Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][C:11](=O)[CH2:12][CH3:13])=[CH:4][C:3]=1[O:16][CH3:17]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CCC(=O)NCC(O)c1ccc(F)c(OC)c1
Agent: Cl
Product: CCCNCC(O)c1ccc(F)c(OC)c1
Yield: 81.4 %

Procedure:
Prepared following the same method as for example 3 starting with the amide from example 18 (585 mg, 2.42 mmol). After refluxing in 6M HCl (aq) the reaction mixture was cooled and extracted with diethyl ether (2×50 ml). The organic layers were discarded and the aqueous layer basified by the addition of potassium carbonate. The aqueous residue was then extracted with ethyl acetate (3×50 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (448 mg, 1.97 mmol, 81%). 1H NMR (CD3OD. 400 MHz) δ: 0.96 (t, 5H) 1.58 (m, 2H), 2.63 (m, 2H), 2.79 (d, 2H), 3.96 (s, 3H), 4.77 (t, 1H), 6.90 (m, 1H) 7.03 (t, 1H), 7.11 (d, 1H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])([OH:10])[CH2:6][CH2:5]1)(=O)C.Cl.[OH-].[Na+]>C(Cl)Cl>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:7]1([OH:10])[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)=[O:19]
Reactant: CC(=O)N1CCC(O)(C(=O)c2ccccc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1ccccc1F)C1(O)CCNCC1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A mixture of 13.3 g of 1-acetyl-4-(2-fluorobenzoyl)-4-hydroxypiperidine and 20 ml of 6N hydrochloric acid was stirred at reflux under nitrogen for 4 hrs. The reaction mixture was allowed to cool and poured onto ca. 100 g of ice. Methylene chloride was added, and the separated aqueous layer was made strongly basic by means of 15% sodium hydroxide solution. The aqueous layer was extracted three times with 80 ml of methylene chloride. The extracts were dried over anhydrous potassium carbonate, filtered and evaporated provide anhydrous 9.5 g (85%) of product, mp 133°-135° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][OH:9].CCN(C(C)C)C(C)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[OH:9][CH2:8][C@@H:3]1[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:25]([C:24]1[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=1[N:29]1[N:33]=[CH:32][CH:31]=[N:30]1)=[O:26]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CO)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
((2S,3R)-3-Methylpiperidin-2-yl)methanol from the previous step in DMA (0.2M) was added DIPEA (2 equiv.) followed by 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.2 eq) and HATU (1.1 equiv.). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMAC. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a brown oil which crystallized (2.6 g). MS (ESI) 315 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:31])[C@H:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:8][C:9]([O:11][CH2:12][CH2:13][CH:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:16]1[C:15]2[CH:14]([CH2:13][CH2:12][O:11][C:9]([NH:8][C@H:7]([C:6]([OH:31])=[O:5])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:10])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C[C@H](NC(=O)OCCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)OCCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
To a stirred solution of 6.63 g (15.6 mmol) of N-[(9H-fluoren-9-ylethoxy)carbonyl]-L-leucine tert-butyl ester in 10 mL of methylene chloride was added 10 mL of trifluoroacetic acid. The mixture was stirred for 2.5 h and solvent was removed at reduced pressure. The crude product was chromatographed on 150 g of flash silica gel eluting with 25% EtOAc in hexane followed by 50% EtOAc in hexane to afford 5.32 g (92%) of product as a white solid, mp 42°-43° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:30])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21]1[O:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)Nc2ccccc2Br)N(C(=O)OCc2ccccc2)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)O[C@@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1
Yield: 57.7 %

Procedure:
To a stirred solution of (2S,4R)-2-(2-bromo-phenylcarbamoyl)-4-tert-butoxy-pyrrolidine-1-carboxylic acid benzyl ester (900 mg, 1.89 mmol) in DME (20 mL) at 25° C. in a sealed tube were added CuI (36 mg, 0.19 mmol), 1,10-phenanthraline (68 mg, 0.38 mmol), and Cs2CO3 (1.847 g, 5.68 mmol). The reaction mixture was refluxed for 14 h. After completion of reaction, water was added, and the mixture was then extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was then purified by column chromatography to give (2S,4R)-2-benzooxazol-2-yl-4-tert-butoxy-pyrrolidine-1-carboxylic acid benzyl ester (430 mg, 57.5% yield) as a yellowish liquid. MS calcd. for C23H27N2O4 [(M+H)+] 395, obsd. 395.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14](=[O:15])[N:13]([CH:16]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:17][CH2:18][C:19]([NH:21][CH2:22][C:23]2[CH:24]([OH:37])[C:25](=[O:36])[CH:26]=[CH:27][C:28]=2[N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[O:20])[C:12]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14](=[O:15])[N:13]([CH:16]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:17][CH2:18][C:19]([NH:21][CH2:22][C:23]2[C:24](=[O:37])[C:25](=[O:36])[CH:26]=[CH:27][C:28]=2[N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[O:20])[C:12]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[N:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC(CCC(=O)NCC1=C(n2ccccc2=O)C=CC(=O)C1O)n1c(-c2ccccc2)ncc(NC(=O)OC(C)(C)C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCC(CCC(=O)NCC1=C(n2ccccc2=O)C=CC(=O)C1=O)n1c(-c2ccccc2)ncc(NC(=O)OC(C)(C)C)c1=O
Reaction time: 3.5 h
Yield: 83.1 %

Procedure:
2-(5-t-Butyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-{2-hydroxy-3-oxo-6-(2-oxo-1,2-dihydropyridine-1-yl)-1-phenylmethyl}hexylacetamide (115 mg, 0.18 mmol) was dissolved in dimethylsulfoxide (2 ml), under argon atmosphere, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (103 mg, 0.54 mmol) and pyridinium trifluoroacetate (17 mg, 0.1 mmol) were added to it, and the mixture was stirred for 3.5 hours. The reaction solution was diluted with ethyl acetate and washed successively with distilled water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=30/1), and thereafter hexane was added to it to precipitate solid. The precipitated solid was collected by filtration whereby the title compound (96 mg, 83% yield) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[S:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([N:18]1[CH2:19][CH2:20][S:16][C:17]1=[S:21])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: S=C1NCCS1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)N1CCSC1=S
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To 15 ml of dimethylformamide were dissolved 3,5-dinitrobenzoyl chloride (2.5 g) and 1,3-thiazolidine-2-thione (1.3 g). To the solution was added dropwise a solution of triethyl amine (1.2 g) and dimethylformamide (2 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 5 hours. The reaction mixture was filtered and the solvent was removed at a reduced pressure. To the residue was added water and the insolubles were filtered off. The filtrate was washed with cold methanol and then with ether to obtain crude crystals. Recrystallization from toluene gives 2.4 g of the desired compound as yellow needle crystals (yield 76.7%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Reactant: O=C(O)c1nc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1cc(F)c(-c2ccc(F)c(C(=O)O)n2)c(F)c1
Yield: 9 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 2,6-difluoro-4-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2,6-difluoro-4-methoxyphenyl)-3-fluoropicolinic acid in 9% yield. LC/MS=284.0 (M+H), Rt=0.74 min.
Reaction SMILES: C(O)CO.[CH3:5][O:6][C:7]1[C:12]([O:13]C)=[C:11]([O:15][CH3:16])[CH:10]=[C:9](C=O)[CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[C:12]=1[OH:13]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: COc1cccc(OC)c1O
Reaction time: 1 h
Yield: 65.5 %

Procedure:
By way of comparison, a test was carried out with a larger amount of ethylene glycol than that of Example 6. By heating under nitrogen with distillation 212 g (1 mole) of TMBA, 194 g (3 moles) of potash in pellets and 800 ml of ethylene glycol, reaction takes place. The temperature passes from 151° to 190° C. in 1 hour 20; it is held for 2 hours at 190° C. After cooling, dilution with water and neutralization to pH 6, there was obtained, by toluene extraction, 101 g of 2,6-dimethoxy phenol namely a yield of 65.6%. After recrystallization in a water/methanol mixture, with 10% of methanol, the product melted at 54°-55° C. By using a larger amount of ethylene glycol, demethylation and decarboxylation were hence produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:34]C(C)(C)C)[N:29]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CO>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[N:29]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC(C)(C)Oc1nccc(-c2ccccc2C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1-c1ccnc(O)n1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(6-chloronaphth-2-ylsulphonyl)-4-[(2-tert-butyloxypyrimidin-4-yl)benzoyl]piperazine (120 mg, 0.213 mmol) in dichloromethane (5 ml) was added a solution of hydrogen chloride in methanol (0.24 ml of ˜4.5 M, 1.06 mmol). A precipitate formed immediately, and the reaction was stirred at ambient temperature for 1 hr. The solvent was removed in vacuo and the residue triturated with methanol. The solid was collected by filtration to give 1-(6-chloronaphth-2-ylsulphonyl)-4-[(2-hydroxypyrimidin-4-yl)benzoyl]piperazine hydrochloride as a colourless solid.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1>>[N:18]1[CH:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1cncnc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncnc1
Yield: 99 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (330 mg, 1.6 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 5-bromopyrimidine (purchased from Acros Scientific) were processed as described in Example 15C to provide the title compound (99% yield). MS (DCI/NH3) m/z 277 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C.ClC(Cl)C.C(COC)OC>>[C:29]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1
Solvent: CC(Cl)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1

Procedure:
A solution of 2-[(trans-4-aminocyclohexyl)amino]-N-benzylquinazoline-7-carboxamide (prepared as described in preparation 7c above) (200.0 mg, 0.53 mmol), acetyl chloride (27.3 mg, 0.53 mmol) and triethylamine (162.0 mg, 1.6 mmol) in 7 ml of a mixed solvents of dichloroethane:dimethoxyethane (1:2) was stirred at room temperature for 16 hours. The crude material was purified by HPLC to give product 15.1 mg, 13.6%. 1H NMR (400 MHz, DMSO-d6) ppm 1.13-1.49 (m, 4H), 1.79 (s, 3H), 1.82 (s, 3H), 1.98 (s, 1H), 3.22-3.41 (m, 4H), 3.43-3.59 (m, 1H), 3.90 (s, 1H), 4.50 (d, J=6.04 Hz, 1H), 7.17-7.29 (m, 1H), 7.31-7.37 (m, 4H), 7.44 (d, J=8.31 Hz, 1H), 7.63 (dd, J=8.18, 1.38 Hz, 1H), 7.75 (d, J=7.81 Hz, 1H), 7.84 (d, J=8.31 Hz, 1H), 7.99 (s, 1H), 9.14 (s, 1H), 9.30 (t, J=5.79 Hz, 1H). HRMS: m/z 418.22213 [M+H]+), calc. 418.22375. MS m/z, (APCI); 418.2 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:23]=[CH:22][C:12]3[N:13]=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])[S:15][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[CH:23]=[CH:22][C:12]3[N:13]=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])[S:15][C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCNC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2s1
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)Nc1nc2ccc(CCc3ccccc3)cc2s1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A suspension of 1-(6-phenylacetylenyl-2-benzothiazolyl)-3-ethylurea (0.048 g, 0.15 mmol) and 10% palladium on carbon (0.016 g, 10% weight purity, 0.015 mmol, 0.10 eq) in 2 mL ethanol was purged with nitrogen gas, followed by bubbling of hydrogen gas. It was stirred under hydrogen atmosphere for about 16 hours. The mixture was taken up in 8 mL MeOH, filtered, concentrated, and dried under vacuum to give 0.037 g (76%) of the desired compound. LC/MS 326.3 (M+1); LC retention time 2.84 min.
Reaction SMILES: [S:1]([O:11][CH2:12][C@@H:13]1[O:15][CH2:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>O1CCCC1>[C:25]1([S:31][CH2:14][C@@H:13]([OH:15])[CH2:12][O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under nitrogen, to a solution of (2R)-1-tosyloxy-2,3-epoxypropane (3.0 g) in tetrahydrofuran (30 ml) were added N,N-diisopropylethylamine (2.5 ml) and thiophenol (1.3 ml) at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give (2S)-3-phenylthio-1-tosyloxy-2-propanol (3.9 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24].Cl.[OH-].[Na+]>CN(C=O)C>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13]([N:21]1[CH2:28][CH2:27][CH2:26][CH:22]1[C:23]([OH:25])=[O:24])=[O:15])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C(=O)N1CCCC1C(=O)O)=C1SC=CS1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.1 %

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (13.2 g) and proline (4.6 g) was dissolved in DMF (60 ml). The mixture was stirred at room temperature for 24 hrs, thereto was added conc-HCl (20 ml) and stirred for a further 2 hrs. The reaction mixture was poured into ice water and basified to pH=12 with aqueous sodium hydroxide solution. The mixture was washed with methylene chloride and the aqueous layer was acidified to pH=2 with dil-HCl. The solid formed was filtered and recrystallized from ethyl acetate and n-hexane to obtain the pure product (12.5 g, 91%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
A mixture of 10.0 g. of β-chloromethylnapthalene, 6.0 g. of sodium carbonate and 9.0 g. of phenylpiperazine in 60 ml. of dimethylformamide is stirred under nitrogen on a steambath for five hours. The reaction mixture is then cooled and filtered. The filtrate is concentrated and stirred with ice water. The formed precipitate is filtered off, dissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(β-napthylmethyl)-4-(phenyl)piperazine having a melting point of 226°-228° C.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[N+:24]([O-])=O)([O-])=O.CO.C(Cl)(Cl)Cl.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(Cl)Cl.[Pt]>[NH2:24][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCOc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1cc(OCc2ccccc2)ccc1OCCOc1ccc(OCc2ccccc2)cc1N
Reaction time: 6 h
Yield: 90 %

Procedure:
Compound 9 (40 g, 77.5 mmol) is dissolved in 400 mL of CH2Cl2 and 1.5 g 5% platinum on charcoal is added. The reaction is shaken under 40 psi H2 for six hours until the reaction is judged complete using thin layer chromatography (1:9 methanol:chloroform). The product reacts with ninhydrin on a TLC plate to give a ruddy brown product with an Rf of 0.3. The reaction mixture is filtered through diatomaceous earth to remove the catalyst, and the resulting filtrate is evaporated under reduced pressure. The resulting semi-crystalline oil is stirred with 400 mL methanol for two hours while protected from light. The resulting light gray crystals are filtered and dried to give 10 in 90% yield.
Reaction SMILES: [O:1]1CCCC1.[F:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[S:16][C:15]([C:17]#N)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C>O>[F:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[S:16][C:15]([CH:17]=[O:1])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(Oc2ccc(F)cc2)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 5-(4-fluoro-phenoxy)-thiophene-2-carbonitrile (6.10 g, 27.8 mmol) described in Manufacturing Example 91-1-1 was added dropwise diisobutyl aluminum hydride (0.97 M n-hexane solution, 43.0 mL, 41.7 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 2 hours at room temperature. The reaction solution was added to water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (3.4 g, 55.0%).