Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>C(Cl)Cl>[C:24]([NH:1][CH:2]([CH3:3])[C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Ala-L-Phe obtained in Experimental Example 6 (100 mg, 0.423 mmol) is suspended in methylene chloride (10 ml), and pyridine (10 ml) and acetic anhydride (1 ml, 11 mmol) are added to the suspension at room temperature. After stirring at room temperature for 24 hours, water is added and the resulting mixture is extracted three times with chloroform. The organic layer is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent is distilled away under reduced pressure to obtain N-[2-(acetylamino)propionyl]phenylalanine.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:12]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:12][C:4]1[CH:3]=[N:2][N:1]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:5]=1
Reactant: c1cnn(-c2ccncc2)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnn(-c2ccncc2)c1
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)pyridine (Intermediate 7; 1.1 g; 7.5 mmol) in acetic acid (10 mL) was added a solution of bromine (6 mL) in acetic acid (10 mL) dropwise. The reaction mixture was stirred for 4 hours, diluted with saturated aqueous Na2S2O3 (20 mL), and extracted with DCM (10 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL), water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 936 mg (55%) of the title compound as a pink solid.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].Cl.[F:11][C:12]1([F:19])[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>>[F:11][C:12]1([F:19])[CH2:17][CH2:16][CH:15]([N:18]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13]1
Reactant: COC(=O)C(Br)CCBr
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Product: COC(=O)C1CCN1C1CCC(F)(F)CC1
Yield: 30 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 4,4-difluorocyclohexylamine hydrochloride 18B yielded methyl 1-(4,4-difluorocyclohexyl)azetidine-2-carboxylate as a brown oil (30%). MS ISP (m/e): 234.1 (100) [(M+H)]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[CH2:23]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]#[CH:25].C(N(CC)C(C)C)(C)C.C(OCC)C>O1CCCC1.[Cu]I.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>[CH2:27]([O:26][CH2:23][C:24]#[C:25][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Reactant: C#CCOCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnnc1C(=NOCc1csc(C#CCOCc2ccccc2)n1)c1ccccc1
Yield: 64.8 %

Procedure:
A solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-methanimine (190 mg, 0.50 mmol), benzyl propargyl ether (149 mg, 1.00 mmol), copper(I) iodide (9.5 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.02 mmol), N,N-diisopropylethylamine (258 mg, 2.0 mmol) in degassed tetrahydrofuran (2.5 mL) was stirred under an Argon atmosphere at 50° C. for 14 h. After the addition of diethylether (2 mL) the suspension was filtered over a pad of silica gel and the filtrate was concentrated in vacuo. Purification on silica gel afforded N-({2-[3-(benzyloxy)prop-1-yn-1-yl]-1,3-thiazol-4-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine as a thick oil (144 mg, yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([OH:31])[C:28]=1[O:29][CH3:30])/[CH:6]=[C:7]1/[C:8]([O:10][CH2:11][C@H:12]/1[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[O:9].[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=2)[C:28]=1[O:29][CH3:30])/[CH:6]=[C:7]1/[C:8]([O:10][CH2:11][C@H:12]/1[CH2:13][C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:9]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1cc(/C=C2/C(=O)OC[C@H]2Cc2cc(OC)c(OC)c(OC)c2)cc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C[C@@H]2COC(=O)/C2=C/c2cc(OC)c(OC)c(OCc3ccc([N+](=O)[O-])cc3)c2)cc(OC)c1OC
Yield: 91.5 %

Procedure:
A solution of (S)-(E)-2-(3,4-dimethoxy-5-hydroxybenzylidene)-3-(3,4,5-trimethoxybenzyl)butanolide (7.5 g, 17.4 mmol), p-nitrobenzyl bromide (4.6 g, 21.3 mmol) and potassium carbonate (3.0 g, 21.7 mmol) in 100 ml of acetone was heated under reflux for 3.5 hours. After the solvent was distilled off under reduced pressure, the residue was added with water and then ethyl acetate. The organic layer was washed successively with 2N-HCl, water, saturated NaHCO3 and saturated NaCl and then, dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off. The residue thus obtained was purified by column chromatography, whereby 9 g of the title compound were obtained as colorless foam (yield: 91%).
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Cl-].[K+]>CC(C)=O>[O:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH:2]1[C:3]#[N:4]
Reactant: C=C(Cl)C#N
Reactant: Nc1ccccc1O
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
Combine 2-chloro-2-propenenitrile (3.0 g, 34.3 mmol), 2-aminophenol (3.27 g, 29.96 mmol), acetone (50 mL), and potassium chloride (5 g, 36.18 mmol). Stir the mixture at ambient temperature for 16 hours. Filter the mixture and wash the filter cake with EtOAc. Concentrate the filtrate under reduced pressure to give a residue. Purify via flash column chromatography using a gradient of 1-50% EtOAc in petroleum ether to elute. Combine the product fractions and remove solvents under reduced pressure to provide the title compound (1.5 g, 21.6%). MS (m/z): 161 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>C([O-])(O)=O.[Na+]>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(O)n1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(C)nc(O)c1

Procedure:
20.0 g (130.6 mmol) of 2-hydroxy-6-methylisonicotinic acid were dissolved in 200 ml of ethanol and treated with 20 ml of concentrated H2SO4. After the reaction mixture had been refluxed for two hours, it was freed from the solvent. The residue was taken up in saturated NaHCO3 solution and extracted three times with DCM. The combined organic phases were dried with Na2SO4 and concentrated, 20.1 g of the title compound being isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[K].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34](=[O:37])(=[O:36])[NH2:35])=[CH:29][CH:28]=1>CS(C)=O.CO>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:35][S:34](=[O:36])(=[O:37])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][CH:31]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(NS(N)(=O)=O)cc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(NS(=O)(=O)Nc2ncnc(Cl)c2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.1 %

Procedure:
To 4,6-dichloro-5-p-tolyl-pyrimidine (Referential Example 7) (2.0 g) dissolved in DMSO (35 ml) was added di-isopropyl-ethyl-amine (1.46 ml) followed by addition of 4-methyl-phenyl sulfamic acid amide potassium salt (2.78 g) [prepared from the product described in Referential Example 19 and potassium tert.-butylate in methanol followed by evaporation of the solvent]. The mixture was stirred for 48 h at rt then poured onto water (500 ml) and diethylether (250 ml) was added and the solution was stirred for 30 min. The layers were separated and the water layer was acidified with acetic acid (2.0 ml) and cooled to 0° C. for 1 h. The precipitated product was filtered off and washed with water and diethylether and dried to give 4-methyl-phenyl sulfamic acid-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-amide (2.02 g). tR=5.00 min (LC); [M+H]+=389.11 (ES+);
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:31][CH2:32][O:33][C@H:28]([CH3:27])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Product: CCOC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 42 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.9 g, 1.9 mmol) was reacted with (2R,3S)-2-methyl morpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34, Step D to give the title compound as a yellow solid (0.43 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:18]=[CH:17][C:6]2[C@:7]3([CH3:16])[C@@H:12]([CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3.[CH3:19]C(C)([O-])C.[K+].CI.C(O)(=O)C>O1CCCC1.CN(C)C=O>[CH3:19][N:11]1[C@H:12]2[C@@:7]([CH3:16])([C:6]3[CH:17]=[CH:18][C:3]([S:2][CH3:1])=[CH:4][C:5]=3[CH2:14][CH2:13]2)[CH2:8][CH2:9][C:10]1=[O:15]
Reactant: CSc1ccc2c(c1)CC[C@H]1NC(=O)CC[C@]21C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Reaction time: 0.08 h

Procedure:
(+)-(4aR)-(10bR)-8-methylthio-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (0.423 grams, 1.62 mmol, 1.0 equivalents) was treated with potassium t-butoxide (1.86 mL as a 1.0 M solution in tetrahydrofuran, 1.15 equivalents) in dimethylformamide (1.6 mL) at approximately 0° C. After stirring 5 minutes, methyl iodide (0.116 mL, 1.15 equivalents) was added and the mixture allowed to stir for 2 hours at 0° C. The mixture was then treated with approximately 100 mg of acetic acid and solvents were removed in a stream of nitrogen. The solid was dissolved in approximately 50 mL of methylene chloride and washed twice with water. The extracts were dried (4 molecular sieves) and filtered over silica gel (2 grams, washed with ethyl acetate containing 2% methanol). The solid from the evaporation of the methylene chloride extracts was chromatographed on silica gel with methylene chloride, ethyl acetate and methanol (50:50:1) as the eluent. (GC).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25])[C:6]([O:8][CH3:9])=[O:7].C(N(C(C)C)C(C)C)C.Cl[C:36]1[C:41]([Cl:42])=[CH:40][C:39]([C:43]([F:46])([F:45])[F:44])=[CH:38][N:37]=1>CN(C=O)C.CCOC(C)=O>[Cl:42][C:41]1[C:36]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([O:13][C:12]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=4[F:2])[C:15]3=[O:25])[CH2:20][CH2:21]2)=[N:37][CH:38]=[C:39]([C:43]([F:45])([F:44])[F:46])[CH:40]=1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a solution of (S)-methyl 3-fluoro-4-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)benzoate hydrochloride (0.1 g, 0.29 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.543 mL, 2.97 mmol) and 2,3-dichloro-5-(trifluoromethyl)pyridine (0.193 g, 0.892 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (50 mL) and washed with water (20 mL), and brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum. The material was purified on silica, using a gradient of DCM to 10% EtOAc/DCM as eluent to yield (S)-methyl 4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (0.10 g, 63% yield).
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][N+:14]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH3:15].[C:28]([Br:33])(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[Br-:33].[C:28]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[C@@H:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][N+:14]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:17])[CH3:18])[CH3:15])(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)[N+](C)(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Reactant: CC(C)C(=O)Br
Agent: [Br-]
Product: CC(C)C(=O)Oc1ccc(CO)cc1[C@H](CC[N+](C)(C(C)C)C(C)C)c1ccccc1

Procedure:
(3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium bromide is acylated with isobutyryl bromide to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1COCC1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[C:38]([C:39]4[CH:44]=[CH:43][N:42]=[C:41]([NH:45][CH3:46])[N:40]=4)=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:27]=2)=[N:17][N:16]=1>O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[C:38]([C:39]5[CH:44]=[CH:43][N:42]=[C:41]([NH:45][CH3:46])[N:40]=5)=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:28][CH:27]=3)=[N:17][N:16]=2)[CH:6]=1
Reactant: Cc1cn[nH]c1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-n4cc(C)cn4)c4ccccc34)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry resealable pressure bottle, under nitrogen, was charged with 4-methylpyrazole (0.086 ml, 1.05 mmol). To this was added THF (1.3 ml, 0.2 M) and reaction mixture cooled to 0° C. 60% wt sodium hydride in mineral oil (44.0 mg, 1.10 mmol) was added slowly. Reaction mixture stirred at 0° C. for 15 minutes and 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.260 mmol) added slowly. Reaction kept at 0° C. for 10 minutes, then warmed up slowly to room temperature and placed in an oil bath. Reaction heated to 65° C. and stirred at this temperature overnight. Reaction mixture was cooled to 0° C. and diluted with water, and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated to afford an orange residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a yellow solid. MS m/z=502 [M+H]+. Calc'd for C28H23N9O: 501.54.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br.Br.[CH:15]12[CH2:21][CH:18]([NH:19][CH2:20]1)[CH2:17][NH:16]2.C1N2CCN(CC2)C1.C(Cl)Cl.CO>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:16]3[CH2:17][CH:18]4[CH2:21][CH:15]3[CH2:20][NH:19]4)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: C1NC2CNC1C2
Agent: Br
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CO
Solvent: CCCCO
Product: Clc1ccc2c(N3CC4CC3CN4)ccnc2c1

Procedure:
4,7-Dichloroquinoline (0.38 g, 1.9 mmol) and 2,5-diazanorbornane dihydrobromide (1.0 g, 3.8 mmol), and DABCO (1.3 g, 11.4 mmol) in n-butanol (20 mL) are reacted according to method B yielding the product after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [OH-].[Na+].C[O:4][N:5]=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=O.[Cl-].[NH4+].[CH3:14][C:15]([CH3:17])=[O:16]>>[CH3:11][C:7](=[CH:8][CH:9]=[CH:14][C:15](=[O:16])[CH3:17])[CH:6]=[N:5][OH:4]
Reactant: CON=CC(C)=CC=O
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(=O)C=CC=C(C)C=NO

Procedure:
An aqueous solution of sodium hydroxide (10%, 21.1 mL) was added slowly to a solution of 2-methyl-but-2-enedial-1-O-methyl-oxime (5 g) in acetone (100 mL) at 0° C. After 2 hrs the mixture was neutralized with a saturated solution of ammonium chloride, extracted with ethyl acetate (3×80 mL), washed with water (100 mL), dried with anhydrous magnesium sulfate and the solvent was evaporated yielding a yellow-orange solid (of formula V, R3 is methyl; 5.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[CH3:15][O:16][C:17]1[C:18]2[CH2:26][NH:25][CH2:24][CH2:23][C:19]=2[N:20]=[CH:21][N:22]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:24][CH2:23][C:19]3[N:20]=[CH:21][N:22]=[C:17]([O:16][CH3:15])[C:18]=3[CH2:26]2)=[N:3][CH:4]=1
Reactant: COc1ncnc2c1CNCC2
Reactant: Clc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncnc2c1CN(c1ccc(Cl)cn1)CC2

Procedure:
2-Bromo-5-chloropyridine (13.42 g, 0.067 mol), tris(dibenzylideneacetone)-dipalladium(0) (1.32 g, 1.43 mmol), sodium tert-butoxide (8.55 g, 0.088 mol), capped with a septum and purged with N2. A mixture of 4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (9.55 g, 0.0549 mol) in dry nitrogen-sparged toluene was added and the reaction mixture was sparged with nitrogen for an additional 30 min. The reaction mixture was then planced in an oil bath at 100° C., and heated overnight. After cooling, the mixture was diluted with ethyl acetate (180 mL), filtered and concentrated in vacuo. The residue was absorbed on 43 g silica, and purified on silica gel columned (0-60% EtOAc/hexane) to afford a light orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH2:17]([NH2:27])[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:27][CH2:17][C:18]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=2)[CH:7]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Yield: 82.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of piperonylamine (0.23 g, 1.52 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.47 g, 81%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 3.96 (2H, d, J=6.4 Hz); 5.94 (2H, s); 6.66-6.85 (3H, m); 6.71 (1H, d, J=16.4 Hz); 7.49-8.07 (5H, m); 8.14 (1H, br t, J=6.4 Hz).
Reaction SMILES: [N:1]#[N:2].[N+:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[S:16]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])(=[O:18])=[O:17])([O-:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(O)CCC.C1C=CC=CC=1>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:37]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:16]([C:11]1[C:12]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:18])=[O:17])[CH2:32][CH2:33][CH3:34]
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2c([N+](=O)[O-])cccc12)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c([N+](=O)[O-])cccc12
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -(5-nitro-1-naphthalenesulfonyl)-L-arginine, 1.0 gram of p-toluenesulfonic acid monohydrate in 5 ml of n-butyl alcohol and 30 ml of benzene was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue, giving a crystalline mass of N2 -(5-nitro-1-naphthalenesulfonyl)-L-arginine butyl ester p-toluenesulfonate in 95% yield; mp. 94° - 95° C.
Reaction SMILES: NC(C)(C)C[O:4][C:5](=[O:27])[C:6]1[C:11]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:8][CH:7]=1.C(Cl)(=O)C(C)(C)C.Cl.[Cl-].[Na+]>O1CCCC1>[C:12]([C:11]1[C:6]([C:5]([OH:27])=[O:4])=[CH:7][N:8]=[C:9]([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH:10]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCN(c2cc(C(=O)c3ccccc3)c(C(=O)OCC(C)(C)N)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(C(=O)c3ccccc3)c(C(=O)O)cn2)CC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 1.15 g (2.9 mmol) of 4-benzoyl-6-(4-methyl-piperazin-1-yl)-nicotinic acid 2-amino-2-methyl-propyl ester in 20 ml tetrahydrofuran were added dropwise 367 mg (3.05 mmol) pivaloyl chloride at 0° C. After stirring the light yellow suspension at the same temperature for 1 hour, 1 M aqueous hydrochloric acid was added. Excess pivaloyl chloride was extracted with dichloromethane, the aqueous layer was made alkaline with 28% sodium hydroxide solution and extracted twice with dichloromethane. The organic layer was dried (magnesium sulfate) and evaporated. The residue was dissolved in methanol, 1 M aqueous sodium hydroxide solution was added slowly at 0° C. and the mixture was heated overnight at 65° C. Methanol was evaporated and the aqueous layer was adjusted to pH 5. The solvent was evaporated to yield the product contaminated with sodium chloride, which was used for the next step without further purification.