Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2].C(OC(=O)C)(=[O:19])C.S(=O)(=O)(O)O.O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([NH:4][C:5]1[C:14]([CH:15]=[O:19])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C)c(NC(C)=O)c(Cl)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c(C=O)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a cooled solution (ice bath) of 10.8 g of methyl 4-acetamido-3-chloro-5-methylbenzoate in 73.8 ml of glacial acetic acid; and 73.8 ml of acetic anhydride were added dropwise 11 mL of concentrated sulfuric acid followed by the portion wise addition of 12.96 g (0.1295 mole) of chromium trioxide over a 25 minute period. The reaction mixture was stirred at 0° C. for 2.5 hours and then poured into a mixture of 612 g of ice and 162 ml of water. The resulting aqueous mixture was extracted with methylene chloride (4×250 ml). The combined organic layers were washed sequentially with water (3×250 ml), 5% aqueous sodium bicarbonate (2×250 ml) and then brine (1×250 ml) and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator. The resulting residue was purified by chromatographic column (silica gel, ethyl acetate:hexane 30:70 followed by ethyl acetate:hexane 50:50), yielding 2.5 g methyl 4-acetamido-3-chloro-5-formylbenzoate.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:36])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1.[OH-].[K+]>>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:26](=[O:36])[C:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:33][CH:32]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccc(CC(=O)Cc2ccc(OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C2=C(c3ccccc3)C(c3ccccc3)=C(c3ccc(OC)cc3)C2=O)cc1
Yield: 91 %

Procedure:
Equivalent weights of benzil and the 1,3-bis(4-methoxyphenyl)propanone prepared in the first step are dissolved in, for example, alcohol and heated to incipient boiling. A condensation reaction is initiated by the addition of a small amount of an aqueous potassium hydroxide solution. The solution is heated at reflux to form a purple-black slurry which on purification results in an excellent yield (91%) of purple-colored crystalline 2,5-bis (4-methoxyphenyl)-3,4-diphenylcyclopentadienone, or α,α′-bis(4-methoxy)-tetracyclone, melting at approximately 186-188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)nitrobenzene (11.9 g) in methanol (100 ml) was added palladium on carbon (1.9 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (10.7 g, yield 99%) as a pale red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=CC=1.C1(N)CC1>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH:21]1[CH2:19][CH2:20]1)=[O:6]
Reactant: O=C(O)c1ccc(I)cc1Cl
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-iodobenzoic acid (3.31 g, 11.7 mmol) was dissolved in ethyl acetate (23 ml), admixed with one drop of N,N-dimethylformamide and thionyl chloride (6.96 g, 59.0 mmol), and heated under reflux overnight. The cooled suspension was concentrated under reduced pressure and taken up in dichloromethane (60 ml). The solution was cooled to 0° C., and pyridine (925 mg, 11.7 mmol) and cyclopropylamine (668 mg, 11.7 mmol) were added dropwise. The reaction mixture was warmed up to room temperature and stirred overnight. Then it was washed with hydrochloric acid (1 M), dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1.C(O)(C)C.C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:12]=2[CH:11]=1
Reactant: NNc1ccc(F)cc1
Reactant: Oc1ccnc(O)c1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Temperature: 165 °C
Reaction time: 1 h

Procedure:
To 2,4-dihydroxypyridine (43.6 g, 392 mmol) in phenyl ether (760 mL) in a three neck flask fitted with a Dean-Stark trap was added 4-fluorophenylhydrazine in phenyl ether (100 mL). The reaction mixture was heated to 165° C. for 1 h, slowly warmed to 230° C., and left to stir at 230° C. for 1 h. The reaction mixture was allowed to cool to 45° C. and treated with isopropanol and toluene. The mixture was filtered, washed with toluene, and dried to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.82 (s, 1H); 11.13 (s, 1H); 7.71 (dd, 1H); 7.45 (dd, 1H); 7.28 (t, 1H); 7.12 (m, 1H); 6.45 (d, 1H). LRMS (APCI) calc'd for (C11H7FN2O) [M+H]+, 203.1. found 203.1.
Reaction SMILES: ClC1C=CC(CC2[C:13]3([C:14]#[N:15])C(C)(CO3)CC2)=CC=1.COC([C:23]1([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:27][CH2:26][C:25]([CH2:29]O)([CH3:28])[C:24]1=[O:31])=O.C[OH:41].[H-].[Na+]>O1CCCC1.O>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:23]2[C:24]3([CH2:13][C:14]([NH2:15])=[O:41])[C:25]([CH3:28])([CH2:29][O:31]3)[CH2:26][CH2:27]2)=[CH:38][CH:37]=1
Reactant: CO
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(C#N)OC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC12CCC(Cc3ccc(Cl)cc3)C1(CC(N)=O)OC2

Procedure:
In 7 ml of tetrahydrofuran, 703 mg of Compound 5-1 obtained in Production Example 9 of Example 1 was dissolved. To the solution thus obtained, 7 ml of methanol and 5 ml of 25% aqueous solution of sodium hydride were added, and the resulting mixture was refluxed in hot water bath of 80° C. for 5 hours. After the reaction, the solvent was distilled away, and the residue was then mixed with water.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH2:28][OH:29]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH2:28][OH:29])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: OC[C@@H]1CCCN1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCC[C@H]1CO

Procedure:
5-((S)-2-Hydroxymethyl-pyrrolidin-1-y1)-1-phenyl- 1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and L-prolinol. Mass spectrum (ES) MH+=421.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:21])[CH3:20])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]#[N:15])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[Na+].Cl>CCO.O.O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:20])[CH3:21])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]([NH2:15])=[O:25])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1
Reactant: [OH-]
Reactant: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1ncc(Oc2cc(C(N)=O)c(OC)cc2C(C)C)c(N)n1
Temperature: 100 °C
Yield: 27.1 %

Procedure:
To a solution of 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.3 g, 0.92 mmol) in EtOH/H2O (1:1, 10 ml) was added a solution of NaOH (0.37 g, 9.17 mmol) in H2O (1 ml). The reaction mixture was heated at 100° C. for 24 hrs and neutralized with 3N HCl. Ethanol was removed in vacuo and the remaining aqueous solution was extracted into methylene chloride. The combined extract was washed with water, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (3 to 8% EtOAc in Hexanes) gave 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide (0.086 g, 27%) as a white solid. (M+H)=346.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:26])[C:7]=2[CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCc1ccc2c(c1)Sc1ccccc1CC2
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: O=S1c2ccccc2CCc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2 gm. of 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin in 200 ml. of methylene chloride at room temperature. Add 1.7 gm. of m-chloroperbenzoic acid. Stir at room temperature for 2 hours. Add 4 gm. of calcium hydroxide and 50 ml. of methylene chloride. Continue stirring for 15 minutes. Filter through celite and evaporate the filtrate to dryness. Crystallize the residue from toluene to obtain the title product (m.p., 144°-146° C.).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35](=[O:37])[CH3:36].CC(C)=O>C(Cl)Cl>[CH3:26][C:6]1[C:5]2[C:10](=[C:11]([CH3:12])[C:2]([O:1][CH2:34][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=2)[O:9][C:8](=[O:13])[C:7]=1[CH2:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: CC(=O)CCl
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (4.00 g, 11.5 mmol), potassium carbonate (4.5 g, 36.9 mmol), chloroacetone (1 mL, 11.5 mmol) and acetone (200 mL) were refluxed overnight. After the solution was allowed to cool to room temperature, CH2Cl2 (200 mL) was added and the resulting solid was filtered off. The remaining solution was cold decolorized with charcoal and the solvent evaporated. The resulting solid was stirred with water, vacuum filtered, and washed with water. After air drying, 4,8-dimethyl-7-(2-oxo)propyloxy-3-(phthalimidomethyl)coumarin (4.06 g, 87.1% ) was obtained as an off-white solid. 1H NMR (CDCl3): δ 7.66-7.83 (m, 4H), 7.48 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 4.62 (s, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][S:26]([CH2:29][C:30]([OH:32])=O)(=[O:28])=[O:27])=[CH:16][CH:15]=1.Br.[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[S:44][C:43](=[O:46])[NH:42][C:41]=2[C:40]([OH:47])=[CH:39][CH:38]=1.Cl>CN(C=O)C.CCOCC.C(N(CC)CC)C>[OH:47][C:40]1[C:41]2[NH:42][C:43](=[O:46])[S:44][C:45]=2[C:37]([CH2:36][CH2:35][NH:34][C:30](=[O:32])[CH2:29][S:26]([CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)(=[O:27])=[O:28])=[CH:38][CH:39]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(O)CS(=O)(=O)CCCOCCc1ccc(F)cc1
Agent: Br
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(CS(=O)(=O)CCCOCCc1ccc(F)cc1)NCCc1ccc(O)c2[nH]c(=O)sc12
Reaction time: 0.67 h

Procedure:
Carbonyl diimidazole (1.94 g) was added to a stirred solution of the acid from step c) (3.64 g) in DMF (15 ml). Stirring was continued for 40 min at room temperature. To this solution was added 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide (3.48 g) followed by triethylamine (1.7 ml). The whole was left overnight. The reaction mixture was then added slowly to a rapidly stirred mixture of 10% aqueous hydrochloric acid and ether (100 ml each). A pale yellow solid gradually settled out and was filtered off, washed with pentane and dried in vacuo. This provided the subtitled compound as a buff coloured material which was used in the next step without further purification.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+:2]=[N-:3].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C>[N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[N+:2]=[N-:3]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reaction time: 24 h
Yield: 78.1 %

Procedure:
A solution of 25.0 g (93.6 mmol) of 5'-azido-5'-deoxythymidine (which can be prepared as in reference 36), 21.1 g (140 mmol) of t-butyldimethylsilyl chloride, and 12.7 g (187 mmol) imidazole in 190 ml of anhydrous DMF was stirred at RT under nitrogen for 18 hr. The DMF was removed under vacuum. The oil was partitioned between ether (500 ml) and 1N NaOH (2×300 ml). The aqueous layers were cooled with ice, and 650 ml of 1N HCl were added. The product was extracted with EtOAc (2×750 ml), and the organic layer was washed with brine, dried, and evap. After remaining under high vacuum for 24 hr, the oil crystallized to give 27.9 g of 5'-azido-3'-O-t-butyldimethylsilyl-5'-deoxythymidine as a white solid: NMR (300 MHz,d6-DMSO) δ11.34 (br,1H), 7.50 (s,1H), 6.16 (t,1H,J=7 Hz), 4.36 (m,1H), 3.84 (m,1H), 3.55 (m,2H), 2.34 (m,1H), 2.05 (m,1H), 1.79 (s,3H), 0.86 (s,9H), 0.08 (s,6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])=[CH:16][CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:24])=[O:23])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCc1ccc(Br)cc1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)CCc2ccc(Br)cc2)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A mixture of 2-amino-5-methyl-benzenesulfonamide (0.1 g, 0.53 mmol) and 2-(4-bromo-phenyl)-ethanesulfonyl chloride (0.14 g, 0.49 mmol) in anhydrous pyridine (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and the organic phase was washed with aqueous hydrochloric acid (1 M, 20 mL), saturated sodium bicarbonate (20 mL) and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC, using 5% methanol in dichloromethane as the eluent, to give 80 mg (38% yield) of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[O:7][C:6]=2[CH:12]=1.[F:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][C@H:21]([CH3:25])[CH2:20]2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:9][C:8]([N:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:17]3[CH:26]=[CH:27][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:20][C@H:21]2[CH3:25])=[O:11])=[C:6]([OH:7])[CH:12]=1
Reactant: O=C1COc2ccc(Cl)cc2O1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1O
Temperature: 95 °C
Yield: 52.9 %

Procedure:
To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.845 g, 4.81 mmol) in toluene (25 mL) was added (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (1.003 g, 4.81 mmol). The resulting mixture was heated to 95° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (˜1 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH:18](=[N:25]C1C=C(Br)C=CC=1)C1C=CC=CC=1.[CH3:33][C:34]([OH:38])(C#C)[CH3:35]>[Cu]I>[CH3:33][CH:34]([CH3:35])[OH:38].[NH2:25][C:18]#[C:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(N=Cc2ccccc2)c1
Reactant: C#CC(C)(C)O
Reactant: O=Cc1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Product: CC(C)O
Product: NC#Cc1ccccc1

Procedure:
The procedure was the same as in Example 2 using benzaldehyde free of benzoic acid, through the steps intended for the ex situ formation of the N-benzylidene 3-aminophenylbromide and the catalyzed reaction with 2-methyl-3-butyn-2-ol, with the exception that no benzoic acid was added. Upon the addition of the CuI, an apparent precipitation of Pd was observed (not seen in the procedure of Example 2). After several hours of reflux no reaction to form an aminophenylacetylene dimethylcarbinol, with or without the N-benzylidene moiety, could be observed by thin-layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.Cl.[NH2:31][C:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.C(N(C(C)C)C(C)C)C>ClCCl>[OH:36][CH2:35][C:32]1([NH:31][C:14]([C:12]2[CH:11]=[N:10][C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH2:34][CH2:33]1
Reactant: COCCOc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1
Reactant: NC1(CO)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ncc(C(=O)NC2(CO)CC2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a suspension of 0.05 g (0.00016 mol) of 6-(4-chloro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid in 2.0 ml dichloromethane was added 0.024 g 1-chloro-N,N,2-trimethyl-1-propenylamine and the mixture was stirred at room temperature for 30 min. To the resulting slightly brown solution was added 0.040 g of (1-amino-cyclopropyl)-methanol hydrochloride and dropwise 0.1 ml N-ethyldiisopropyl-amine. The mixture was stirred at ambient temperature for 30 min. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate to yield 0.035 g (55% yield) of the title compound as off white solid. MS (ISP) (M+H+)=378.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][NH:30][CH2:31]2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]2[CH:32]([CH2:31][N:30]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[N:8]=3)[CH2:29]2)[CH2:33]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (25 mg, 0.088 mmol) in 1,2-dichloroethane (1 mL) was added hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (21 mg, 0.10 mmol). The mixture was stirred at RT for 5 min before sodium triacetoxyborohydride (28 mg, 0.130 mmol) was added. The resulting solution was stirred at RT for 1 h. The crude reaction mixture was partitioned between DCM and brine. The organic layer was isolated, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (26 mg, 61%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)=[N:7][CH:6]=1)[NH2:4].[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH:32]([CH3:36])[C:33](Cl)=O.CO>N1C=CC=CC=1>[CH:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:8]2[S:9][C:5]([C:3]3[N:4]=[C:36]([CH:32]([N:23]4[C:24](=[O:31])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:22]4=[O:21])[CH3:33])[O:1][N:2]=3)=[CH:6][N:7]=2)=[CH:12][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(Oc2ncc(C(N)=NO)s2)cc1
Reactant: CC(C(=O)Cl)N1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N4C(=O)c5ccccc5C4=O)n3)s2)cc1
Temperature: 25 °C

Procedure:
To a solution of Example 40B (616 mg, 2.1 mmol) in pyridine (15 mL) was added 2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (CAS#5364-22-7) (598 mg, 2.52 mmol) and the solution was stirred for an hour at room temperature and then at reflux for an additional hour. The reaction mixture was cooled down, methanol was added, and after stirring for 15 minutes the solvent was removed under vacuum. The title compound was purified via silica-gel column chromatography using a gradient of 25 to 50% ethyl acetate in hexane to provide 855 mg, 1H NMR (300 MHz, CDCl3) δ ppm 7.84-7.96 (m, 3H) 7.73-7.83 (m, 2H) 7.15-7.24 (m, 2H) 6.86-6.99 (m, 2H) 5.68 (q, J=7.35 Hz, 1H) 4.43-4.63 (m, 1H) 1.98 (d, J=7.35 Hz, 3H) 1.35 (d, J=5.88 Hz, 6H). MS (DCI): m/z 477 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](=[N:28][NH2:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[C:16]1([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:28][NH:29][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NN=C(c1ccccc1)c1ccccc1
Yield: 63.9 %

Procedure:
A solution of 20.0 g (0.10 mole) of t-butyloxycarbonyl-L-serine, 19.6 g (0.10 mole) of benzophenone hydrazone, and 24.7 g of 2-ethoxy-1(2H)-quinolinecarboxylic acid ethyl ester in 250 ml of methylene chloride was stirred at room temperature for 16 hours. The solution was extracted with successive 100 ml portions of 1N hydrochloric acid, water, saturated sodium bicarbonate solution, water and brine, then dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulting syrup was dissolved in ethyl acetate and crystallized by the addition of hexane to afford 24.5 g (64%) of product, mp 150.0°-152.5° C.