Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])([CH3:11])[CH2:3][C@:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.C([Mg]CCCC)CCC.[Li+].[CH3:31][Si:32]([C:35]#[C-:36])([CH3:34])[CH3:33]>COCCOC>[OH:5][C@@:4]([C:7]([F:8])([F:9])[F:10])([CH2:6][C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH2:3][C:2]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])([CH3:11])[CH3:1]
Reactant: [C-]#C[Si](C)(C)C
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C(N)=O
Agent: CCCC[Mg]CCCC
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C[C@@](O)(CC#C[Si](C)(C)C)C(F)(F)F)c1ccccc1C(N)=O
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled, solution of (trimethylsilyl)acetylene (72.6 mL, 514 mmol) in 500 mL of ethylene glycol dimethyl ether was added n-butyllithium (185 mL of 2.5 M solution in hexanes, 462 mmol). The reaction mixture, which turned from a colorless to a yellowish solution, was stirred for 50 minutes to give a solution of 462 mmol of lithium (trimethylsilyl)acetylide. A stirred solution of 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzamide (26.5 g, 92.3 mmol) in ethylene glycol dimethyl ether (250 mL) was cooled to −30° C. Dibutylmagnesium (50.8 mL of 1 M solution in heptane, 50.8 mmol) was added and the mixture stirred for 45 minutes. The above solution of lithium (trimethylsilyl)acetylide was added and the stirring continued at −20° C. After 5 minutes, cooling bath was removed and the reaction mixture was stirred for 3 hours and 15 minutes. The reaction was quenched with 600 mL of saturated ammonium chloride solution and extracted with four 250 mL portions of ethyl acetate. The combined organic extracts were washed with two 250 mL portions of brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to give 2-((R)-3-hydroxy-1,1-dimethyl-3-trifluoromethyl-6-trimethylsilanylhex-5-ynyl)benzamide as brownish oil (27 g).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[OH-].[NH4+:18]>C(O)(C)(C)C>[NH2:1][C:2]1[N:18]=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]([OH:3])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)c1oc(N)nc1C(C)(C)C
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1nc(N)nc(C(C)(C)C)c1O
Yield: 34 %

Procedure:
A solution of 1-[2-amino-4-(1,1-dimethylethyl)-5-oxazolyl]-2,2-dimethyl-1-propanone (15 g) in t-butanol (80 mL) and concentrated ammonium hydroxide (80 mL) is heated at 180° C. for 60 hours in a steel bomb. The reaction mixture is cooled and concentrated to half its volume on the rotovap. The product is extracted into ether (3×250 mL). The ether extract is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica, 20% EtOAc/hexane) to give pure 2-amino-4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidine (4.5 g, 34%) which crystallizes from cold hexane; mp 92°-93° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[C:18]4[CH:19]=[C:20]([OH:25])[C:21]([Br:24])=[C:22]([Br:23])[C:17]=4[O:16][CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+]([O-])(O)=[O:27].O>CC(O)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[C:18]4[C:19](=[O:27])[C:20](=[O:25])[C:21]([Br:24])=[C:22]([Br:23])[C:17]=4[O:16][CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(-n2ccnc2)cc1)c1coc2c(Br)c(Br)c(O)cc12
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(=O)c2c(C(=O)c3ccc(-n4ccnc4)cc3)coc2C(Br)=C1Br
Temperature: 60 °C
Yield: 74.1 %

Procedure:
To a solution of (4-(1H-imidazol-1-yl)phenyl)(6,7-dibromo-5-hydroxybenzofuran-3-yl)methanone (55 mg, 0.119 mmol) in AcOH (1 mL) was added nitric acid—69% (36.7 μl, 0.595 mmol) at room temperature. The mixture was heated to 60° C. for 1 hour then cooled to room temperature, poured onto iced water (3 mL) and the suspension filtered under vacuum to furnish 42 mg of a red/orange solid. 1H NMR (DMSO-d6) was consistent with two species—product and starting material. The material was re-subjected to the above conditions for a further hour and then worked up as before to afford compound x (25 mg, 44%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C1N2CCN(CC2)C1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([Br:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C1(C)C=CC=CC=1>[Br:33][C:32]1[CH:34]=[CH:35][C:29]([S:26]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.15 g, 8.76 mmol) and DABCO (1.57 g, 14.0 mmol) in PhMe (10 mL) at RT was added a solution of brosyl chloride (3.14 g, 12.3 mmol) in PhMe (5 mL). A white precipitate formed, the reaction mixture was stirred for 20 min and filtered. The filtrate was partitioned between EtOAc and saturated aqueous NaHCO3. The layers were separated and the organic was washed with 1 M HCl, water and brine, dried over Na2SO4, filtered and concentrated. The resulting oil, 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate 23 (4.0 g, 98% yield), was used without further purification. LRMS (M+Na)+ Calcd.: 488. found 488.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH2:40][CH3:41])=[C:7]([CH2:25][C:26]([N:28]([CH2:37][CH2:38][OH:39])[CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:9]([O:11]CC=C)[CH:10]=1)C=C.C([O-])=O.[NH4+]>O1CCOCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:40]([C:6]1[C:5]([OH:4])=[CH:10][C:9]([OH:11])=[C:8]([C:15](=[O:24])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([N:28]([CH2:37][CH2:38][OH:39])[CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:27])[CH3:41]
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(OC)cc2)c(CC(=O)N(CCO)CCN2CCOCC2)c1CC
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)N(CCO)CCN1CCOCC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
2-[3,5-Diallyloxy-2-ethyl-6-(4-methoxybenzoyl)phenyl]-N-(2-hydroxyethyl)-N-(2-morpholinoethyl)acetamide (0.31 g, 0.55 mmol) obtained in Example 110, Step 2 was dissolved in 1,4-dioxane (1.5 mL), and ammonium formate (0.14 g, 2.2 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.012 g, 0.017 mmol) were added thereto, followed by stirring at 100° C. for 1.5 hours in an atmosphere of argon. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by C18 silica gel column chromatography (water-water/acetonitrile=1/1) to obtain Compound 111 (0.14 g, 51%). Melting Point: 235-237° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I-].C[N+]1C=CN([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1OC
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N(C)c4ccccc4)cc3oc2=O)cc1OC
Yield: 13.5 %

Procedure:
The title compound (30 mg, 13% yield, oil) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:32](=[O:33])[CH2:31][N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCN(C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 173) (150 mg, 0.59 mmol) and commercially available (4-methyl-piperazin-1-yl)-acetic acid (77 mg, 0.68 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (210 mg, 96%); MS: m/e=448.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCO[C:17](OCC)(OCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[C:11]2[N:10]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NNc1nc2ccccc2nc1Cl
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CCO
Product: Clc1nc2ccccc2n2c(-c3ccccc3)nnc12
Temperature: 25 °C

Procedure:
2-Chloro-3-hydrazinoquinoxaline (2.2 g., 0.011 mole) was mixed with 6 ml. of triethyl orthobenzoate and heated at 100° C. for 30 minutes. After cooling the orange mixture to room temperature, ethanol was added. Filtration of the resultant precipitate afforded 2.1 g. of crude product which was further purified by means of trituration with warm methanol, followed by filtration and air drying to ultimately yield 1.58 g. (51%) of pure 4-chloro-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline as an orange solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C@@:23]1([CH2:37][CH2:38]O)[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([CH3:36])[C:27]([CH3:35])=[C:28]([OH:34])[C:29]=2[CH3:33])[O:24]1>C(Cl)Cl>[CH3:22][C@@:23]1([CH2:37][CH2:38][Br:20])[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([CH3:36])[C:27]([CH3:35])=[C:28]([OH:34])[C:29]=2[CH3:33])[O:24]1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCO)O2
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCBr)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
5.5 g of triphenylphosphine were dissolved in 100 ml of anhydrous methylene chloride, 3.4 g of bromine were added dropwise, the reaction mixture was stirred for 30 minutes at room temperature, 5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were added, and the mixture was refluxed for one hour and then poured onto sodium carbonate solution. The aqueous phase was extracted with methylene chloride, the combined organic phases were washed with sodium chloride solution, dried and evaporated down, and the residue was recrystallized from methanol. 5.3 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were obtained. [α]D20 =-15 (c=2, MeOH), mp.=120° C.
Reaction SMILES: ClC1C=C(C2(CO)CCN(C(OC(C)(C)C)=O)CC2)C=CC=1.[F:23][C:24]1[CH:25]=[C:26]([C:30]2([CH2:43][OH:44])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:30]2([CH:43]=[O:44])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2cccc(F)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CO)(c2cccc(Cl)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C=O)(c2cccc(F)c2)CC1

Procedure:
Using standard Swern oxidation reaction conditions (see step (v)/Example 80 or step (iii)/Example 81), tert-butyl 4-(3-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.5 g, 1.61 mmol) was oxidized to yield tert-butyl 4-(3-fluorophenyl)-4-formylpiperidine-1-carboxylate which was directly taken through to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[S:21]1[C:25]2([CH2:29][C@@H:28]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[NH:27][CH2:26]2)[S:24][CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:17])[C:18]([N:27]1[C@H:28]([C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:29][C:25]2([S:21][CH2:22][CH2:23][S:24]2)[CH2:26]1)=[O:20])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1)SCCS2
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2

Procedure:
To a cold (0°) solution of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine (720 mg., 2.57 mmole) and (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester, p-toluenesulfonate (1.06 g., 1.1 eq.) in 8 ml. of dry dimethylformamide under argon is added dropwise a solution of 0.61 ml. (1.1 eq.) of diphenylphosphoryl azide in 1 ml. of dimethylformamide. The reaction mixture is worked up according to the procedure of Example 95(f) to yield (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>O1CCCC1.CN(C)C=O>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1)=[O:32]
Reactant: O=C(Cl)c1ccco1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccco4)cc23)CC1
Yield: 73.1 %

Procedure:
To a solution of 0.780 gm (3.2 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 10 mL dimethylformamide were added 0.536 mL (3.85 mMol) triethylamine followed by the dropwise addition of 0.348 mL (3.5 mMol) 2-furoyl chloride. After 18 hours the reaction mixture was cooled in an ice bath. The reaction mixture was the partitioned between 100 mL ethyl acetate and 100 mL 2N sodium hydroxide. The phases were separated and the aqueous extracted again with ethyl acetate. Organic extracts were combined and washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica), eluting with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give 0.789 gm (73.1%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][CH:19]3O)=[CH:12][CH:13]=1)=[O:6].C1C=C[NH+]=CC=1.Br[Br-]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH:18]=[CH:19]3)=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3O)nc1)c1ccc(Cl)c(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccc(Oc2cccc3c2CC=C3)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
1.50 g of 3,4-dichloro-N1-[6-(1-hydroxy-2,3-dihydro-1H-inden-4-yloxy)-3-pyridinyl]benzamide obtained in Example 34 was dissolved in 15 ml of acetic acid, and 1.16 g of pyridinium bromide perbromide was added to the resulting reaction solution and the mixture was stirred at 80° C. After 4 hours, the reaction solution was poured into iced water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane (1:3)) to obtain 430 mg of the titled compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[N:10][CH:11]=1)=O)[CH3:2].B.C(O)(=O)C.Cl>O1CCCC1>[CH2:1]([N:3]([CH2:4][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[N:10][CH:11]=1)[CH2:15][CH3:16])[CH3:2]
Reactant: CCN(CC)C(=O)c1cnc2occc2c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CC)Cc1cnc2occc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of N,N-diethyl furo[2,3-b]pyridine-5-carboxamide (3.6 g, 16.5 mmol) in dry tetrahydrofuran (35 mL), under a nitrogen atmosphere, was added 1M borane in THF (52 mL, 52 mmol). This solution was warmed at 60° C. for 2-3 hours and then glacial acetic acid (3 mL, 52 mmol) was carefully added. After 0.5 hours, dilute hydrochloric acid (10%) was added to the reaction and the aqueous layer was separated and made basic with sodium hydroxide solution. The product was extracted into methylene chloride, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and the solvent evaporated to give crude oily product (2.6 g). This material was distilled under vacuum to give purified produt (1.2 g, 36% yield), bp: 120°-121° C./1.5 mmHg. A small portion was treated with ethanolic hydrogen chloride to give the hydrochloride salt which was recrystallized from isopropanol, mp: 206°-208° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH:35]([CH3:37])[CH3:36])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in methylene chloride (1 mL) was added 1.0 M isopropyl chloroformate in toluene (35 μL). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.5 mg, 12%). LCMS calculated for C21H26N5O2S (M+H)+: m/z=412.2. Found: 412.1.
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:3](OCCCl)=[O:4].[C:16]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[CH2:17][OH:18].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:3]([O:18][CH2:17][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: CC(C)OC(=O)CO
Reactant: CC(O)(C(=O)OCCCl)c1ccccc1
Solvent: CCOCC
Solvent: CC(C)(C)c1ccccc1
Product: CC(C)OC(=O)COC(=O)C(C)(O)c1ccccc1

Procedure:
A 4.5 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl 2-hydroxy-2-phenylpropionate, 0.25 M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.30 g Lipase P30. After mixing for 8 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-phenylpropionate to the title compound was estimated (by GC, Method B) to be approximately 10%. The GC peak assigned to the title compound was confirmed by HRMS calcd for C13H14O5TMs (M--CH3) 323.1314, obsd 323.1366.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[N:16]=[N:15]1)[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[N:16]=[N:15]1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc(C(=O)OC)cc2OCC)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1-n1cc(C(=O)O)nn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
To a solution of ethyl 1-[2-ethoxy-4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazole-4-carboxylate (0.92 g) obtained in Example 320c) in ethanol (10 ml) were added 8N aqueous sodium hydroxide solution (0.72 ml) and water (2 ml), and the reaction mixture was stirred at 100° C. for 1 hr. After ethanol was evaporated under reduced pressure, 1N hydrochloric acid was added to the obtained aqueous solution, and the resultant precipitant was collected by filtration to give the title compound as a white powder (0.87 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](/[O:19][CH3:20])\[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH:28][C:29](=[O:47])[N:30]([CH3:46])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](/[O:19][CH3:20])\[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([N:30]([CH3:46])[C:29]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:47])[CH:36]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(/OC)C(=O)OC)ccc1I
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(/OC)C(=O)OC)cc2OCCCC)c1
Temperature: 90 °C
Yield: 64.6 %

Procedure:
0.4 g (1 mmol) of methyl (E)-3-(3-butoxy-4-iodophenyl)-2-methoxyacrylate prepared as described in Example 24c, 0.5 g (1.33 mmol) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]urea prepared according to Example 35b and 1 mL (2 mmol) of aqueous 2 M potassium phosphate solution are dissolved in 15 mL of dimethylformamide. After bubbling nitrogen through the reaction mixture for 10 minutes, 2 mg (0.01 mmol) of palladium (II) acetate and 7 mg (0.02 mmol) of 2-(dicyclohexylphosphine)biphenyl are added. The reaction mixture is heated at 90° C. for 3 hours with vigorous stirring. After cooling, the reaction is worked up by addition of water and extraction with ethyl acetate. The organic phases are combined, washed with water and with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.33 g (64%) of methyl (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methoxyacrylate in the form of a colorless oil.