Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.I[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+].C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Into a reactor were introduced 0.214 g (2.00 mmol) of p-toluidine and 4 mL of dioxane under a nitrogen atmosphere. The amine was dissolved in the solvent. To this solution were added 0.515 g (2.2 mol) of p-iodoanisole, 0.231 g (2.4 mmol) of sodium t-butoxide, 4.5 mg (1 mol % based on the amine) of palladium acetate, and 15.6 mg (2 mmol % based on the amine) of the 1,1-diphenyl-2-(dicyclohexylphosphino)propene obtained in Example 2. The resultant reaction mixture was stirred at 100° C. for 8 hours and then cooled. Saturated aqueous ammonium chloride solution was added thereto, and this mixture was extracted with toluene. The extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by column chromatography to obtain 0.351 g (82%) of N-p-methoxyphenyl-N-p-tolylamine as yellow crystals. The results obtained are shown in Table 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].CN(C=O)C.[CH2:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[OH2:2].[CH2:37]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[CH2:37]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (500 mg) and 70 mg of 60% oily sodium hydride were mixed with 5 ml of DMF and stirred at room temperature for 1 hour. Then, to the mixture was added dropwise 3 ml of DMF solution containing 0.17 ml of benzylchloride. After stirring for 4 hours at room temperature, the reaction mixture was poured into a large amount of water and organic substances were extracted with chloroform. The chloroform layer was washed with water and dehydrated. Chloroform was distilled off and the residue was recrystallized from ethanol to give 150 mg of 1-benzyl-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril hemihydrate, m.p. 131.5°-132.5° C., yellow powders. Elemental Analysis for
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:29][S+](C)(C)=O>C1COCC1.CS(C)=O.C(OCC)(=O)C>[C:1]1([C:7]2([C:9]3[CH:14]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]4)=[N:11][CH:10]=3)[CH2:29][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C3(c4ccccc4)CC3)cn2)CC1
Temperature: 80 °C
Reaction time: 96 h
Yield: 10.5 %

Procedure:
To a solution of tert-butyl 4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate (366 mg, 1.0 mmol) in THF (20 mL) was added trimethylsulfoxonium iodide (1.1 g 5.0 mmol) in dimethyl sulfoxide (7 mL). The reaction mixture was stirred at 80° C. for 4 days, and diluted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1) to give tert-butyl 4-(5-(1-phenylcyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (40 mg, 10%) as a yellow solid. MS (ES+) C22H28N4O2 requires: 380, found: 381 [M+H]+.
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[CH2:19]([NH:26][C:27](=[O:34])[C@H:28]([C@H:30]([CH2:32][CH3:33])[CH3:31])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Pd].CO>[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].[CH2:19]([NH:26][C:27](=[O:34])[C@H:28]([C@H:30]([CH2:32][CH3:33])[CH3:31])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1
Temperature: 22 °C

Procedure:
A solution of N-carbobenzyloxy-L-proline-L-isoleucine benzylamide (36.60 g, 80.95 mmol), 10% palladium on carbon (0.957 g), and methanol (700 mL) was degassed and purged repeatedly (15 times) with hydrogen, and stirred under an atmosphere of hydrogen at 22° C. When TLC analysis indicated the reaction was complete, the solution was purged with argon, filtered through a plug of celite, and concentrated in vacuo to provide 23.71 g, (92%) of L-proline-L-isoleucine benzylamide as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[O:12])[N:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH2:33][N:32](C(OC(C)(C)C)=O)[CH:31]([C:44]([O:46]CC)=[O:45])[CH2:30]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[O:12])[N:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH2:33][NH:32][CH:31]([C:44]([OH:46])=[O:45])[CH2:30]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Oc4cccnc4)c3)ccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)n(-c2ccc3c(c2)CC(C(=O)O)NC3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A solution of 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (available from Example 179, 0.102 g, 0.160 mmol) in 3N HCl in MeOH (5 mL) was stirred for 1 h. The solvent was evaporated. The residue was dissolved in THF (2 mL). 2N NaOH was added (2 mL) and then MeOH until homogenous. The solution was stirred at RT for 1 h. The solvents were evaporated, the residue was purified by reverse phase chromatography followed by coevaporation with THF/HCl to yield 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (20 mg, 100%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.66 (d, J=2.8 Hz, 1H), 8.59 (d, J=5.2 Hz, 1H), 8.22 (ddd, J=9.2, 2.8, and 0.8 Hz, 1H), 8.05 (dd, J=8.8, 5.6 Hz, 1H), 7.58 (t, J=2.0 Hz, 1H), 7.54-7.46 (m, 3H), 7.42 (t, J=8.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.89 (dd, J=8.4, and 2.4 Hz, 1H), 6.57 (s, 1H), 6.59 (d, J=16.0 Hz, 1H), 4.51 (d, J=16.0 Hz, 1H), 4.49 (dd, J=11.2, and 5.2 Hz, 1H), 3.60 (dd, J=18.0, and 4.8 Hz, 1H), 1.37 (s, 9H), acid, amine and urea protons not visible, one proton is buried under the MeOH peak; MS (EI) m/z: 527.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.8 %

Procedure:
To a solution of phenol 4 (3.0 g, 9.88 mmol) in DMF (20 mL) were added TBDMSCl (1M in CH2Cl2, 20 mL, 19.8 mmol), imidazole (2.1 g, 29.6 mmol) and DMAP (0.25 g, 1.98 mmol) at room temperature. The mixture was stirred at ambient temperature for 14 hours. The mixture was extracted with EtOAc/H2O (75 mL/250 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 21 (4.12 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[C:26]1([CH3:29])[CH:25]=[CH:24][C:23]([O:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]3[CH:11]=[CH:10][C:5]4[NH:6][C:7](=[O:9])[S:8][C:4]=4[CH:3]=3)[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Reactant: Cc1ccc(OC2CCN(C(=O)CCl)CC2)cc1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)CNc3ccc4[nH]c(=O)sc4c3)CC2)cc1

Procedure:
The title compound is prepared from 6-amino-3H-benzothiazole-2-one and 2-chloro-1-(4-p-tolyloxy-piperidin-1-yl)-ethanone according to the method described in Example 206. Melting Point: 189-191° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[C:16]([NH:21][C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[CH3:32]>CN1CCCC1=O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][C:12]([CH3:32])=[C:11]2[N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:31]
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccc(=O)cc1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of 4-hydroxypyridine (114 mg) in N-methylpyrrolidone (3 ml) was added sodium hydride (60% in oil, 28.9 mg) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added 4-chloro-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (200 mg), and the mixture was stirred for 1.5 hours at 120° C. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate-methanol-dichloromethane) and crystallized from diethyl ether to give 8-(2,6-dichlorobenzoylamino)-3-methyl-4-(1,4-dihydro-4-oxopyridin-1-yl)quinoline (185 mg) as white crystal.
Reaction SMILES: C(P(CCCC)CCCC)CCC.N1CCCCC1.N1CCCCC1.N(C(O)=O)=NC(O)=O.[CH:34]1([C:37]2[CH:41]=[N:40][N:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][C:49]([F:52])([F:51])[F:50])[C:38]=2[CH2:53][OH:54])[CH2:36][CH2:35]1.[C:55]([O:59][C:60](=[O:70])[NH:61][C:62]1[CH:67]=[CH:66][C:65](O)=[CH:64][C:63]=1[CH3:69])([CH3:58])([CH3:57])[CH3:56]>C1(C)C=CC=CC=1>[C:55]([O:59][C:60](=[O:70])[NH:61][C:62]1[CH:67]=[CH:66][C:65]([O:54][CH2:53][C:38]2[N:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][C:49]([F:52])([F:50])[F:51])[N:40]=[CH:41][C:37]=2[CH:34]2[CH2:35][CH2:36]2)=[CH:64][C:63]=1[CH3:69])([CH3:58])([CH3:57])[CH3:56]
Reactant: OCc1c(C2CC2)cnn1-c1ccccc1OC(F)(F)F
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(O)N=NC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Tri-n-butylphosphine (1.9 mL, 7.5 mmol) and azodicarboxylic acid dipiperidine (1.90 g, 7.54 mmol) are added to a mixture of [4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (1.50 g, 5.03 mmol), (4-hydroxy-2-methyl-phenyl)-carbamic acid tert-butyl ester (1.35 g, 6.03 mmol) and toluene at room temperature. After 1 h, additional tri-n-butylphosphine (0.6 mL) is added and the mixture is stirred for 2 h. The mixture is concentrated and the residue is purified by flash chromatography (20 to 50% EtOAc/heptane) to give the title compound (1.92 g, 76%). LC-ES/MS m/e 504.2 (M+1).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[O:4]1[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]1.S(=O)(=O)(O)O.[CH2:22]([OH:27])[CH2:23][CH:24]([OH:26])[CH3:25].C(=O)([O-])O.[Na+]>O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:27][CH2:22][CH2:23][CH:24]([OH:26])[CH3:25]
Reactant: CCCCCCCCCCC1CO1
Reactant: CC(O)CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Product: CC(O)CCOCCCCCCCCCCCCO
Temperature: 52.5 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Separately, a 100 ml mixing vessel equipped with a calcium chloride-containing tube was charged with 36.9 g (0.20 mole) of 1,2-epoxydodecane. While the charged 1,2-epoxydodecane was stirred and cooled with water, a concentrated sulfuric acid was gradually dropped in an amount of 0.4 g (0.004 mole) into the cooled 1,2-epoxydodecane. After stirring for 15 minutes, the resultant mixture was placed into the dropping apparatus attached to the reaction vessel and was dropped into 1,3-butanediol contained in the reaction vessel and maintained at a temperature of 50 to 55° C. over a time of 2 hours. Then the reaction of the mixture was carried out at a temperature of 50 to 55° C. for one hour. After the exhaustion of the starting material, namely 1,2-epoxydodecane was confirmed by a thin-layer chromatography, the reaction was stopped. A saturated aqueous sodium hydrogen carbonate solution was mixed in an amount of 50 ml into the resultant reaction liquid in the reaction vessel, the resultant mixture was stirred for 10 minutes to neutralize the reaction liquid. The reaction liquid was subjected to an extraction procedure using diethyl ether to extract the reaction product. The resultant extraction liquid was concentrated by using rotary evaporator. A 1,3-butanediol monohydroxydodecyl ether mixture was obtained in an amount of 52.8 g (yield: 98.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: CNOC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccnc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of (2-chloropyridin-3-yl)acetic acid (Intermediate 3; 2.0 g, 11.6 mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (1.19 g, 12.2 mmol), N-methylmorpholine (3.8 mL, 34.8 mmol) and EDC (2.3 g, 12.2 mmol). The mixture was stirred at room temperature for 48 hours, diluted with DCM (100 mL), washed with 10% HCl (aq) solution (200 mL) and brine (200 mL), dried (Na2SO4), filtered and the solvents removed in vacuo. The crude product was purified by column chromatography (SiO2, 1:1 EtOAc:DCM) to give the title compound as a white waxy solid (2.2 g, 88%). δH (DMSO-d6) 8.31 (1H, dd, J 4.7, 1.9 Hz), 7.81 (1H, dd, J 7.5, 1.9 Hz), 7.40 (1H, dd, J 7.5, 4.7 Hz), 3.93 (2H, s), 3.76 (3H, s), 3.15 (3H, s). LCMS (pH 3) RT 2.22 minutes, (ES+) 215 35Cl (M+H)+, 217 37Cl (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Reactant: NCC(F)(F)F
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NCC(F)(F)F
Yield: 97 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.28 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (115 mg, 97%) which was obtained as a brown solid. MS: m/e=427.0 [M−]−.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([N:35]1[CH2:42][CH2:41][CH:40](O)[C@@H:36]1C(O)=O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([O:27][C@H:41]5[CH2:40][CH2:36][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:42]5)=[CH:25][CH:26]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)[C@@H]1C(=O)O
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O)cc3)C2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Reaction time: 18 h

Procedure:
To a solution of compound 26d (100 mg, 0.273 mmol) and (R)—N—Boc-3-hydroxyproline in THF was added DIAD at 0° C. The resulting reaction mixture was stirred for 18 h. After dilution with water and extraction with EtOAc (3×), the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel using 5% MeOH/CH2Cl2 to give compound 434 (95 mg). 1H NMR (CDCl3): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s., 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H+) 506.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=1)([O-])=O.[N+](C1C2C=COC=2C=CC=1)([O-])=O>>[O:10]1[C:6]2[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccc2ccoc2c1
Agent: O=[N+]([O-])c1cccc2occc12
Product: Nc1ccc2c(c1)OCC2

Procedure:
Following the procedure of Example C but substituting 6-nitrobenzofuran for the 4-nitrobenzofuran there is obtained 2,3-dihydro-6-benzofuranamine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[Li+].[Cl-].[CH2:19]=[CH:20][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH2:20]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2cnnn2)ccc1CC(=O)O

Procedure:
To a solution of [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid (100 mg, 0.35 mmol) in 10 mL of toluene was added LiCl (44 mg, 1.05 mmol), Pd(PPh3)4(10 mg), CH2═CHSnBu3 (222 mg, 0.7 mmol), and the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified by prep-TLC to give [2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid.
Reaction SMILES: C(S[CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1)(C)(C)C.[Cl:31]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:31][CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of 439 mg (1.0 mmol) of p-nitrobenzyl 2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 20 ml of dry methylene chloride is cooled to -50° C. and a solution of 166 mg of chlorine in 1.6 ml of carbon tetrachloride is added. After stirring for 30 minutes at -50° C., the solvent is evaporated in vacuo and the residue is recrystallized from methylene chloride/hexane, the product (348 mg) being obtained as a crystalline solid as a 6:4 mixture of the two diastereomeric title compounds.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:32])/[CH:5]=[CH:6]/[C:7]1[S:11][CH:10]=[C:9]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.[CH:33]([C:35]1[N:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)=O>>[CH3:2][O:3][C:4](=[O:32])/[CH:5]=[CH:6]/[C:7]1[S:11][CH:10]=[C:9]([CH:12]=[CH:33][C:35]2[N:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[CH:8]=1
Reactant: COC(=O)/C=C/c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: [Cl-]
Product: COC(=O)/C=C/c1cc(C=Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)cs1
Yield: 94.8 %

Procedure:
By a method similar to Production Example 108, step 4, ({5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]thiophen-3-yl}methyl)(triphenyl)phosphonium chloride (1.724 g, 3.600 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (874.1 mg, 3.000 mmol) were condensed to give tert-butyl 4-[6-(2-{5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]thiophen-3-yl}vinyl)pyridin-3-yl]piperazine-1-carboxylate (1.295 g, yield 94.7%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:23]([O-:24])=[O:22])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16]
Reactant: CSc1nc(-c2ccncc2)cc(=O)n1C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CSc1nc(-c2ccncc2)c([N+](=O)[O-])c(=O)n1C
Reaction time: 2 h

Procedure:
3-Methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.0 g, 4.3 mmol) in 10 mL dry acetonitrile at 0° C. under nitrogen was added nitronium tetrafluoroborate (0.5 M in sulfolane, Aldrich Chemical, 17.2 mL, 8.6 mmol) at such a rate as to not let the internal temperature rise above 5° C. The suspension slowly became a homogeneous solution. The reaction was monitored by mass spec and after 2 h, no remaining starting material was observed. The acetonitrile was removed under reduced pressure and the resulting solution was loaded directly onto 90 g of silica. The product was eluted with 0% to 5% methanol/dichloromethane. M+1=279; NMR (CDCl3) s (3H; 2.7 ppm), s (3H; 3.6 ppm), d (2H; 7.5 ppm), d (2H; 8.7 ppm).