Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)C)c1OC(F)F
Temperature: 70 °C
Yield: 21.5 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and isobutylbromide (67 mg, 0.492 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 21.4%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:15])=[C:6]([C:10]([CH3:14])=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)([O-:3])=[O:2].B.C1C[O:20][CH2:19][CH2:18]1>C1COCC1>[C:19]([O:9][CH2:7][C:6]1[C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[CH3:15])(=[O:20])[CH3:18]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1C(=O)O
Reactant: C1CCOC1
Agent: B
Product: CC(=O)OCc1c(C)cc(C)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-nitro-2,4,6-trimethylbenzoic acid (6.7 g, 31.9 mmol) in anhydrous THF (100 mL) was added 1 m solution of BH3.THF in THF (63.8 mL, 63.8 mmol) dropwise at 0° C. The reaction mixture was stirred overnight at RT, cooled to 0° C. and quenched with water. The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 1-acetoxymethyl-3-nitro-2,4,6-trimethylbenzene as a light yellow oil (6.3 g, 89%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]([CH:30]=2)[C:15]([NH:17][C:18]2[C:19]([CH3:29])=[C:20]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:21]([O:23]C)=[O:22])=[O:16])[CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]([CH:30]=2)[C:15]([NH:17][C:18]2[C:19]([CH3:29])=[C:20]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:21]([OH:23])=[O:22])=[O:16])[CH2:5]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(O)C3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCCC(O)C2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of aqueous 4N NaOH (2.00 ml) is added to a stirred solution of methyl 3-[[5-(3-hydroxy-1-piperidyl)-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.3 g, 0.75 mmol) in THF:MeOH (5 ml:2 ml). After 3 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as an off-white solid (0.274 g, 94%). Mass spectrum (m/z): 383.2 (M+1).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:14]([NH2:16])[CH3:15]>C(#N)C>[CH2:14]([NH:16][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH3:15]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CCN
Solvent: CC#N
Product: CCNCC(O)COc1ccc(C#N)cc1

Procedure:
86.0 g of 4-(oxiranylmethoxy) benzonitrile was dissolved in 250 ml acetonitrile and mixed with 29.7 g ethylamine in an autoclave. The mixture was heated in a boiling water-bath over night, evaporated and the residue was dissolved in 2 M hydrochloric acid. This acid waterlayer was washed twice with ether, alkalized with 10 M sodium hydroxide and extracted with three portions of dichloromethane.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35]>CCCCC.C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([OH:35])[C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[O:17][CH3:16]
Reactant: COc1cccnc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cnccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (57.8 mL) was added to THF (200 ml) at −78° C. 2-Bromomesitylene (3.6 mL) was added dropwise, keeping the temperature below −60° C., and the mixture stirred at −78° C. for 1 h. 3-Methoxypyridine (3.6 mL) was added dropwise at −78° C. and then the mixture was allowed to warm to −5° C. over 2 h. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (3.26 g) in THF (100 mL) was added portionwise keeping the temperature below −60° C. The reaction mixture was stirred at −78° C. for 1 h. The cooling bath was removed and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated to low volume. Upon standing, 0.73 g of a pale yellow solid separated which was filtered off, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C.C1COCC1.C[N+](C)(C)C.[F-]>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 90 μl (0.32 mmol) of (6-bromohexyloxy)tert-butyldimethylsilane. The protecting group was cleaved off in THF using 7 equivalent of TMAF. The product was purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:8]#[C:9]Br.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]#[N:8])[CH2:4][CH2:3]1
Reactant: N#CBr
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C#N)CC1

Procedure:
In the manner given in Example 1, N-methylpiperazine is treated with cyanogen bromide and aqueous sodium hydroxide to give 4-methyl-1-piperazinecarbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12](=[O:15])[CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:28])[F:27])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:12]([O:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:19][C:18]2[C:21]([F:31])=[C:22]([F:30])[C:23]([C:26]([F:27])([F:29])[F:28])=[C:24]([F:25])[C:17]=2[F:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:15])[CH2:13][CH3:14]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: CCC(=O)Oc1ccc(N)cc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CCC(=O)Oc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 51 %

Procedure:
According to the similar procedure in Synthesis Example 14-4, by using 5-amino-2-propanoyloxybenzoic acid (0.32 g, 1.53 mmole) which was prepared from Synthesis Example (15-2), DMF (10 ml), TEA (0.05 ml), tetrabutyl ammonium iodide (3 mg), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (0.38 ml, 2.30 mmole), 0.34 g (51.0% yield) of was obtained 2-propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[C:8]2[C:33]([O:35]C)=[O:34])(=[O:4])=[O:3].[OH-].[Na+].CO>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[C:8]2[C:33]([OH:35])=[O:34])(=[O:3])=[O:4]
Reactant: COC(=O)c1c(CN2CCC(=O)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)O)c2c1
Yield: 126.2 %

Procedure:
Methyl 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.796 g, 1.529 mmol) and 3N NaOH (5.097 mL, 15.29 mmol) were suspended in tetrahydrofuran (5.097 mL) and methanol (5.097 mL) and heated to 50° C. for 20 h. The tetrahydrofuran and methanol were removed under reduced pressure, and the residue was diluted with water. The mixture was purified via Oasis SPE cartridge to afford 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.977 g). This material was used without further purification. MS (m/z) 507.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reaction time: 72 h
Yield: 80 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperidin -4-ethanol (5.0 g, 22 mmol) in methylene chloride (100 mL) was treated with pyridinium chlorochromate (5.2 g, 24 mmol), and diatomaceous earth (5 g). After 3 days, the mixture was filtered through diatomaceous earth, concentrated, and the residue purified by column chromatography (SiO2: 20 to 30% EtOAc:hexanes) affording 4.0 g (81%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[C:7]([C:16](OCC)=[O:17])[C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:42])[NH:28][S:29]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)(=[O:31])=[O:30])=[CH:23][C:22]=1[C:43]([N:45]1[CH2:54][CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH2:2][CH2:3][CH3:4].[BH4-].[Li+]>C1COCC1>[CH2:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]=[C:7]([CH2:16][OH:17])[C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:28][S:29]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)(=[O:30])=[O:31])=[O:42])=[CH:23][C:22]=1[C:43]([N:45]1[CH2:54][CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CO)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A 25 mL round bottom flask was charged with ethyl 5-butyl-4-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1-phenyl-1H-pyrazole-3-carboxylate (Example 223, 23 mg, 0.031 mmol). THF (1.0 mL) and then 2M lithium borohydride solution in THF (0.078 mL, 0.16 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with sat. aq. sodium bicarbonate solution and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC to give the title compound (7.3 mg, 34%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.65 (s, 1H), 8.12-7.91 (m, 6H), 7.63-7.57 (m, 2H), 7.50-6.99 (m, 9.5H), 6.91-6.89 (m, 0.5H), 4.65-4.32 (m, 4H), 3.44-3.15 (m, 2H), 2.88-2.49 (m, 4H), 1.39-0.86 (m, 4H), 0.55-0.49 (m, 3H); MS(ESI+) m/z 699.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:6][CH2:5][CH:3]1[CH2:4][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: OCC1COC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1COC1
Temperature: 0 °C

Procedure:
Oxetan-3-ylmethanol (1.85 g, 21.0 mmol) was dissolved in methylene chloride and cooled to 0° C. Triethylamine (5.31 g, 52.2 mmol) was added followed by slow addition of methanesulfonyl chloride (2.89 g, 25.2 mmol). The mixture was allowed to warm to ambient temperature for 2 h and quenched with sat. sodium bicarbonate (14 mL). The aqueous solution was extracted with methylene chloride 3×. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude oxetan-3-ylmethyl methanesulfonate (quant.).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1)=[O:10])#[CH:2].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH3:17][C:15]1[CH:14]=[CH:13][C:12]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:11]([C:9]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[C:1]#[C:2][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[CH:16]=1
Reactant: Brc1ccccc1
Reactant: C#CC1CCCCN1C(=O)c1cc(C)ccc1-n1nccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCCC2C#Cc2ccccc2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of (2-ethynylpiperidin-1-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (25 mg, 0.085 mmol), bromobenzene (25 mg, 0.15 mmol), CuI (4.9 mg, 0.025 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF (0.5 mL) was purged subsurface with nitrogen. Palladium tetrakis (9.8 mg, 0.0085 mmol) was added and the reaction was heated at 90° C. overnight. The reaction was stirred over excess Quadrapure TU overnight, then filtered and dried. The residue was subjected to purification via reverse phase HPLC to provide the title compound which gave a high resolution mass spectrum (ES+) m/z of 371.1872, calculated for M+H+ [C23H22N4O: 371.1866].
Reaction SMILES: O.[OH:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br.O>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][O:5][C:4](=[O:6])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[CH:9][CH:8]=1)[OH:2]
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of hydroxy-(4-hydroxy-phenyl)-acetic acid monohydrate (10 g) in DMF (50 mL) was added K2CO3 (29.7 g), followed by 3,4-dichlorobenzyl bromide (16.1 mL). The mixture was stirred at room temperature for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc. The organic layer was washed with water 1N HCl, brine, dried over Na2SO4, and concentrated. The resulting solid was triturated with diethyl ether and filtered to provide [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3,4-dichloro-benzyl ester as a white solid (9.4 g). 1H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.41 (m, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.20 (m, 1H), 6.97 (m, 2H), 6.06 (d, 1H), 5.16 (d, 1H), 5.1 (m, 4H).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[OH:13]>CN(C=O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[OH:13]
Reactant: [C-]#N
Reactant: Oc1cc(CBr)ccc1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)c(O)c1
Temperature: 60 °C

Procedure:
A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) was heated at 60° C. for 30 min. The slurry was cooled to room temperature and treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g, 15.7 mmol) in DMF (50 mL). The resultant mixture stirred at room temperature for 23 h, and then was diluted with water and extracted with ethyl acetate (5×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to afford impure (4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5 mg) in MeOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile 73 (100.0 mg), the resulting mixture was stirred at room temperature for 10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from 2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride in presence of triethylamine) were added. The reaction mixture was stirred at room temperature overnight. DCM (80 mL) was added and the organics washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried with MgSO4. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS (EI) m/z (M+H+) 324.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCCCOc1ccc(O)cc1
Product: CCCCOc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized from ethanol (22%, white crystals). HPLC-MS m/z=300.1 (M+1), Rt: 5.20.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:28]3)=[O:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([Si:34]([CH:35]([CH3:36])[CH3:37])([CH:38]([CH3:40])[CH3:39])[CH:41]([CH3:43])[CH3:42])[CH:29]=[CH:28]3)=[O:24])[CH2:19]1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3CCN(C(=O)OC(C)(C)C)C3)ccc21
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3(Cc4ccccc4)CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 12.1 mL) was added to a solution of 3-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.90 g, 4.03 mmol) in THF (25 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and then benzyl bromide (1.9 mL, 16.12 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl, then diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 1.55 g (69% yield) of 3-benzyl-3-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]3)[C:6]=12.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:28].[ClH:28].[F:1][C:2]1[CH:3]=[C:4]([C:24]([F:26])([F:25])[F:27])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)cc(F)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCn2c(C(F)(F)F)cc(F)c2C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (310 mg, 0.80 mmol) in CH2Cl2 (2 mL) was added a solution of HCl (2.0 mL of 4 M, 8.0 mmol) in 1,4-dioxane. The reaction mixture was allowed to stir at room temperature for 1 hour. The volatiles were removed under reduced pressure providing 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (290 mg, 99%) as a pink solid. ESI-MS m/z calc. 291.1, found 292.3 (M+1)+; Retention time: 0.75 minutes (3 minute run).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](O)=[O:14])=[O:4].[CH3:22]O>>[CH3:1][O:2][C:3]([N:5]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([O:14][CH3:22])=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2)=[O:4]
Reactant: CO
Reactant: COC(=O)N(c1ccccc1)c1ccccc1CC(=O)O
Product: COC(=O)N1c2ccccc2C=C(OC)c2ccccc21
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of [2-(methoxycarbonyl-phenyl-amino)-phenyl]-acetic acid (16 g, 55.5 mmol) and polyphosphoric acid (29 g, 167 mmol in terms of P2O5) is heated to 100° C. for 4 hours. To the reaction mixture, methanol (50 ml) is added dropwise at 65° C. with stirring. The resulting suspension is cooled to room temperature, filtered and washed with methanol (40 ml). The white crystals are dried to yield 12.2 g of pure title compound (80%).