Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=O)[CH3:4].[CH:9]([NH2:11])=[O:10].[OH-].[Na+].[Na+].[Cl-]>O.C(O)=O>[C:6]([C:2]1[O:10][CH:9]=[N:11][C:3]=1[CH3:4])(=[O:8])[CH3:7]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CC(=O)c1ocnc1C
Temperature: 140 °C
Yield: 26.4 %

Procedure:
A mixture of 3-chloro-2,4-pentanedione (26.8 g), formamide (18.0 g), and formic acid (50.0 g) was heated in a 140° C. oil bath and refluxed for 4 hours. The resulting dark mixture was poured into 100 ml of water, basified with 50% NaOH solution, and saturated with NaCl. The mixture was extracted with ethyl ether (3×100 ml). The ether solution was dried over sodium sulfate and concentrated. The residue was vacuum-distilled to yield 6.59 g of 5-acetyl-4-methyloxazole as a colorless liquid, 84° C. (15 torr). NMR: 2.51 (s, 3H), 2.52 (s, 3H), 7.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[CH2:24](I)C>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][CH3:24])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Cl)c1
Reactant: CCI
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-4-thiocyanoaniline (40 g., 0.22 mole) in ethanol (250 ml.) is added to a stirred solution of sodium sulfide nonahydrate (58.5 g., 0.22 mole) in water (110 ml.) and the mixture is warmed (50° C.) for 45 minutes. Ethyl iodide (36.6 g., 0.22 mole) is added and stirring is continued for 2 hours at 50° C. and then at room temperature overnight. The reaction is poured into water (3 liters) and the product extracted with either. The combined extracts are washed with water and dried (CaSO4). Removal of the drying agent and solvent gives 2-chloro-4-ethylthioaniline, an oil.
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:45])[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)([OH:37])[C:33]([F:36])([F:35])[F:34])=[C:27]([Cl:46])[CH:26]=1.[CH3:47][O:48][C:49](=[O:57])[C:50]1[CH:55]=[CH:54][C:53](Cl)=[N:52][CH:51]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[CH3:47][O:48][C:49](=[O:57])[C:50]1[CH:55]=[CH:54][C:53]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:45])[C:32]([OH:37])([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=3)[C:33]([F:36])([F:35])[F:34])=[C:27]([Cl:46])[CH:26]=2)=[N:52][CH:51]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)nc1
Temperature: 100 °C

Procedure:
A mixture of bis(pinacolato)diboron (28 mg), potassium acetate (29 mg), bis(triphenylphosphine)palladium(II)chloride (2 mg), and 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 41 mg) in dioxane (2 ml) was heated at 100° C. for 1.5 h. After cooling to room temperature, water (0.2 ml), methyl-6-chloronicotinate (CAS Reg. No. 73781-91-6, 34 mg), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palldadium(II) dichloromethane complex (11 mg) and Cs2CO3 (98 mg) were added. The mixture was heated to 100° C. for 3 h and then purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (22 mg) as a yellow solid. MS (m/e)=465.1 [M+H+].
Reaction SMILES: CS(O)(=O)=O.CS(O[CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[CH:17])(=O)=O.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[CH:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: C#CCOCCCOS(C)(=O)=O
Agent: CS(=O)(=O)O
Product: C#CCOCCCNC(C)(C)C

Procedure:
A solution of 1 g of methane sulphonic acid and 1 g of 7d in 10 ml of tert-C4H9NH2 was heated at 60° C. for 24 hr in a closed vial. The reaction mixture was concentrated and the residue was diluted with 15 ml of 1M aq. K2CO3. Then, the product was extracted with ethyl acetate. The organic layer was washed once with sat. NaCl solution, dried and concentrated to provide 830 mg of 7e as a yellowish oil.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:38][C:39]([F:47])([F:46])[CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:42]([CH2:41][CH2:40][C:39]([F:47])([F:46])[F:38])(=[O:44])=[O:43])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic piperidin-1-ylamide, from Ex 2, Step 1, (0.89 g, 2.00 mmol) was dissolved in dichloromethane (20 ml), cooled to 0° C. and triethylamine (0.35 ml, 2.4 mmol) added followed by 3,3,3-trifluoropropanesulfonyl chloride (prepared by an analogous method to that described in WO00/010968 for the butyl homologue) (0.35 ml, 2.40 mmol). The reaction mixture was stirred at room temperature overnight. TLC showed remaining starting material and so another portion of triethylamine and 3,3,3-trifluoropropanesulfonyl chloride was added and the reaction mixture stirred for additional 2 hrs. Water was added and the product was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Flash chromatography (hexane:EtOAc 1:3-EtOAc) followed by recrystallization (hexane:EtOAc) afforded 700 mg (59%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH2:28][CH3:29])=[C:11]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=3[N:18]=2)[CH:12]=1>N1C=CC=CC=1>[CH2:28]([O:27][C:10]1[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][C:11]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(C)(=O)=O)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
Methanesulphonyl chloride (0.157 g, 0.00137 mol) was added to a stirred solution of 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.45 g, 0.00137 mol) in dry pyridine (30 ml) at 0° C. The mixture was stirred for 18 hours at room temperature and then evaporated under vacuum. The residue was suspended in saturated aqueous sodium bicarbonate solution (50 ml) and the mixture extracted with dichloromethane (2×30 ml). The organic extracts were combined, washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. The residue was triturated with ether, chromatographed on silica gel (12 g), eluting with a 98.5:1.5 mixture of dichloromethane and methanol, and the required product crystallized from ethyl acetate-hexane to give the title compound as a white powder (0.32 g, 58%), m.p. 205-206° C. Found: C,53.63; H,5.66; N,17.24. C18H23N5O4S requires C,53.32; H,5.72; N,17.27%.
Reaction SMILES: NCCNC1N=CC=CC=1.ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)N=1>N1C=CC=CC=1>[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: NCCNc1ccccn1
Solvent: c1ccncc1
Product: NCCNc1ccc([N+](=O)[O-])cn1

Procedure:
The preparation of the material 6-[(2-aminoethyl)amino]pyridine with various substitutents on the pyridine can be found in the precedures for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine, Example 74, and its analogues.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[Br:20]Br.[K+].[Br-]>ClCCl>[Br:20][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH:2]([OH:1])[C:7]([CH3:8])([CH3:9])[O:6][C:5]=2[CH:10]=1
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Reactant: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 4 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.4 g, 5.0 mmol) and bromine (0.27 mL, 5.2 mmol) in dichloromethane (30 mL). Purification by flash chromatography using 1% methanol in dichloromethane as the eluant and recrystallization from dichloromethane/hexanes gave the product, 3.87 g (78%), as a colorless solid: mp 200°-202° C.; IR (KBr): 3442, 2942, 1616, 1571 and 1488 cm-1 ; MS: m/z 360 (MH+); 1H NMR (CDCl3): δ1.29(s, 3H), 1.46(s, 3H), 1.82(m, 4H), 2.51(m, 2H), 3.12(m, 1H), 3.27(m, 1H), 3.46(d, J=5.0 Hz, 1H, exchanges with D2O), 3.78(d, d, J=9.0 Hz, J=5.0 Hz, 1H, simplifies to d, J=9.0 Hz, with D2O), 5.74(d, J=9.0 Hz, 1H) and 7.58(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.[ClH:13].[Cl:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.[OH-].[Na+].Cl>COCCOCCOC.C(OCC)(=O)C.CCOCC>[ClH:14].[ClH:13].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CC(C)(C)c1cc(Br)ccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
A suspension of 4-bromo-2-tert-butylaniline (Reference Example 8, 25.0 g, 110 mmol) and bis(2-chloroethyl)amine hydrochloride (21.5 g, 120 mmol) in diethylene glycol dimethyl ether (157 mL) was stirred for 3 days at 170° C. It was cooled to room temperature, added 1 M sodium hydroxide solution (50 mL), and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product. It was diluted with ethyl acetate and ether (50:50) and added 1 M hydrochloric acid solution to provide 1-(4-bromo-2-tert-butylphenyl)piperazine dihydrochloride (16.2 g, 40%) as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][OH:7].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>O>[Cl:19][CH2:18][CH:17]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6][O:7]1
Reactant: COc1cccc(CCO)c1OC
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1OC)CCOC2CCl
Yield: 82.6 %

Procedure:
A mixture of 30 g of 2,3-dimethoxyphenethyl alcohol, 30 g of chloroacetaldehyde diethyl acetal and 50 ml of concentrated hydrochloric acid was heated at 60°-80° C for 1 hour and, after cooling, the reaction mixture was diluted with water. The resultant oily precipitate was extracted into ethyl acetate, rinsed with water, dehydrated and concentrated under reduced pressure. The residue was then recrystallized from petroleum ether. By the above procedure was obtained 33 g of 1-chloromethyl-5,6-dimethoxyisochroman as colorless needles, melting point: 63°-65° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:22][OH:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[CH2:29]([O:23][CH2:22][C:7]1[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]=1[CH:24]([CH3:25])[CH3:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COCc2ccccc2)c1-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
4.5 g (12.5 mmol) of the compound from Example 4 in 50 ml of dimethylformamide are added dropwise under nitrogen to a suspension of 414 mg (13.8 mmol) of 80% strength sodium hydride in 20 ml of dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at the same temperature. Subsequently, 1.65 ml (13.8 mmol) of benzyl bromide in 20 ml of dimethylformamide are added dropwise and the mixture is stirred for a further 3 h at room temperature. The mixture is poured into 300 ml of water at 0° C. and extracted three times using 150 ml of ether each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 1:10).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[NH2:11])=O)C.[CH:16]([NH2:18])=O>>[N:11]1[C:10]2[S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:4]([OH:3])=[N:18][CH:16]=1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: NC=O
Product: Oc1ncnc2sc3ccccc3c12
Temperature: 25 °C

Procedure:
The solution of 10 millimol IX in 15 milliliter milliliter formamide was stirred at 100° C. for 3 hours then cooled down to room temperature. The reaction mixture was poured onto crushed ice with continuous stirring then collected by filtration. The product was washed with water and n-hexane, then dried.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>>[N+:10]([C:4]1[CH:3]=[C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-chloro-2-nitrobenzonitrile (1.50 g) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole (2.74 g) using the method of Example 39(a). Yield 1.75 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.57 (m, 3H), 1.84 (m, 1H), 1.97 (m, 1H), 2.38-2.47 (m, 1H), 3.68-3.75 (m, 1H), 4.03 (m, 1H), 5.33 (dd, 1H), 6.84 (d, 1H), 7.69 (d, 1H), 8.13 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:20][CH:21]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[(4-chloro-benzyl)-isobutyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane cooled at 0° C. was added trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate and concentrated. The product was used without any further purification.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].[CH2:36]([N:38](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH3:36])=[O:28])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(CCc2ccccc2)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.012 g (0.19 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.056 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-278) as a white solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[O:26][CH:27]=[CH:28][C:29]=2B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:25]2[O:26][CH:27]=[CH:28][C:29]=2[C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Reactant: OB(O)c1ccoc1-c1ccccc1
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: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccoc1-c1ccccc1
Temperature: 80 °C
Yield: 6.7 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (300 mg, 0.940 mmol), (2-phenylfuran-3-yl)boronic acid (265 mg, 1.41 mmol), Na2CO3 (299 mg, 2.82 mmol) and Pd(PPh3)4 (54.3 mg, 0.047 mmol) in DME (3.6 mL) and water (1.1 mL) was heated to 80° C. for 4 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=80/20 to 0/100) and recrystallized with AcOEt/heptane to yield the title compound (23.9 mg, 7% yield) as a pale yellow solid: mp 159-163° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.63 (1H, d, J=8.0 Hz), 6.99 (1H, d, J=1.9 Hz), 7.32-7.43 (3H, m), 7.54-7.60 (2H, m), 7.69-7.76 (2H, m), 7.78-7.82 (1H, m), 7.85 (1H, d, J=1.9 Hz), 7.85-7.92 (1H, m), 8.96 (1H, d, J=8.0 Hz). Anal. Calcd for C21H13F3N2O2.0.3H2O: C, 65.05; H, 3.54; N, 7.22. Found: C, 65.20; H, 3.63; N, 7.29.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]1[O:17][C@H:16]1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1[O:40][C@H]1CCCC(OC)=O.[Na+].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][C@@H:9]([OH:40])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[CH:15]\[C@@H:16]([OH:17])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(=O)OC
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(=O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Product: CCCCC/C=C\C[C@@H](O)/C=C/C=C/C=C\[C@@H](O)CCCC(=O)O

Procedure:
The LTA4 substrate was freshly prepared by alkaline hydrolysis of LTA4 methyl ester (Cayman Chemical Co., USA). After incubating for 10 minutes in the presence of LTA4 (1 μM in 50 mM Tris-HCl, 0.15 M NaCl, 0.5% BSA, pH 7.4), the reaction is stopped by diluting 1/20 in 0.1 M potassium phosphate buffer containing 1.5 mM NaN2, 0.4 M NaCl, 1 mM EDTA, 0.1% BSA, pH 7.4, −4° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[O:18][CH2:19][CH2:20][O:21][C:13]=23)[CH3:11])[CH:3]=1.[CH3:22][NH:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:21]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[C@H:10]([CH3:11])[CH2:9][NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([C:27]3[CH:26]=[N:25][C:24]([NH:23][CH3:22])=[N:29][CH:28]=3)[CH:3]=2)[O:18][CH2:19][CH2:20]1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(CNc1cc(Cl)ncn1)c1ccnc2c1OCCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNc1ncc(-c2cc(NC[C@@H](C)c3ccnc4c3OCCO4)ncn2)cn1
Temperature: 80 °C

Procedure:
As shown in step 7-vi of Scheme 7, 6-chloro-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]pyrimidin-4-amine (410 mg) was dissolved in IPA (0.75 mL). N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (23 mg) was added, followed by the addition of 2M Na2CO3 (122 μL) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (7 mg). The reaction vessel was sealed and heated at 80° C. overnight. The mixture was cooled, diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by reversed-phase HPLC, 5-50% ACN/H2O/0.1% TFA. Fractions containing pure product were collected, dissolved in MeOH, passed through a carbonate cartridge, and concentrated under reduced pressure to provide (S)—N6-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-N2′-methyl-[4,5′-bipyrimidine]-2′,6-diamine (Compound 462): ESMS=380.39 (M+H); 1H NMR (300 MHz, methanol-d4) δ 8.75 (s, 2H), 8.47 (s, 1H), 7.65 (d, J=5.3 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 6.76 (s, 1H), 4.46-4.34 (m, 2H), 4.32-4.19 (m, 2H), 3.59 (ddd, J=12.0, 11.5, 7.3 Hz, 3H), 2.99 (s, 3H), 1.32 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[C:14](=[O:16])[NH:17][C:18]2[C:19]([C:25]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nccn1Cc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1nccn1Cc1ccccc1
Yield: 43 %

Procedure:
Synthesized from (1-benzyl-1H-imidazol-2-yl)-acetic acid (Tetrahedron Letters, 37 (51), 9259, 1996) and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 43%.