Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[S:23][C:24]3[C:33]4[N:32]=[C:31]([NH:34][C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([S:41](=[O:44])(=[O:43])[NH2:42])[CH:36]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:45]=2)=[O:21])[CH2:16]1)(C)(C)C>ClCCl>[NH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[S:23][C:24]3[C:33]4[N:32]=[C:31]([NH:34][C:35]5[CH:36]=[C:37]([S:41]([NH2:42])(=[O:43])=[O:44])[CH:38]=[CH:39][CH:40]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:45]=2)=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 ml) was added to a suspension of {1-[8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (87 mg, 0.15 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100 A column, gradient 10%-100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to afford the title compound as a yellow solid. MS (ES+) 470, (ES−) 468. δH (d6 DMSO) 2.0-2.5 (4H, m), 3.70-4.05 (3H, m), 4.31-4.44 (2H, m), 7.37 (2H, s), 7.52 (1H, d), 7.60 (1H, t), 8.02-8.13 (6H, m), 8.69 (1H, s), 9.55 (1H, d), 10.57 (1H, s).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17](=[O:25])[C:16]=1[C:26]#[N:27]>C1(C)C=CC=CC=1>[O:25]=[C:17]1[C:16]([C:26]#[N:27])=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1
Reactant: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2[nH]c1=O
Temperature: 110 °C
Yield: 87.8 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (8.0 g, 41 mmol) was added to a solution of Compound 115 (4.1 g, 20 mmol) in toluene (50 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0–2% methanol in dichloromethane gradient to yield 6.4 g (88%) of white solids. M.P. 264° C. 1H NMR (DMSO-d6): δ 3.7 (m, 4H), 3.9 (m, 4H), 7.16 (t, J=4.8 Hz, 1H), 7.23 (t, J=5.9 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.61 (t, J=8.3 Hz, 1H), 7.8 (m, 2H), 11.90 (b, 1H); EIMS: 364 (M+H).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][OH:27].[Cl:29][C:30]1[N:35]=[CH:34][C:33](O)=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:35]=[CH:34][C:33]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:32][N:31]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: CN(C)CCO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN(C)CCOc1cnc(Cl)nc1

Procedure:
Compound 112B was prepared in a similar manner to the synthesis of step 1 of Example 35 by substituting compound 34D and compound 31F with 2-(dimethylamino)ethanol and compound 112A, respectively: ESI (+)MS: 201 (M+H)−.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)O
Reactant: CN(C)CCN
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)NCCN(C)C
Yield: 94.1 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and N,N-dimethylethane-1,2-diamine (0.056 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)propanamide as a white solid (0.228 g, 93.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[OH-].[CH2:18]([N+:25](C)(C)C)[C:19]1C=CC=C[CH:20]=1.C(#N)C=C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:19][C:18]#[N:25])[C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=C1Nc2ccc(Br)cc2C12OCCCO2
Agent: [OH-]
Solvent: C=CC#N
Solvent: CN(C)C=O
Product: N#CCCN1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Temperature: 52 °C
Yield: 711.1 %

Procedure:
At room temperature, to a solution of 5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.50 g, 8.80 mmol) in N,N dimethylformamide (39 mL) was added benzyltrimethylammonium hydroxide (40% aq. solution, 0.347 mL, 0.88 mmol, 0.1 mole % ) followed by the dropwise addition of acrylonitrile (1.16 mL, 17.6 mmol, 2 eq). The reaction mixture was heated at 52° C. for 2 hr., cooled to room temperature, quenched with H2O (400 mL) and extracted with Et2O (3×). The combined organic extracts were dried and concentrated. The crude product was purified on Biotage KP silica gel eluting with 96/4 CH2Cl2/CH3CN to give the title compound as a yellow solid (2.11 g, 71% ). NMR (300 Mz, DMSO-d6): consistent; MS: (API-ES+) m/z 361 [M+Na].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][S:8][C:6]=2[N:7]=1.N[C:27]1N=C(N)C2C(C)=CSC=2N=1.C1C2CC3C(=CC=CC=3)NC=2C=CC=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:27][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=4)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Cc1csc2nc(N)nc(N)c12
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Agent: c1ccc2c(c1)Cc1ccccc1N2
Product: Nc1nc(N)c2c(CN3c4ccccc4Cc4ccccc43)csc2n1

Procedure:
N-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminothieno[2,3-d]pyrimidi-5-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.4 mmol) in Step 1 and 9,10-dihydroacridine (134 mg, 0.8 mmol) in Step 3. The final product and its intermediates can b purified by chromatography.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=3)[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.[OH-].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=3)[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4c(ccn4C(=O)OC(C)(C)C)c3)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
Methyl 3-(4-{[3-(1-tert-butoxycarbonyl-1H-indol-5-yl)benzyl]oxy}phenyl)propanoate (3.8 g, 7.83 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and methanol (30 mL), and the mixture was ice-cooled. An aqueous solution (10 mL) of 85% potassium hydroxide (1.0 g, 15.1 mmol) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from diethyl ether-hexane to give 3-(4-{[3-(1H-indol-5-yl)benzyl]oxy}phenyl)propanoic acid (2.2 g, yield 76%) as colorless needle crystals. MS: m/z 372 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]1[NH:4][C:5]([CH3:25])=[C:6]([C:23]#[N:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[CH2:27][C:28]#[N:29]>CCO>[C:28]([CH2:27][S:1][CH2:2][C:3]1[NH:4][C:5]([CH3:25])=[C:6]([C:23]#[N:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:29]
Reactant: N#CCCl
Reactant: CCOC(=O)C1=C(CS)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(CSCC#N)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of 2-mercaptomethyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (3 g), 2-chloroacetonitrile (1 g) and 1,4-diazabicyclo-2,2,2-octa ne (0.8 g) in EtOH (30 ml) is heated at reflux temperature for six hours. Then the reaction is cooled to room temperature and after usual work-up and purification by columnchromatography (SiO2 90 g; eluent Et2O/AcOEt 90/10) gives 1.8 g of 2-(cyanomethylthio)methyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32].[C:33]([O:38][CH2:39][CH3:40])(=[O:37])[C:34]#[C:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:39]([O:38][C:33]([C:34]1[C:35]([CH3:36])=[N:14][N:15]2[C:16]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:20]=12)=[O:37])[CH3:40]
Reactant: CC#CC(=O)OCC
Reactant: COc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
A solution of 3.99 g (6.15 mmol, 72% purity) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methoxypyridinium 2,4,6-trimethylbenzenesulphonate (Example 161A) in 70 ml of N,N-dimethylformamide was admixed with 1.38 g (12.31 mmol) of ethyl 2-butynoate (CAS: 4341-76-8) and 2.55 g (18.46 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 18 hours and added dropwise to 150 ml of water. The resulting precipitate was filtered off and dried under reduced pressure, which gave 477 mg (12% yield, 57% purity) of product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]([CH3:15])([CH3:14])[CH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.CN([CH:19]=[O:20])C>>[CH3:6][C:7]([CH3:15])([CH3:14])[CH2:8][N:9]1[CH:13]=[C:12]([CH:19]=[O:20])[CH:11]=[N:10]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)Cn1cccn1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)Cn1cc(C=O)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask charged with anhydrous DMF (400 mL) was cooled to 0° C., to which phosphorous oxychloride (114 g, 0.74 mol) was added dropwise, and the temperature was kept below 10° C. The stirring was continued for 1 h and it was allowed to rise to room temperature. Then it was cooled to 0° C. again, and a solution of 1-(2,2-dimethyl-propyl)-1H-pyrazole (51.1 g, 0.37 mol, CAS registry 725746-83-8) in DMF (100 mL) was added dropwise. Then it was heated to 100° C. overnight. After cooling, the reaction was quenched by slow addition of cold water, and it was neutralized with aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The resulting residue was purified by column chromatograph on silicagel (petroleum ether-EtOAc 10:1) to give the title compound as light yellow oil: ESIMS [M+H]+=167; 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.42 (s, 1H), 7.98 (s, 1H), 3.99 (s, 2H), 0.90 (s, 9H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[CH:5]=1.CC(C[AlH]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[OH:11]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1ccc(Br)c(O)c1
Reaction time: 2.75 h

Procedure:
To a suspension of 4-bromo-3-hydroxybenzoic acid methyl ester 70 (6.97 g, 30.2 mmol) in dichloromethane (360 mL) at 0° C. was added DIBALH (100 mL of a 1 M in toluene, 100 mmol) portionwise. Significant gas evolution was observed. The resultant mixture was warmed to room temperature and stirred for 2.75 h. After this time, the reaction mixture was quenched by the addition of saturated aqueous sodium potassium tartrate (600 mL) and saturated aqueous ammonium chloride (100 mL). The resultant biphasic mixture was stirred vigorously for 2 h, and then extracted with dichloromethane (3×). The organic layers were dried over Na2SO4 and filtered, to give 71. 1H NMR (400 MHz CDCl3) δ: 1.70 (br s, 1H), 4.64 (d, J=4.5 Hz, 2H), 5.55 (br s, 1H), 6.82 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H). MS (EI) m/z (M−H−) 201.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:10]>C(O)C>[OH:10][CH:7]([CH3:8])[CH2:6][CH2:9][C:3]1[CH:8]=[CH:7][C:6]2[C:5](=[CH:9][CH:3]=[CH:4][CH:5]=2)[CH:4]=1
Reactant: Cc1ccccc1
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Then, 99 g (0.5 mole) of the compound (XLVII-1) was suspended in 1000 ml of ethanol, 9.5 g (0.25 mole) of sodium borohydride was added thereto, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction 1500 ml of toluene and 500 ml of water were added thereto to effect extraction, and the organic layer was separated. The organic layer was washed with water and then concentrated to obtain 100 g of 2-(3-hydroxybutyl)naphthalene (XII-2) (yield: 100%) as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:32])[C@H:19]([C:22]2[C:27]([F:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=2[F:31])[O:20][CH3:21])=[CH:12][CH:11]=1)=[NH:9])(C)(C)C.C(O)=O>O>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:32])[C@H:19]([C:22]2[C:27]([F:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=2[F:31])[O:20][CH3:21])=[CH:14][CH:15]=1)(=[NH:7])[NH2:9]
Reactant: COc1cc(F)c([C@H](OC)C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)c(F)c1
Solvent: O=CO
Solvent: O
Product: COc1cc(F)c([C@H](OC)C(=O)NCc2ccc(C(=N)N)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (S)-[(4-{[2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid tert-butyl ester in water was treated with formic acid. The solution was stirred for 8 hrs at rt, then concentrated, redissolved twice in water, concentrated and dried to give (S)-N-(4-carbamimidoyl-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide formiate (78 mg) as white foam. MS 364.1 ([M+H]+)
Reaction SMILES: N#N.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:34]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
Under a stream of nitrogen N,N′-carbonyldiimidazole (3.62 g, 22.3 mmol) followed by piperidine (3.74 g, 43.9 mmol) is added to a solution of 1-(tert-butoxycarbonyl)-4-phenyl-4-piperidinecarboxylic acid (3.40 g, 11.1 mmol) in dry THF (50 mL). The mixture is heated to reflux 18 h, then cooled to ambient temperature and concentrated by means of evaporation. The remanence is redissolved in ethyl acetate (150 mL) and successively washed with NaHCO3 (50 mL, aq, sat.), dilute HCl (50 mL) at pH 3, brine (50 mL), then dried (MgSO4) and evaporated to dryness. This intermediate is purified by silica gel chromatography eluting with ethyl acetate-heptane-triethylamine (40:50:10) to furnish 1.01 g (24%) of 4-phenyl-4-(piperidine-1-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester as a white crystalline solid. This is dissolved in a mixture of MeOH (10 mL) and THF (10 mL), then 2M HCl in MeOH (5 mL) is added and the mixture is stirred at ambient temperature for 2 h. Water (20 mL) is added and pH is adjusted to pH 12 by addition of 2M NaOH. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (30 mL). Combined organic fractions are dried (MgSO4) and concentrated in vacuo to furnish 0.47 g (63%) of (4-Phenyl-piperidine-4-yl)-piperidin-1-yl-methanone. LC/MS (m/z) 273.1 (M+H+); tR=1.65 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([P:17]([OH:20])(=[O:19])[OH:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C([O-])([O-])=O.[Na+].[Na+].O.CO.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([P:17]([OH:20])(=[O:18])[OH:19])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(P(=O)(O)O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccc(P(=O)(O)O)cc2)cc1

Procedure:
Compound 3f (8.05 g) was dissolved in a mixture of 1 M Na2CO3 (15 ml), water (55 ml) and methanol (30 ml) (pH 8.0) and hydrogenated at room temperature at normal pressure using 10% Pd/C (200 mg) as catalyst. After absorption of the theoretical amount of hydrogen (about 4 hr), the filtrate of the reaction mixture was concentrated to 70 ml and acidified with 2 N HCl to pH 6.0. The monosodium salt of compound 5f precipitated. It was washed with water and dried at about 40° C. C13H13N2O4P (292.4); C13H12N2O4PNa (314.4) monosodium salt of compound 5f.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[NH2:31][C@H:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C@H:33]1[F:45].[Cl:46][C:47]1[N:48]=[C:49]([C:54](O)=[O:55])[NH:50][C:51]=1[CH2:52][CH3:53]>CC(N(C)C)=O.O>[Cl:46][C:47]1[N:48]=[C:49]([C:54]([NH:31][C@H:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][C@H:33]2[F:45])=[O:55])[NH:50][C:51]=1[CH2:52][CH3:53]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
1-Hydroxybenzotriazole hydrate (114 mg, 0.845 mmol), WSC hydrochloride (162 mg, 0.845 mmol) and triethylamine (118 μL, 0.845 mmol) were added to a solution of tert-butyl cis(±)-4-amino-3-fluoropiperidine-1-carboxylate obtained in Example (196a) (123 mg, 0.564 mmol) and 4-chloro-5-ethyl-1H-imidazole 2-carboxylic acid obtained in Example (1d) (118 mg, 0.676 mmol) in DMA (3 mL) at room temperature, and the mixture was stirred at 70° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1 v/v) to obtain 159 mg of the title compound (75%) as a pale yellow foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[C:43]([NH2:48])[CH:42]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:48][C:43]1[CH:42]=[C:41]([F:40])[CH:46]=[CH:45][C:44]=1[NH:47][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum. To the residue was added 5 ml of absolute ethanol. The solids were collected by vacuum filtration, washed with absolute ethanol and dried under vacuum to give the title compound (193 mg, 73% yield) as a brown solid. LC-MS (m/z) 266 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][CH:20]=2)[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=1)=[O:6]>CO>[N:27]1([C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:16]3[C:10]4[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=4[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:17]=3)=[CH:24][CH:23]=2)=[O:26])[CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2c(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)O)cc2O1
Temperature: 60 °C
Yield: 77.5 %

Procedure:
Aqueous NaOH (3 N, 2.1 mL, 6.3 mmol) was added to a solution of 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (35b) (802 mg, 2.10 mmol) in 10 mL CH3OH. The mixture was heated to 60° C. for 3 hr, concentrated, diluted with H2O (60 mL) and acidified with 1N aqueous HCl to Ph ˜1. The aqueous phase was extracted with CH2Cl2 (60 mL), dried with MgSO4 and concentrated to give a white solid (598 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1 H) 7.67 (d, J=7.33 Hz, 2 H) 7.02-7.10 (m, 3 H) 6.99 (s, 1 H) 4.32 (s, 2 H) 4.03 (s, 2 H) 2.89 (s, 2 H) 2.21-2.30 (m, 2 H) 1.42 (s, 6 H); LCMS for C21H21NO5 m/z 468.00 (M+H)+.