Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.O>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCCCc1ccccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCCCc1ccccc1Br
Yield: 97 %

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1>[C:1]([N:5]=[C:6]=[N:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 21.0 g of N-t-butyl-N'-(3,5-dichlorophenyl)thiourea produced in Example A-1 in 200 ml of THF were added 21.4 g of DCC and 0.73 g of triethylamine. The mixture was refluxed for 3 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-t-butyl-N'-(3,5-dichlorophenyl)carbodiimide as an oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].O[Li].O>C1COCC1.CO.O>[CH2:1]([S:3][C:4]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1c(SCC)nc2cnccc2c1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCSc1nc2cnccc2c(C)c1C(=O)O
Temperature: 75 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a solution of ethyl 2-(ethylthio)-4-methyl-1,7-naphthyridine-3-carboxylate [synthesized according to the methods described for example 1, sections a-d] (2.30 g, 8.33 mmol, 1 eq) in a mixture of THF (30 ml) and methanol (15 ml) was added a solution of LiOH.H2O (3.50 g, 83.33 mmol, 10 eq) in water (7.5 ml) at RT. The resulting mixture was stirred at 75° C. for 5 h. Afterwards the solvents were evaporated and the residue was washed with EtOAc (80 ml). The aq. layer was acidified with a 4M aq. HCl (50 ml) and extracted with EtOAc (3×100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and evaporated to provide 2-(ethylthio)-4-methyl-1,7-naphthyridine-3-carboxylic acid (0.85 g, 3.43 mmol, 41%) which was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[C:7](C=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[NH:21][N:20]=[C:19](N)[CH:18]=1.O.[CH3:24][N:25](C)C=O>>[NH2:25][C:24]1[N:20]2[N:21]=[C:17]([CH3:16])[CH:18]=[C:19]2[N:11]=[CH:10][C:9]=1[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13][CH:12]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc(CC#N)c(C=O)c1
Solvent: O
Product: Cc1cc2ncc(-c3ccc(C(C)(C)C)cc3)c(N)n2n1

Procedure:
10.5 g of p-tert.-butyl-2-formylbenzyl cyanide and 4.8 g of 3(5)-amino-5(3)-methylpyrazole in 40 ml of dimethylformamide were refluxed for 3 hours. The mixture was cooled, and 150 ml of water were then added dropwise. The crystals were filtered off under suction and then washed with water and dried under reduced pressure at 50° C. 11.3 g of 7-amino-2-methyl-6-(4'-tert.-butylphenyl)-pyrazolo[1,5-a]pyrimidine of melting point 218° C. were obtained (Compound 5).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.C.C[OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:28])=[N:9][N:8]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Reactant: CO
Product: O=C(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C

Procedure:
Heating of a mixture of 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine (Example 4 in WO 98/35958) and charcoal in boiling methanol for about 7 days in an open vessel leads to partial oxidation of the methylen-bridge of 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine. After cooling to RT, unchanged 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine crystallizes out and can be filtered off. Chromatography (SiO2; dichloromethane/methanol 98:2) of the concentrated filtrate then leads to [4-(4-chloranilino)phthalazin-1-yl](pyridin-4-yl)ketone and rac. [4-(4-chloranilino)phthalazin-1-yl](pyridin-4-yl)methanol (see Expl. 78 in WO 98/35958). [4-(4-Chloranilino)phthalazin-1-yl](pyridin-4-yl)ketone: 1H NMR (DMSO-d6) δ9.88 (bs, 1H, HN), 8.79 (d, 2H, pyridine), 8.71 (d, 1H), 8.63 (d, 1H), 8.07 (m, 2H), 7.97 (d, 2H, chloranilino), 7.77 (d, 2H, pyridine), 7.45 (d, 2H, chloranilino); IR (KBr): 3287, 3139, 3066, 1667 (CO), 1620 cm−1; FAB MS (M+H)+=361. rac [4-(4-Chloranilino)phthalazin-1-yl](pyridin-4-yl)methanol: m.p. 197-197.5 dec; 1H NMR (DMSO-d6) δ9.32 (bs, 1H, HN), 8.57 (d, 1H), 8.49 (d, 2H, pyridine), 8.22 (d, 1 H), 8.00 (d, 2H, chloranilino), 7.93 (m, 1H), 7.84 (m, 1H), 7.41 (d, 2H, pyridine); 7.40 (d, 2H, chloranilino), 6.77 (d, 1H, HO), 6.30 (d, 1H, HC-OH); IR (KBr): 3386 (OH), 3122, 2852, 1619, 1600, 1521, 1493, 1406 cm−1; FAB MS (M+H)+=363.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH:30][C:10]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]4[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=4[F:1])[O:9][N:8]=3)=[O:12])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31]
Reactant: Cc1cc2c(CCN)c[nH]c2cc1Cl
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(CCNC(=O)c3cc(Cc4cc(F)ccc4F)on3)c[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.180 g, 0.752 mmol), 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine intermediate 142(0.157 g; 0.752 mmol), HATU (0.286 g; 0.753 mmol) and N,N diisopropylethylamine (0.324 mL; 1.88 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane and eluent 1 to 10% ethyl acetate in dichloromethane) and by preparative HPLC method 2 to yield 0.0051 g (2%) of N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.C(O[B:18]([O:23][CH:24]([CH3:26])[CH3:25])[O:19][CH:20]([CH3:22])[CH3:21])(C)C.OC(C(O)(C)C)(C)C>O1CCCC1>[F:8][C:4]1[N:3]=[C:2]([B:18]2[O:19][C:20]([CH3:21])([CH3:22])[C:24]([CH3:25])([CH3:26])[O:23]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cccc(Br)n1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 67.1 %

Procedure:
A solution of 2-bromo-6-fluoropyridine (1.0 g) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (2.59 M hexane solution, 2.24 ml) in tetrahydrofuran (10 ml). The mixture was stirred at the same temperature for 45 minutes, and thereto was added dropwise a solution of triisopropoxyborane (1.28 g) in tetrahydrofuran (10 ml). The mixture was stirred at the same temperature for 2 hours, warmed, and further stirred at room temperature for one hour. Subsequently, a solution of pinacol (0.91 g) in tetrahydrofuran (10 ml) was added dropwise thereto, and stirred at room temperature for 20 minutes. Insoluble materials were filtered off. The filtrate was extracted with 2.5% sodium hydroxide, and the extract was cooled to 0° C., and was made weakly acidic with 2N aqueous hydrochloric acid solution. It was extracted with diethyl ether, washed with a small amount of brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was solidified with hexane to give 6-fluoro-2-pyridylboronic acid pinacol ester (850 mg) as a colorless solid. APCI-Mass m/Z 224 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[C:43]([F:46])[CH:44]=[CH:45][C:36]=5[F:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Fc1ccc(F)c2c1CCNC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)ccc(F)c5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (245 mg, 0.517 mmol), 5,8-difluoro-1,2,3,4-tetrahydroisoquinoline (175 mg, 1.03 mmol), cupric acetate (94.8 mg, 0.517 mmol), pyridine (84 μL, 1.0 mmol), 4 Å molecular sieves (139 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 3 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.88-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 3.31 (t, J=6.0 Hz, 2H), 4.17 (s, 2H), 4.22-4.36 (m, 3H), 6.92-6.97 (m, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.63 (s, 1H), 7.67 (s, 1H), 7.72 (d, J=1.2 Hz, 1H). MS(ES+): m/z=511.16 (100) [MH+]. HPLC: tR=2.93 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23](=[O:33])[CH2:24][O:25]CC2C=CC=CC=2)=[O:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O.C(O)(=O)C.[Pd]>[OH:25][CH2:24][C:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([NH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:17])=[O:33]
Reactant: O=C(COCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 80.7 %

Procedure:
(S)-N-(Phenylmethyl)-2-[[(S)-2-[(phenylmethyloxy)acetyl]-1-pyrrolidinyl]carbonyl]-1-pyrrolidinecarboxamide (40.0 g) was dissolved in a mixed solvent of methanol (200 ml), water (40 ml) and acetic acid (20 ml). Palladium-black (4.0 g) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The catalyst in the reaction mixture was filtered off and the filtrate was concentrated to give the title compound (25.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:13]2[N:9]([CH:10]=[N:11][C:12]=2[CH3:14])[C:8]2[N:7]=[CH:6][S:5][C:4]=2[N:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:10]1[N:9]2[C:13]([C:2]([CH3:1])=[N:3][C:4]3[S:5][CH:6]=[N:7][C:8]=32)=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1ncn2c1c(C)nc1scnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(Br)n2c1c(C)nc1scnc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
5,6-dimethyl-3-thia-1,4,7,8a-tetraaza-as-indacene (300 mg, 1.469 mmol) was dissolved in acetonitrile (50 ml) and 1-bromopyrrolidine-2,5-dione (131 mg, 0.734 mmol) was added. The resulting mixture was stirred at about 20° C. for about 1 h. After removal of the solvent under reduced pressure, the crude product was purified by prep-HPLC to give 60 mg of the title compound (yield: 15%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:36]3[O:35][CH2:34][O:33][C:32]=3[CH:31]=[CH:30][C:29]=2[Cl:37])[CH:24]=[CH:23][N:22]=1.N12CCCN=C1CCCCC2.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.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]>[Cl:37][C:29]1[CH:30]=[CH:31][C:32]2[O:33][CH2:34][O:35][C:36]=2[C:28]=1[NH:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:13][C:11]2[CH:10]=[C:9]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)[N:26]=1
Reactant: Clc1nccc(Nc2c(Cl)ccc3c2OCO3)n1
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccc2c(c1Nc1ccnc(Nc3cc(N4CCOCC4)nc(N4CCOCC4)c3)n1)OCO2
Temperature: 120 °C
Yield: 29.5 %

Procedure:
2,6-Dimorpholinopyridin-4-amine (140 mg, 0.53 mmol), 2-chloro-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)pyrimidin-4-amine (150 mg, 0.53 mmol), 1,8-diazabicyclo-[5.4.0]-undec-7-ene (0.158 mL, 1.06 mmol), bis(dibenzylideneacetone)palladium(0) (45.5 mg, 0.08 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (92 mg, 0.16 mmol) were dissolved in dioxane (3 mL) and sealed into a microwave tube. The reaction was degassed, purged with nitrogen and heated at 120° C. overnight. The reaction mixture was filtered off and washed thoroughly with dichloromethane. The filtrate was concentrated to dryness, diluted with dichloromethane (15 ml), washed with water (30 ml) and brine (15 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford N4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-N2-(2,6-dimorpholinopyridin-4-yl)pyrimidine-2,4-diamine (80 mg, 29.6%) as a pale beige foam. NMR Spectrum: (DMSOd6) 3.09-3.25 (m, 8H), 3.57-3.70 (m, 8H), 6.00 (s, 2H), 6.17 (d, 1H), 6.52 (s, 2H), 6.91 (d, 1H), 7.04 (d, 1H), 8.02 (d, 1H), 9.02 (s, 1H), 9.03 (s, 1H); Mass spectrum: MH+ 512.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:28]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O.ClC1([N+]([O-])=O)C=CC=NC1>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[CH:17][CH:18]=[CH:19][N:28]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: O=[N+]([O-])C1(Cl)C=CC=NC1
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1[N+](=O)[O-])C(=O)O
Yield: 64 %

Procedure:
was prepared by a similar method as (2S) 2-tert-butoxycarbonylamino-3-(2-nitrophenyl-amino)propionic acid in Step A of the synthesis of 600a/103, except that 3-chloro-3-nitro pyridine was used instead of 2-fluoronitrobenzene, to give 4.05 g (64%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:26]2[C:27]3[C:22](=[CH:21][C:20]([CH3:19])=[CH:29][CH:28]=3)[CH2:23][CH2:24][CH2:25]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: Cc1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 48.4 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added 6-methyl-1,2,3,4-tetrahydro-quinoline (26.5 mg, 0.18 mmol, 1.2 equiv; [CAS RN 91-61-2]), N-ethyldiisopropylamine (97.0 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68.4 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 10 min. Removal of the solvent mixture under reduced pressure and purification by preparative (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) on reversed phase eluting with a gradient of acetonitrile/water provided 30 mg (49%) of the title compound. MS (ISP): 413.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:35][CH3:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[C:19]([O:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15].[Br:37]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Br:37][C:22]1[CH:21]=[C:20]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])[C:19]([O:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[CH:18][C:17]=1[C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:35][CH3:36])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)COc1ccc(-c2ccc(OCC(C)CC)c(OCC(C)CC)c2)cc1OCC(C)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)COc1ccc(-c2cc(OCC(C)CC)c(OCC(C)CC)cc2Br)cc1OCC(C)CC
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
339 g (679.7) mmol of 3,3′,4,4′-tetra(2-methylbutyloxy)biphenyl were dissolved in 800 ml of ethyl acetate. 120.98 g (679.7 mmol) of N-bromosuccinimide were then added in solid form over a period of 15 minutes under protective gas, in the absence of light and with cooling to 0-5° C. The suspension was slowly warmed to room temperature under a blanket of protective gas and was then stirred vigorously at room temperature for 4 hours. 500 ml of ethyl acetate and 300 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml each time of ethyl acetate. The combined organic phases were washed twice with 50 ml each time of water and dried over MgSO4. The oil obtained was filtered through silica gel with the aid of hexane. Taking off the solvent gave 361.2 g (625.3 mmol, 92%) of 2-bromo-4,5,3′,4′-tetra(2-methylbutyloxy)biphenyl as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][C@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][C@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate (53.5 g) and triethylamine (130 ml) were dissolved in dichloromethane (500 ml), and methanesulfonyl chloride (42 ml) was added dropwise while cooling the solution to −10° C. to −15° C. After stirring for 20 minutes at the same temperature, the mixture was heated to room temperature over 30 minutes and further stirred for 2 hours. The reaction mixture was cooled to 0° C., 0.5N hydrochloric acid (800 ml) was added dropwise, and the mixture was extracted with dichloromethane. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methane-sulfonyloxy)cyclohexane-1-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]([C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[CH:28]=1)=[O:23]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:33][C:30]3[CH:31]=[CH:32][C:26]4[O:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:28][C:27]=4[CH:29]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to give N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine. LCMS: retn, time: 26.76 min.; purity: 97%; MS (m/e): 435 (MH+); 1H NMR (DMSO-d6): δ 9.41 (2H, sl), 8.27 (1H, s), 8.21 (1H, d, J 3.9 Hz), 7.98 (1H, m), 7.77-7.60 (3H, m), 7.37 (1H, t, J 8.1 Hz), 7.22 (1H, d, J 8.1 Hz), 3.98 (3H, s), 1.34 (9H, s).