Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reactant: C=CCN
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 64.3 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 2.85 g (0.05 mole) of 2-propenylamine. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the reddish oil which separated solidified upon standing. The solids were collected by filtration, 5.9 g. Upon repeated trituration with boiling isopropyl ether, the combined triturates upon cooling yielded 4 g (64.4%) of fine white crystals, m.p. 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15]([CH2:17]Cl)=O)[CH3:11]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:19])=[C:15]([CH3:17])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1cnc(N)c(N)c1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Yield: 26.4 %

Procedure:
A stirred mixture of 2,3-diamino-5-methyl-pyridine (4.0 g, 32.5 mmol) and (5.9 g, 36.0 mmol) of ethyl—chloroacetoacetate in 75 ml abs. ethanol was refluxed over night. The ethanol was evaporated under reduced pressure. The residue was dissolved in 2 M HCl and washed 3 times with diethyl ether, pH was adjusted to 9 and extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel with dichloromethane: methanol 95:5 as eluent to give the title product 2.0 g (28%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[CH2:6])[CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: C=Cc1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1
Temperature: 25 °C

Procedure:
3-Amino styrene (1.36 g, 11.4 mmol) was added to a solution of 2′,4′-difluorobiphenyl-4-sulphonyl chloride (3.0 g, 10.3 mmol) in DCM (25 mL) at 0° C. Pyridine (6.0 mL, 74 mmol) was then added and the mixture was allowed to stir and warm to room temperature overnight. The reaction was partitioned between further DCM (100 mL) and 2 M HCl (30 mL), stirred and separated. The DCM layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. The solvent was evaporated and the title compound obtained as an orange gum (3.46 g) which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(#N)C>[CH2:38]([O:37][C:33]([CH2:34][CH2:35][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][C:12]\2=[O:13])[CH:3]=[N:2]1)=[O:36])[CH3:39]
Reactant: C=CC(=O)OCC
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (Example 98(a), 6.0 g) in acetonitrile (100 ml) were added ethyl acrylate (4.7 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.4 ml). The resulting mixture was stirred at room temperature for 15 minutes, and the reaction was stopped by an addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and solvents were evaporated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (6.12 g, yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.Cl.[C:13](=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:13][O:9][C:8](=[O:10])[C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:11])=[N:4][CH:5]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
The solution of 2.0 g (11.5 mmol) 3-chloro-2-hydroxypyridine-5-carboxylic acid in 28 mL (35 mmol) hydrochloric acid (1.25M in methanol) was stirred for 5 h under reflux. The reaction was allowed to cool to room temperature, poured on 100 mL 10% aqueous sodium bicarbonate solution and 100 mL ethyl acetate, extracted and washed with 100 mL brine. The aqueous layer was extracted a second time with 100 mL ethyl acetate and the combined organic layers dried with magnesium sulfate, filtered and concentrated under vacuum. The light yellow residue was suspended in 30 mL tert-butyl methyl ether, stirred for 1 h at room temperature and filtered to give the desired compound as a white solid (55%) which was pure enough for the next step. MS (Turbo Spray): m/z=188.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 1.5 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-2-fluorobenzonitrile (4.62 g; 29.7 mmol) in cone. H2SO4 (42 mL) was treated dropwise with cone. HNO3 (3.9 mL) at 1-2° C. After stirring at 1-2° C. for 2 h the mixture was poured into ice and filtered to give the sub-title compound. Yield: 5.18 g (87%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:22])[N:12]=1.N>>[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:1]([O-:4])=[O:2])[C:17]=2[Cl:22])[N:12]=1
Reactant: Nc1nc(N)c2c(Cl)cccc2n1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nc(N)c2c(Cl)c([N+](=O)[O-])ccc2n1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
Nitric acid (90%), 125 mL, was stirred and cooled to -10° C., and 125 mL of 98% sulfuric acid was added dropwise. Upon completion of addition, the reaction mixture temperature was brought to 0° C., and 19.7 grams (0.10 mole) of 2,4-diamino-5-chloroquinazoline (Compound 2, prepared in a manner analogous to that of Step E of Example 1) was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for about 18 hours. The reaction mixture was then poured into 1500 mL of ice. The resultant mixture was made basic with 700 mL of aqueous 30% ammonia, keeping the temperature below 30° C. The mixture was cooled in an ice-bath, and the resultant solid was collected by filtration. The solid was stirred with 1000 mL of tetrahydrofuran and 500 mL of water. The mixture was filtered to remove a solid. The filtrate was diluted with 500 mL of ethyl acetate and then was concentrated under reduced pressure to a solid residue. The two solids were combined, washed with ethyl acetate, and dried, yielding 22.2 grams of 2,4-diamino-5-chloro-6-nitroquinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13](=O)[N:14]([C:22]3[C:23](=[O:36])[N:24]([CH2:33][CH2:34][CH3:35])[C:25](=[O:32])[N:26]([CH2:29][CH2:30][CH3:31])[C:27]=3[NH2:28])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].[OH-].[K+]>CC(O)C.O>[CH2:15]([N:14]1[C:22]2[C:23](=[O:36])[N:24]([CH2:33][CH2:34][CH3:35])[C:25](=[O:32])[N:26]([CH2:29][CH2:30][CH3:31])[C:27]=2[N:28]=[C:13]1[C:8]12[CH2:7][CH2:6][C:5]([C:3]([OH:2])=[O:4])([CH2:12][CH2:11]1)[CH2:10][CH2:9]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCn1c(N)c(N(Cc2ccccc2)C(=O)C23CCC(C(=O)OC)(CC2)CC3)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCn1c(=O)c2c(nc(C34CCC(C(=O)O)(CC3)CC4)n2Cc2ccccc2)n(CCC)c1=O

Procedure:
To a stirred solution of 4-[(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-benzyl-carbamoyl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (430 mg, 0.843 mmol) in i-PrOH (20 ml) was added 2 N KOH (4.0 eq, 3.37 mmol, 1.7 ml) and the resulting mixture was heated at reflux for 26 h. The cool reaction mixture was concentrated in vacuo to give a semi-solid residue that was diluted with water and extracted with CHCl3. The aqueous phase was acidified with concentrated HCl to afford a white precipitate that was collected and dried (381 mg, 91%). MS: 479 (MH+).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3].[CH3:12][NH:13][CH2:14][C:15]#[CH:16].[ClH:17]>C(O)C>[ClH:17].[CH3:3][CH:2]([N:13]([CH2:14][C:15]#[CH:16])[CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(C)Br
Reactant: C#CCNC
Agent: Cl
Solvent: CCO
Product: C#CCN(C)C(C)CCCCCCCC
Yield: 100 %

Procedure:
2-Bromodecane (8.84 g, 40 mmoles) and N-methylpropargylamine (5.52 g, 80 mmoles) were heated in absolute ethanol (50 mL) for 72 h. to give, after treatment with 40 mmoles of ethanolic hydrochloric acid, the title compound in a yield of 100% (75% after recrystallization from methanol-ether), m.p.=130°-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][CH3:37].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:27])[NH:39][C:35]([CH3:38])([CH3:34])[CH2:36][CH3:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: CCC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.3 g of the compound obtained in EXAMPLE 111 step B), 0.5 ml of 1,1-dimethylpropylamine, 0.5 ml of DIPEA, 0.35 g of BOP and 20 ml of DCM is stirred for 3 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl and with a 1N solution of NaOH and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 0.15 g of the expected product after crystallization from iso ether.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].Br[CH2:52][CH2:53][OH:54]>O.[OH-].[Na+]>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:52][CH2:53][OH:54])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: OCCBr
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CCO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 20 h
Yield: 47 %

Procedure:
N,N'-Bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(2,3-dihydroxypropylaminocarbonyl)-phenyl]urea (0.216 g, 0.157 mmol) was dissolved in a mixture of water (6 ml) and 2M aqueous NaOH (0.9 ml) together with 2-bromoethanol (0.067 ml). The mixture was stirred for 20 h, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification using preparative HPLC gave 105 mg (47%) of the product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH2:14][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH:8]=[CH:9]2)=[C:16]([O:23][CH3:24])[CH:17]=1)#[N:20]
Reactant: COc1cc(C#N)ccc1CBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C#N)ccc1Cn1ccc2ccc([N+](=O)[O-])cc21
Yield: 78 %

Procedure:
6-Nitroindole was alkylated with 4-bromomethyl-3-methoxybenzonitrile in the presence of potassium carbonate using the general procedure described in Ex 1(a) to give 1-(4-cyano-2-methoxybenzyl)-6-nitroindole (W) in 78% yield as a solid, m.p. 190.5°-191° C. (b) The nitrile W was converted to the corresponding tetrazole, 1-(2-methoxy-4-[1-(H)-tetrazol-5-yl]benzyl)6-nitroindole (X), obtained in 86% yield as a yellow-green solid, m.p. 258°-260° C. (d) using the general procedure of Example 67.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]([CH3:25])=[CH:19][C:17]=1[OH:18].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:25][C:20]1[C:21](=[O:24])[C:22]([CH3:23])=[C:16]([CH3:15])[C:17](=[O:18])[C:19]=1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1cccnc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1=C(C)C(=O)C(C(c2ccccc2)c2cccnc2)=C(C)C1=O
Yield: 72.9 %

Procedure:
to a solution of 1.0 g (5.4 mmol) of phenyl-(3-pyridyl) methanol and 823 mg (5.4 mmol) of 2,3,5-trimethylhydroquinone in 15 ml of dichloroethane, 0.5 ml (9.4 mmol) of concentrated sulfuric acid was added, and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, from which the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was washed with water, dried, and oxidized with air, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (isopropyl ether-ethyl acetate (1:1)), to give 1.25 g (72.7%) of 3,5,6-trimethyl-2-[phenyl-(3-pyridyl)methyl]-1,4-benzoquinone. The physical data are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11][C:12]1[C:13](F)=[CH:14][C:15]([F:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>>[Br:11][C:12]1[C:13]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:14][C:15]([F:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Br)c(F)cc1F
Reactant: COc1cc(Cl)ccc1O
Product: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2OC)cc1F
Yield: 41.5 %

Procedure:
Prepared according to Preparation 3 with 4-chloro-2-methoxyphenol (0.13 mL, 1.07 mmol) and methyl 5-bromo-2,4-difluorobenzoate (Preparation 18, 255 mg, 1.02 mmol) at room temperature for 18 hours. The crude product was purified by silica gel chromatography eluting with 5% EtOAc in Heptane to afford the title compound as a white solid (0.165 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](=[O:18])[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[NH:19][C:20]1[N:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][C:24]3=[C:32]([C:35]([NH:37][C@@H:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:39][NH:40]C(=O)OC(C)(C)C)=[O:36])[O:33][N:34]=[C:23]3[C:22]=2[N:21]=1>CO.Cl.O1CCOCC1>[NH2:40][CH2:39][C@@H:38]([NH:37][C:35]([C:32]1[O:33][N:34]=[C:23]2[C:22]3[N:21]=[C:20]([NH:19][C:4]4[CH:5]=[CH:6][C:7]([C:9](=[O:18])[NH:10][CH:11]5[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]5)=[CH:8][C:3]=4[O:2][CH3:1])[N:29]=[CH:28][C:27]=3[C:26]([CH3:31])([CH3:30])[CH2:25][C:24]=12)=[O:36])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1noc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)c3ccccc3)c1CC2(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1noc(C(=O)N[C@H](CN)c3ccccc3)c1CC2(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.8 %

Procedure:
To a mixture of tert-butyl [(2S)-2-({[8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,3-h]quinazolin-3-yl]carbonyl}amino)-2-phenylethyl]carbamate 110 mg (0.151 mmol) in MeOH (1 mL), 0.378 mL of 4 N HCl in dioxane was added. The reaction was stirred at room temperature for 12 h, the solvent was evaporated to dryness and the solid treated with Et2O (20 mL) and the precipitated collected by filtration to give the title compound as a pale yellow solid (96 mg; 91% yield).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: C1CCNCC1
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Yield: 93.4 %

Procedure:
To 5-Fluoro-2-nitro-benzamide (850 mg, 4.07 mmol) in THF (100 mL), was added piperidine (381 mg, 4.47 mmol) and diisopropyl ethyl amine (780 mL, 4.07 mmol) and the solution was heated to 70 C in a sealed tube for 12 h. The resulting yellow precipitate was collected to give 2-Nitro-5-piperidin-1-yl-benzamide 948 mg (100% yield) HPLC tr=3.58 min (100%), FIA m/e 250.2 (M+H) 248.8 (M-H); HNMR (500 MHz, dmso): δ 7.95 (1H, d), 7.85 91H, bs), 7.50 (1H, bs), 6.97 (1H, d), 6.80 (1H, s), 3.50 (4H, m), 1.70-1.50 (6H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2.[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[Cl:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][C:14]=3[CH3:13])[C:18]([NH:20][C:21]3[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=3)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(Cl)nncc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a 150 mL round-bottomed flask was added 6-bromo-1-chlorophthalazine (18, 357 mg, 1465 μmol), tetrakis(triphenylphosphine)palladium (84.7 mg, 73.3 μmol), 4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (500 mg, 1465 μmol), sodium carbonate (466 mg, 4396 μmol). The reagents were dissolved in DME:water mixture (15 mL, 4:1). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was evaporated and residue dissolved in ethyl acetate (20 mL) and washed with water (2×20 mL) and dried over MgSO4 and rotovaped to yield the title compound 24 as a crude product. The crude product 24 was adsorbed on silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 65% to 80% EtOAc in DCM, to provide 3-(1-chlorophthalazin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide (24).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][S:42]([C:45]1[CH:46]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=1)(=[O:44])=[O:43]>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:51]([C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([S:42]([CH3:41])(=[O:44])=[O:43])[CH:46]=2)(=[O:53])=[O:52])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (3 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-(methylsulfonyl)benzenesulfonyl chloride (307 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a pale-yellow oil (yield 504 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1cccc(F)c1
Yield: 80.69 %

Procedure:
3-(3-Fluorophenyl)acrylic acid (I-78a: 6.4 gm, 38.5 mmol) in methanol (100 mL) was reduced with 10% Pd/C (640 mg) to afford the crude product, 5 g (80.69% yield).