Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:48])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33]C5CCCCO5)[CH:28]=4)=[C:25]([CH3:40])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:41]C5CCCCO5)[CH:23]=4)[O:18]3)=[CH:13][CH:12]=2)[CH2:4]1>C(O)(=O)C.O>[F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:48])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)=[C:25]([CH3:40])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:41])[CH:23]=4)[O:18]3)=[CH:13][CH:12]=2)[CH2:4]1
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OC[C@H](C)N3CC[C@@H](CF)C3)cc2)Oc2ccc(OC3CCCCO3)cc21
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(c2cccc(O)c2)C(c2ccc(OC[C@H](C)N3CC[C@@H](CF)C3)cc2)Oc2ccc(O)cc21
Yield: 70.4 %

Procedure:
(3R)-3-(fluoromethyl)-1-((2S)-1-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)propan-2-yl)pyrrolidine (785 mg, 1.19 mmol) was stirred in 80% acetic acid/H2O (6.0 mL) at room temperature for 2 days. The solvents were removed on a rotary evaporator, and the residue was dissolved in ethyl acetate. The organic layer was washed with sat'd aqueous NaHCO3, washed with water, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This crude material was then purified by silica gel chromatography (0-4% MeOH/DCM) to afford 2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol (410 mg, 70%) as pale pink solid. 1H NMR (DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.18 (d, 2H), 7.12 (t, 1H), 6.79 (d, 2H), 6.73 (m, 1H), 6.68 (dt, 1H), 6.65 (m, 1H), 6.61 (m, 1H), 6.49-6.45 (m, 2H), 5.83 (s, 1H), 4.35-4.30 (m, 1H), 4.23-4.18 (m, 1H), 3.99-3.93 (m, 1H), 3.74-3.70 (m, 1H), 2.69-2.60 (m, 2H), 2.58-2.52 (m, 2H), 2.45-2.32 (m, 2H), 2.02 (s, 3H), 1.82-1.75 (m, 1H), 1.36-1.30 (m, 1H), 1.07 (d, 3H); LCMS: 490.2 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:9].[Cl:10][C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][NH:14][C:15]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[C:12]([C:17]([F:19])([F:18])[F:20])=[N:13][N:14]([CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2=[O:9])[C:15]=1[CH3:16]
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Reactant: O=C1OCCCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C1CCCCOC1=O
Temperature: 65 °C
Yield: 19.5 %

Procedure:
To a solution of 3-bromooxepan-2-one (1 g, 5.18 mmol) in DMF (10 mL) was added 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.956 g, 5.18 mmol), followed by potassium carbonate (1.07 g, 7.74 mmol). The reaction mixture was then heated at 65° C. for 8 h. After cooling to room temperature, the reaction mixture was partitioned between water (20 mL) and ethyl acetate (30 mL). The organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gave the title product as a white solid (0.3 g, 1.01 mmol, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:12]=3)[C:4]=2[CH:3]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([CH:26]5[CH2:27][O:24][CH2:25]5)[CH2:19][CH2:18]4)[N:12]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCNCC2)n1
Reactant: O=C1COC1
Solvent: ClCCCl
Product: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCN(C3COC3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A mixture of 6-chloro-1-[6-(1,4-diazepan-1-yl)-2-pyridyl]pyrazolo[4,3-c]pyridine (0.4094 mmol; 134.6 mg), oxetan-3-one (0.4912 mmol; 35.40 mg), and Molecular sieve (4A) in 1,2-dichloroethane (12 ml) was stirred at room temperature for 4 hours. STAB (0.6141 mmol; 137.0 mg) was added. The reaction was stirred for 3 days. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford 6-chloro-1-[6-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]-2-pyridyl]pyrazolo[4,3-c]pyridine (99.2 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:15]([CH3:33])[CH:16]2[CH2:32][CH2:31][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a suspension of tert-butyl 8-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (3.9 A: 0.15 g, 0.32 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 3.5 M). The mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The residue was diluted with DCM (20 mL) and saturated Na2CO3 solution (20 mL). The organic layer was separated and the aqueous layer was extracted with a mixture of DCM and MeOH (10/1 (v/v), 20 mL×5). The combined organic layers was washed with brine (30 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/2N NH3 in MeOH (v/v)=5/1) to afford 3.10 A as a brown solid (0.10 g, 84%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][CH:2]([F:19])[CH2:3][O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate(2,2-difluoroethyl)ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60° C. for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 162”).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Product: O=C(O)CCCCCNC(=O)CCCCCNC(=O)OCc1ccccc1

Procedure:
The second step was to activate the N-benzyloxycarbonyl-6-aminocaproic acid obtained by following the procedure of Example 3 A. above, with ethyl chloroformate followed by reaction with a second 6-aminocaproic acid linker to yield N-(N'-benzyloxycarbonyl-6-aminocaproyl)-6-aminocaproic acid. This second step was carried out as follows. A solution of 52.1 g (0.19M) of N-benzyloxycarbonyl-6-aminocaproic acid (thoroughly dried) dissolved in 640 mL of toluene and 20 mL of triethylamine, was cooled to between -5° to -10° C. in an isopropanol/dry ice bath before ethyl chloroformate (19.1 mL, 0.199M) was slowly added to give a white precipitate. The precipitate was removed by filtration and discarded. To the filtrate cooled in an ice-water bath there was added over 45 minutes a solution of 25.7 g (0.19M) of 6-aminocaproic acid in 100 mL of cold 2N NaOH. After stirring for 1 hr at 0° C. and then overnight at room temperature, the pH was adjusted to 8 with 6N NaOH and 1.2 L of H2O was added. The 1.3 L aqueous phase was washed with ethyl ether (3×200 mL), cooled in an ice bath, and acidified with concentrated HCL to give a white solid. The solid was filtered, thoroughly washed with water and stored in a desiccator. The partially dried solid was treated with 350 mL of hot ethyl acetate to give two layers. The ethyl acetate layer was dried (Na2SO4), filtered, concentrated to about 250 mL, and cooled to 4° C. to yield 19 g (27% yield) of N-(N'-benzyloxycarbonyl-6-aminocaproyl)-6-aminocaproic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
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: CCO
Product: COc1cc(Br)cc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C
Yield: 35.8 %

Procedure:
A solution of 2-(3-bromo-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.43 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (65 mg, 0.216 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA85 (28 mg, 36% yield). ESI-MS (M+H)+ m/z calcd 362.1, found 362.0.
Reaction SMILES: [C@H:1]1([CH2:11]N)[C@@H:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].CO>O>[CH3:11][C@H:1]1[C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[CH2:4][CH2:3][CH2:2]1
Reactant: NC[C@@H]1CCCN2CCCC[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCN2CCCC[C@H]12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The lupinane amine.2HCl (1-[(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanamine, CAS #: 75532-84-2, commercially available from ChemBridge, San Diego) (1.0 eq) was combined with 2,4-dichloro-5-X-pyrimidine (X=H, F, Cl, Me, CF3, CN, CONH2, OMe, NMe2) (1.0 eq) and NaHCO3 (1.2 eq). A mixture of MeOH:H2O (4/1) (concentration of the reaction mixture: ca. 0.1-0.5 M) was added and the resulting suspension was stirred for 1 d at RT. After the completion of the reaction was confirmed by TLC and HPLC, silica gel was added to the reaction mixture and solvents were evaporated under reduced pressure. The resulting solid was loaded on a CombiFlash column and further purified by flash chromatography eluting with DCM/MeOH—NH3 (2M) (gradient 0->10%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6]([OH:12])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.Cl>O1CCOCC1.O>[Cl:19][C:20]1[CH:25]=[C:24]([NH:2][CH:3]2[CH2:8][CH2:7][C:6]([OH:12])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1
Reactant: NC1CCC(O)(C(=O)O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1(O)CCC(Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A 100 mL round bottom flask was charged with 4-amino-1-hydroxycyclohexanecarboxylic acid hydrochloride (0.28 g, 1.431 mmol), potassium carbonate (0.435 g, 3.15 mmol) and water (1.908 mL). To the mixture was added 2,4-dichloro-5-nitropyridine (0.276 g, 1.431 mmol) as a solution in dioxane (0.954 mL). After the resulting mixture was stirred at 60° C. for 24 hours, it was cooled to RT and treated with 2N aqueous HCl to bring the pH to about 4-5. The aqueous layer was extracted with DCM (3×40 mL). The combined organic portions were dried over sodium sulfate and concentrated to afford 4-(2-chloro-5-nitropyridin-4-ylamino)-1-hydroxycyclohexanecarboxylic acid as a yellow solid (0.28 g, 62.0% yield). MS m/z=316.2 [M+H]. Calc'd for C12H14ClN3O5: 315.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.C(=O)(O)[O-:19].[Na+].ClC1C=CC=C(C(OO)=O)C=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:19]
Reactant: O=C([O-])O
Reactant: c1cnc(Sc2cccc3cccnc23)nc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(c1ncccn1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 ml. of tetrahydrofuran containing 170 mg. (0.71 mmol) of 8-(2-pyrimidylthio)quinoline was added 300 mg. of sodium bicarbonate and the mixture cooled to 0° C. m-Chloroperbenzoic acid (85%, 153 mg., 1.0 molar equivalent) in 5 ml. of the same solvent was added dropwise. After the addition was complete the reaction was allowed to warm to 25° C. and was stirred overnight. The reaction mixture was poured into a sodium bicarbonate solution and the product extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with a small amount of ethyl acetate and filtered to yield title product, 84 mg., m.p. 152°-155° C.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]4([C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:10]=3[CH:9]=2)=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Br:52]N1C(=O)CCC1=O>C(OCC)(=O)C>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:2]=[CH:3][C:4]([N:7]([C:33]2[CH:34]=[CH:35][C:36]([Br:52])=[CH:37][CH:38]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[C:27]5[C:32]4=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:10]=3[CH:9]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2ccc(N(c3ccccc3)c3ccc4c(c3)C3(c5ccccc5-c5ccccc53)c3ccccc3-4)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc3c(c2)C2(c4ccccc4-c4ccccc42)c2ccccc2-3)cc1
Reaction time: 25 h
Yield: 84.3 %

Procedure:
To a 100 mL three-neck flask were added 3.0 g (5.4 mmol) of N-(1,1′-biphenyl-4-yl)-N-phenyl-9,9′-spirobi[9H-fluoren]-2-amine, 20 mL of toluene, and 40 mL of ethyl acetate. To the solution was added 0.93 g (5.2 mmol) of N-bromosuccinimide (abbreviation: NBS), and the mixture was stirred for 25 hours. After the stirring, the mixture was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and then the organic layer was dried over magnesium sulfate. This mixture was separated by gravity filtration, and the filtrate was concentrated to give a solid. This solid was purified by silica gel column chromatography. In the column chromatography, hexane and then toluene:hexane=1:5 were used as developing solvents. The resulting fraction was concentrated to give a solid. The obtained solid was recrystallized from ethyl acetate/hexane to give 2.8 g of a white solid in a yield of 83%.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:18]1([CH2:17][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: C1CNCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Yield: 78.5 %

Procedure:
A mixture of hexahydro-1H-1,4-diazepine (3.44 g, 34.4 mmol) and 1-(chloromethyl)-4-(benzyloxy)benzene (2.0 g, 8.6 mmol) was treated with triethylamine (4.8 ml, 34.4 mmol) in 100 mL tetrahydrofuran and heated at reflux for 4 h. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 2.0 g of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, 2H), 7.39 (dd, 2H), 7.32 (dd, 1H), 7.26 (d, 2H), 6.93 (d, 2H), 5.05 (s, 2H), 3.60 (s, 2H), 2.96 (m, 2H), 2.89 (m, 2H), 2.68 (m, 2H), 2.65 (m, 2H), 1.75 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:8][F:9])[C:3](=O)[CH2:4][S:5][CH3:6].Cl.[NH2:12][OH:13].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]([CH3:10])([CH2:8][F:9])[C:3](=[N:12][OH:13])[CH2:4][S:5][CH3:6]
Reactant: NO
Reactant: CSCC(=O)C(C)(C)CF
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSCC(=NO)C(C)(C)CF
Yield: 74.4 %

Procedure:
99 g (0.6 mol) of 3,3-dimethyl-4-fluoro-1-methylthiobutan -2-one, 46 g (0.66 mol) of hydroxylamine hydrochloride and 66.7 g (0.66 mol) of triethylamine in 300 ml of ethanol were heated under reflux for 6 hours. The solvent was then removed in vacuo, the residue was partitioned between methylene chloride and water and the methylene chloride phase was separated off and dried with sodium sulphate. After distilling off the solvent, the residue was distilled in vacuo. 80 g (75% of theory) of 3,3-dimethyl-4-fluoro-1-methylthio-2-hydroximino-butane of boiling point 133° C./13 mm Hg were obtained. ##STR31## 78 g (0.43 mol) of 3,3-dimethyl-4-fluoro-1-methylthio-hydroximinobutane were dissolved in 300 ml of methylene chloride, and 26 g (0.46 mol) of methyl isocyanate were added dropwise. During this addition, the temperature of the reaction solution rose to about 35° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[C:31]([CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]5[S:17]([C:20]4[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=4)(=[O:19])=[O:18])[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN)cccc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cccc32)cc1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
A tube was charged with 53 (415 mg, 1.38 mmol), 46 (486 mg, 2.07 mmol), DIPEA (1.0 ml) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (3.3 to 5% MeOH) to afford 330 mg (48%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-4-yl)methyl)pyrimidine-2,4-diamine (50) as yellow solid: MS (ESI) m/z=500.3 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][N:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=1.[CH2:19]1[O:27][CH:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[OH:27][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][N:2]([CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:6]=1)[CH3:1]
Reactant: c1ccc(C2CO2)cc1
Reactant: CNCCc1ccn(S(=O)(=O)c2ccccc2)c1
Solvent: CC#N
Product: CN(CCc1ccn(S(=O)(=O)c2ccccc2)c1)CC(O)c1ccccc1

Procedure:
A mixture of N-methyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (4 g), styrene oxide (2.06 g) and acetonitrile (50 ml) were refluxed for 2 days. The solution was evaporated and the brown oil was purified by chromatography on silica, eluting with dichloromethane, chloroform then with increasing amounts of methanol (1→25%) in chloroform to give the title product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:29])=[N:9]2)=[CH:4][CH:3]=1.C[O:31]CCOC.O1CCCC1.[OH-].[K+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:20]([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]([OH:31])=[O:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCOC
Reactant: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Temperature: 30 °C
Reaction time: 34 h
Yield: 85 %

Procedure:
To a reactor was charged racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone (170 kg), 1,2-dimethoxyethane (730 L), tetrahydrofuran (THF, 990 L). The slurry was heated to 30° C. and a solution of potassium hydroxide (140 Kg) in water (1730 L) was added. The slurry was stirred at 34° C. for 34 hours. The solution was cooled to 20° C. and the lower aqueous layer was removed and replaced with water (1000 L). The solution was adjusted to pH 9.0 with 4N hydrochloric acid. The solution was vacuum distilled at 30° C. to remove the THF. Water (550 L) was added and the pH of the reaction was adjusted to 11.5 with 2N potassium hydroxide. The solution was filtered to remove residual racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone. To the liquors was added methylene chloride (1200 L) and the pH was adjusted to 1.4 with 4N HCl. The aqueous layer was removed. The organic layer was washed with water (700 L) and the water was discarded. The organic layer was concentrated under vacuum and replaced with methanol (500 L). The slurry was cooled to 10° C., water was added (500 L), and the mixtrue was cooled to 0° C. The resulting precipitate was isolated by filtration and dried under vacuum at 50° C. to afford 150 kg (85%) of racemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl ]-benzoic acid as a white solid. DCl/MS: M+H+ at 426, 100%. M.P. 173–4° C. UV maxima at 236 nm, 268 nm, and 353 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][C:10]#[N:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH2:9][C:10]#[N:11])[S:5][CH:6]=1
Reactant: CC#N
Reactant: O=Cc1cc(Br)cs1
Product: N#CCC(O)c1cc(Br)cs1

Procedure:
Addition of CH3CN to 4-bromothiophene-2-carbaldehyde following the method used in Example 2 gave 3-(4-bromothiophen-2-yl)-3-hydroxypropanenitrile as a light brown oil which was used in the next step without additional purification. Yield (1.95 g, 80%).