Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=1)[OH:10].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:5]([O:4][C:2]([NH:7][CH2:8][CH:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=1)[OH:10])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCC(O)C1=CC2(CCCC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCC(O)C1=CC2(CCCC2)c2ccccc21
Reaction time: 2 h

Procedure:
Ethyl chloroformate (2.06 g) is added dropwise at about 7° C. to a stirred mixture of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (3.35 g) in chloroform (50 ml) and sodium hydroxide (0.9 g) in water (20 ml). After 2 hours, the chloroform phase is separated and the aqueous phase is extracted twice with chloroform. The combined chloroform solutions are dried and concentrated under reduced pressure. The crude 2-ethoxycarbonylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol thus obtained is dissolved in tetrahydrofuran (50 ml) and added dropwise to lithium aluminium hydride (1.8 g) in tetrahydrofuran (150 ml). After refluxing for 3 hours, the mixture is cooled and decomposed with a slight excess of saturated sodium sulphate solution. The solid precipitate is filtered off and washed with tetrahydrofuran. The combined filtrate and washings are dried and the solvent is removed, finally under reduced pressure. The residual oil crystallizes on scratching. Crystallization from diisopropyl ether gives the title compound; m.p. 134° C. 2-Ethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is similarly obtained when using acetic anhydride instead of ethyl chloroformate and reduction of the crude N-acetyl derivative. The free base is obtained as an oil, which is converted to the hydrochloride by treatment with hydrogen chloride in diethyl ether, m.p. 227° C. after crystallization from isopropyl alcohol. An identical product is obtained by reduction of crude 2-acetamido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol acetate obtained by the treatment of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol with acetylchloride in diethyl ether containing an excess of triethylamine, removal of the precipitated triethylamine hydrochloride by filtration and evaporation of the filtrate.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22].CC1C=CC(S(O[CH2:34][C@@H:35]2[CH2:37][O:36]2)(=O)=O)=CC=1>>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:34][C@@H:35]4[CH2:37][O:36]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1O
Product: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@@H]1CO1
Yield: 12.5 %

Procedure:
The title compound (147 mg, 0.400 mmol, 12.5%) was obtained as light brown crystals from a 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product (1.00 g, 3.21 mmol) and (2S)-oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of 5-bromo-2-iodopyridine (600 mg, 2.11 mmol), (4-methoxyphenyl)boronic acid (353 mg, 2.32 mmol), tetrakis(triphenylphosphine)palladium(0) (122 mg, 0.106 mmol), and 2M Na2CO3 aq. (2.11 mL, 4.22 mmol) in toluene (10 mL) was heated at 80° C. for 40.5 hours under nitrogen. After cooling to room temperature, water was added and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered through a Celite pad. The filtrate was concentrated and the residue was purified by column chromatography (CH2Cl2 only) to afford the desired product (538 mg, 97%) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.69 (d, J=2.3 Hz, 1H), 7.92 (dt, J=8.6 Hz and 2.3 Hz, 2H), 7.82 (dd, J=8.6 Hz and 2.3 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 6.99 (dt, J=8.6 Hz and 2.3 Hz, 2H), 3.87 (s, 3H). LCMS: 264 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:19][CH:18]=2)[C:14]([CH2:27][O:28][C:29]2[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=2[CH3:38])=[C:13]([CH3:39])[N:12]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:19][CH2:18]2)[C:14]([CH2:27][O:28][C:29]2[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=2[CH3:38])=[C:13]([CH3:39])[N:12]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCN(CC(N)=O)CC2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2CCN(CC(N)=O)CC2)n1
Reaction time: 16 h

Procedure:
To a solution of 2-(4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidin-4-yl)-5,6-dihydropyridin-1(2H)-yl)acetamide (131 mg, 0.25 mmol) in EtOAc (5 mL) is added 5% Pd/C (100 mg). The mixture is hydrogenated at room temperature and atmosphere pressure for 16 h. After filtered though celite, the solution is concentrated and purified by silica gel column chromatography to provide the title product. [mass expected (528.7); mass found (M+1: 529.4)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([S-:11])[CH3:10].[Na+]>CN(C=O)C>[CH2:9]([S:11][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)[CH3:10]
Reactant: CC[S-]
Reactant: Nc1cccc(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cccc(N)n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 204 %

Procedure:
2-Amino-6-bromopyridine (0.88 g) and sodium ethanethiolate (0.46 g) were dissolved in DMF (10 mL) stirred at RT for 20 h and subsequently at 60° C. for further 20 h to complete the reaction according to HPLC analysis. The mixture was concentrated in vacuo, partitioned between AcOEt and water, the layers were separated and the organic layer dried over Na2SO4, filtered and evaporated to give to give 6-ethylsulfanyl-pyridin-2-ylamine as brown oil (1.6 g) that was used directly in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[C:12]([NH:16][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1F
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a suspension of 4-chloro-2-fluorobenzoic acid (0.3494 g, 2.00 mmol) in methylene chloride (10 ml) were added t-butyl amine (0.32 ml, 3.05 mmol) and HOBt (0.3248 g, 2.40 mmol), and then WSC HCl (0.4596 g, 2.40 mmol) was added and stirred for 3 hours. The reaction mixture was added into water and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (0.4403 g; 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C1(O)C=CC=CC=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:11](=[O:13])[O:9][C:3]=2[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1O
Agent: Cl
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1[nH]c2ccc(F)cc2o1
Temperature: 60 °C

Procedure:
2-amino-5-fluorophenol [4.0 grams (g) (0.03 moles) (M)] was dissolved in 40.0 ml pyridine. The mixture was cooled with an ice bath while triphosgene [3.5 g (0.03 M)] was added. The mixture was heated to 60° C. for 3.0 hours. Thin layer chromatography showed that some of the starting phenol was still present. The mixture was then cooled; triphosgene [0.35 g 0.003 M)] was added and heated to reflux for 4.0 hours. The mixture was cooled, methylene chloride and 10% hydrogen chloride solution was added and stirred to room temperature.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[C@@:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])([OH:24])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[C:33]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])([OH:24])[CH2:10][CH2:9]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reaction time: 1 h

Procedure:
100 cm3 of a 5.2N solution of hydrogen chloride in dioxane are added to a solution of 7.63 g of (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindol-4-ol in 66 cm3 of dioxane at room temperature. The reaction mixture is stirred at this temperature for 1 hour and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with acetonitrile, filtered off and then dried. 4.88 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2 -methoxyphenyl)-perhydroisoindol-4-ol hydrochloride are obtained in the form of white crystals which melt at 271° C. (Maquenne block).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br.[CH3:13][C:14]1([CH3:24])[CH:16]([CH:17]=[C:18]([Cl:20])[Cl:19])[CH:15]1[C:21]([OH:23])=[O:22].[OH-].[K+].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][C:14]1([CH3:24])[CH:16]([CH:17]=[C:18]([Cl:20])[Cl:19])[CH:15]1[C:21]([O:23][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH:2]([F:12])[F:1])[CH:5]=1)=[O:22]
Reactant: FC(F)Oc1cccc(CBr)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(OC(F)F)c1
Yield: 75.8 %

Procedure:
6.81 g (0.03 mol) of 3-difluoromethoxy-benzyl bromide and 6.27 g (0.03 mol) of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid were dissolved in 150 ml of toluene, 0.5 g of tetrabutylammonium bromide and 2 g of powdered KOH (industrial product, 87% pure) were added and the mixture was heated to the boil for 2-3 hours. After cooling, the reaction mixture was poured into 150 ml of water, the toluene phase was separated off, washed with 100 ml of water and dried with sodium sulphate and the toluene was distilled off in vacuo. Last residues of solvent were removed by incipient distillation at a bath temperature of 60°-80° C./0.2 to 1 mm Hg. 8.3 g (78% of theory) of 3-difluoromethoxy-benzyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylate were obtained as a viscous oil with the refractive index nD20 =1.5110.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][CH2:26][CH2:27][S:28](=[O:30])(=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:31]>C(O)C>[ClH:31].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][CH2:26][CH2:27][S:28](=[O:30])(=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C2c2ccc(F)c(Br)c2)S(=O)(=O)CCC1
Agent: Cl
Solvent: CCO
Product: O=C1CNCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCS1(=O)=O)N2
Temperature: 25 °C

Procedure:
A solution of the product from Example 9B (0.25 g) in ethyl alcohol was treated with 6N HCl (1 mL), refluxed for 2 hours, cooled to ambient temperature and concentrated. The residue was purified by flash chromatography over silica gel (15% ethanol/ammonia saturated methylene chloride) to provide the title compound (0.09 g) as the free base which was converted to the hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=C)=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].CC([OH:22])(C)C>O1CCOCC1.O.O=[Os](=O)(=O)=O>[F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:22])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: C=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-4-vinyl-benzene (80 mg, 0.3 mmol) was dissolved in dioxane (6 ml) and water (5 ml). NaIO4 (181 mg, 0.84 mmol) and OsO4 (0.18 ml of a 2.5 % t-BuOH solution) were added. The mixture was allowed to stir at room temperature for 2 h, and then it was partitioned between ethyl acetate and brine. The ethyl acetate was washed with three additional times with brine, dried over MgSO4, and the solvent was removed under vacuum to give the title product (47 mg (61%), 0.18 mmol). 1H NMR (CDCl3): δ=10.08 (s, 1H), 8.04 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 5.82 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[Si]([C:21]([F:24])([F:23])[F:22])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([OH:15])[C:21]([F:24])([F:23])[F:22])=[C:4]([F:16])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: OC(c1cnccc1-c1ccc(Cl)cc1F)C(F)(F)F
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A stirred solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.8 g, 7.64 mmol) (prepared as described in Example 5, Part B) and TMS-CF3 (0.521 mL, 3.52 mmol) in dichloromethane (20 mL) was stirred at 0° C. for 20 min. TBAF (1.0 M in THF) (0.4 mL, 1.528 mmol) was added dropwise slowly and the solution stirred for 90 min. Water was added and the solution extracted with dichloromethane (2×25 mL). The combined organic layers were washed with brine, dried over sodium sulphate, concentrated and purified by Prep. TLC using 25% ethyl acetate in hexane to give 1-(4-(4-chloro-2-fluorophenyl)pyridin-3-yl)-2,2,2-trifluoroethanol (1 g, 2.64 mmol, 35% yield) as a yellow oil. LCMS (ESI) m/e 306.0 [(M+H)+, calcd for C13H9ClF4NO 306.02]; LC/MS retention time (Method C): tR=2.05 min.
Reaction SMILES: [H-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18](Br)[C:19]#[CH:20].C(O)(=O)C>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:20][C:19]#[CH:18])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C#CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 35% potassium hydride in oil (6.04 g, 35% w/w, 53 mmols of potassium hydride) in 240 ml of sieve dried tetrahydrofuran was cooled to 0° C. The cold mixture was treated with homoterephthalic acid dimethyl ester (10.0 g, 48 mmols). The mixture was stirred at 0° C. for 1 hour. Propargyl bromide (53 mmols) was added and the mixture stirred at 0° C. for 30 min., then at room temperature for 16 hours. The resulting mixture was treated with 4.8 ml of 50% acetic acid, then poured into 480 ml of water. The mixture was extracted with ether (2×250 ml). The ether extracts were combined, dried over magnesium sulfate, and concentrated to a brown oil. Chromatography on 250 g of flash silica gel (10% ether in hexane eluent) gave the product as a white solid mp 63°-65° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:14].C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: OCC(O)COCc1ccccc1
Reaction time: 18 h
Yield: 90 %

Procedure:
3-Benzyloxy-1,2-epoxypropane (263 g, 1.60 mol), water (1,300 mL) and 70% perchloric acid (1.5 mL) were placed in a 2.0 L 3-necked flask equipped with condenser and thermometer. The mixture was heated to 80° for 18 hours. After heating and stirring for 18 hours at 80° the reaction mixture was neutralized with 5% sodium bicarbonate solution. The water was removed by rotary evaporation. Final removal of residual water was accomplished by azeotropic distillation using 300 mL of benzene. After evaporation of the benzene the product was distilled to yield 264 g (90%) of 3-benzyloxy-1,2-propanediol: bp 127°-136° C. (0.04 mm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[O:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29](Cl)=[O:30])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>O1CCCC1>[O:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([N:10]3[CH2:11][CH2:12][N:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)=[O:30])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc2c(c1)CCO2)N1CCN(c2ncccn2)CC1
Temperature: 60 °C
Yield: 77.6 %

Procedure:
To a solution of 8.2 g of 1-(2-pyrimidinyl)-piperazine and 5g of anhydrous triethylamine in 200 ml of anhydrous tetrahydrofuran, there were added dropwise a solution of 9.1 g of 5-coumaranyl carboxylic acid chloride in 20 ml of tetrahydrofuran. After the completion of the addition, the reaction mixture was heated at 60° C for 2 hours, then the so-formed precipitate was suction-filtered off. The filtrate was evaporated under reduced pressure and the crystalline residue was washed with water then recrystallized in 70 ml of ethanol. There were obtained 12 g of 1-(5-coumaranyl carbonyl)-4-(2-pyrimidinyl) piperazine, melting (K) at 149°-150° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:39]([C:30]4[CH:31]=[CH:32][C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:29]=4)(=[O:41])=[O:40])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc5ccccc5c4)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and naphthalene-2-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:4]=1)=O.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24]/[N:25]=[CH:1]\[C:3]1[S:7][C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(C=O)s2)CC1
Product: CC(C)(C)CC/N=C\c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A mixture of t-butyl 4-(5-formylthiazol-2-yl)piperidine-1-carboxylate (250 mg, 0.84 mmol, 1 eq) and 3,3-dimethylbutan-1-amine (94 mg, 0.93 mmol, 1.1 eq) was stirred with molecular sieves at RT for 18 hr. After filtration, the excess solvent was concentrated in vacuo to give (z)-tert-butyl 4-(5-((3,3-dimethylbutylimino)methyl)thiazol-2-yl)piperidine-1-carboxylate (290 mg, 90% yield) with consistent 1H-NMR data. 1H NMR (CDCl3) δ 8.37 (s, 1H), 7.94 (s, 1H), 4.00 (m, 2H), 3.53 (t, J=8.1 Hz, 2H), 2.87 (m, 2H), 2.02 (m, 2H), 1.61-1.46 (m, 5H), 1.47 (s, 9H), 0.94 (s, 9H) ppm.
Reaction SMILES: [NH2:1]C(OCC)=O.[F-].[K+].[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][O:15][C:14](=O)[O:13]1>CS(C)=O>[CH3:9][O:10][CH2:11][CH:12]1[O:13][C:14](=[O:15])[NH:1][CH2:16]1
Reactant: CCOC(N)=O
Reactant: COCC1COC(=O)O1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCC1CNC(=O)O1
Temperature: 140 °C
Reaction time: 77 h
Yield: 68.9 %

Procedure:
Urethane (82.4 g, 0.925 mol) was dissolved in dimethyl sulfoxide (400 mL), and thereto were added potassium fluoride (48.8 g, 0.841 mol) and 4-methoxymethyl-1,3-dioxolan-2-one (111 g, 0.841 mol), in order. The mixture was stirred for 77 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by distillation to give the subject 5-methoxymethyloxazolidin-2-one (76.0 g, yield 68.9%).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1)=[O:4].[H][H]>[C].[Pd].CO.O>[CH3:1][NH:2][C:3]([O:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)OC1CN[C@H](C(=O)O)C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CNC(=O)O[C@H]1CN[C@H](C(=O)O)C1

Procedure:
A solution of 2.7 g. (0.0084 mole) of trans-N-carbobenzyloxy]-4-[[(methylamino)carbonyl]oxy]-L-proline in 100 ml. of methanol-water (2:1) is treated with 1 g. of 5% palladium-carbon and 45 lb. of hydrogen and shaken on a Parr hydrogenator for 6 hours. The catalyst is filtered off under nitrogen, washed with methanol and the combined filtrates are evaporated, finally at 0.1-0.2 mm, to give 1.5 g. (96%) of a residue which gradually crystallizes to give trans-4-[[(methylamino)carbonyl]oxy]-L-proline as a greyish solid; m.p. 213°-215° (dec.), preceded by gradual darkening and sintering. [α]D26 -12° (c, 0.25% in 1:3 ethanol-methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1.N>O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]2[C:10](=[C:16]([C:17]3[CH:25]=[CH:24][C:20]([CH3:21])=[CH:19][CH:18]=3)[C:4]3[C:5]([N:8]=2)=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:11]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: N
Solvent: O
Product: Cc1ccc(-c2c3cc(C)ccc3nc3ccc(C)cc23)cc1

Procedure:
1 mol of 4,4'-dimethyldiphenylamine and 1 mol of 4-methylbenzoic acid are heated for 1 hour at 200° C. in 5000 g of polyphosphoric acid. After cooling, water and ammonia are added to the reaction mixture and the product is filtered off by suction and purified (m.p. 210°-211° C.).