Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:12]1)=[O:9].C=O.[C:50](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:50])[C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:13][CH2:12]1)=[O:9]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C)c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Moisture was removed from a mixture of the compound (120 mg, 0.205 mmol) obtained in Example 43a and a 35% aqueous formaldehyde solution (85 μL, 1.02 mmol) azeotropically with toluene 3 times. The resulting mixture was dissolved in ethanol (6 mL), sodium triacetoxyborohydride (65 mg, 0.307 mmol) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (118 mg; yield, 96%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([C:8]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[C:17]3[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:14][C:15]=2[NH:16]3)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]1[CH:38]=[CH:39][C:40]([C:43](O)=[O:44])=[N:41][CH:42]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:43](=[O:44])[C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:42][N:41]=3)[C:3]=2[CH3:35])=[C:9]2[C:17]=1[NH:16][C:15]1[CH:14]=[C:13]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:12]=[CH:11][C:10]2=1)(=[O:23])[NH2:22]
Reactant: O=C(O)c1ccc(F)cn1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NC(=O)OCc4ccccc4)ccc3c12
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(F)cn2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NC(=O)OCc4ccccc4)ccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-9H-carbazol-2-ylcarbamate (Example 51-2, 100 mg, 0.215 mmol), 5-fluoropicolinic acid (45.6 mg, 0.323 mmol), HOAT (44.0 mg, 0.323 mmol), and EDC (83 mg, 0.431 mmol) in DCM-THF (80:20, 12 mL) was treated with DIEA (0.150 mL, 0.861 mmol) and the solution was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC to provide benzyl 8-carbamoyl-5-(3-(5-fluoropicolinamido)-2-methylphenyl)-9H-carbazol-2-ylcarbamate as a white solid (47 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.48 (1 H, s), 10.41 (1 H, s), 9.83 (1 H, s), 8.74 (1 H, d, J=3.0 Hz), 8.27 (1 H, dd, J=8.8, 4.8 Hz), 8.09-8.21 (1 H, m), 7.96-8.03 (2 H, m), 7.94 (1 H, d, J=7.8 Hz), 7.85 (1 H, d, J=7.5 Hz), 7.29-7.51 (7 H, m), 7.15-7.21 (1 H, m), 6.91-6.98 (2 H, m), 6.79 (1 H, d, J=8.8 Hz), 5.16 (2 H, s), 1.96 (3 H, s). Mass spectrum m/z 588.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH3:32].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH2:31][CH3:32])[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCNCCCN
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCN)C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, N-(3-aminopropyl)ethylamine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.82 minutes; C22H25Cl2N5O2 (462.38); mass spectrum: (M−H)−=461/463/465 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(N[C:29](=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:30]([CH3:29])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CC(C)C(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and propiophenone (II), MS (m/e) 434, 392, 329, 297, 288, 261,243, 152, 132 and 105; IR (neat) 2983, 1682, 1253, 1027 and 970 cm-1 ; NMR (CDCl3) 8.03, 7.57, 7.47, 4.1, 2.4, 2.0 and 1.29 δ; CMR (CDCl3) 203, 136, 133, 128.6, 128.5, 62, 38, 34, 29, 17 and 16 δ.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5](C(OCC)=O)[C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1.[OH-].[Na+]>Cl>[CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1
Reactant: CCOC(=O)C1C(=O)C(C)OC12CCN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1OC2(CCN(C)CC2)CC1=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4,5]decane-4-carboxylate (3.08 g) was dissolved in 50 ml of 1N-HCl, and the solution was heated under reflux for eight hours. The reaction mixture was allowed to cool to room temperature, then cooled in an ice-water bath, and basified by addition of 20% aqueous solution of caustic soda. This alkaline solution was extracted thrice with about 80 ml of chloroform, and the combined extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure from the dried solution left 2 g of yellow residue, which was purified by silica gel column chromatography by using, as eluent, a mixed solvent of chloroform/methanol (20:1 by volume), giving 1.8 g of 2,8-dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one as oil. It was dissolved in ether, and ethanolic hydrogen chloride was added, thus giving its hydrochloride as crystals.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]3[C@H:14]([CH2:15]3)[CH2:13][N:12]2C(OCC2C=CC=CC=2)=O)=[N:7][CH:8]=1>CO.CCOC(C)=O.[Pd]>[C@H:14]12[CH2:15][C@H:16]1[CH2:17][C@@H:11]([CH2:10][NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:29])([F:1])[F:28])=[CH:8][N:7]=1)[NH:12][CH2:13]2
Reactant: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2C[C@H]1CNc1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: FC(F)(F)c1ccc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)nc1
Reaction time: 0.42 h

Procedure:
In a 250 ml hydrogenation flask phenylmethyl (1S,4S,6S)-4-({[5-(trifluoromethyl)-2-pyridinyl]amino}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D11 (0.275 g) was dissolved in MeOH (20 ml) and Pd/C (0.0722 g, 0.068 mmol) was added. The resulting suspension was hydrogenated at atmospheric pressure. After 25 min UPLC (Acid GEN_QC) showed a main side product with rt=0.99, peak observed: 284 (M+1). The Pd/C was filtered on a celite pad, the solvent was removed under reduced pressure to give an off-white semisolid. This solid was dissolved in anhydrous EtOAc (20 ml) and Pd/C (0.0722 g, 0.068 mmol) was added. The suspension was hydrogenated at atmospheric pressure for 50 minutes (total time). The Pd/C was filtered on a celite pad, the solvent was removed under reduced pressure to give a yellowish solid, which was purified via Biotage SP4 (NH 25+M column; Cy/EtOAc: 1/0 to 75/25 15 CV, 75/25 3 CV, to 0/1 20 CV) to give the title compound D12 (0.100 g). HPLC (walk-up): rt=3.19 min MS: (ES/+) m/z: 272 (M+1). C13H16F3N3 requires 271. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22-8.32 (m, 1 H), 7.57-7.64 (m, 1 H), 7.21-7.28 (m, 1 H), 6.60 (d, 1 H), 3.12-3.26 (m, 1 H), 2.89-3.10 (m, 3 H), 2.37-2.47 (m, 1 H), 1.83-1.94 (m, 1 H), 1.05-1.18 (m, 1 H), 0.69-0.98 (m, 2 H), 0.42-0.52 (m, 1 H), 0.28-0.39 (m, 1 H).
Reaction SMILES: [CH2:1]1[C@@H:8]2[C@@H:4]([CH2:5][C:6](=[O:9])[CH2:7]2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]([CH3:17])([CH2:15]O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:17])[CH2:13][O:14][C:6]2([CH2:7][CH:8]3[CH:4]([CH2:3][C:2](=[O:10])[CH2:1]3)[CH2:5]2)[O:9][CH2:15]1
Reactant: CC(C)(CO)CO
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC2(CC3CC(=O)CC3C2)OC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
To a of solution cis-tetrahydropentalene-2,5-(1H,3H)-dione (2.99 g, 21.6 mmol) and 2,2-dimethylpropane-1,3-diol (2.254 g, 21.6 mmol) in toluene (70 mL) was added p-toluenesulfonic acid monohydrate (0.206 g, 1.08 mmol) and the mixture was heated at 110° C. for 24 hrs with a Dean Stark apparatus. The reaction mixture was cooled to room temperature, poured over solid K2CO3, stirred 5 mins then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (12 to 100% EtOAc in hexanes) to give 5,5-dimethyltetrahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′(3′H)-one (2.224 g, 9.92 mmol, 45.8% yield) as a colorless oil which solidified upon standing. MS ESI: [M+Na]+ m/z 225.7.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH:9]=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>ClCCl>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][CH:2]([CH2:8][CH:9]=[C:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:36])=[O:35])=[CH:32][CH:33]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)C(N)CC=C1CCOCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(CC=C1CCOCC1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-amino-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (163) (1.0 g, 4.7 mmol) in anhydrous dichloromethane (30 mL) was added Hunig's base (1.6 mL, 9.4 mmol) followed by 4-nitrobenzenesulfonyl chloride (1.14 g, 5.2 mmol) and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was diluted with dichloromethane and washed with 0.1 N HCl, the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-70% hexanes/EtOAc to afford the title compound as an off-white solid in quantitative yield.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: Brc1nn2ccnc2s1
Solvent: ClCCl
Product: Fc1ccc(Nc2nn3ccnc3s2)cc1
Temperature: 135 °C
Yield: 10.2 %

Procedure:
A mixture of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1.0 g, 4.90 mmol) and 4-fluoroaniline (1.86 mL, 19.60 mmol) was heated under microwave irradiation at 135° C. for 15 minutes. On cooling, the mixture was diluted with dichloromethane (10 mL) and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 1:9). The residue obtained was treated with dichloromethane (5 mL) and filtered to give (4-fluoro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl-amine as a beige solid (117 mg, 10% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=1[F:36])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1
Yield: 14.1 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.16 g, 0.27 mmol) and isobutylamine (0.15 g, 2.01 mmol), the title compound was obtained as a pale yellow solid (0.026 g; 14.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 7.84 (d, J=5.3 Hz, 1H), 7.60-7.72 (m, 1H), 7.46-7.51 (m, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H), 7.21 (t, J=9.1 Hz, 2H), 7.12 (d, J=0.5 Hz, 1H), 5.42 (d, J=4.9 Hz, 1H), 3.70 (t, J=4.6 Hz, 4H), 3.44 (t, J=4.6 Hz, 4H), 3.02 (t, J=6.2 Hz, 2H), 0.87 (d, J=6.7 Hz, 9H). MS (ESI) 621.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O.C(OCC)(=O)C>[Si:16]([O:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C=C(C(=O)OCC)C(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C(=O)OCC)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 10 h
Yield: 95.5 %

Procedure:
To a suspension of ethyl 2-(1-hydroxyethyl)acrylate (40 g) and imidazole (28.3 g) in N,N-dimethylformamide (200 ml)was added portionwise t-butyldimethylsilyl chloride (46 g) at 0° C. After the mixture was stirred for 10 hours, the reaction mixture was poured into a mixture of water and ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with water, 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The evaporation of the solution gave ethyl 2-[1-(t-butyl-dimethylsilyloxy)ethyl]acrylate (68.5 g).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH2:21][C:22]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>C(Cl)Cl>[O:19]([CH2:20][CH2:21][C:22]1([CH2:28][CH2:29][OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCC1(CCO)CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.1 %

Procedure:
tert-Butylchlorodiphenylsilane (34.4 mL, 0.132 mol) was added dropwise to a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (21.7 g, 0.126 mol) in methylene chloride (280 mL) while cooling on ice. After stirring the mixture for 14 hours at room temperature, 25% aqueous ammonium chloride (300 mL) was added and extraction was performed. The organic layer was washed with saturated aqueous sodium chloride, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (500 g Merck Art. 9385, hexane:ethyl acetate=4:1) to obtain the title compound as a colorless oil (36.8 g) (2 steps, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24]
Reactant: COC(=O)C(CN1C(=O)c2ccc(Cl)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)C(CN1C(=O)c2ccc(Cl)cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (269 mg, 59%) in the same manner as described in the above example 6 (1) from methyl 3-(5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.52 g, 1.48 mmol) and pyridinium p-toluenesulfonate (51 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[C:17]([OH:19])=O.CC[N:22](CC)CC>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[C:17]([NH2:22])=[O:19]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1c(Br)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (6.13 mmol) was added to a solution of the acid (5-bromobenzo[1,3]dioxole-4-carboxylic acid) (3.25 mmol) in anhyd CH2Cl2 (30 ml) and the stirred mixture was refluxed for 2 h. Then the mixture was concentrated to dryness under reduced pressure. To this residue was added a solution of amine from step g (2.45 mmol) in anhyd CH2Cl2 (15 ml) and anhyd Et3N (3.67 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated to dryness and diluted with CH2Cl2, then washed with 10% HCl, aq NaHCO3 solution and brine. The residue was dissolved in chloroform and subjected to flash chromatography to provide 5-bromobenzo[1,3]dioxole-4-carboxamide), N-(5-(biphenyl[1,1′]-4-yl)-6,7-dimethoxynaphthalen-1-yl) (1H NMR (CDCl3) δ 3.66 (s, 3H), 4.04 (s, 3H), 6.16 (s, 2H), 7.47-7.50 (m, 10H), 7.70-7-74 (m, 6H)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](C2CCC(C)(C)CC2)=[CH:8][C:9]=1N(C(CO)CO)C([C@H]1CC[C@H](C)CC1)=O)=[O:4].C=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Agent: C=O
Product: COC(=O)c1cccs1

Procedure:
5-(4,4-Dimethyl-cyclohexyl)-3-[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was prepared from 5-(4,4-dimethyl-cyclohexyl)-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester using paraformaldehyde following a procedure described earlier (example 38, step IV).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)cc1
Yield: 88.3 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 mL)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated 4-methoxyphenylboronic acid (28 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (47 mg, 88%). LC-MS m/e 437.31 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: Fc1ccc(CBr)cc1F
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(Cc3ccc(F)c(F)c3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=324.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,4-difluoro-benzylbromide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1ccncc1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cnccc1C

Procedure:
Intermediate 20A was prepared from Intermediate 1A and methyl 2-bromo-5-nitrobenzoate by the procedure described for the preparation of Intermediate 1C. MS (ES): m/z=273.1 [M+H]+.