Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2([NH2:30])[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)(C)(C)[CH3:2].Cl.C(OC(NC1(C(O)=O)CCN(S(C2C=CC(C)=CC=2)(=O)=O)CC1)=O)(C)(C)C.C(C1C=CC(N)=CC=1)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2([NH2:30])[CH2:15][CH2:16][N:17]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:9][CH:10]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(N)(C(=O)Nc3ccc(C(C)(C)C)cc3)CC2)cc1
Agent: CCc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)(C(=O)O)CC2)cc1
Agent: Cl
Product: CCc1ccc(NC(=O)C2(N)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-Amino-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-tert-butyl-phenyl)-amide; hydrochloride (example 77) the title compound was prepared from 4-tert-Butoxycarbonylamino-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (example 77, step 2) and 4-ethyl-aniline with subsequent cleavage of the Boc group with HCl. The compound was purified with preparative HPLC on reversed phase. MS (m/e): 402.4 [(M+H)+].
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[C:24]([O:27][CH3:31])[CH:23]=[CH:22][CH:21]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)ON=c1cc(-c2cc3c(O)cccc3cn2)oc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2cnc(-c3cc(=NOC(C)(C)C)c4ccccc4o3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a ice-water bath cooled solution of 2-(5-hydroxy-isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (80 mg, 0.22 mmol) in dimethylformamide (2.5 ml) was added sodium hydride (60% in mineral oil, 13 mg, 0.33 mmol) under argon and the mixture was stirred at room temperature for 1 hour. The solution was cooled to 0° C. and iodomethane (15 μl, 0.24 mmol) was added. The resulting solution was stirred at room temperature for 20 hours and then hydrolyzed with brine. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and then purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 80/20) to yield 2-(5-methoxy-isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (65 mg, 79%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][C:2]1=[O:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[C:6]2[NH:1][C:2](=[O:11])[NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2scc(Br)c2[nH]1
Temperature: 110 °C
Reaction time: 30 h
Yield: 89.2 %

Procedure:
To a solution in which thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione (5.0 g, 29.5 mmol) was dissolved in glacial acetic acid (200 mL), bromine (4.55 mL, 89.0 mmol) was added. The reaction mixture solution was stirred at 110° C. for 30 hours, cooled to room temperature, and then slowly added to ice water (400 mL). Drying of thus prepared solid followed by filtration, washing several times with water and drying yielded the target compound 7-bromothieno[3,2-d]pyrimidin-2,4(1H,3H)-dione (6.5 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:14][OH:15])[CH2:3]1
Reactant: NO
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(=NO)c2ccccc21
Temperature: 80 °C
Yield: 97.4 %

Procedure:
To a solution of 3,3-dimethylindan-1-one (1.16 g, 7.21 mmol) and hydroxylamine hydrochloride (1.31 g, 18.8 mmol) in MeOH (20.0 mL) was added a solution of sodium hydroxide (765 mg, 19.1 mmol) in water (10.0 mL). The mixture was heated to 80° C. for 2 h. The cooled reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was separated and concentrated in vacuo to afford the title compound as an oil (1.23 g, 97%). LC/MS: Rt=1.61 min, ES+ 176 (AA standard).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].Cl.O.C1C[O:24][CH2:23]C1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:23]1=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccccc1Nc1ccccc1N
Agent: Cl
Solvent: O
Product: COC(=O)c1ccccc1-n1c(=O)[nH]c2ccccc21
Reaction time: 16 h
Yield: 78 %

Procedure:
To a solution of 2-(2-Amino-phenylamino)-benzoic acid methyl ester (75 mg, 0.31 mmol) in THF (1.0 mL) is added COI (100 mg, 0.62 mmol) at room temperature. The mixture is stirred at the same temperature for 16 hours. Then 3 mL of 1.0 M HCl solution is added along with 20 mL of water. The mixture is extracted with EtOAc (3×30 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 65 mg (78%) of 2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-benzoic acid methyl ester.
Reaction SMILES: O(C1N(C2C=CC=CC=2)C2C(C=1C(O)=O)=CC=CC=2)C1C=CC=CC=1.[O:26]([C:33]1[N:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:35]2[C:40]([C:41]=1[CH:42]=[O:43])=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:50]1([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:60]([O:59][C:57]([N:50]1[CH2:56][CH2:55][CH2:54][N:53]([C:42]([C:41]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:33]=2[O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:43])[CH2:52][CH2:51]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: O=Cc1c(Oc2ccccc2)n(-c2ccccc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C(O)c1c(Oc2ccccc2)n(-c2ccccc2)c2ccccc12
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2c(Oc3ccccc3)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxy-1-phenyl-1H-indole-3-carboxylic acid (164 mg, 499 μmol; available by oxidation of 2-phenoxy-1-phenyl-1H-indole-3-carbaldehyde (DE 2707268) analogously as described in example 11, step 5), tert-butyl 1-homopiperazinecarboxylate (100 mg, 499 μmol), EDC (105 mg, 549 μmol) and HOAT (78.2 mg, 574 μmol) in DMF (2 ml) was added NMM (165 μl, 1.49 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was filtered and purified by preparative HPLC. The eluate was lyophilized overnight to give 169 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([F:31])=[C:26](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2]>C(O)C.[Pd]>[Cl:21][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([F:31])=[C:26]([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Cc1cc(Cl)cc(B(O)O)c1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: Cc1cc(Cl)cc(-c2ncnc3[nH]c(C4=CCN(S(C)(=O)=O)CC4)cc23)c1F
Temperature: 120 °C

Procedure:
A 4 mL vial was charged with a stir bar, a solution of Example 41A (27.50 mg, 0.09 mmol) in 1 mL of ethanol, a solution of (5-chloro-2-fluoro-3-methylphenyl)boronic acid (24.85 mg, 1.5 eq, 0.13 mmol) in 220 μL of ethanol, a 1.0 M aqueous solution of cesium carbonate (175.84 μL, 2 eq, 0.18 mmol), and Siliacat® DPP-Pd (Silicycle®, 0.27 mmol/g loading, 32.56 mg). The loaded vial was seal capped and placed in an Anton Paar Synthos 3000 microwave reactor (900 W maximum) and heated to 120° C. for 15 minutes. Upon completion, the solids were collected by filtration and dried under vacuum. The dried material was then re-dissolved in 1.4 mL of dimethyl sulfoxide/methanol 1:1 (v/v) solution, and purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100A AXIA™ column (30 mm×75 mm) A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient 10-100% A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A) to yield the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 2.37 (d, J=2.1 Hz, 3H), 2.65 (s, 2H), 2.95 (d, J=5.2 Hz, 3H), 3.18 (s, 1H), 3.40 (t, J=5.7 Hz, 2H), 3.95 (d, J=3.4 Hz, 2H), 6.57 (d, J=3.8 Hz, 1H), 6.59-6.64 (m, 1H), 7.60 (d, J=5.8 Hz, 2H), 8.85 (s, 1H). MS (ESI+) m/z 421.1 (M+H)+. Examples 42 through 59 were prepared essentially as described in Example 41B, substituting the appropriate boronic acid.
Reaction SMILES: [ClH:1].[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]2[O:29][C@@H:14]32)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3].O>O1CCCC1>[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]([Cl:1])[C@H:14]3[OH:29])[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3]
Reactant: Cl
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Concentrated hydrochloric acid (0.1 ml) was adde*d to a solution of 97 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione in 4 ml of tetrahydrofuran, and the solution was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 102 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: FC(F)(C[CH2:18][CH2:19][N:20]1C(=O)C=CC1=O)C(F)(F)C(F)(C1C=CC=CC=1)C([O-])=O.[C:28](=O)([O:36][C:37]1[CH:42]=CC=CN=1)[O:29][C:30]1[CH:35]=CC=CN=1>C(Cl)Cl.CCOCC>[NH2:20][CH2:19][CH2:18][CH:28]([O:29][CH2:30][CH3:35])[O:36][CH2:37][CH3:42]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: O=C1C=CC(=O)N1CCCC(F)(F)C(F)(F)C(F)(C(=O)[O-])c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(CCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 981 mg (3 mmol) of pentafluorophenyl-6-maleimido-hexane-1-carboxylate (1) (Example 11) dissolved in dry methylene chloride (30 ml) was added 10 g (1 mmol) of •-amino-•-amino PEG (2) (MW 10,000, n=226) dissolved in 50 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for 2 h and the product 3 obtained as a white powder by precipitation in ether (100 ml). The product was then dried under vacuum for 4 h.
Reaction SMILES: CC[O-].[Na+].[CH2:5]([O:7][C:8](=[O:32])[CH2:9][C:10]([NH:12][C:13]1[C:14]([C:27]([O:29]CC)=O)=[N:15][CH:16]=[C:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:18]=1)=[O:11])[CH3:6].Cl>CCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:17]2[CH:18]=[C:13]3[C:14]([C:27]([OH:29])=[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:32])[C:10](=[O:11])[NH:12]3)=[N:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2M solution of NaOEt in EtOH (5.87 mL, 11.74 mmol) was added to a solution of ethyl 3-[(3-ethoxy-3-oxopropanoyl)amino]-5-(4-fluorobenzyl)pyridine-2-carboxylate (2.28 g, 5.87 mmol) in EtOH (23 mL) and the mixture was stirred at rt for 1 h. The mixture was neutralized with conc. HCl and concentrated in vacuo. Trituration of the resulting material with a mixture of EtOH and 1:1 brine/water followed by filtration afforded the product as a beige solid: 1H NMR (d6-DMSO) δ 11.54 (1H, br s), 8.54 (1H, d, J=1.4 Hz), 7.44 (1H, s), 7.32 (2H, dd, J=8, 6 Hz), 7.17 (2H, t, J˜9 Hz), 4.23 (2H, q, J=7 Hz), 4.12 (2H, s), 1.26 (3H, t, J=7 Hz); HRMS calcd for C18H15FN2O4+H+: 343.1094. Found: 343.1088.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]([CH2:25][C:26](=O)[N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:22][CH2:23][CH3:24])[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:7]2[C:8]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:22][CH2:23][CH3:24])[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN(CC(=O)N1CCCCC1)c1cccc2c1OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(CCN1CCCCC1)c1cccc2c1OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.8 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-{N-[2-oxo-2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.63 g, 6.51 mmol) in tetrahydrofuran (7 ml) was added a solution (50 ml) of 1M BH3 THF complex in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 11 hr. 4N Hydrochloric acid was added to the reaction mixture under ice-cooling, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was adjusted to pH 8 with 4N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=35:1-15:1) to give methyl 12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.25 g, yield 92%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:13]([CH3:26])[CH:12]=1>ClCCl>[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:13]([CH3:26])[CH:12]=1
Reactant: COC(=O)c1ccc(CCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Reaction time: 2 h
Yield: 71 %

Procedure:
Trifluoroacetic acid (40 ml) was added slowly to a stirred solution of 4-(2-tert-butoxycarbonyl-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.2 (4.9 g, 17.6 mmol) in dichloromethane (80 ml) at room temperature. The mixture was stirred for 2 h then concentrated in vacuo and azeotroped with dichloromethane. The residue was recrystallised in EtOAc to yield the title compound (2.77 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14]I.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:14])[C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CI
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(Cl)c2c(n1)N(C)C(=O)CO2

Procedure:
Using the method of Sazonov, et al., Khimiya Geterotsiklicheskikh Soedinenii, 9, 1285-1288 (1972), 4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one was prepared. To a mixture of 8.0g (0.0402 mole) of 4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one and 17.9 ml of methyl iodide was added 8.75g of 25% sodium methoxide in 250 ml of methanol, and the solution was heated at its reflux temperature for three hours. The solvent was removed by evaporation under vacuum, and the solid was separated by filtration, washed with water, and dried. The yellow solid was 4-chloro 6,7-dihydro-2,8-dimethylpyrimido[5,4-b][1,4]oxazin-7-one, m.p. 142°-143° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[BH4-].[Na+]>C(O)C>[OH:22][CH:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:1])=[C:3]([O:27][CH2:28][C:29]#[N:30])[CH:4]=[CH:5]2)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3c(C)c(OCC#N)ccc3c2)oc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(O)c1c(-c2ccc3c(C)c(OCC#N)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 1 of Example 11, 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.874 g, 2.20 mmol) was reduced with sodium borohydride (0.495 g, 13.1 mmol) in ethanol (25 mL). 2-({6-[3-(1-hydroxypentyl)-1-benzofuran-2-yl]-1-methyl-2-naphthyl}oxy)acetonitrile was obtained as a yellow gum (0.838 g,). 1HNMR (300 MHz, DMSO-d6): δ8.3 (s, 1H), 8.15 (d, 1H, J=9.2 Hz), 8.0 (t, 1H, J=8.5 Hz), 7.9 (t, 1H, J=7.7 Hz), 7.55 (q, 3H, J=8.2 Hz), 7.25-7.35 (br, 1H), 5.45 (d, 1H, J=5.4 Hz), 5.35 (s, 2H), 5.1-5.2 (br, 1H), 2.55 (s, 3H), 1.8-2.0 (br, 2H), 1.2-1.3 (br, 2H), 1.35 (t, 2H, J=7.3 Hz), and 0.8 ppm (t, 3H, J=7.3 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:19]=2)[C:12]([C:15]([NH2:16])=[O:36])=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (60 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (47 mg). MS 405.3 (M+H); UV 202.9, 254.8, 304.6 nm; t 0.471 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C([NH+](CC)CC)C.[C:28](Cl)(=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:31][CH:30]([CH3:32])[CH2:29][C:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:33]
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: CC(C)CC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in CH2Cl2 (2 mL) was treated with triethylammonium methylpolystyrene carbonate (80 mg, 0.25 mmol) then isovaleryl chloride (30 mg, 0.25 mmol) and shaken at room temperature for 6 h. The reaction mixture was treated with tris-(2-aminoethyl)amine polystyrene (0.20 g, 0.75 mmol), shaken at room temperature for 16 h, treated with polystyrene methylisocyanate (0.18 g, 0.25 mmol) and CH2Cl2 (2 mL), shaken for a further 6 h then filtered and concentrated in vacuo to give the title compound (35 mg, 55%) as a yellow solid.
Reaction SMILES: Cl.C(#N)C.C([Si]([O:12][C@@H:13]([C@@H:28]([CH3:31])[CH:29]=[CH2:30])/[C:14](/[CH3:27])=[CH:15]/[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(C)C)(C)(C)C>[Cl-].[Na+].O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][CH2:16]/[CH:15]=[C:14](\[CH3:27])/[C@@H:13]([OH:12])[C@@H:28]([CH3:31])[CH:29]=[CH2:30])=[CH:24][CH:23]=1
Reactant: C=C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)/C(C)=C/COCc1ccc(OC)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C=C[C@H](C)[C@H](O)/C(C)=C/COCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
1N hydrochloric acid (100 ml) was added to an acetonitrile (300 ml) solution of tert-butyl({(1S,2E)-4-[(4-methoxybenzyl)oxy]-2-methyl-1-[(1S)-1-methylprop-2-en-1-yl]but-2-en-1-yl}oxy)dimethylsilane (41.8 g, 107 mmol). After the reaction solution was stirred at room temperature for ten and a half hours, it was poured into brine and extracted with ethyl acetate. After the organic layer was washed with brine, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=4:1→3:1→2:1) and was obtained title compound (26.8 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].C([SiH](CC)CC)C.C(OCC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C=Cc1ccc(OC)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCc1ccc(OC)c(OC)c1
Temperature: 60 °C
Yield: 41.4 %

Procedure:
In a 5 mL flask opened to the air, to a clear solution of 3,4-dimethoxystyrene (100 μL, 0.755 mmol) in benzene (0.8 mL) was added triethylsilane (240 μL, 0.816 mmol). The flask was placed in a 60° C. bath and iodo[bis(triphenylphosphine)]dioxorhenium(V) (32 mg, 0.037 mmol) was added. The resulting brown solution was heated at 60° C. for 12 hours. The crude reaction mixture was directly applied to a SiO2 column and chromatographed eluting with 4:1 hexanes:diethyl ether to afford 3,4-dimethoxyethylbenzene (52 mg, 57% yield) as a colorless liquid. The reaction was repeated using pent-2-enal and t-butyl acrylate as the electrophilic reactants, as indicated in the first two schemes above (wherein “TES” represents triethylsilyl).