Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (255 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (496 mg), potassium carbonate (415 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column. chromatography, and methyl [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (501 mg, yield 72%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: N1CCC(C2C=C(N)N3N=CC(C4C=NC5C(C=4)=CC=CC=5)=C3N=2)CC1.C[Si](C)(C)CCOC[N:33](COCC[Si](C)(C)C)[C:34]1[N:39]2[N:40]=[CH:41][C:42]([C:43]3[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=3)=[C:38]2[N:37]=[C:36]([CH:49]2[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51][CH2:50]2)[CH:35]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN(C(OC(C)(C)C)=O)CC2)C=1>>[CH3:48][N:46]1[CH:47]=[C:43]([C:42]2[CH:41]=[N:40][N:39]3[C:34]([NH2:33])=[CH:35][C:36]([CH:49]4[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]4)=[N:37][C:38]=23)[CH:44]=[N:45]1
Reactant: Cn1cc(-c2cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)cc(C4CCN(C(=O)OC(C)(C)C)CC4)nc23)cn1
Agent: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: Nc1cc(C2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Cn1cc(-c2cnn3c(N)cc(C4CCNCC4)nc23)cn1

Procedure:
3-(1-Methyl-1H-pyrazol-4-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine was synthesized in a manner similar to the synthesis of 5-(piperidin-4-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but with tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:52])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=5)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[C:16]2=[NH:51])[CH:6]=1)C.O[Li].O>C1COCC1.CO.O>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH2:37][N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:17]4[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:4]([OH:52])=[O:3])[C:16]4=[NH:51])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)=[CH:45][CH:46]=1
Reactant: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(N4CCN(Cc5ccccc5-c5ccc(Cl)cc5)CC4)cc3)c3ccccc32)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Yield: 10.9 %

Procedure:
To a solution of 3-[3-(3-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (140 mg, 0.20 mmol) in THF (1.2 ml), MeOH (1.2 ml) and H2O (0.6 ml) at 0° C. was added LiOH.H2O (16 mg, 0.39 mmol). The reaction was warmed to rt where it was maintained for 20 h. After this time, the mixture was concentrated under reduced pressure and then partitioned between saturated NaHCO3 and dichloromethane to adjust the pH to ˜8. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by preparative HPLC provided 3-[3-(3-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid (15 mg, 11%). HPLC-MS 686 [M+1]+, 344.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(S(F)(F)[F:47])CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:39])[F:40])[CH2:35][CH2:36]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([F:47])[CH2:18][CH2:19]2)[C:10]1=[O:21]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Treat a 0° C. solution of 1-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-3-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.090 g, 0.15 mmol) in CH2Cl2 (5 mL) with (diethylamino)sulfur trifluoride (0.049 g, 0.305 mmol) and stir for 1 hour at 0° C. under N2. Quench the reaction with saturated NaHCO3, dilute with ethyl acetate, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.019 g (85%) of the titled product. Rf=0.56 (9/1 CH2Cl2/methanol). ES MS (m/z): 600 (M+).
Reaction SMILES: [CH2:1]([NH:18][C:19](=[O:39])[O:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][O:28][CH2:29][CH:30]([OH:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:18][C:19](=[O:39])[O:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][O:23][C@H:22]1[CH2:27][O:28][CH2:29][CH:30]([OH:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][S:53]([C:50]1[CH:51]=[CH:52][C:47]([CH3:57])=[CH:48][CH:49]=1)(=[O:55])=[O:54])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COCC(O)CCCCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COCC(O)CCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.458 g of dl-trans-2-[(2,8-dihydroxyoctyloxy)methyl]tetrahydropyran-3-yl N-heptadecylcarbamate (prepared as described in Preparation 75), 0.27 ml of triethylamine and 5 mg of 4-dimethylaminopyridine were dissolved in 10 ml of methylene chloride. 0.188 g of p-toluenesulfonyl chloride were added to the mixture, whilst ice-cooling, after which the mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through 12 g of silica gel and by medium pressure liquid chromatography through a Lobar B column. 0.492 g of the title compound was obtained, as a white wax, from the fractions eluted with mixtures of hexane and ethyl acetate ranging from 3:2 to 1:1 by volume.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:18])=[CH:6][CH:5]=1.[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>O.CN(C=O)C>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:8][C:7]3[CH:19]=[CH:20][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[C:10]2=[O:18])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2n1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(OC(F)(F)F)cc2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of compound R (770 mg, 2.5 mmol) in abs. DMF (20 mL) there were added 4-nitrobenzyl bromide (540 mg, 2.5 mmol), potassium carbonate (828 mg, 6 mmol), and a catalytic amount of potassium iodide under a blanket of argon. The reaction mixture was heated to from 80° to 85° C. over a period of 5 h. Following cooling, the reaction mixture was poured into a mixture of ice (200 g) and 2N hydrochloric acid solution in H2O (10 mL), and the reaction mixture was stirred for 1 hour. The resulting solid matter was separated through a frit and recrystallized from ethanol (20 mL). The desired product 1-(4-nitrobenzyl)-3-(4-trifluoromethoxybenzyl)-1,3-dihydrobenzimidazol-2-one (T) was obtained in a yield of 830 g (74% of theory).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[C:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: OB(O)C1=CCCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCC2)C1
Yield: 68.1 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.21 mmol), a solution of cyclopenten-1-ylboronic acid (204 mg, 1.82 mmol) in ethanol (1.4 ml), 2N aqueous sodium carbonate solution (5 ml), and tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.146 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (260 mg, 68.1%) as an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH3:19][C:20]1[CH:21]([C:30](=[O:32])[CH3:31])[C:22]2([CH:27]=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24][CH2:23]2.C=C1C=CCC2(CCCC2)[CH:35]1[C:44](=[O:46])C.CC1C=CCC2(CCCC2)C=1C(=O)C.C(=O)C.Cl>C1COCC1>[OH:46][CH:44]([CH3:35])[CH2:31][C:30]([CH:21]1[C:20](=[CH2:19])[CH:29]=[CH:28][CH2:27][C:22]21[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:32]
Reactant: C=C1C=CCC2(CCCC2)C1C(C)=O
Reactant: CC(=O)C1C(C)=CC=CC12CCCC2
Agent: CC(=O)C1=C(C)C=CCC12CCCC2
Agent: CC=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C=C1C=CCC2(CCCC2)C1C(=O)CC(C)O
Reaction time: 0.33 h
Yield: 68 %

Procedure:
At −70° C. under N2, a solution of diisopropylamine (0.91 ml, 6.5 mmol) in anhydrous THF (10 ml) was treated dropwise with a solution of 1.6M n-BuLi in hexane (4 ml, 6.5 mmol). The resulting solution was stirred for 20 min., and treated dropwise with a solution of a 3:90:7 mixture of 1-(7-methylspiro[4.5]deca-7,9-dien-6-yl)ethanone, 1-(7-methylenespiro[4.5]dec-8-en-6-yl)ethanone, and 1-(7-methylspiro[4.5]deca-6,8-dien-6-yl)ethanone (0.94 g, 4.98 mmol) in anhydrous THF (4 ml). The resulting solution was stirred for 45 min. at −50° C., treated with a solution of acetaldehyde (1.2 ml, 20 mmol) in anhydrous THF (4 ml). The resulting solution was stirred at −40° C. for 1 h, poured into a mixture of ice and 2N HCl, and extracted three times with MTBE (25 ml). The combined organic phases washed with a saturated aqueous solution of NaCl, dried (MgSO4), and concentrated. FC (40 g SiO2, hexane/MTBE 10:1) of the crude product (1.3 g) gave 3-hydroxy-1-(7-methylenespiro[4.5]dec-8-en-6-yl)butan-1-one (0.788 g, 68%, 3:1 diast. mixture)
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:14]=[C:15]([NH2:27])[S:16][C:17]=1[C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([S:25][CH3:26])[N:19]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:26][S:25]([C:20]1[N:19]=[C:18]([C:17]2[S:16][C:15]([NH2:27])=[N:14][C:13]=2[CH3:12])[CH:23]=[C:22]([CH3:24])[N:21]=1)=[O:9]
Reactant: CSc1nc(C)cc(-c2sc(N)nc2C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2sc(N)nc2C)nc(S(C)=O)n1
Temperature: 25 °C

Procedure:
m-CPBA (57-86% purity, 6.0 g, 20-30 mmol) is added in portions to a rapidly stirring solution/suspension of 4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-ylamine (6.0 g, 23.8 mmol) in dry dichloromethane (200 ml) at 0° C. After the addition (15 minutes) the reaction is allowed to warm slowly to room temperature. The mixture is cautiously added to saturated sodium bicarbonate solution (300 ml), shaken, and the organic extract is separated and dried (MgSO4). This first extract contains a 1:1 mixture of sulfoxide and sulfone. The aqueous phase is then partitioned with chloroform to extract the titled compound as yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1>[Pd].C(OC(=O)C)C>[CH3:1][C:2]([CH3:28])([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CC(C)(C=Cc1ccc(Cl)cc1)COCc1cccc(Oc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(CCc1ccc(Cl)cc1)COCc1cccc(Oc2ccccc2)c1
Yield: 53.1 %

Procedure:
1% (by weight) Palladium on carbon (0.15 g) was added to a solution of 3,3-dimethyl-1-(4-chlorophenyl)-4-(3-phenoxybenzyloxy)but-1-ene (0.3 g) in ethylacetate (15 cm3). The stirred reaction mixture was then kept under an atmosphere of hydrogen until the uptake of gas had ceased. The reaction mixture was then removed from the hydrogenation apparatus, filtered, and the filtrate concentrated by removal of the solvent by evaporation. The crude residual oil was purified by column chromatography using a silica gel column and eluting with hexane containing ethyl acetate (varying from 5% to 10% by volume) to give 3,3-dimethyl-1-(4-chlorophenyl)-4-(3phenoxybenzyloxy)butane (0.16 g) as a colourless oil. 1H nmr (CDCl3) ppm: 0.95 (s,6H); 1.55 (m,2H); 2.5 (m,2H);
Reaction SMILES: [FH:1].C(N(C(C)C)CC)(C)C.O.[F:12][C:13]([F:23])([F:22])[CH:14]([O:19][CH2:20]Cl)[C:15]([F:18])([F:17])[F:16]>>[CH2:20]([F:1])[O:19][CH:14]([C:15]([F:18])([F:17])[F:16])[C:13]([F:23])([F:22])[F:12]
Reactant: FC(F)(F)C(OCCl)C(F)(F)F
Reactant: F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FCOC(C(F)(F)F)C(F)(F)F
Temperature: 10 °C
Yield: 95 %

Procedure:
In an efficient fume hood, liquid hydrogen fluoride (85.1 g, 4.25 mol) was transferred into a 1 liter Teflon® reaction vessel chilled in a dry ice/acetone cold bath. The vessel was fitted with a dry ice condenser, thermocouple, and addition funnel and a portion of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (80.1 g) was added. A solution of diisopropylethylamine (249.0 g, 1.93 mol) in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (271.0 g) was slowly added while maintaining the internal temperature in the range of -5°to 10° C. After completing the addition, the mixture was transferred to a 2 liter glass boiling flask and the Teflon® vessel was rinsed out with a solution of diisopropylethylamine (307.0 g, 2.38 mol) in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (180.0 g) which was also transferred to the glass flask. An additional 850 g of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether was added to the reaction flask to bring the total to 1381.1 g (6.38 mol). This mixture was heated at reflux for 16 hours. After cooling to ambient temperature, water (700 mL) was added to the reaction mixture and, after vigorous shaking, the resultant layers were separated. The lower organic layer was further washed with 700 mL of dilute hydrochloric acid (35 mL of 12 N HCl in 665 mL of water). The organic layer (1259.7 g) was analyzed by NMR and gas chromatography and was shown to consist of 63.6% fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane) and 35.4% recovered chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, giving a 95% yield of sevoflurane based on starting material consumed.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[OH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][CH:41]([OH:40])[CH2:42][CH2:43]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OC1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC(O)CC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 80.1 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.2 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with 4-hydroxypiperidine (159 mg, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-hydroxypiperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (80.6 mg, yield 80%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7].Br[CH2:19][CH2:20][CH:21]=C>>[CH3:1][C:2]1[N:3]([CH2:21][CH:20]=[CH2:19])[C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1cc(C(=O)CCc2ccccc2)[nH]c1C
Reactant: C=CCCBr
Product: C=CCn1c(C(=O)CCc2ccccc2)cc(C)c1C
Yield: 86.6 %

Procedure:
The title compound was prepared as a yellow oil in 86.6% yield in a similar procedure to that described in Referential Example 97 by using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and 3-bromomethyl-1-propene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:35].[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16]1)[N:9]=[CH:8][NH:7][C:6]2=[O:35]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a suspension of 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (90 mg, 0.18 mmol) in methanol (3 ml) was added 2M aqueous sodium hydroxide (180 μl, 0.35 mmol). After stirring for 2 hours at ambient temperature, the mixture was adjusted to pH10 with 2M hydrochloric acid. The volatiles were removed under vacuum and the residue was suspended in water, filtered, washed with water followed by ether and dried under vacuum at 60° C. to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (55 mg, 79%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:15][C:14]1[C:13]([I:16])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(OCc2ccccc2)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 80 %

Procedure:
24.1 g (72 mmol) of methyl 3-tert-butyl-4-hydroxy-5-iodobenzoate are dissolved in 200 mL of dimethylformamide. 3.47 g (86 mmol) of 60% sodium hydride are added slowly and the reaction medium is stirred for 1 hour. 9.4 mL (79 mmol) of benzyl bromide are then added and the medium is stirred at room temperature for 2 hours, and is then hydrolysed and extracted with ethyl ether. The organic phase is washed 3 times with water and then concentrated under reduced pressure. The residue is purified by chromatography (eluent: 98 heptane/2 ethyl acetate). A yellow oil is obtained (m=24.3 g; yield=80%).