Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)/[C:29](=[N:33]/[OH:34])/[CH2:28][CH2:27][CH2:26]2)=[CH2:22].[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2([CH2:48][CH2:49][C:50](OCC)=O)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2([CH2:48][CH2:49][C:50]3[O:34][N:33]=[C:29]4[C:30]5[C:25]([CH2:26][CH2:27][C:28]=34)=[CH:24][C:23]([CH:21]=[CH2:22])=[CH:32][CH:31]=5)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: CCOC(=O)CCC1(c2ccc(F)cc2)CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Temperature: -20 °C
Yield: 41.6 %

Procedure:
To a stirring solution of the diisopropylamine (0.230 mL, 1.617 mmol) in 2.5 mL of THF at −60° C. was added 2.5 M n-butyl lithium in hexanes (0.657 mL, 1.644 mmol) dropwise. The solution was allowed to stir with a gradual warm up to about −20° C. This freshly generated LDA solution was slowly added to a stirring solution of the 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.151 g, 0.808 mmol) in 1 mL of THF at ice bath temperature and the reaction mixture was stirred at this temperature for 15 min. To this mixture was then slowly added a solution of ethyl 3-(1-(4-fluorophenyl)cyclohexyl)propanoate (Intermediate 7, 0.15 g, 0.539 mmol) in 2 ml of THF. The reaction was warmed to room temperature and stirred for 4 hrs. It was quenched with saturated aq ammonium chloride and partitioned between ethyl acetate and water. The organic layer was then dried over anhyd. magnesium sulfate, concentrated and dried in vacuo. The residue was taken in 3 ml of toluene and treated with p-toluenesulfonic acid monohydrate (0.205 g, 1.078 mmol) and the mixture was then heated at 60° C. for slightly over an hour. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated. aq. sodium bicarbonate and brine. It was dried over anhyd. magnesium sulfate, concentrated and chromatographed (40 g REDISEP® silica cartridge; eluted with 10% ethyl acetate-hexanes) to yield 3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (89.8 mg, 0.224 mmol, 41.5% yield) as a pale oil. LC/MS M+1=402.22.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([O:14][CH:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[CH:15]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:27])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:16]
Reactant: COC(=O)c1cccc(OC(C)c2ccc3ccccc3c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1cccc(C(=O)O)c1C(=O)O)c1ccc2ccccc2c1
Yield: 59.5 %

Procedure:
A mixture of 3-(1-naphthalen-2-yl-ethoxy)-phthalic acid dimethyl ester (0.9 g, 2.5 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 2 h. The mixture was cooled and the solvent was removed under vacuum. The residue was dissolved in water (100 mL) and washed with CH2Cl2 (3×100 mL), acidified (HCl), and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.50 g of 3-(1-naphthalen-2-yl-ethoxy)-phthalic acid, in 60% yield; 1H NMR (DMSO-d6) δ 1.60 (d, J=6.2 Hz, 3H), 5.79 (q, J=6.2 Hz, 1H), 7.21-7.31 (m, 2H), 7.38 (dd, J=7.1 Hz, J=1.3 Hz, 1H), 7.46-7.57 (m, 3H), 7.83-7.93 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([NH2:42])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.C(OCC)(=O)C.Cl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23](=[O:25])[NH:42][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:33]4[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=4)[N:41]=3)=[CH:26][CH:27]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1cccc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)Nc3cccc(-c4ccc(Cl)cc4)n3)cc1)c2Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
A solution of 4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.18 g, 0.40 mmol) in thionyl chloride (5 mL) was stirred and heated to gentle reflux for 30 minutes. The solution was cooled to ambient temperature and concentrated. The residual light yellow solid was dissolved in dichloromethane (4 mL). To the resulting stirred solution at ambient temperature was added 6-(4-chlorophenyl)pyridin-2-amine hydrochloride (96.6 mg, 0.40 mmol), followed by N,N-diisopropylethylamine (0.28 mL, 1.60 mmol). A solution formed, and stirring was continued at ambient temperature for 3 hours. The solution was diluted with ethyl acetate (20 mL) and 1M hydrochloric acid (10 mL), then transferred to a separatory funnel. After shaking, the organic layer was washed successively with 10 mL portions of water, 10% sodium carbonate, and brine, dried over sodium sulfate and evaporated. The residual oil was purified by chromatography on silica gel, eluting with 80/20 hexanes/ethyl acetate, to afford the desired compound as a colorless oil (0.15 g, 58% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:2]1([CH2:16][C@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCN(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-propionic acid, sodium salt and 4-phenyl-piperazine were condensed to give the title compound as a beige solid, mp=192-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OC(C)(C)C)(=O)[NH:15][NH2:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:15][NH2:16])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid (9.83 g, 50 mmol), tert-butyl carbazate (7.93 g, 60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.54 g, 55 mmol), 1-hydroxybenzotriazole monohydrate (7.43 g, 55 mmol), and triethylamine (12.65 mL, 125 mmol) in N,N-dimethylformamide (100 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. A 4 M solution (62.5 mL) of hydrochloric acid in 1,4-dioxane and methanol (200 mL) were added to the partially purified product, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, hexane was added to the obtained partially purified product, and the solid was collected by filtration to obtain the title compound (9.06 g, 86%) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C:4]=2[C:3]=1[C:18]([O:20]CC)=O.C(O)(=O)C.[CH:27](N)=[NH:28]>CN(C=O)C>[O:20]=[C:18]1[NH:28][CH:27]=[N:1][C:2]2[S:10][C:9]3[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:5][C:4]=3[C:3]1=2
Reactant: N=CN
Reactant: CCOC(=O)c1c(N)sc2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2sc3nc[nH]c(=O)c3c2C1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
5-tert-Butyl 3-ethyl 2-amino-6,7-dihydrothieno[3,2-c]pyridine-3,5(4H)-dicarboxylate from Example 73A (780 mg, 2.39 mmol) was dissolved in DMF (8 mL), and formamidine acetate (373 mg, 3.58 mmol) was added. The reaction mixture was heated to 100° C. overnight. The solvent was then removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the precipitate was collected by suction filtration to yield 414 mg (56%) of the title compound as a tan solid. The mother liquor was concentrated and purified by preparative HPLC to yield a second batch of 36 mg (5%).
Reaction SMILES: C([N:9]1[CH2:17][C@@H:16]2[C@@H:11]([N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:14][O:15]2)[CH2:10]1)(=O)C1C=CC=CC=1.Cl>O>[CH2:18]([N:12]1[C@@H:11]2[C@@H:16]([CH2:17][NH:9][CH2:10]2)[O:15][CH2:14][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)N1C[C@H]2OCCN(Cc3ccccc3)[C@H]2C1
Agent: Cl
Solvent: O
Product: c1ccc(CN2CCO[C@@H]3CNC[C@@H]32)cc1

Procedure:
91 g (0.265 mol) of cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane with 200 ml of concentrated hydrochloric acid and 140 ml of water are heated under reflux overnight. After cooling, the benzoic acid is filtered off with suction, the solution is reduced to half the volume and made alkaline with potassium carbonate and extracted with chloroform, the extract is dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[Cl:50][C:51]1[N:55]([CH2:56][CH2:57][CH2:58][OH:59])[N:54]=[CH:53][C:52]=1[C:60]1[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]2[C:76]([C:77]([F:80])([F:79])[F:78])=[CH:75][N:74]=[C:73]([NH:81][C:82]3[CH:96]=[CH:95][C:85]([CH2:86][P:87](=[O:94])([O:91]CC)[O:88][CH2:89][CH3:90])=[CH:84][C:83]=3[O:97][CH3:98])[N:72]=2)=[CH:62][CH:61]=1>>[Cl:50][C:51]1[N:55]([CH2:56][CH2:57][CH2:58][OH:59])[N:54]=[CH:53][C:52]=1[C:60]1[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]2[C:76]([C:77]([F:78])([F:79])[F:80])=[CH:75][N:74]=[C:73]([NH:81][C:82]3[CH:96]=[CH:95][C:85]([CH2:86][P:87](=[O:91])([OH:94])[O:88][CH2:89][CH3:90])=[CH:84][C:83]=3[O:97][CH3:98])[N:72]=2)=[CH:62][CH:61]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4Cl)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4Cl)nc3C(=O)NC)n2)c(OC)c1
Yield: 83.1 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[5-chloro-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 51B, 161 mg, 0.222 mmol) to afford 129 mg of the title compound (83%). 1H NMR (400 MHz, CD3OD) δ 9.05 (br. s., 1H), 8.29-8.35 (m, 2H), 7.81 (d, J=8.8 Hz, 1H), 7.69 (d, J=7.3 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 4.35 (t, J=7.1 Hz, 2H), 3.79-3.92 (m, 5H), 3.59-3.65 (m, 2H), 3.03 (s, 1H), 2.95 (s, 4H), 2.09 (quin, J=6.6 Hz, 2H), 1.16 (t, J=6.9 Hz, 3H). MS (ESI): m/z=699.54/701.60 [M+H]+. UPLC: tR=1.21 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]=[CH:8][CH:9]=[CH2:10]>>[Cl:1][C:2]1([F:6])[C:3]([F:5])([F:4])[CH2:10][CH:9]=[CH:8][CH2:7]1
Reactant: C=CC=C
Reactant: FC(F)=C(F)Cl
Product: FC1(F)CC=CCC1(F)Cl

Procedure:
4-chloro-4,5,5-trifluorocyclohexene was prepared in the same manner as in Example 12 except that chlorotrifluoroethylene (CTFE) and 1,3-butadiene were continuously injected into the flow reactor at the rates of 65.2 g/hr and 30.3 g/hr, respectively. Then, 8.6 g of unreacted chlorotrifluoroethylene (CTFE) was recovered. The resultant was purified by steam distillation, and then the water layer was removed to give 64.9 g of the mixture (GC%=61%).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([CH3:27])=[O:26]>CCOC(C)=O>[OH:26][C:25]1([CH3:27])[CH2:24][S:2][CH:1]=[N:3][CH:4]1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: COc1ccc(COC(=O)CNC=S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2N=CSCC2(C)O)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A mixture of p-methoxybenzyl N-thioformyl-glycinate (4.79 g., 20 mMols), anhydrous powdered K2CO3 (8.29 g., 60 mMols), Me2CO (50 ml.), and ClCH2COCH3 (2.0 ml., 25 mMols) is stirred in a capped flask at room temperature for 6.5 hrs. The mixture is diluted with EtOAc (100 ml.) and filtered. The filtrate is evaporated in vacuo to an oil which is taken up in Et2O, washed twice with H2O and brine, dried with MgSO4, filtered, and evaporated in vacuo to an orange semi-solid (5.36 g.). The crude product is dissolved in warm PhH (25 ml.) and the solution is left in a refrigerator. The pale yellow crystals of p-methoxybenzyl 5-hydroxy-5-methyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylate (2.23 g.) are collected, washed with cold PhH and petroleum ether, and dried in vacuo: mp 102°-103° C. (micro hot stage); ir (CHCl3) 2.97, 5.82, 6.21, 6.62, 7.97, 8.51, 9.62, and 12.04μ; nmr (CDCl3) δ1.35 (s, 3, CH3), 2.75 (d of d, l, J=12 Hz and J=1Hz, SCH), 3.07 (d, l, J=12Hz, SCH), 3,25 (br s, l, OH), 3.82 (s, 3, OCH3), 4.17 (d of d, l, J=2Hz and J=1Hz, H4), 5.18 (s, 2, CH2Ar), 6.87 and 7.33 (two d's 4, J=9Hz, ArH), and 8.23 (d, l, J=2Hz, H2); mass spectrum m/e 295 (M+), 222, 131, and 121.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([C:12](=[O:20])[C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12](=[O:20])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2ccc(CC(=O)O)c(=O)c-2cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)NC1CCC2=C(CC1)C(=O)C(CC(=O)O)C=C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Zinc dust (5.3 g) is added in portions to a stirred suspension of the 7-acetylamino-1-oxo-benzocyclohepten-2-yl-acetic acid (6 g) in 80% aqueous acetic acid (70 ml), warmed at 100° C.; the stirring is continued for 1 hour. The inorganic materials are removed by filtration and washed with warm 80% aqueous acetic acid (70 ml).The eluates are collected and acetic acid is distilled off under vacuum. The residual aqueous phase is extracted with ethyl ether, the combined extracts are dried on Na2SO4 and the solvents are evaporated. The crude material is triturated with hexane-ethyl ether to give 7-acetylamino-1-oxo-benzocycloheptan-2-yl-acetic acid (5.1 g) m.p. 198° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CCCCCC>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)cn1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nc(C=O)cn1Cc1ccccc1
Yield: 81 %

Procedure:
A slurry of 9.0 g (0.446 mole) of 1-benzyl-4-hydroxymethyl-2-methylimidazole, 750 ml of methylene chloride and 50.0 g (0.575 mole) of manganese dioxide was stirred at room temperature for two hours. It was then filtered, the filter cake washed with methylene chloride and the combined filtrate and wash solutions evaporated under reduced pressure to give an oil. The oil was taken up in 100 ml of diethyl ether, 100 ml of hexane added and the solution seeded with a few crystals of the title compound. Concentration of the solution under a nitrogen sweep with periodic replacement of hexane afforded a crystalline product which was isolated by filtration: 7.2 g, 81% yield; m.p. 57°-60° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:23]([NH:22][CH2:21][CH2:20][CH2:19][Cl:18])=[O:24])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C=NCCCCl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)NCCCCl)C1O
Reaction time: 5 h
Yield: 41.4 %

Procedure:
400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 40 ml of dichloromethane were stirred at room temperature, and 192 μl (1.87 mmol) of 3-chloropropyl isocyanate were added thereto and stirred for 5 hours. The crystals precipitated were taken out by filtration to obtain 250 mg of the intended compound as pale yellow crystals. (yield: 41%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:36])(=[O:35])[NH:25][CH:26]3[CH2:31][CH2:30][CH:29]4[CH2:32][CH:27]3[C:28]4([CH3:34])[CH3:33])=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[CH3:33][C:28]1([CH3:34])[CH:27]2[CH2:32][CH:29]1[CH2:30][CH2:31][CH:26]2[NH:25][S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:8]2([NH:7][C:6](=[O:37])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][O:12][C:11]([CH3:14])([CH3:15])[O:10][CH2:9]2)=[CH:23][CH:22]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(S(=O)(=O)NC3CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(S(=O)(=O)NC3CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A mixture of the product of Step B (0.075 g, 0.14 mmol) and 10% Pd/C (0.04 g) in EtOH (10 ml) was stirred for 16 h under H2. The catalyst was removed by filtration through Celite pad and the filtrate was evaporated to dryness, to give the desired product (0.067 g; 87%), as creamy gum. 1H-NMR (CDCl3) 0.84 (s, 3H); 1.09 (s, 3H); 1.44 (m, 10H); 1.85 (m, 6H); 2.10 (m, 1H); 2.29 (m, 1H); 2.67 (m, 2H); 2.90 (m, 2H); 3.66 (m, 2H); 3.82 (m, 2H); 4.33 (s, 1H); 5.10 (s, 1H); 7.32 (m, 2H); 7.74 (m, 2H).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[C:2]1([C:1]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:14]=3)=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NNC(=O)c1ccnc(NC(=O)c2ccccc2)c1)c1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2nnc(-c3ccccc3)o2)ccn1)c1ccccc1
Yield: 32.5 %

Procedure:
To a solution of N-(4-(2-benzoylhydrazinecarbonyl)pyridin-2-yl)benzamide (0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added (methoxycarbonylsulfamoyl)-triethylammonium hydroxide (0.35 g, 0.63 mmol) at ambient temperature. The resulting solution was refluxed for 7 hours and concentrated in vacuo to dryness. The residue was purified by column chromatography to give N-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide (0.03 g 32%): mp 151-155° C.; 1H NMR (300 MHz, CDCl3) δ 9.03-9.00 (m, 2H), 8.41 (br s, 1H), 8.19-7.97 (m, 2H), 7.97-7.94 (m, 2H), 7.84-7.83 (m, 1H), 7.61-7.48 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 168.1, 167.6, 164.9, 154.7, 151.1, 135.9, 135.4, 134.7, 134.3, 131.3, 131.1, 129.4, 127.3, 125.4, 119.0, 112.9; MS (ES+) m/z 343.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[S:13][CH2:14][CH3:15].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:21](=[O:22])[O:23][CH2:24][CH3:25])=[CH:8][C:7]=1[S:13][CH2:14][CH3:15]
Reactant: CCSc1cc(N)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)c(SCC)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(3,4-Dichlorophenoxy)-3-(ethylthio)benzenamine, (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed in 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]carbamate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[C:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[C:29]([CH3:42])[CH:28]=2)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:42][C:29]1[CH:30]=[C:31]([C:2]2[S:6][C:5]([CH:7]=[C:8]3[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:3]=2)[CH:32]=[C:27]([NH:26][C:22]2[N:21]=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=2)[CH:28]=1
Reactant: Cc1cc(Nc2nccc(C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)C1CCC(=Cc2ncc(Br)s2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(=Cc2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1
Temperature: 80 °C

Procedure:
Ethyl 4-[(5-bromo-1,3-thiazol-2-yl)methylidene]cyclohexanecarboxylate (223 mg, 0.676 mmol), 4-methyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (220 mg, 0.676 mmol) and 1,1′-bis(diphenylphosphino)-ferrocenedichloro palladium(II) dichloromethane complex (49.5 mg, 0.068 mmol) were combined in a flask that was then sealed and flushed with nitrogen (2×). Dioxane (4 mL) and sodium carbonate (2 M in water, 1.015 mL, 2.029 mmol) were added, and the reaction was flushed again with nitrogen (2×). The mixture was heated to 80° C. for 1 hour and then cooled to room temperature, diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (5-60% EtOAc in hexanes) afforded ethyl 4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)methylidene]cyclohexanecarboxylate as a yellow foam. MS ESI calc'd. for C25H29N4O2S [M+H]+ 449. found 449. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.34 (d, J=5.0, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.51 (s, 1H), 7.07 (s, 1H), 6.74 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.55-3.47 (m, 1H), 3.31 (s, 2H), 2.66-2.57 (m, 1H), 2.44-2.24 (m, 7H), 2.04-1.97 (m, 2H), 1.61-1.46 (m, 2H), 1.17 (t, J=7.1 Hz, 3H).