodium hydrogen sulfite (200 mL) was then slowly added dropwise at 0° C., and the reaction mixture was extracted three times with ether. The organic layers were combined, washed with aqueous saturated sodium hydrogen sulfite, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.67 g of Compound (e).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[Cl:21])[C:17](=O)[N:16]([C:23]1[C:24]([CH3:42])=[C:25]([CH3:41])[C:26]3[O:30][C:29]([CH3:32])([CH3:31])[CH:28]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]=3[C:39]=1[CH3:40])[C:15]2=O.O>O1CCCC1>[Cl:21][C:20]1[CH:19]=[C:18]2[C:14](=[CH:13][C:12]=1[Cl:11])[CH2:15][N:16]([C:23]1[C:24]([CH3:42])=[C:25]([CH3:41])[C:26]3[O:30][C:29]([CH3:31])([CH3:32])[CH:28]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]=3[C:39]=1[CH3:40])[CH2:17]2
Reactant: Cc1c(C)c(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)c(C)c2c1OC(C)(C)C2c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)c(N2Cc3cc(Cl)c(Cl)cc3C2)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.9 %

Procedure:
To a solution of aluminum chloride (1.01 g, 7.59 mmol) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (276.5 mg, 7.29 mmol) and the resulting mixture was stirred for 10 minutes. To this mixture was added a solution of 5,6-dichloro-2-[2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione (907.4 mg, 1.89 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was refluxed with heating for 2 hours. The reaction mixture was cooled down to room temperature and water was added into the mixture. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 153 mg (18% yield) of the title compound. Melting point: 194-196° C.