Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=O)[CH3:13].Cl.[C:27]([O:31][NH2:32])([CH3:30])([CH3:29])[CH3:28].Cl>N1C=CC=CC=1>[C:27]([O:31][N:32]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:18][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])=[CH:16][C:15]=1[Cl:25])[CH3:13])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)ON
Reactant: CC(=O)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a mixture of 0.43 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone and 10 ml of pyridine was added 0.15 g of O-tert-butylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 0.45 g (yield, 90%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-tert-butyloxime, nD25.5 1.5170.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.C1CCN2C(=NCCC2)CC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12])=[CH:5]2
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2[nH]c(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.43 g of 5-methyl-2-indolecarboxylic acid are dissolved in 15 ml of DMF; 2.11 g of DBU are added and the mixture is then left stirring for 1 hour at RT. 2.61 g of benzyl bromide are added dropwise and the mixture is then left stirring for 6 hours at RT. This mixture is concentrated under vacuum and the residue is taken up in EtOAc, washed with water, with saturated Na2CO3 solution, with sulphate buffer and then with saturated aqueous NaCl. It is dried over Na2SO4 and then concentrated. The residue crystallizes from pentane and 3.3 g of the expected compound are obtained: m.p.=150-152° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)N1CCC(=NNC(=O)c2ccccc2)CC1
Yield: 81.5 %

Procedure:
20 g (0.142 mol) of 1-acetyl-4-piperidone were dissolved in 400 mL of absolute ethanol and 21.2 g (0.156 mol) of benzoylhydrazine were added. The resulting solution was refluxed for 6 hours under stirring. The solvent was then removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethylether and 30 g (83% yield) of the title compound were collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][CH:24]=[CH2:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: C=CCBr
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon, was added 0.6 g of sodium hydride (50% in oil). This mixture was stirred for 1 hour, then 1.07 ml of allyl bromide was added. The mixture was stirred overnight, then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed as described in Example 1. The active fractions were combined, evaporated and the solid recrystallized from ethyl acetate-hexane, giving 1.46 g of the desired product as tan crystals, mp 114°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:16])(=O)=O.O.[OH-].[Na+]>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]([CH3:12])[C:2]=1[NH2:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
The solution prepared in Step A (195 g, 475 mmol) was diluted with acetonitrile (50 mL), and heated to 50° C. Then a solution of sulfuryl chloride (70.6 g, 523 mmol) in acetonitrile (100 mL) was added over 3.25 h at 50-55° C. Immediately after completion of the addition, the mixture was cooled to 5° C., water (150 g) was added, and the pH of the solution was adjusted to 6.0 by slow addition of 50% aqueous sodium hydroxide (103 g). After stirring for 10 minutes at this temperature, the organic layer was separated, and the aqueous layer was extracted with acetonitrile (50 mL). The organic layers were combined, dried (MgSO4), and partially evaporated to a weight of 193.7 g. Quantitative HPLC of this solution showed 41.5 wt % of the title compound (80.4 g, 84.8% yield).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.Cl>>[Cl:5][S:1]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)(=[O:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Product: O=S(=O)(Cl)N1CCOCC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
With intensive cooling, 32.7 ml of sulfuryl chloride are added at approximately 0° C. to 23.5 ml of morpholine. The suspension is then carefully heated to 60° C., causing the onset of hydrogen chloride evolution. After 5 h at 60° C., the evolution of hydrogen chloride is complete. The cooled brown reaction mixture is poured onto ice, and the precipitating oil is extracted with ether, washed with water, 5% sodium hydrogen carbonate solution and water and dried with sodium sulfate. The organic phases are concentrated by evaporation and distilled at elevated temperature and reduced pressure (90° C.; 1 mbar) to yield the title compound: 1H-NMR (200 MHz, DMSO-d6): 3.80 and 3.29 (2t, 5 Hz, per 4 H).
Reaction SMILES: BrBr.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:6][CH:5]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CCOCC.O1CCOCC1>[N:24]([CH:11]([C:10]([C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)=[O:23])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[N+:25]=[N-:26]
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: [N-]=[N+]=NC(CC(=O)OCc1ccccc1)C(=O)c1ccc(Br)cc1
Reaction time: 6 h
Yield: 95 %

Procedure:
Bromine (2.5 mL, 46.1 mmol) was added to a solution of Example J5, benzyl 4-(4-bromophenyl)-4-oxobutanoate (16 g, 46.1 mmol) in ether (200 mL) and 1,4-Dioxane (50 mL) and the solution was stirred for 6 hours before being concentrated by rotory evaporation and taken up in acetonitrile (450 mL). Sodium azide (3.0 g, 46.1 mmol) was added and the reaction mixture stirred 18 hours. The solvent was removed upon concentration and the residue taken up in ethyl acetate and wash with water, brine, dried Na2SO4, and filtered. Concentration gave benzyl 3-azido-4-(4-bromophenyl)-4-oxobutanoate 17 g (95%) which was carried forward without further purification. Tin (II) chloride dehydrate (24.9 g, 131 mmol) was added to a solution of benzyl 3-azido-4-(4-bromophenyl)-4-oxobutanoate (17 g, 43.8 mmol) in CH3OH (550 mL) and stirred for 14 hours at 65° C. The reaction was concentrated by rotory evaporation and dried under high vacuum for 18 hours to give a mixture of benzyl and Example J6, methyl 3-amino-4-(4-bromophenyl)-4-oxobutanoate, (transesterification had occurred) and carried forward with purification. RT=1.3 minutes (condition 1); LCMS: Anal. C11H12BrNO3 Calcd. 286.0. found: 286.14 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(CO)c(NC3CCOCC3)c2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C=O)c(NC3CCOCC3)c2)CC1
Reaction time: 5 h
Yield: 50.3 %

Procedure:
85 mg (0.982 mmol) of manganese dioxide is added at room temperature to a solution of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol (100 mg, 0.327 mmol) in a mixture of ethyl acetate (10 ml) and dichloromethane (9 ml). The reaction mixture is placed in an ultrasonic bath for 5 hours. The reaction mixture is filtered, the solvents are evaporated and the crude product is purified by chromatography to yield 50.0 mg (yield-50.3%) of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzaldehyde in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([O:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])C>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]([CH2:14][CH2:13][O:12][CH3:10])[CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCNCCOCC
Reactant: BrCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CCN(CCOC)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
4-Bromobenzylbromide (4.01 g) was added to a solution of N-(2-ethoxyethyl)ethanamine (3.64 g) in DMF (40 ml). After stirring at ambient temperature for 18 h, the mixture was partitioned between diethyl ether and water. The organic phase was extracted with 2N aqueous hydrochloric acid which was then taken to pH 10 by addition of 2N sodium hydroxide solution. This was then extracted with diethyl ether which was dried and the solvent removed under vacuum to yield the title compound as a yellow oil (4.25 g). 1H NMR (DMSO-D6) 0.95 (t, 2H), 2.45 (q, 3H), 2.55 (t, 2H), 3.2 (s, 3H), 3.36 (t, 2H), 3.52 (s, 2H), 7.24 (d, 2H), 7.46 (d, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=[O:20])[CH2:13][CH2:12]1>C1COCC1>[OH:20][CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]1)[CH:5]1[S:6][CH2:7][CH2:8][NH:3][C:4]1=[O:9]
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: O=C1CSCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2C(O)C2SCCNC2=O)CC1
Temperature: 25 °C

Procedure:
Sodium hydride (930 mg, 23.3 mmol of 60% oil dispersion) was washed with hexanes under a nitrogen atmosphere and suspended in 100 mL of anhydrous THF. Thiomorpholin-3-one (1.0 g, 8.55 mmol) was added, followed immediately by 2-(4-methylpiperazin-1-yl)-benzaldehyde (1.58 g., 7.75 mmol). The reaction was then heated to reflux overnight, cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous ammonium chloride (NH4Cl) and saturated brine and then dried with MgSO4. Purification using flash chromatography gave 2-{hydroxy-[2-(4-methylpiperazin-1-yl)phenyl]-methyl}-thiomorpholin-3-one as a white solid, m.p. 137-139° C. Mass spectrum 322 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([Sn](C)(C)C)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.Br[C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][N:30]2[S:36]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>CN(C=O)C.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>[F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([C:26]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][N:30]4[S:36]([C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)(=[O:37])=[O:38])=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1c(F)nn2S(=O)(=O)c1ccccc1

Procedure:
A solution of 3-fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (0.65 g), 4-bromo-6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indole (0.69 g) and Pd(PPh3)4 (0.17 g) in DMF (5 ml) was heated to 120° C. for 18 h. The mixture was concentrated in vacuo and purified by silica cartridge (100 g) by Flashmaster II using a gradient of cyclohexane and ethyl acetate to give the title compound, 0.48 g as an orange solid.
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11](SC)[NH:10][CH:9]2[CH3:16].[NH3:17]>C(#N)C.C(N(CC)CC)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH2:17])[NH:10][CH:9]2[CH3:16]
Reactant: N
Reactant: COc1cccc2c1N=C(SC)NC2C
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc2c1N=C(N)NC2C
Temperature: 80 °C
Yield: 46 %

Procedure:
A solution of 8-methoxy-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (610 mg, 1.7 mmol) in a mixture of acetonitrile (6 ml) and aqueous ammonia (25%, 1.2 ml) was heated in a sealed tube on a shaker for 48 h at 80° C. The title compound (158 mg, 46%, MS: m/e=192.1 [M+H+]) was isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 1-99% CH3CN in 0.05% triethylamine (aq) over 5.0 min, λ=230 nm, flow rate 40 ml/min) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:20][CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][S:24]([CH2:23][CH2:22][CH2:21][Cl:20])(=[O:26])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)(CCCCl)NCCCN1CCN(Cc2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(4-benzyl-1-piperazinyl)propylamine (2.01 g/8.61 mmol) in tetrahydrofuran (15 ml) were added 2 N NaOH (5.6 ml/ 11.2 mmol) and 3-chloropropanesulfonylchloride (2.00 g/11.3 mmol), and the mixture was stirred for 1 day. The reaction mixture was quenched with water (50 ml) and the whole was extracted with ethyl acetate (50 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][N:20]=3)[C:15](=[O:30])[N:14]([CH3:31])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:32]1[N:41]=[CH:40][C:39]2[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=2)[C:33]1=[O:47])(=O)C.[Li+].[OH-]>O1CCOCC1>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:26]([CH3:28])[CH3:27])=[O:29])=[CH:21][N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[N:13]=3)[CH:10]=[CH:9][CH:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N(C)C)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
In a 500 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(dimethylcarbamoyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (1.142 g, 1.79 mmol) was combined with dioxane (25 ml) and 1M LiOH (10 ml) to give a light yellow suspension. The reaction mixture was stirred at 25° C. for 17 h. The crude reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and water. An emulsion was obtained and the aqueous was extracted exhaustively with DCM. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 4% MeOH in DCM) to afford 0.471 g (44%) of the title compound as a white solid. (M+H)+=598 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.68 (s, 1H), 8.46 (d, J=2.6 Hz, 2H), 8.29 (d, J=2.6 Hz, 1H), 7.79 (dd, J=8.3, 2.3 Hz, 1H), 7.64-7.69 (m, 1H), 7.53-7.63 (m, 3H), 7.50 (t, J=2.1 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 4.43 (s, 2H), 3.92 (s, 3H), 3.11 (s, 6H), 1.43 (s, 9H).
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:6][N:7]([CH3:29])[CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[N:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9]1>>[CH3:6][N:7]([CH3:29])[CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH:3]([CH3:5])[CH3:4])=[N:23][CH:22]=3)=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CC(C)CBr
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1
Product: CC(C)COc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cn1

Procedure:
1-Bromo-2-methylpropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:17]([O-:19])=[O:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Fluoro-4-methylbenzoic acid (1 g, 6.49 mmol) in H2SO4 (19 ml, 356 mmol) was cooled to 0° C. in an ice salt water bath and treated dropwise with mixture of H2SO4 (0.763 ml, 14.31 mmol) and nitric acid (0.65 ml, 14.54 mmol) over 10 min. The reaction mixture was stirred at 0° C. for 3 hrs and poured into ice/water (200 ml) and stirred for a further hour. The resulting suspension was collected by filtration, dried in vacuo and collected in EtOH, azeotroping to dryness to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([O-:26])=[O:25])#[N:2].[Na+].[C:28](Br)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([O:26][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:25])#[N:2]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=C(CC(=O)[O-])c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1=C(CC(=O)OC(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Reaction time: 5 h

Procedure:
A mixture of .06 mole of sodium 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetate and 0.05 mole of trityl bromide in 100 ml. anhydrous benzene is refluxed with rapid stirring under nitrogen for 5 hours. The hot reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is recrystallized from methyl ethyl ketone to give trityl 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetate.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.[N:46]1([CH2:53][CH2:54]N2CCC(N)CC2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>>[N:46]1([CH2:53][CH2:54][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:16][CH2:17]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCCCCC6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120, see example 86) and amine 5 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[NH2:1][C:2]1[N:11]=[C:10]([Cl:19])[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(=O)[nH]c(N)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(Cl)nc(N)nc2c1
Yield: 92.3 %

Procedure:
A solution of methyl 2-amino-4-oxo-3,4-dihydroquinazoline-7-carboxylate (500 mg, 2.28 mmol) and phosphoryl chloride (4 mL, 42.9 mmol) was stirred at 110° C. for 6 h. The starting material was consumed and the reaction mixture was concentrated to give the crude product (500 mg, 92.2%) as an oil. 1H NMR (300 MHz, DMSO) δ 3.9 (s, 3H), 7.79 (dd, 1H), 8.05 (d, 1H), 8.13 (d, 1H); Analytic LCMS (M+H)+: m/z=238.0.