Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:18]([CH:34]3[CH2:36][CH2:35]3)=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:37])([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1.CCO.CCOCC>[CH:34]1([C:18]2[C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[C:10]([CH3:37])[CH:11]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[N:19]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)ccc1OC(C)(C)C(=O)O
Reaction time: 23 h

Procedure:
0.386 g (0.7 mmol) of the above prepared 2-{4-[4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 12 ml of THF/EtOH (1:1), treated at 0° C. with 2.12 ml (2.1 mmol) of 1N LiOH, and kept at ambient temperature for 23 h. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl solution. The water phases were extracted with ether (2×). The organic phase was dried (Na2SO4) and evaporated. The crude product was precipitated in ether/pentane (RT to 4° C.) and filtered to give 0.289 g of the title compound as white crystals of mp. 127–128° C., dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:17])=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:36][C:29]=12)[NH2:23]>>[F:19][C:20]1[CH:21]=[C:22]([NH:23][C:15]([C:10]2[C:9](=[O:18])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[I:14])=[O:17])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:36][C:29]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1
Reactant: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1)c1c(I)ccn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared by procedure G using 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (141.25 mg; 0.39 mmol; 1.20 eq.) instead of 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid and using 3-fluoro-4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline (105.00 mg; 0.33 mmol; 1.00 eq.) instead of 4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline, and was obtained as a brown solid (106 mg, 49%). (HPLC (method F): 94%, RT: 4.43 min); MS (m/z) 662 [M+H]+, RT: 3.8 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:23]([NH2:34])[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1.Cl>>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH2:23][N:34]2[C:17](=[O:19])[C:9]3[CH:8]=[C:7]4[CH2:6][CH:5]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])[CH2:13][C:12]4=[CH:11][C:10]=3[C:14]2=[O:16])[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: COc1ccc(CN)cc1OC
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(OC)c(OC)c1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with veratrylamine (0.20 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 106 as a white solid (m.p. 233-235° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].Cl>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 125.8 %

Procedure:
1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (18 mL) and cooled to 0° C. 2N NaOH (7.03 mL, 14.06 mmol) and 30% peroxide (14.07 mL) were added and the reaction was stirred at room temperature for 45 minutes. The reaction was acidified to pH=2 by addition of 2N HCl and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 1-benzyl-1H-pyrazol-4-ol (1.54 g) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.25-7.21 (m, 3H), 7.08-7.07 (m, 3H), 6.91 (s, 1H), 5.06 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8](=[N:10][OH:11])[NH2:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH:18](OCC)(OCC)OCC>B(F)(F)F.CCOCC>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]2[N:9]=[CH:18][O:11][N:10]=2)=[CH:4][C:3]=1[C:14]([F:15])([F:16])[F:17]
Reactant: NC(/C=C/c1ccc(Cl)c(C(F)(F)F)c1)=NO
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: FC(F)(F)c1cc(/C=C/c2ncon2)ccc1Cl
Reaction time: 2 h
Yield: 71 %

Procedure:
5.2 g (0.02 mol) of (E)-4-chloro-3-trifluoromethyl-cinnamamide oxime are introduced into 50 ml of triethyl orthoformate and 2 drops of boron trifluoride etherate are added at room temperature. The mixture is then stirred for 2 hours at reflux temperature and the entire batch is concentrated in vacuo. The residue is taken up in 100 ml of methylene chloride and washed in succession with 100 ml of 2N hydrochloric acid, saturated sodium carbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is subsequently distilled off. 3.9 g (71.0% of theory) of (E)-3-(4-chloro-3-trifluoromethyl-styryl)-1,2,4-oxadiazole are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CS(=O)[O-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
A stirred suspension of 4-bromobenzyl bromide (1.0 g, 4.0 mmol) and sodium methanesulfinate (2.04 g, 20 mmol) in DMF (10 mL) is heated 1 h at 60° C. The reaction mixture is then cooled to RT, diluted with water (200 mL) and extracted into EtOAc (3×25 mL). The combined EtOAc phases are washed with water (2×50 mL) and brine (25 mL) then dried (MgSO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]([C:4]12[CH2:13][C:8]3([OH:14])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([Cl:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3].CN(C)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]([C:4]12[CH2:13][C:8]3([O:14][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([Cl:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(Cl)C12CC3CC(O)(C1)CC(C(=O)Cl)(C3)C2
Agent: CN(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC12CC3CC(C(=O)Cl)(C1)CC(C(=O)Cl)(C3)C2

Procedure:
The 1,3-dichloroformyl-5-hydroxyadamantane was dissolved in methylene chloride. To this solution were added a small amount of trimethylamine, and then an equimolar amount of trimethylsilyl chloride. Reaction was carried out at room temperature to obtain 1,3-dichloroformyl-5-trimethylsiloxyadamantane.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[C:4]([CH3:8])=[N:3]1.Cl[C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=[O:20])[C:13]([Cl:28])=[CH:12][N:11]=1>>[Cl:28][C:13]1[C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:15][C:10]([NH:7][C:5]2[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:11][CH:12]=1
Reactant: CNC(=O)c1cc(F)ccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1nn(C)cc1N
Product: CNC(=O)c1cc(F)ccc1Nc1cc(Nc2cn(C)nc2C)ncc1Cl

Procedure:
1,3-Dimethyl-1H-pyrazol-4-amine and 2-(2,5-dichloropyridin-4-ylamino)-5-fluoro-N-methylbenzamide were reacted according to the procedure of example 3.40 to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-5-fluoro-N-methylbenzamide (16.1 mg) as a beige solid. 1H NMR spectrum: (300 MHz, DMSO) δ 2.06 (3H, s), 2.77 (3H, d), 3.69 (3H, s), 6.60 (1H, s), 7.40 (1H, m), 7.55 (2H, m), 7.81 (1H, s), 7.93 (1H, s), 8.01 (1H, s), 8.72 (1H, m), 9.70 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =389
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]([NH2:34])([CH3:33])[CH3:32]>>[C:31]([NH:34][C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][N:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=2)[CH:24]=[CH:23][CH:22]=1)=[O:21])([CH3:33])([CH3:32])[CH3:30]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)N
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12

Procedure:
5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.10 g, 0.20 mmol) and 2-methylpropan-2-amine (0.020 g, 0.30 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.88 (d, J=7.02 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J=1.22 Hz, 1H), 7.95-8.02 (m, 3H), 7.87-7.93 (m, 3H), 7.58-7.64 (m, 1H), 7.47 (dd, J=7.32, 1.83 Hz, 1H), 7.33 (t, J=9.00 Hz, 2H), 2.82 (d, J=4.58 Hz, 3H), 1.43 (s, 9H). LCMS: retention time: 2.940 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 445 (MH+).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][CH2:32][CH2:33][C:34]#[CH:35]>>[CH2:35]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH2:34][CH2:33][C:32]#[CH:31]
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C#CCCC
Agent: [Cl-]
Agent: [Na+]
Product: C#CCCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 4-pentine chloride are treated as described in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=3)[S:12][C:11]=2[C:22]2[N:26]=[CH:25][N:24](C3CCCCO3)[N:23]=2)[OH:9])=[CH:4][CH:3]=1.C(O)(C)(C)C.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=3)[S:12][C:11]=2[C:22]2[NH:26][CH:25]=[N:24][N:23]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1ncn(C2CCCCO2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1nnc[nH]1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of (4-Chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol (0.261 g, 0.554 mmol), tert-butyl alcohol (3.9 mL, 41 mmol), 1,4-dioxane (2.6 mL, 33 mmol) and 4.00 M HCl in dioxane (3.66 mL, 16.6 mmol) was heated at 70° C. for 2 h. The mixture was cooled down. A small amount of water was added, followed by the addition of sodium bicarbonate (0.745 g, 8.87 mmol). The mixture was stirred for 10 min and then evaporated in vacuum. The residue was purified by (HPLC to afford 4-chlorophenyl)[5-(2-fluoropyridin-4-yl)-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol as a white solid. LCMS: (AA) ES+ 387.2, 389.1; 1H NMR (300 MHz, d4-methanol) δ: 8.51 (s, 1H), 8.18 (d, J=5.41 Hz, 1H), 7.73 (s, 1H), 7.60-7.44 (m, 3H), 7.37-7.23 (m, 3H), 6.76 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Br:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[F:20])=[O:28]
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.141 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.029 g, 0.141 mmol), HATU (0.064 g, 0.169 mmol) and DIPEA (0.029 mL, 0.169 mmol) in DMF (1 mL) was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative LCMS (acetonitrile:water with 0.1% formic acid) to give the title compound (15 mg, 19.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (br. s., 1H), 7.77 (s, 1H), 7.57 (d, 1H), 7.45 (s, 1H), 7.40 (d, 1H), 7.25 (t, 1H), 4.18-4.59 (m, 2H), 2.21 (s, 3H). ES MS: m/z 541, 543.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][S:5][C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12].C(OO)(=[O:22])C>C(O)(=O)C.O>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12])=[O:22]
Reactant: Cc1cc(O)c(SCc2ccc(Cl)cc2Cl)c(=O)o1
Reactant: CC(=O)OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)Cc2ccc(Cl)cc2Cl)c(=O)o1

Procedure:
3-(2,4-Dichlorobenzylthio)-4 -hydroxy-6-methyl-2-pyrone (13.0 g., 0.041 mole) and 40% peroxyacetic acid (7.8 g., 0.041 mole) were dissolved in glacial acetic acid (200 ml.). The solution was allowed to stand at room temperature for two weeks, then was diluted with water and extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness, leaving 12.6 g. (93 percent) of an off-white solid. Recrystallization from benzene gave the pure product as white needles, m.p. 144°-146°C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2](/[CH:19]=[CH:18]/[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: OCc1ccc(Cl)cc1Br
Reactant: C=Cc1ccc(F)cc1
Product: OCc1ccc(Cl)cc1/C=C/c1ccc(F)cc1

Procedure:
The title compound was prepared from (2-bromo-4-chlorophenyl)methanol and 4-fluoro-1-vinylbenzene according to the procedure for the preparation of Example 119, part B. 1H NMR (400 MHz, CDCl3): δ 1.72 (1H, t, J=5.6 Hz), 4.77 (2H, d, J=5.2 Hz), 6.98-7.08 (3H, m), 7.22-7.34 (3H, m), 7.47-7.50 (2H, m), 7.60 (1H, d, J=1.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])C([O-])=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11]
Reactant: Nc1c(Cl)cc(C(=O)[O-])cc1Cl
Solvent: O
Product: Nc1c(Cl)cccc1Cl
Temperature: 250 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
0.2 mole=41.2 g 3,5-dichloro-4-amino-benzoate were initially introduced into an autoclave together with 250 ml of water. The mixture was heated to 250° C. and stirred at this temperature for eight hours. The product was then recovered by steam distillation. 26 g of 2,6-dichloroaniline were obtained in a purity of 99.8%, corresponding to a yield of 80%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:66][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-allyloxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry isopropyl alcohol (3 ml) is added benzyl amine (86.5 mg). The mixture is stirred at r.t. for 30 minutes, and then cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH3:26])[C:20](=[O:27])[CH:19]=[C:18]2[CH3:28].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:25]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:24][CH:23]=2)[C:18]([CH3:28])=[CH:19][C:20]1=[O:27])[CH3:26]
Reactant: CCn1c(=O)cc(C)c2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1c(=O)cc(C)c2cc(N3CCN(c4cnccc4C)C3=O)ccc21
Yield: 27.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 99 mg, 0.5597 mmol) was reacted with 6-bromo-1-ethyl-4-methyl-1H-quinolin-2-one (150 mg, 0.5597 mmol), 1,4-dioxane (5 mL), copper iodide (10.66 mg, 0.05597 mmol), trans-1,2-diamino cyclohexane (19.22 mg, 0.1679 mmol) and potassium carbonate (77.37 mg, 1.1194 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 56 mg of the product (28.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:9]=[C:8]([CH:10]=O)[C:7]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:6]1)=[O:4].[NH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(=O)C>CO>[CH3:1][O:2][C:3]([N:5]1[CH:9]=[C:8]([CH:10]=[N:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:6]1)=[O:4]
Reactant: COC(=O)n1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Reactant: NN1CCOCC1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)n1cc(C=NN2CCOCC2)c(-c2ccc([N+](=O)[O-])o2)n1
Yield: 70 %

Procedure:
Stir together 6.7 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde, 2.85 g of 4-aminomorpholine and 1.6 ml of glacial acetic acid in 125 ml of methanol for 3 hours at room temperature. Cool the resulting admixture on ice to produce a precipitate. Vacuum filter the precipitate and then suspend it once more in ethanol to obtain a 70% yield of 4-[1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazol-4-ylmethyleneamino]morpholine [m.p. 184° C (with decomposition)].
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:17])[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@H:19]([C@H:21]1[CH2:25][N:24]([C@@H](C2C=CC=CC=2)C)[C:23](=[O:34])[CH2:22]1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:19]([C@H:21]3[CH2:25][NH:24][C:23](=[O:34])[CH2:22]3)[CH3:20])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cc(-c2ccccc2)cc2ncccc12
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccccc2)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 21 h
Yield: 17.8 %

Procedure:
30 mg of 7-Phenylquinolin-5-ol, 32.5 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one and 150 mg of triphenylphosphine were dissolved in 3 mL of DCM. 125.5 mg of Di-tertbutyl-azodicarboxylate (DBAD) was added and the mixture stirred for 21 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash column chromatography (FCC) (20 SiO2; cyclohexane→cyclohexane: ethylacetate: MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 2 mL of trifluoroacetic acid (TFA) and heated 45 min at 150° C. in the microwave. The mixture was purified with rpHPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 8 mg of Example 1 as solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H][H]>CCO.Cl.[Rh]>[CH:1]1([C:11]([OH:13])=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1
Reactant: [H][H]
Reactant: O=C(O)c1nccc2ccccc12
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: O=C(O)C1NCCC2CCCCC21
Yield: 56.8 %

Procedure:
A solution of 1-isoquinolinecarboxylic acid (50 g, 0.288 mol) in EtOH (150 mL) and 60 mL of 5N HCl was reduced over 5% Rh/Al2O3 (14 g) at 52 bar (750 psi) of hydrogen in a high pressure apparatus at 50° C. for 17 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. The solid was triturated with water, filtered and dried to give DL-perhydro-1-isoquinolinecarboxylic acid (DL-1-Piq-OH) (30 g, 48%) FD-MS 184 (MH+).