Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21][CH:22]=[O:23])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][CH2:21][CH:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:23])(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1ccc(S(=O)(=O)CCC=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)CCC(O)c2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
Part B: To 11.4 mL (3.2 g, 23 mM) of a 2.0 M phenylmagnesium chloride solution in THF at zero° C., was added 2.6 g (11 mmol) of 3-[(4-methoxyphenyl)sulfonyl]propan-1-al from Part A in 20 mL of THF. After 1.5 hours, the reaction mixture was cooled to zero° C. and 20 mL of saturated ammonium chloride solution was added, followed by ethyl acetate and water, the organic layer was separated and washed with 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 2.7 grams of crude product. This was chromatographed on silica gel using 35%-40% ethyl acetate/hexane to yield 1.7 g of pure 3-[(4-methoxyphenyl)sulfonyl]-1-phenylpropan-1-ol, m/z=324 (M+NH4).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:6][C:5]=2[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][NH:39][CH2:40][C:41]1[O:42][C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[C:45]=1[CH3:46].CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH3:38][N:39]([CH2:40][C:41]1[O:42][C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[C:45]=1[CH3:46])[C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:2](=[O:1])[CH2:3][CH2:4][C:5]=2[CH:6]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1oc2ccccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)oc2ccccc12
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7.5 L, 5 v) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (1.49 kg, 4.98 mol, 1.0 eq.). To the yellow suspension, HOBT (0.74 kg, 5.48 mol, 1.1 eq.), EDCI (1.15 kg, 5.98 mol, 1.2 eq) and N-methyl-1-(3-methylbenzofuran-2-yl)methanamine (0.96 kg, 5.48 mol, 1.1 eq) were added. During the addition an exotherm was observed and the temperature increased from 20.3° C. to 36.4° C. To the resulting thick suspension was added DIPEA (1.93 kg, 14.94 mol, 3 eq.) and an exotherm was observed to 41.9° C. During the addition the suspension changed to a clear brown solution. The resulting solution was stirred at 38-42° C. After about 45 min a new solid started to form. After stirring for 1.5 h, ˜1 mL of suspension was taken, the progress of the reaction was monitored by HPLC and the results indicated >95% reaction completion. After another 16 hours of stirring at the same temperature, 1H NMR and HPLC analysis indicated the reaction was complete. Half of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask containing a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. The contents of both flasks were allowed to cool to 20-25° C. and each reaction mixture was diluted with H2O (8 L, 5.3 v) over 15 min. Both reaction mixtures showed an exotherm during the water addition to 30-35° C. The resulting suspensions were allowed to stir at 20-25° C. for 3.5 h. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with water (4×1.4 v), heptane (1×1.4 v) and ethyl acetate (3×1 v). The damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 120 h to a constant weight to give 1.67 kg of the title compound as yellow solid. The material was analyzed indicating 98.48 area % HPLC purity with 146 ppm residual Pd.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][O:20][CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COCCl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-amino-5-nitrophenol (4.62 g) in N,N-dimethylformamide (150 no) was added potassium carbonate (12.44 g), and thereto was added dropwise chloromethylmethylether (2.73 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel; solvent; n-hexane/ethyl acetate=2/1) to give [2-(methoxymethoxy)-4-nitrophenyl]amine (4.76 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH2:28].ClCCl>CCCCCC>[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH:28][C:10](=[O:12])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH3:13]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-3-nitro-phenyl)-propionic acid (0.60 g, 2.70 mmol), SOC2 (0.96 mL, 13.0 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (0.77 g, 3.50 mmol). After normal workup, the pure objective compound (0.98 g, 82%) was obtained as white solid by recrystallization (dichloromethane:n-hexane=1:3): m.p 122° C.; 1H NMR (200 MHz, CDCl3) δ 1.60 (d, J=7.2 Hz, 3H, CH3), 3.65-3.84 (m, 4H, CO2CH3 & CH), 7.55 (dd, J=8.8, 2.2 Hz, 1H, ArH), 7.84 (d, J=2.2 Hz, 1H, ArH), 8.44 (d, J=2.0 Hz, 1H, ArH), 9.51 (br s, 1H, NH).
Reaction SMILES: C1(=O)[N:5]([C:6]2[N:11]=[C:10]([NH:12][C:13](=[O:33])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:9]=[CH:8][CH:7]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21](=[O:32])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N3C(=O)c4ccccc4C3=O)n2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N)n2)cc1
Yield: 29.8 %

Procedure:
To a stirred solution N-(6-phthalimidopyridin-2-yl)-2-[(4-tert-butylbenzoyl)amino]benzamide (230 mg, 0.44 mmol) in ethanol (15 mL) was added hydrazine hydrate (0.22 g, 4.4 mmol). After refluxing the mixture for 30 min, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution, twice with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in a minimal amount of chloroform and chromatographed (silica gel, eluting with a gradient of chloroform to 2% methanol/98% chloroform. The appropriate fractions were combined and concentrated In vacuo to give 51 mg (30%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](C1COC(=O)N1)C1C=CC=CC=1>C1COCC1>[CH3:23][O:20][C:19]([CH:17]1[CH2:18][CH:16]1[C:12]1[CH:11]=[C:10]([F:22])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([F:15])[CH:13]=1)=[O:21]
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=C(O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Solvent: C1CCOC1
Product: COC(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Yield: 75 %

Procedure:
Mixture (41 mg) of 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid obtained in Step A and 4-benzyloxazolidine-2-on was dissolved in THF (2 mL), and CH2N2 (0.25M in Et2O, 1 mL, 0.158 mmol) was added thereto. The mixture was reacted at room temperature for 1 hour, and then the reactant was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (22.7 mg, two-step yield 75%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:37]C=2C=1.[Cl-].N.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:37])=[O:18])=[CH:15][CH:14]=1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCc1ccc(C(N)=O)cc1
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 4-[2-{(2R)-2-[(1E,3S)-3-hydroxy-oct-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid (71.90 mg, 0.2 mmol) in DMF (1 mL) was added EDC (57.51 mg, 0.3 mmol), HOBt (40.54 mg, 0.3 mmol), ammonia chloride (21.40 mg, 0.4 mmoL) and DIPEA. The mixture was stirred for overnight. After evaporation of the solvent, the residue was purified through RP-HPLC using ACN and H2O/0.1% TFA to afford the desired product (70 mg) as a white solid. 1HNMR (CD3OD, ppm) δ 0.879 (m, 3H), 2.297 (br, 6H), 1.49 (m, 2H), 1.75 (m, 1H), 2.19 (m, 1H), 2.34 (m, 2H), 2.89 (m, 2H), 3.17 (m, 1H), 3.73 (t, J=7.0 Hz, 1H), 4.04 (t, J=6.2 Hz, 2H), 5.45 (dd, J=8.8 and 15.1 Hz, 1H), 5.66 (dd, J=6.6 and 15.1 Hz, 1H), 7.30 (d, J=7.7 Hz, 2H), 7.82 (d, J=7.7 Hz, 2H), (m/z): 381.4 (+Na+).
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: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
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: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28](O)=[O:29])=[CH:22][C:21]=1[Cl:31])([CH3:19])([CH3:18])[CH3:17].CN1CCOCC1>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[CH:22][C:21]=1[Cl:31])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ncc(OCC(=O)O)cc1Cl
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ncc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1Cl
Yield: 30.6 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (192 mg, 0.751 mmol) was reacted with (6-tert-butyl-5-chloro-pyridin-3-yloxy)-acetic acid (183 mg) DMTMM (1.1 eq, 229 mg) and NMM (1.2 eq, 100 μl) in THF to give the title compound (102 mg, 30.6%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.C(Cl)(=O)C(Cl)=O.O.[OH-].[NH4+:31]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:31])=[O:8])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C(N)=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a suspension of 4-methoxy-5-benzyloxy-2-nitrobenzoic acid (10.0 g, 33.3 mmol) in anhydrous THF (100 mL) was added oxalyl chloride (4.90 mL, 56.2 mmol) followed by one drop of anhydrous DMF. The mixture was stirred at RT for 16 h, upon which the mixture was poured into water (300 mL) and ammonium hydroxide (50 mL). A solid was separated out, which was collected by filtration and dried under vacuo. The solid was taken up in refluxing methanol (500 mL) and the insoluble solid was collected via filtration and dried under vacuum to give 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.50 g, 21.5 mmol, 65%). HPLC retention time 6.154 min.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([NH:14][NH2:15])=[O:13].C[Al](C)C.[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35](OC)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([NH:15][NH:14][C:12](=[O:13])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: NNC(=O)CN1CCc2ccccc2C1
Reactant: COC(=O)c1cccc(Nc2cc(C)nc3ccccc23)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1C
Product: Cc1cc(Nc2cccc(C(=O)NNC(=O)CN3CCc4ccccc4C3)c2)c2ccccc2n1
Yield: 63.2 %

Procedure:
Ethyl(3,4-dihydro-1H-isoquinolin-2-yl)acetate (90). To a solution of 40 (1.33 g, 10.0 mmol) in acetonitrile (50 mL) were sequentially added potassium carbonate (5.53 g, 40.0 mmol) and ethyl bromoacetate (1.67 g, 10.0 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 90 (2.1 g, 99%). Step 2. (3,4-Dihydro-1H-isoquinolin-2-yl)acetic hydrazide (91). A solution of 90 (2.0 g, 9.12 mmol) and hydrazine (5.1 g, 91 mmol) in ethanol (30 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give 91 (1.87 g ˜100%) which was used without further purification. Step 3. 3-(2-Methylquinolin-4-ylamino)-N′-(2-3,4-dihydro-1H-isoquinolin-2-yl-acetyl)benzoic hydrazide (92). To a solution of 91 (205 mg, 1.0 mmol) in xylene (5 mL) was added trimethyl aluminum (2 M solution in hexanes, 0.75 mL, 1.5 mmol). The mixture was stirred under nitrogen for 10 minutes before the addition of methyl 3-(2-methylquinolin-4-ylamino)benzoate (49) (150 mg, 0.5 mmol). The reaction was heated at reflux overnight, quenched with water (2 mL), basified to pH 9 (2 N NaOH), and extracted with 7:3 CH2Cl2/MeOH. The organic layer was dried (K2CO3) and concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient elution) to give 92 as a pale yellow oil (147 mg, 63%). Step 4. {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]phenyl}-(2-methylquinolin-4-yl)amine. A mixture of 92 (195 mg, 0.42 mmol) in phosphorous oxychloride (0.5 mL) was heated overnight before mixing cautiously with ice water (2 mL). The mixture was extracted with 7:3 CH2Cl2/MeOH, and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution) to give the desired product as a pale yellow solid (69 mg, 37%).
Reaction SMILES: C(C[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(O)=O.C(Cl)(=O)C(Cl)=O.[C:31]1([C:37]2[O:38][C:39](=[O:52])[CH:40]([CH2:42][C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][CH:44]=3)[N:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[C:37]([NH:41][CH:40]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39](=[O:52])[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1OC(c2ccccc2)=NC1Cc1c[nH]c2ccccc12
Reactant: CN(CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[[[(2-Carboxyethyl)methylamino]carbonyl]-L-proline, phenylmethyl ester (3.2 g., 10 mmole) is taken into 33 ml. of dry tetrahydrofuran with stirring at 5°. Oxalyl chloride (1.05 ml., 12 mmole) is added dropwise followed by 4 drops of dimethylformamide. After 20 minutes the ice bath is removed and after stirring for one hour at room temperature the reaction mixture is concentrated to dryness, taken into 20 ml. of tetrahydrofuran, chilled and added dropwise to 2-phenyl-4-[(1H-indol-3-yl)methyl]-5(4H)-oxazolone (3.0 g., 10.5 mmole) in 16 ml. of dry tetrahydrofuran with stirring in an ice bath. Triethylamine (1.7 ml., 12 mmole) is then added to the reaction mixture. After 15 minutes the ice bath is removed and the reaction is run overnight at room temperature. The triethylamine hydrochloride salt is filtered off and the filtrate is concentrated to dryness, taken into 10.6 ml. of pyridine, 33.3 mg. of 4-dimethylamino pyridine is added, and the mixture is stirred for 3 hours. Acetic acid (10.6 ml.) is added and the reaction is heated for 45 minutes at 100° under an argon atmosphere. The reaction mixture is concentrated to dryness, taken into ethyl acetate, and washed with saturated sodium bicarbonate and dilute hydrochloric acid. The crude product (4.6 g.) is purified on a silica gel column in ethyl acetate: benzene (2:1) to yield 523 mg. of (±)-1-[[[3-(benzoylamino)-4-(1H-indol-3-yl)-2-oxbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13](S)=[N:12][CH:11]=2)=[CH:4][CH:3]=1.BrCC1C=CC(OC(F)(F)F)=CC=1B(O)O.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Agent: OB(O)c1cc(OC(F)(F)F)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1)c1cccnc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
As described in Method B, N-(4-fluoro-phenyl)-6-mercapto-nicotinamide IIa (372 mg, 1.5 mmol) and 2-bromomethyl-5-trifluoromethoxy-phenylboronic acid (572 mg, 1.5 mmol) were suspended in DMF (15 ml). To the reaction flask DIPEA (261 μL, 1.5 mmol) was added and the reaction was stirred for 30 minutes. Reaction completion was monitored by LC-MS. Cold water (100 mL) was added and the precipitate was collected by filtration and washed several times with cold water to afford 724.8 mg (88% yield, >90% purity by LC-MS) of the off-white solid product, 6-(2-boronic pinacol ester-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide. ESI-MS m/z=549.1 [M+H]+.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]#[N:16])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH-:17].[Na+].OO>CS(C)=O>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]([NH2:16])=[O:17])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:2]1)[CH2:4]2
Reactant: [OH-]
Reactant: CSc1nc(NC23CC(C2)C3)ncc1C#N
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1nc(NC23CC(C2)C3)ncc1C(N)=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirring solution of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carbonitrile (566 mg, 2.436 mmol) in DMSO (7 mL) was added 6 M aqueous sodium hydroxide solution (2.030 mL, 12.18 mmol) and 30% aqueous hydrogen peroxide solution (1.381 mL, 12.18 mmol) at 0° C. The mixture was then stirred at 50° C. for 30 min and then was poured into ice water (50 mL). The solids that formed were stirred in an ice bath for 30 min, filtered, washed with water, and then dried in a vacuum oven overnight at 45° C. to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carboxamide (410 mg, 1.638 mmol, 67.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 7.03-8.34 (m, 2H), 2.43-2.48 (m, 1H), 2.35 (br. s., 3H), 2.09 (s, 6H). MS (ESI) m/z 251.3 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.I[C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[C:15](C(C)C)[CH:14]=1.[OH:25]CCN.O=S(Cl)Cl>>[OH:25][CH2:4][C:5]1([NH2:6])[CH2:3][CH2:2][CH2:8][CH2:7]1.[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:20]2[S:21][CH2:15][C:16]3([CH2:14][CH2:13][CH2:18][CH2:17]3)[NH:19]2)=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: NCCO
Reactant: CC(C)c1cc(I)ccc1N=C=S
Reactant: CC(C)c1cc(I)ccc1N
Solvent: O=S(Cl)Cl
Product: CC(C)c1cc(I)ccc1N=C1NC2(CCCC2)CS1
Product: NC1(CO)CCCC1

Procedure:
4-Iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-isopropylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2-isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.