Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[CH:3]=1.[BH4-].[Na+].Cl>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])[CH:3]=1
Reactant: CC(=O)CCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a solution of 4-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(3-oxobutyl)benzenesulfonamide (0.42 g, 1 mmol) in MeOH (15 mL) was added NaBH4 (0.13 g, 3 mmol). The mixture was stirred at r.t. for 2 hrs. The reaction mixture was concentrated, the residue was purified by pre-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 5%-33%, 23 min), concentrated, acidified with HCl and freeze-dried to give 4-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(3-hydroxybutyl)benzenesulfonamide (230 mg, yield 55%) as HCl salt. 1H NMR: (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 7.56 (d, 1H), 7.42 (d, 1H), 7.22 (d, 1H), 7.13-7.10 (m, 1H), 6.42 (d, 1H), 6.36-6.33 (m, 1H), 4.85 (s, 2H), 3.69-3.65 (m, 1H), 2.87-2.80 (m, 2H), 1.55-1.49 (m, 2H), 1.08 (d, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:18]1[CH:26]2[CH:21]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25]2)[CH2:20][NH:19]1.COCCO.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:8][C:6]1[N:7]=[C:2]([N:19]2[CH2:18][CH:26]3[CH:21]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25]3)[CH2:20]2)[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC2C1
Temperature: 115 °C

Procedure:
The product from Example 68A (40 mg, 0.16 mmol) was mixed with tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (55 mg, 0.24 mmol) and to this was added 2-methoxyethanol (0.65 mL), and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol); the reaction was heated at 115° C. for 16 hours, cooled, diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The aqueous layer was extracted with CH2Cl2 (15 mL). The combined organics were dried (MgSO4), filtered, concentrated and chromatographed and eluted with a gradient of 1:0 to 0:1 CH2Cl2:EtOAc to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:12]=2[O:11][N:10]=1)=[O:2].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN1CCCC1=O>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:23])=[O:20])=[CH:17][C:12]=2[O:11][N:10]=1)=[O:2]
Reactant: O=Cc1ccccc1-c1noc2cc(C(=O)O)ccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc2c(-c3ccccc3C=O)noc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 3-(2-formylphenyl)benzo[d]isoxazole-6-carboxylic acid (Compound 6) (60.2 g) in N-methyl-2-pyrrolidinone (600 mL) at room temperature was added in one portion 1,1′-carbonyldiimidazole (40.2 g) and the solution stirred at room temperature under nitrogen for 2 h then poured into specific gravity 0.880 aqueous ammonia solution. The suspension was stirred mechanically at room temperature for 2 h then filtered. The still moist collected solid was triturated in methanol (200 mL) at room temperature then filtered, this material was triturated again with methanol (100 mL) then filtered and dried in vacuo to give the title product (54.92 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])=[N:10]2)=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[C:21]([C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)(=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(-n2nc(C(O)c3ccccc3)cc2-c2ccc(C)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(-n2nc(C(=O)c3ccccc3)cc2-c2ccc(C)cc2)cc1
Reaction time: 0.5 h

Procedure:
Compound 77 (3.7 g, 10 mM) was dissolved in CH2Cl2 (100 ml) and pyridinium chlorochromate (3.44 g, 16 mM) was added with vigorous stirringand stirred for 30 min. Et2O (150 ml) was added and the mixture was sonicated for 5 min and filtered through florisil (100-200 mesh), the Florisil washed with additional Et2O and the combined Et2O layer evaporated in vacuo to yield the title compound of sufficient purityfor subsequent steps.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:20]([C:22]([OH:40])([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][C:35](=[O:39])[CH2:36][CH2:37]Br)=[CH:27][CH:26]=2)[CH3:23])=[O:21])([OH:19])[CH3:18])=[CH:12][CH:11]=1)=[O:5].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:20]([C:22]([OH:40])([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][C:35](=[O:39])[CH:36]=[CH2:37])=[CH:27][CH:26]=2)[CH3:23])=[O:21])([OH:19])[CH3:18])=[CH:14][CH:15]=1)(=[O:5])[CH:3]=[CH2:2]
Reactant: CC(O)(Cc1ccc(OCCOC(=O)CCBr)cc1)C(=O)C(C)(O)Cc1ccc(OCCOC(=O)CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)OCCOc1ccc(CC(C)(O)C(=O)C(C)(O)Cc2ccc(OCCOC(=O)C=C)cc2)cc1
Temperature: 25 °C

Procedure:
5.2 g (14.5 mmol) 4-(2-(3-bromopropionyloxy)ethoxy)phenyl-2-hydroxy-2-propyl ketone was dissolved in 45 ml acetone. 30 mg BHT and 3.0 g (21.75 mmol) K2CO3 were added and the reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool down to room temperature and the inorganic salts were removed by filtration. The solvent was removed under reduced pressure and the residue was treated with 50 ml n.-hexane. 4-(2-acryloyloxyethoxy)phenyl-2-hydroxy-2-propyl ketone was isolated by filtration. 3 g of 4-(2-acryloyloxyethoxy)phenyl-2-hydroxy-2-propyl ketone (75%) was isolated as a white crystalline compound.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3C(=[CH:7][CH:8]=[CH:9][CH:10]=3)C[C:4]=2[CH:3]=1.[CH3:15][C:16]([CH3:19])([O-])[CH3:17].[K+].CI>CS(C)=O.O1CCCC1>[CH3:15][C:16]1([CH3:19])[C:4]2[CH:3]=[C:2]([I:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:17]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)(C)[O-]
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20 parts of 2-iodofluorene was dissolved in a mixed solution of 114 parts of dimethyl sulfoxide (DMSO) and 23 parts of tetrahydrofuran (THF), and the thus obtained mixture was then stirred at 25° C. for 10 minutes. Thereafter, while stirring, 8.7 parts of potassium-tert-butoxide was added to the mixture. Twenty minutes later, 13.2 parts of methyl iodide was added to the mixture, and further twenty minutes later, 8.7 parts of potassium-tert-butoxide was added thereto. Further, twenty minutes later, 13.2 parts of methyl iodide was added thereto, and the obtained mixture was then stirred at 25° C. for 2 hours. After completion of the stirring, the THF was distilled away from the reaction solution, and it was then extracted with toluene-water. The toluene phase was dried over magnesium sulfate, and the toluene was then distilled away, thereby obtaining a brown tarry solid. This brown tarry solid was separated and purified by column chromatography (hexane-ethyl acetate) to obtain 21 parts of 9,9-dimethyl-2-iodofluorene in the form of a colorless crystal.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=1.CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[C:52]([CH3:57])[N:51]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:5]([NH:6][C:7]3[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[N:9]=[C:10]([C:12]([CH2:13][F:14])([CH3:15])[CH2:16][F:17])[CH:11]=3)=[O:4])=[C:52]([CH3:57])[N:51]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Add [5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (2.7 mmol, 1.2 g) and DIEA (2.9 mmol, 0.5 mL) over a solution of 4-(5-amino-6-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.9 mmol, 0.9 g) in 4 mL of DMSO and stir at 85° C. overnight. Cool down, add water and extract with CH2Cl2. Combine the organic layers and wash with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 4-(5-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-6-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 10 to 50%). MS(ES+): m/z=584 [M+H]).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([OH:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28].CO>CN(C)C=O.C(O)C>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](=[O:31])[O:19][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH3:28]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(-c2cc3ccccc3c(O)n2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(CC)C(=O)Oc1nc(-c2ccc(OC)cc2)cc2ccccc12
Yield: 5 %

Procedure:
The procedure is as in Example 37, starting with 3-(4-methoxyphenyl)-1-isoquinolinol (10 g), triethylamine (16 g) and diethylcarbamoyl chloride (21.7 g) in dimethylformamide (100 cc). After chromatograpy on silica gel, initially with a cyclohexane/ethyl acette (1:1 by volume) mixture and the second time with a tolune/methanol (98:2 by volume) mixture as eluants, and crysallization in 80% strength aqueous ethanol, 3-(4-methoxypenyl)-1-isoquinolyl diethylcarbamate (0.7 g), m.p. 84° C., is obtained.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.N(OCCC(C)C)=O.[ClH:44]>C(#N)C.[Cu](Cl)Cl>[Cl:44][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[S:27][CH:28]=2)[N:3]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
15.00 g (28.84 mmol) of 2-amino-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 1A) were initially charged in 200 ml of acetonitrile, and 6.76 g (57.69 mmol) of isopentyl nitrite and 7.76 g (57.69 mmol) of copper(II) chloride were added. The mixture was stirred at 70° C. for 6 h. After cooling to RT, 750 ml of 1N hydrochloric acid were added and the mixture was stirred for 30 min. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After removal of the solvent, the crude product was purified by column chromatography on silica gel (mobile phase: toluene/ethyl acetate 4:1). This gave 10.8 g (69% of theory, purity 90%) of the desired target compound. For further purification, the product may, if appropriate, be triturated with diethyl ether.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:21])([CH3:22])[N:9]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:30](=[O:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)CCC(=O)O)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reaction time: 6 h
Yield: 45.5 %

Procedure:
A solution of 10.2 grams (33 mmol) of 4-n-butylamino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 8), 3.3 grams (33 mmol) of triethylamine, and 30 ml of tetrahydrofuran is added to a solution of 3.0 grams (30 mmol) of succinic anhydride in 20 ml of tetrahydrofuran over a 5-minute period. The reaction mixture is stirred for six hours and then diluted with ethyl acetate (200 ml). The organic solution is washed with 1N hydrochloric acid (2×50 ml), washed with water (50 ml), washed with saturated sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil which crystallizes on standing. Recrystallization from heptane affords 5.6 grams (46% yield) of the title compound as a white solid melting at 110°-1130° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>C(O)(C)(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:21]3[N:20]=[C:19]([NH2:18])[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=3)[CH2:13][CH2:12]2)=[CH:8][CH:9]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: COC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
Compound 47 (0.05 g, 0.21 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxy quinazoline (0.05 g, 0.19 mmol) in tert-butanol (5 mL) at 25° C. The mixture was subsequently stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.07 g (83%) of the title compound: TLC (Rf =0.35; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 12.15 (s, 1H), 8.75 (d, 2H), 7.73 (s, 1H), 7.69 (d, 2H, J=8.7), 7.51 (s, 1H), 6.66 (d, 2H, J=8.4), 6.57 (d, 1H, J=7.3), 4.52 (d, 2H, J=13.2), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (m, 1H), 3.73 (s, 3H), 3.43 (m, 2H), 2.05 (m, 2H), 1.44 (m, 2H); 13C NMR (CDCl3) δ 166.3, 161.4, 155.2, 151.7, 151.0, 146.7, 136.0, 131.0, 115.8, 111.3, 104.9, 101.6, 99.2, 56.2, 56.0, 51.2, 47.9, 43.4, 31.0; Anal. (C23H27N5O4 ·1HCl) C, H, N.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:26]4[CH2:27][C:28]5[S:29][CH:30]=[CH:31][C:32]=5[C:25]=4[N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C(Cl)Cl>[Br:8][C:30]1[S:29][C:28]2[CH2:27][C:26]3[C:22]([C:19]4[CH:20]=[CH:21][C:16]([N:13]5[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]5)=[CH:17][CH:18]=4)=[N:23][N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:25]=3[C:32]=2[CH:31]=1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Reaction time: 2 h
Yield: 80 %

Procedure:
NBS (0.18 g, 1.0 mmol) was added to a solution of 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.5 mmol) in CH2Cl2 (5.0 mL). After 2 hours, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.223 g, 0.4 mmol) as brown solid in 80% yield.
Reaction SMILES: C([O:10][CH2:11][C@@H:12]1[O:21][C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=O)CCCCCCC.[OH-].[K+].CO>>[O:21]1[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:12]1[CH2:11][OH:10]
Reactant: CCCCCCCC(=O)OC[C@@H]1O[C@@H]1CCCCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCC[C@H]1O[C@H]1CO
Yield: 97.2 %

Procedure:
4.1 g of (-)-(2S, 3R)-1-capryloxy-2,3-epoxy-8-methylnonane was hydrolyzed with potassium hydroxide/methanol to yield 2.3 g of (-)-(2S, 3R)-2,3-epoxy-8-methyl-1-nonanol.
Reaction SMILES: O[C:2]1([C:18]2[O:19][C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:23]1([C:21]2[N:22]=[C:18]([C:2]3[CH:3]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=3)[O:19][C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(CC2CCCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(CC2CCCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 94.1 %

Procedure:
A mixture of 1-hydroxy-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cycloheptane (5.2 g) and p-toluenesulfonic acid (500 mg) in toluene (50 ml) was stirred under reflux for 4 hours. The solution was washed with water, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(4,5-diphenyloxazol-2-yl)-7-(3-methoxybenzyl)-1-cycloheptene (4.7 g). MS (m/z): 436 (M+ +1) IR (Neat): 1600 cm-1NMR (CDCl3, δ): 1.3-2.0 (6H, m), 2.4 (2H, m), 2.83 (1H, dd, J=10.0, 14 Hz), 3.00 (1H, dd, J=6.0, 14.0 Hz), 3.78 (3H, s), 6.7-7.0 (3H, m), 7.20 (1H, t, J=8 Hz), 7.2-7.8 (11H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=O)[C:10](Cl)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:10][CH2:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C1=Nc2ccccc2OC1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
To a mixture of 2.29 g (21.0 mmol) of o-aminophenol in 25 mL of dry toluene was added portion wise 11 mL of 2N oxalyl chloride/CH2Cl2 (22.0 mmol) solution. The mixture was refluxed for 4 h, cooled to room temperature, filtered and the solid was washed with xylene and water, and dried to leave 3.10 g (90%) of 2a as pale-green solid. The analytical sample was obtained by crystallization from acetone, mp 263°-264° C. (lit, 264°-266° C.; Bernard et al, J. Med. Chem. 28:240 (1985)). 1H NMR (CDCl3 +DMSO-d6), 6.932 (m, 4), 11.970 (m, 1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(CO)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(COS(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a partial suspension of (1-methyl-1H-pyrazol-4-yl)methanol (75 mg, 0.67 mmol) in CH2Cl2 (4 mL) at 0° C. was added triethylamine (0.19 mL, 1.34 mmol) followed by methanesulfonyl chloride (57 μL, 0.74 mmol). The cloudy reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give 110 mg of methanesulfonic acid 1-methyl-1H-pyrazol-4-ylmethyl ester a colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[CH2:37]([NH:44][C:7]([C:6]1[S:5][C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])=[N:3][C:2]=1[CH3:1])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylic acid (0.30 g, 1.00 mmol) and 4-methylmorpholine (0.15 mL, 1.10 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.15 mL, 1.3 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.20 mL, 1.80 mmol) was added. The reaction mixture was kept stirring for 17 hours at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 7% yield (0.030 g): mp 234-236° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=5.7 Hz, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.39-7.12 (m, 8H), 4.35 (d, J=5.7 Hz, 2H), 4.14-3.92 (m, 4H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 156.7, 152.7, 150.7, 139.5, 138.9, 128.8, 128.1, 127.1, 126.6, 123.3, 118.3, 117.8, 42.4, 42.3, 41.2, 17.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.[NH3:34]>O1CCOCC1>[NH2:34][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Reactant: N
Solvent: C1COCCO1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(N)nc3)nc3c2CCC3)n[nH]1

Procedure:
To a solution of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (250 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was added aqueous ammonia (5 mL) and the reaction mixture was allowed to reflux in steel bomb at 130° C. for 18 h. The reaction mixture was concentrated under vacuum to obtain an oily crude product which was purified by reverse phase HPLC to afford 8 mg of (S)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.20 (d, 6H), 2.00-2.20 (m, 4H), 2.75-2.95 (m, 5H), 3.50-3.90 (m, 4H), 4.90-4.98 (m, 1H), 6.40 (s, 1H), 6.50 (d, 1H), 7.40 (s, 1H), 7.90 (s, 1H). The other enantiomer is prepared using the chiral (R) starting material.