Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:38]=[CH:37][C:36]([C:39]4[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=4)[C:42](O)=[O:43])=[CH:35][C:29]=3[C:30]=2[C:31](=[O:34])[NH:32][CH3:33])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[CH2:12]([N:11]([CH3:10])[C:42]([C:41]1[CH:40]=[C:39]([C:36]2[CH:37]=[CH:38][C:28]3[O:27][C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[C:30]([C:31]([NH:32][CH3:33])=[O:34])[C:29]=3[CH:35]=2)[CH:47]=[CH:46][CH:45]=1)=[O:43])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CNCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N(C)Cc4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
DIPEA (50 μL, 0.29 mmol) and N-methylbenzylamine (20 μL, 0.16 mmol) were added to a stirred suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol) and HATU (25 mg, 0.066 mmol) in DMF (0.5 mL) and the reaction was stirred at r.t. overnight. The reaction was then diluted with MeOH, filtered, purified by prep HPLC, and concentrated to give the title compound as a tan powder (12 mg, 47% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (br. s., 1H) 8.01 (dd, J=8.39, 5.65 Hz, 2H) 7.66-7.93 (m, 5H) 7.58 (br. s., 1H) 7.42-7.50 (m, 1H) 7.35-7.42 (m, 4H) 7.31 (d, J=5.80 Hz, 1H) 7.23 (d, J=4.58 Hz, 1H) 4.72 (br. s., 1H) 4.54 (br. s., 1H) 2.83-3.00 (m, 6H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.85 min, (ES+) m/z (MH+)=493. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=16.26 min, purity=99%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=12.81 min, purity=98%.
Reaction SMILES: C([NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19])=[O:8])(=O)C(C)C.[OH-:20].[K+]>>[Cl:18][C:14]1[CH:15]=[CH:16][C:17]([NH:9][C:7]([NH2:6])=[O:8])=[C:12]([CH2:11][C:10]([OH:19])=[O:20])[CH:13]=1
Reactant: CC(C)C(=O)NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: [OH-]
Agent: [K+]
Product: NC(=O)Nc1ccc(Cl)cc1CC(=O)O

Procedure:
The title compound was prepared in 43% yield by hydrolysis of N-isobutyryl-5-chloro-2-oxindole-1-carboxamide with 1N potassium hydroxide, substantially according to the procedure of Preparation 1. After hydrolysis was complete and the reaction mixture was acidified, the product precipitated. It was recovered by filtration and recrystallized from ethanol to give the title compound as colorless crystals, m.p. 187.5° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1>CN(C=O)C>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)[CH:23]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(N)c2[N+](=O)[O-])cn1

Procedure:
A solution of 3-chloro-2-nitro-aniline (CXXI) (1.0 g, 5.8 mmol), potassium carbonate (2.4 g, 17.4 mmol), and 4-methylimidazole in dry DMF was heated overnight at 120° C. under nitrogen. The reaction was cooled and the solvent was evaporated in vacuo. The residue was suspended in a saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to provide 3-(4-methyl-imidazol-1-yl)-2-nitro-phenylamine (CXXIX). 1H NMR (CDCl3, 400 MHz) δ ppm 2.19 (s, 3H), 6.53 (m, 1H), 6.79 (m, 1H), 6.93 (m, 1H), 7.32 (m, 1H), 7.60 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C@:14]2([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([O:32]2)[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=C(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@@]2(Cc3ccccc3)O[C@H]2C1
Reaction time: 2 h

Procedure:
To a solution of 36.0 g (117 mmol) of 4-benzyl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester in 250 ml CH2Cl2 were added 40.9 g (166 mmol, ˜70%) MCPBA. The reaction mixture was stirred for 2 hours and a 1N NaOH-solution was added. The aqueous phase was extracted twice with CH2Cl2 and the combined organic layers were washed with 1 N NaOH, dried over MgSO4 and the solvent was removed under reduced pressure to give 37.6 g (116 mmol, 99%) of (1R,6S) and (1S,6R)-6-benzyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester as an oil.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCC(C(=O)c3ccc(F)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and (4-fluoro-phenyl)-piperidin-4-yl-methanone via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H26FNO6 [M+H]+: 444.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To a solution of 5-bromo-2-(tert-butoxycarbonyl)aminopyridine (25.0 g, 91.5 mmole) in DMF (400 mL) was added portionwise with stirring a 60% dispersion of NaH in mineral oil (4.0 g, 100 mmole). The reaction was stirred for 15 min, then methyl bromoacetate (15 mL, 158.5 mmole) was added dropwise over 15 min. After stirring for 18 h at room temperature the reaction was concentrated to dryness. The remaining residue was taken up in EtOAc (200 mL) and H2O (200 mL) and filtered to remove insoluble material. The EtOAc phase was separated, washed with brine, dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (10% EtOAc/Hexane) gave the title compound (16.56 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 7.73 (d, J=2.5 Hz, 1 H), 7.71 (d, J=2.5 Hz, 1 H), 4.69 (s, 2 H), 3.75 (s, 3 H), 1.51 (s, 9 H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][NH:15][C:16]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:12]=2)[C:7]([NH:24][C:25]([NH2:27])=[NH:26])=[N:6][CH:5]=1.Cl.N[C:30](N)=N.COC(=O)C1(CCCC1)NCC1C=C2C(C(Cl)=CN=C2Cl)=CC=1.Cl>CS(C)=O.C(Cl)Cl.CO.O>[CH3:30][O:22][C:21](=[O:23])[C:16]1([CH2:17][CH2:18][CH2:19][CH2:20]1)[NH:15][CH2:14][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([Cl:3])=[CH:5][N:6]=[C:7]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:12][CH:11]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(CNC3(C(=O)O)CCCC3)cc12
Reactant: N=C(N)N
Agent: COC(=O)C1(NCc2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)C1(NCc2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 4.6 %

Procedure:
N-({4-Chloro-1-guanidino-7-isoquinolinyl}methyl)cycloleucine dihydrochloride ##STR99## NaH (52 mg, 80% dispersion in mineral oil, 1.73 mmol) was added to a slurry of guanidine hydrochloride (265 mg, 2.77 mmol) in DMSO (2.5 ml) and the mixture heated to 50° C. for 20 mins. N-[(1,4-Dichloro-7-isoquinolinyl)methyl]cycloleucine methyl ester (245 mg, 0.69 mmol) in DMSO (2.5 ml) was added and after heating at 90° C. for 41/2 h, the solution was poured into water (50 ml). The mixture was extracted with EtOAc (2×), the combined organic extracts washed with water, brine and then dried (Na2SO4). The residue was purified by column chromatography upon silica gel eluting with CH2Cl2 -MeOH -0.880 NH3 (90:10:1) to give a yellow solid. This was dissolved in a CH2Cl2 -MeOH solution and acidified with ethereal HCl (1N), concentrated in vacuo and the crude product recrystallised from EtOH to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)methyl]cycloleucine methyl ester (30 mg, 0.08 mmol) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9]2)[CH:5]=[C:4]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]4[NH:38][CH:39]=[CH:40][C:33]=34)=[C:27]([F:41])[CH:26]=2)[N:3]=1>C(O)C.[Pd]>[F:41][C:27]1[CH:26]=[C:25]([NH:24][C:4]2[CH:5]=[C:6]([CH:8]3[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH:30]=[CH:29][C:28]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[NH:38][CH:39]=[CH:40][C:33]=12
Reactant: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCNC2)n1

Procedure:
At room temperature, 1.36 g (2.46 mmol) of benzyl 3-(2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)piperidine-1-carboxylate (from example LXXIV) and 0.4 g of 10% palladium-on-carbon in ethanol are stirred under an atmosphere of hydrogen for 24 hours. The suspension is filtered off with suction through Celite®, and the filtrate is concentrated.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([OH:13])=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[N:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=1>C(#N)C>[Cl:34][C:31]1[N:30]=[N:29][C:28]([NH:27][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([F:1])[C:3]=2[OH:14])=[O:13])=[CH:33][CH:32]=1
Reactant: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Reactant: Nc1ccc(Cl)nn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1c(F)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
300 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid and 266 mg of carbonyldiimidazole were added to 5 ml of acetonitrile. The mixture was stirred for 1 hour under heat refluxing condition. Thereafter, 212 mg of 3-amino-6-chloropyridazine was added to the mixture, and this was further stirred for 1 hour under heat refluxing condition. The reaction mixture was cooled to room temperature and crystals were produced. The crystals were collected by filtration to obtain 250 mg of N-(6-chloro-3-pyridazinyl)-5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (present compound 19):
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[S:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:14]=1
Reactant: Clc1cc(Sc2c(Cl)cccc2Cl)ccn1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Sc3c(Cl)cccc3Cl)ccn2)n1
Yield: 65.2 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.196 g, 1.72 mmol), 2-chloro-4-(2,6-dichlorophenylthio)pyridine (0.500 g, 1.72 mmol), potassium phosphate (0.402 g, 1.89 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.050 g, 0.86 mmol) were reacted to provide N-(4-(2,6-dichlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (0.413 g, 65% yield) as a white powder. 1H NMR (d6-DMSO) δ 11.03 (s, 1H), 8.09 (d, 1H), 7.77 (d, 2H), 7.64 (t, 1H), 6.58 (s, 1H), 6.57 (d, 1H), 6.52 (s, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[S:15](Cl)(=[O:17])=[O:16]>>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[S:15]([NH:3][CH2:1][CH3:2])(=[O:17])=[O:16]
Reactant: CCN
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using ethylamine and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CDCl3) δ 8.43-8.38 (m, 1H), 7.93-7.86 (dd, J=8.3, 0.9, 1H), 7.70-7.62 (m, 1H), 5.08 (s, 1H), 3.11-2.96 (m, 2H), 1.19-1.09 (t, J=7.2, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH2:20][C:21]2[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.[N:30]#[C:31][NH2:32].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:31]([NH:32][C:27]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)[CH:17]=[C:9]2[C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[N:26]=1)=[O:29])#[N:30]
Reactant: N#CN
Reactant: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(C(=O)NC#N)n1
Temperature: 25 °C
Reaction time: 35 h
Yield: 74.1 %

Procedure:
To a solution of 6-[2-(2,5-difluorophenyl)-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylic acid (70 mg) in dichloromethane (1.8 mL) were successively added cyanamide (8.2 mg), 4-dimethylaminopyridine (48 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg). This mixture was stirred for 35 hours at room temperature. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-methanol) to obtain the title compound (55 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.37 (2H, s), 6.45 (1H, d, J=7.4 Hz), 6.66 (1H, s), 6.79 (1H, dd, J=2.4, 8.9 Hz), 7.10-7.45 (4H, m), 7.50-7.85 (3H, m). ESI-MS (m/z): 419 (M+H)+
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([OH:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:4][CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[N:29]=[C:30]=[O:31]>ClCCl>[CH3:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]=1[NH:29][C:30]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([OH:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:4][CH2:3]1)=[O:31]
Reactant: COc1ccccc1OCC(O)CN1CCC(N)CC1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: ClCCl
Product: COc1ccccc1OCC(O)CN1CCC(NC(=O)Nc2c(C)cccc2C)CC1

Procedure:
A solution of 1-(4-aminopiperidyl)-3-(2-methoxyphenoxy)propan-2-ol (40 mg) and 2,6-dimethylphenylisocyanate (30 μl) in dichloromethane (1 ml) was refluxed for 2 hours, after which time a further 20 μl of 2,6-dimethylphenylisocyanate was added, and the mixture refluxed for a further 2 hours. Solvent was removed under reduced pressure, and the residue flash chromatographed (0–6% methanol/dichloromethane), to provide [(2,6-dimethylphenyl)amino]-N-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl](4-piperidyl)}carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[Br-].[F:27][C:28]1[CH:33]=[CH:32][C:31]([Zn+])=[CH:30][CH:29]=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.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:8][CH2:9][C:10]=1[C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)=[O:4]
Reactant: Fc1ccc([Zn+])cc1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 6 h

Procedure:
To a mixture of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (10.1 g, 25.9 mmol), 4-fluorophenylzinc bromide solution (0.5 M in THF, 86.3 ml, 43.1 mmol) and 290 ml THF was added tetrakis(triphenylphosphine)palladium(0) (0.83 g, 0.72 mmol) at RT. After stirring for 6 h the reaction was quenched with ice. The mixture was diluted with tert-butyl methyl ether and washed with 2 M aqueous sodium carbonate solution. The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (heptane/ethyl) gave the title compound as a lightly yellow amorphous residue (6.8 g, 71%).
Reaction SMILES: O1CCCC1.[H-].[Na+].[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[C:18]([O:36][CH2:37][CH2:38][OH:39])=[N:19][N:20]([CH3:35])[C:21]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:16][C:11]=2[O:10][CH2:9]1.[Cl:40][C:41]1[CH:42]=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1>CC(N(C)C)=O>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[C:18]([O:36][CH2:37][CH2:38][O:39][C:44]4[N:45]=[CH:46][C:41]([Cl:40])=[CH:42][N:43]=4)=[N:19][N:20]([CH3:35])[C:21]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
In an oven-dried flask a solution of tetrahydrofuran (50 ml) and dimethylacetamide (3 ml) was treated with sodium hydride as a 60% dispersion in oil (460 mg) under an atmosphere of nitrogen. The reaction was stirred for 5 min and then treated with N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (1.0 g) (Preparation 13). The reaction was stirred for 3 h and was then treated with 5-chloro-2(methylsulfonyl)pyrimidine (460 mg). After stirring for a further 3 h the reaction mixture was concentrated and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous was extracted with ethyl acetate (3×75 ml) and the combined organics were dried over sodium sulfate. The solvent was removed and the crude residue was purified on a silica (40 g) column eluting with 20% ether in dichloromethane rising to 45% ether in dichloromethane to yield the title compound as an off-white foam (560 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:16]O>>[CH3:16][O:12][C:11](=[O:13])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:2]([CH3:1])[CH3:14]
Reactant: CN(C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C

Procedure:
100 ml of methanol and 10 g (0.05 mol) of N,N-dimethylphenylalanine (prepared in accordance with Y. Ikutani, Bull. Chem. Soc. Jpn. 41, 1679 (1968)) are placed in a 350 ml sulfonating flask having an anchor mixer, thermometer, reflux condenser and gas introduction tube and, with stirring, saturated with HCl gas. The solution is stirred at reflux for 8 hours, then cooled, and the solvent is evaporated in a rotary evaporator. The residue is taken up in 250 ml of methylene chloride and washed first with 10% aqueous NaHCO3 solution and then with H2O until neutral. The reaction mixture is then dried over MgSO4, filtered and concentrated by evaporation. The residue is purified by flash chromatography (hexane/ethyl acetate=7:3), yielding 5.0 g of N,N-dimethylphenylalanine methyl ester in the form of a slightly yellow liquid. NMR analysis and IR spectrum agree with the said structure.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:37]([C:34]1([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:36][CH2:35]1)#[N:38]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC1(NC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CC1
Reaction time: 1 h
Yield: 20.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 60 mg, 0.139 mmol), 1-aminocyclopropanecarbonitrile-HCl (24.74 mg, 0.21 mmol), HATU (68.8 mg, 0.181 mmol), and 4-methylmorpholine (56.3 mg, 0.556 mmol) were dissolved in DMF (1 mL). After stirring 1 h, this was purified by prep HPLC (PHENOMENEX® 21.0×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.8 min) to provide single enantiomer N-(1-cyanocyclopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.028 mmol, 20.46% yield): LCMS=496.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.52-7.79 (7 H, m), 5.16 (1 H, s), 1.42-1.61 (2 H, m), 1.12-1.34 (2 H, m); HPLC peak RT=9.9 min (Method A).