Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>O>[CH2:12]1[CH:11]=[CH:10][CH2:9][CH:8]([CH:5]2[CH2:4][CH:3]=[CH:2][CH2:7][CH2:6]2)[CH2:13]1
Reactant: OC1CCC(C2CCC(O)CC2)CC1
Solvent: O
Product: C1=CCC(C2CC=CCC2)CC1

Procedure:
The step (i) and the step (ii) differ from each other in the pressure. The reaction liquid in the step (i) contains an unreacted 4,4′-dihydroxybicyclohexyl compound, a reaction intermediate in which only one of the two hydroxylated-cyclohexane rings of the 4,4′-dihydroxybicyclohexyl compound has undergone intramolecular dehydration into a cyclohexene ring, the target bicyclohexyl-3,3′-diene compound, by-produced water, the dehydration catalyst, and the reaction solvent in coexistence. In the step (i), the by-product water is distilled out (evaporated), but it is not desirable to distill out the reaction intermediate in this step for the following reasons. Specifically, (1) distilling out of the reaction intermediate causes reduction in the yield of the target compound, because the reaction intermediate can be converted into the target compound via further intramolecular dehydration; and (2) the reaction intermediate is generally a sublimable solid, and such a sublimated reaction intermediate may deposit in a pathway for distillation of by-product water in a distillation column, if used, to block or clog the distillation pathway, and this may cause increase in the inner pressure of the reactor, thus causing troubles such as a rupture or damage of the reactor and scattering of the reaction liquid. Accordingly, dehydration in the step (i) is carried out, while distilling off by-product water, at a pressure greater than 20 Torr (2.67 kPa) so as to avoid distillation of the reaction intermediate. The pressure is preferably greater than 20 Torr and equal to or less than normal pressure (atmospheric pressure) (greater than 2.67 kPa and equal to or less than 0.1 MPa), more preferably greater than 100 Torr and equal to or less than normal pressure (greater than 13.3 kPa and equal to or less than 0.1 MPa), and further preferably greater than 200 Torr and equal to or less than normal pressure (greater than 26.7 kPa and equal to or less than 0.1 MPa). From the viewpoint of operational ease, the pressure is typically preferably normal pressure (atmospheric pressure). The temperature (reaction temperature) in the step (i) is from 130° C. to 230° C. (e.g., 130° C. to 200° C.), preferably from 140° C. to 200° C. (e.g., 140° C. to 195° C.), and more preferably from 140° C. to 185° C. Dehydration at an excessively high temperature may cause side reactions such as isomerization, and dehydration at an excessively low temperature may cause an insufficient reaction rate. The reaction period is, for example in the case of preparation on the order of about 3 liters, from about 1 to 10 hours, and preferably from about 2 to 6 hours. In the alicyclic alcohol sequential addition process, the reaction period from the time point upon the completion of the addition of the starting material is, for example, from about 0.5 to 10 hours, and preferably from about 1 to 6 hours.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:8]1[CH:7]=[CH:6][S:5][C:4]=1[C:1](=[O:3])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:21]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A mixture of 2-(2-acetylthiophen-3-ylamino)-2-phenylacetic acid (I4) (188 mg, 0.68 mmol), (R)-quinuclidin-3-ol (104 mg, 0.82 mmol), HOBT (125 mg, 0.82 mmol) and DCC (169 mg, 0.82 mmol) in dry THF (8 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by preparative HPLC. The fractions containing the product were combined and evaporated under vacuum. The residue was dissolved in 2M K2CO3 and extracted twice with EtOAc to obtain (2-acetyl-thiophen-3-ylamino)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (48 mg, 18% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].C(O)C.[H][H]>O.[Ni]>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1cccc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-nitroaniline (14.10 g, 81.71 mmol), Raney-nickel (5.02 g of a 50% slurry in water), and ethanol (200 mL) were combined in an autoclave which was pressurized to 15 psig with hydrogen. The resulting mixture was allowed to stir overnight at RT. The mixture was then filtered through a pad of celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to afford 10.43 g (89%) of a viscous, brown oil, which darkened upon standing. MS (EI): m/z 143.1 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:55])([F:54])[C:13]1[CH:14]=[C:15]([C:23]([CH3:53])([CH3:52])[C:24]([N:26]([CH3:51])[C:27]2[C:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:50])=[CH:29][C:30]([N:33]3[CH2:37][C@H:36]([OH:38])[CH2:35][C@H:34]3[CH2:39][O:40][C:41](=[O:43])[CH3:42])=[N:31][CH:32]=2)=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl.COC(C)(C)C>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C:23]([CH3:52])([CH3:53])[C:24]([N:26]([CH3:51])[C:27]2[C:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:50])=[CH:29][C:30]([N:33]3[CH2:37][C:36](=[O:38])[CH2:35][C@H:34]3[CH2:39][O:40][C:41](=[O:43])[CH3:42])=[N:31][CH:32]=2)=[O:25])[CH:14]=[C:13]([C:12]([F:55])([F:54])[F:11])[CH:18]=1
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@@H]1CC(=O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 0.08 ml (0.9 mmol) oxalyl chloride in 2 ml dichloromethane were added dropwise at −78° C. 0.13 ml (1.9 mmol) dimethyl sulfoxide and after a period of 3 min. a solution of 0.50 g (0.78 mmol) (2S,4R)-acetic acid 1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethyl ester in 2 ml dichloromethane. After stirring at −78° C. for 30 min. 0.7 ml (4 mmol) N,N-diisopropylethylamine were added. The reaction mixture was allowed to warm to room temperature during 1 h, diluted with tert-butyl methyl ether and washed with an aqueous ammonium chloride solution. The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.47 g (94%) of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:21][C:22]([CH2:24][O:25][N:26]=[C:27]([C:50]1[N:51]=[CH:52][S:53][CH:54]=1)[C:28]([NH:30][CH:31]1[C:48](=[O:49])[N:33]2[C:34]([C:38]([O:40][CH:41]([O:43][C:44](=[O:47])[CH2:45][CH3:46])[CH3:42])=[O:39])=[CH:35][CH2:36][S:37][C@H:32]12)=[O:29])=[O:23])(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:22]([CH2:24][O:25][N:26]=[C:27]([C:50]1[N:51]=[CH:52][S:53][CH:54]=1)[C:28]([NH:30][CH:31]1[C:48](=[O:49])[N:33]2[C:34]([C:38]([O:40][CH:41]([O:43][C:44](=[O:47])[CH2:45][CH3:46])[CH3:42])=[O:39])=[CH:35][CH2:36][S:37][C@H:32]12)=[O:29])([OH:23])=[O:21]
Reactant: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3cscn3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOCC(=O)O)c3cscn3)C(=O)N12
Reaction time: 2 h
Yield: 51.9 %

Procedure:
Trifluoroacetic acid (1.4 ml) was added to a suspension of 1-propionyloxyethyl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylate (syn isomer) (1.2 g) in methylene chloride (10 ml) and anisole (0.8 ml) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. To the resulting solution was added diisopropyl ether (50 ml) and the mixture was stirred. The precipitates were collected by filtration, washed with diisopropyl ether. The precipitates were added to a mixture of ethyl acetate and water, and the mixture was adjusted to pH 7.5 with 20% aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether and filtered to give 1-propionyloxyethyl 7-[2-carboxymethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylate (syn isomer) (0.47 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[O:8][C:9]([CH3:24])=[C:10]([CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:11]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[O:8][C:9]([CH3:24])=[C:10]([CH2:12][O:13][Si:14]([CH:18]([CH3:20])[CH3:19])([CH:21]([CH3:23])[CH3:22])[CH:15]([CH3:17])[CH3:16])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Yield: 104.4 %

Procedure:
A solution of 3-(5-methyl-4-triisopropylsilanyloxymethyl-furan-2-yl)-acrylic acid ethyl ester (34) (1.0 g) in ethyl acetate (70 mL) was treated with 5% w/w palladium on carbon (350 mg) and hydrogenated at 1 atmosphere for exactly 1¼ hours at room temperature. The reaction mixture was filtered through filter-aid and then concentrated in vacuo to afford compound 35 as a clear oil (1.05 g). LC/MS System A: Rt=5.52 mins.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[S:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1.ClCCCl.[OH-].[Na+]>[Cl-].[Cl-].[Zn+2].CC(=O)CC>[NH2:9][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=[C:12]2[CH2:11][S:10][CH2:14][C:13]=12
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCSC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCC(C)=O
Product: Nc1c2c(nc3ccccc13)CSC2
Reaction time: 2 h
Yield: 14.5 %

Procedure:
Anthranilonitrile (4.80 g)and tetrahydrothiophen-3-one (8.17 g) were stirred until a homogeneous mixture was obtained and then freshly fused ZnCl2 (8.0 g) was added and the reaction mixture heated at 120°. After 2 hours, 30 ml of 1,2-dichloroethane was added and the reaction mixture refluxed for an additional 2 hours. At the end of this time the reaction mixture was distributed between 10% NaOH solution and 2-butanone, after which the organic phase was separated, dried, concentrated and purified by flash chromatography (5% i-PrOH/CH2Cl2). Combination of the product-containing fractions gave 1.19 g of product that was pure to thin layer chromatography. This product was combined with that obtained in another run and recrystallized from EtOAc-pentane to give analytically pure material, mp 220° (d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)c(-c2ccc(O)cc2)c(F)c1
Yield: 92.5 %

Procedure:
342 mg of the product of Stage C were stirred overnight at 20° C. under a hydrogen atmosphere in 30 ml of ethyl acetate and with 113 mg of 9.5% palladium on activated charcoal. The reaction mixture was filtered and evaporated under reduced pressure to obtain 232.6 mg of the expected product.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]CNC(CCC(O)=O)=O)[C:4]2=[CH:3][CH:2]=1.[N+](C1C=C([N+]([O-])=O)C2C3C(=CC([N+]([O-])=O)=CC=3)C(=O)C=2C=1)([O-])=O>>[CH3:3][CH2:2][CH2:1][CH2:6][CH2:5][CH2:7][CH2:8][CH2:9][CH:10]([CH3:4])[CH3:11]
Reactant: O=C(O)CCC(=O)NCCc1cccc2ccccc12
Agent: O=C1c2cc([N+](=O)[O-])ccc2-c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Product: CCCCCCCCC(C)C

Procedure:
One half of the exposure zone (5.7 cm. by 5.7 cm.) of NESA glass plate 12 was coated with a 20 micron thick layer of a dark charge exchange layer 13 composed of 2,4,7-trinitro-9-fluorenone and a Butvar binder as described in the formulation given in Example 6. The other half of the NESA glass plate 12 was left uncoated.
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].[C:17]1([S:23]([NH:26][C:27]2[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=2)[C:30](OC2C=CC([N+]([O-])=O)=CC=2)=[O:31])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(S(NC2C=C(C=CC=2)C(O)=O)(=O)=O)C=CC=CC=1.[N+](C1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[C:17]1([S:23]([NH:26][C:27]2[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=2)[C:30]([NH:16][CH2:15][CH2:14][S:13][CH2:12][C:10]2[N:11]=[C:7]([NH:3][C:4]([NH2:6])=[NH:5])[S:8][CH:9]=2)=[O:31])(=[O:24])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N=C(N)Nc1nc(CSCCNC(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)cs1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 83.4 %

Procedure:
A mixture of 5.5 g of 2-(2-guanidinothiazol-4-ylmethylthio)ethylamine dihydrochloride, 3.65 g of triethylamine and 3.7 g of 4-nitrophenyl 3-benzenesulfonamidobenzoate (m.p. 175°-178° C., prepared from 3-benzenesulfonamidobenzoic acid and 4-nitrophenol in methylene chloride in the presence of dicyclohexylcarbodiimide) is stirred at the temperature of 40° C. for 90 minutes, then it is evaporated under reduced pressure to dryness. The residue is taken up with 150 ml of ethyl acetate and washed twice with 10 ml of water. The solution is dried on anhydrous sodium sulfate, evaporated and the residue is chromatographied on silica with a chloroform:ethanol 4:1 mixture. Thus, 3.8 g of 3-benzenesulfonamido-N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]benzamide are obtained as an oil which is dissolved in absolute ethanol and treated with fumaric acid in absolute ethanol. Thus, 3.6 g of crude product are obtained, which, after crystallization from 40 ml of 95% ethanol, gives 2.4 g of neutral fumarate of 3-benzenesulfonamido-N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]benzamide, SR 57963 A, C20H22N6O3S4.1/2C4H4O4 ; m.p. 139°-141° C.
Reaction SMILES: C1(N[C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)CCCCC1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCN(CC)CC>[CH:17]1([NH:9][C:30](=[O:31])[CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)C(c1ccccc1)c1c2ccccc2nn1-c1ccccc1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with phenyl-acetyl chloride (CAS Reg. No. 103-80-0) in the presence of Et3N to give the title compound as yellow foam. MS: m/e=410.1 [M+H+].
Reaction SMILES: C(OCC)(=O)CC(C)=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH2:17].[CH:18]1([C:21]2N(C(C)C)N=[CH:23][C:22]=2[CH:29]=[O:30])CC1>>[CH3:18][C:21]1[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[N:17]=[CH:23][C:22]=1[CH:29]=[O:30]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: NNc1ccccn1
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1-c1ccccn1

Procedure:
5-Methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared from ethyl acetoacetate and 2-pyridyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]#[C:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[C:4]#[N:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:12]([C:11]1[NH:1][C:2]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=2[C:4]#[N:5])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])cc(C#N)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C#N)c2[nH]1
Yield: 51.1 %

Procedure:
To a solution of 2-amino-3-(3,3-dimethylbut-1-ynyl)-5-nitrobenzonitrile (1.7 g, 7.0 mmol) in THF (35 mL) was added TBAF (9.5 g, 28 mmol) at room temperature. The mixture was heated at reflux overnight. The reaction mixture was cooled and the THF was removed under reduced pressure. Water (50 ml) was added to the residue and the mixture was extracted with EtOAc. The organics were dried over Na2SO4 and the solvent was evaporated under vacuum to obtain 0.87 g of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile which was used directly in the next step without purification.
Reaction SMILES: C[C:2]1[C:11]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[C:4]([CH2:12]C(O)=O)[CH:3]=1.P(=O)(O)(O)O>>[CH3:12][C:4]1[C:5]2[C:11]([CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:2][CH:3]=1
Reactant: Cc1cc(CC(=O)O)c2cccccc1-2
Agent: O=P(O)(O)O
Product: Cc1ccc2cccccc1-2
Temperature: 0 °C
Yield: 88.6 %

Procedure:
5.91 g of compound B is dissolved in 60 ml. of phosphoric acid and the mixture is heated (90°-80° C.) on a water bath for 15 minutes. After cooling the mixture is poured into 300 ml of ice-water and extracted with n-hexane. The organic layer is separated, washed with water, dried over anhydrous sodium sulfonate and fractionated by silicagel column chromatography using benzene as eluent to give 3.72 g (90.1%) of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:8][C:7]1[C:2]2[N:3]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:1]=2)[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(-c2cn3cc(Cl)cc(Br)c3n2)cc1
Reaction time: 6 h

Procedure:
17 g (82 mmol) of 2-amino-3-bromo-5-chloropyridine dissolved in 150 ml of ethanol are reacted with 29 g of 2-bromo-1-(4-chlorophenyl)-1-ethanone and 14 g of sodium hydrogen carbonate. The mixture is brought to the refluxing temperature for 6 h and cooled. The precipitate is filtered off and rinsed with CH2Cl2, and the filtrate is concentrated under reduced pressure. After recrystallization of the evaporation residue in ethyl acetate, the compound melts at 178° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.C(COC)OC.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
To a stirring mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.45 g, 53 mmol), dimethoxyethane (200 mL) and water (50 mL) was added 1-(benzyloxy)-4-bromobenzene (14 g, 53 mmol), sodium carbonate (16.9 g, 160 mmol) and bis-(triphenylphosphine)palladium(II) chloride (1.867 g, 2.66 mmol) at rt. The reaction mixture was purged with nitrogen for 15 min, then heated at 80° C. for 4 h. The mixture was allowed to cool to rt and then was filtered through Celite and diluted with 200 mL of water. The mixture was then extracted three times with 200 mL of ethyl acetate and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluting with 20% ethyl acetate/petroleum ether to obtain 16 g of tert-butyl 4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (16 g, 82% yield) as an off-white solid. LCMS (method O) RT 1.32 min, m/z 366 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 1.47 (s, 9H), 2.42 (d, J=1.50 Hz, 2H), 3.52 (t, J=11.40 Hz, 2H), 3.97 (s, 2H), 5.11 (s, 2H), 6.04 (s, 1H), 6.98 (d, J=9.00 Hz, 2H), 7.30-7.46 (m, 7H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:21]1([CH3:38])[CH:26]=[CH:25][C:24](S(OCC2CCCCC2)(=O)=O)=[CH:23][CH:22]=1>>[CH:21]1([CH2:38][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CCCCC2)c(=O)[nH]c1=O
Yield: 63.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (233 mg, yield: 63.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)=[O:10].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][CH2:34]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:34][CH2:33][O:32][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:13][CH:12]=1)=[O:10]
Reactant: ICCOC1CCCCO1
Reactant: O=C(Cc1ccccc1Cl)c1ccc(OCCN2CCCCC2)cc1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)C(CCOC1CCCCO1)c1ccccc1Cl

Procedure:
2-(2-Chlorophenyl-1-[4-(2-piperidinylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-one is prepared by PTC reaction according to the method described in the example 4d using 2-(2-chlorophenyl)-1-[4-(2-piperidinylethoxy)phenyl]ethanone (1.5 g, 4.2 mmol) and 2-tetrahydropyranyloxy-1-iodoethane (1.3 g, 5.1 mmol) as the starting materials. The product (1.6 g) is used for the following reaction step without further purification.