Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:37]([N:39]([CH2:40][CH3:41])[CH2:30][CH2:29][CH2:28][NH:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:36])=[CH:3][C:2]=1[F:1])[CH3:38]
Reactant: CCNCC
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 50 °C
Reaction time: 7 h
Yield: 50.2 %

Procedure:
3.50 g (6.65 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 100 mL of dimethylformamide under argon atmosphere, 6.88 mL (66.5 mmol) of diethylamine and 9.18 g (66.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 7 hours. Then, 6.88 mL (66.5 mmol) of diethylamine and 9.18 g (66.5 mmol) of potassium carbonate were further added and the mixture was stirred at 50° C. for 16 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-9:1) to give 1.68 g of 5-(3-diethylaminopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 50%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][N:30]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[S:31]([CH3:34])(=[O:33])=[O:32])=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][N:30]([C:35]1[CH:36]=[CH:37][C:38]([NH:39]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:40][CH:41]=1)[S:31]([CH3:34])(=[O:33])=[O:32])=[O:28])[CH3:25]
Reactant: CCOC(=O)CN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Examples 89 and 187 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-aniline in DMF.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 1,1 '-bis(diphenylphosphine)-ferrocene (1.69 g, 3.05 mmol) and palladium acetate (515 mg, 2.29 mmol) in DMF (250 ml), is heated at 50° for 10 minutes. After the solution has cooled to room temperature methyl p-iodobenzoate (20 g, 76 mmol), 4-fluorobenzenboronic acid (20 g, 143 mmol) and K2CO3 (15.8 g, 114 mmol) are added. The resulting mixture is then heated to 90° for 24 hours. After once again cooling to room temperature the reaction mixture is filtered through Celite and the flitrate washed with EtOAc (3×100 ml). The combined organic portions are then washed with 2N HCl (100 ml), saturated NaCl solution (100 ml), 1N NaOH (100 ml), dried over MgSO4, and concentrated in vacuo. The resulting brown solid is chromatographed (silica gel; hexanes, 1% EtOAc/hexanes) to afford methyl 4'-fluoro-4-biphenylyl-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[OH:15]O>CC(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:3]=1
Reactant: OO
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(NC(=O)C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of N-(4-methylpyridin-2-yl)pivalamide (10 g, 52 mmol) in AcOH (300 ml) was added H2O2 (7.0 ml, 68 mmol) dropwise at 0° C. The mixture was stirred overnight at 70° C. The reaction mixture was quenched with water, extracted with ethyl acetate (200 mL×3) and washed with saturated Na2SO3 solution. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (5% ethyl acetate in petroleum ether) to afford 4-methyl-2-pivalamidopyridine 1-oxide (8.4 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 10.38 (br s, 1H), 10.21 (br s, 1H), 8.34 (s, 1H), 8.26 (d, J=6.9 Hz, 1H), 6.83 (d, J=6.9 Hz, 1H), 2.37 (s, 3H), 1.33 (s, 9 H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4]>C1COCC1.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNC(=O)CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
36.5 g (113 mmol) of Z-Gly-Gly-OtBu were dissolved in 11 THF followed by the addition of 3.65 g palladium on charcoal (10%). The mixture was stirred under H2 atmosphere (1 atm) for 3 h at room temperature. The suspension was purged with N2, filtered (PTFE-filter: 0.45 μm) and the filtrate was concentrated under reduced pressure yielding 20.3 g (95%) Gly-Gly-O-tBu as a yellow oil. The crude material was pure enough for further synthesis.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>>[Cl:18][C:19]1[N:20]=[N:21][C:22]([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]([F:1])([F:16])[F:17])[CH2:7][CH2:8]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Product: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1

Procedure:
The title compound was prepared in the same manner as described for Example 1 Step 3 from 4-[2-(trifluoromethyl)phenoxy]piperidine and 3,6-dichloropyridazine. 1H NMR (400 MHz, acetone-d6): δ 1.89-1.99 (m, 2H), 2.11-2.23 (m, 3H), 3.78-3.84 (m, 2H), 3.91-3.97 (m, 2H), 4.98-5.04 (m, 1H), 7.12 (t, 1H), 7.41 (q, 3H), 7.61-7.67 (m, 2H). MS (+ESI) m/z 358 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.C[Mg]Br.[CH3:16][N:17]=[C:18]=[O:19]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:16][NH:17][C:18]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[CH3:12])=[O:19]
Reactant: COc1ccc2cc(C)[nH]c2c1
Reactant: CN=C=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)[nH]c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a stirred solution of 6-methoxy-2-methyl-1H-indole (500 mg, 3.1 mmol) (prepared according to JACS 1988, 110, 2242) in 8 mL anhydrous THF maintained at room temperature was added methylmagnesium bromide (1.13 ml, 3.0 M solution in diethyl ether, 3.41 mmol). After stirring for 1 hour at room temperature, a solution of 0.5M zinc chloride in THF (7.44 ml, 3.72 mmol) was introduced and the mixture was stirred for 1 hour at room temperature before addition of methyl isocyanate (424 mg, 7.44 mmol). The resulting mixture was stirred at ambient temperature overnight, quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 2-5% MeOH in CH2Cl2 to give 200 mg product (30% yield). 1H NMR (300 MHz, CD3OD) δ7.55 (1H, d, J=8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 6.70 (1H, dd, J=2.2, 8.6 Hz), 3.73 (3H, s), 2.90 (3H, s), 2.52 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 219, found 219.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:8][CH:7]=1)[OH:5].[OH-].[Li+].Cl>C1COCC1>[C:26]([O:25][C:23]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14](/[CH:13]=[CH:12]/[C:9]1[CH:8]=[CH:7][C:6]([CH:4]([OH:5])[C:3]([OH:31])=[O:2])=[CH:11][CH:10]=1)=[O:30])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C(O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a solution of (E)-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-hydroxy-acetic acid methyl ester (10.0 g, 23.5 mmol) in THF (100 mL) was added aqueous lithium hydroxide (1 M, 47 mL). After stirring at room temperature for 1 h, the pH was adjusted to 3 by addition of 0.5 N HCl. The resulting mixture was extracted with ethyl acetate (100 mL×2). The combined organics were washed with brine, dried over Na2SO4, and concentrated to afford the crude product as a pale-green solid (9.8 g, quantitative yield) which was used without further purification.
Reaction SMILES: ClC1C=C(C[CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH2:32]([S:39]CC(O)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:32]([S:39][CH2:9][CH2:10][N:11]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:12](=[O:24])[NH:13][C:14]1[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)CSCc1ccccc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCSCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using benzylsulfanyl-acetic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([O:9][CH:10]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]3[O:24][CH2:25][O:26][C:18]=3[CH:17]=2)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:29][CH2:30][CH3:31])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].[NH4+:34].[OH-].Cl>CO.C(Cl)(Cl)Cl>[NH4+:34].[OH-:2].[C:1]([C:5]1[CH:28]=[CH:27][C:8]([O:9][CH:10]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]3[O:24][CH2:25][O:26][C:18]=3[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:29][CH2:30][CH3:31])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1cc(OC)c2c(c1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step A (4.3 g, 12 mmol) in methanol (25 mL) was added aqueous 2N NaOH (10 mL) and the reaction mixture was stirred at room temperature. The rapid progress of mono-deesterification was monitored by TLC analysis using CHCl3 --MeOH--NH4OH:(80:15:1). After 15 min, the reaction mixture was cooled to 0° C. and neutralized with aqueous 2N HCl. Methanol was removed in vacuo and the resulting mixture was acidified with aqueous 2N HCl. The oily product which precipitated was extracted into methylene chloride (3×40 mL) and the combined organic phase was washed with water, brine and then dried over MgSO4. Removal of the solvent in vacuo afforded the crude product which was then purified by flash-chromatography on silica gel using CHCl3 --MeOH--NH4OH:(80:10:1) to give desired product as the ammonium salt. The salt was treated with aqueous 1N HCl (20 mL) to provide the titled compound as a white solid (3.4 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)[CH2:2][C:3]#[CH:4].CC1CCCO1.[CH3:29][C:30]1([CH3:37])[C:34]([CH3:36])([CH3:35])[O:33][BH:32][O:31]1>[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].C(N(CC)CC)C.ClCCl>[CH3:29][C:30]1([CH3:37])[C:34]([CH3:36])([CH3:35])[O:33][B:32](/[CH:4]=[CH:3]/[CH2:2][CH2:1][N:5]2[CH2:6][C:7]3([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]3)[CH2:20][CH2:21][CH2:22]2)[O:31]1
Reactant: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC1(C)OBOC1(C)C
Agent: [Zr+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(CC/C=C/B3OC(C)(C)C(C)(C)O3)C2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a mixture of tert-butyl 8-but-3-ynyl-3,8-diazaspiro[5.5]undecane-3-carboxylate (2.41 moles; 750.86 g), zirconocene chloride (240.73 mmoles; 62.08 g), triethylamine (240.73 mmoles; 33.55 mL; 24.36 g), and 2-methyltetrahydrofuran (738 mL), add 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.53 moles; 323.49 g). Heat the mixture to 60° C. and stir overnight. Cool the mixture and pass through a plug of silica eluting with dichloromethane. Concentrate the filtrate under reduced pressure to give the final title compound, tert-butyl 4-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (1072 g, about 94% purity, 96% yield).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[C:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>ClC(Cl)C>[C:25]1([CH2:31][CH2:32][NH:33][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: NCCC1=CCCCC1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: O[C@H](CNCCC1=CCCCC1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-(1-cyclohexenyl)ethylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS-80%, [M+H]+=411.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[CH:57]=[N:56][C:55]([CH3:58])=[N:54]1)=[O:45].Cl[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[CH:57]=[N:56][C:55]([CH3:58])=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 20. (−)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol) and triethylamine (13.1 μL, 0.0938 mmol) in tetrahydrofuran (3 ml), was added iodoethane (5.6 μL, 0.070 mmol). Analysis show 60% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 9), 226 (74), 211 (28), 141 (47), 71 (bp).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])/[C:5](/Br)=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P([Pd-4](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)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])/[C:5](/[C:19]1[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=1)=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)/C(Br)=C/C1CCCC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/C1CCCC1)c1ccc(SC)cc1
Yield: 85.6 %

Procedure:
Following the method of example 54c, reaction of (Z)-2-bromo-3-cyclopentyl-acrylic acid ethyl ester (56.8 g, 229 mmol) with 4-(methylthio)benzene boronic acid (46.3 g, 276 mmol) and tetrakis(triphenylphosphino)palladium(0) (10.4 g, 3 mol %) in a mixture of toluene (1600 ml), ethanol (421 ml) and 2 M aqueous sodium carbonate solution (420 ml) affords the title compound as an oil (56.9 g). MS (m/e): 291.2 (M+H).
Reaction SMILES: Cl.C(OC([N:9]1[C@H:13]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:41])[C@@H:22]([N:27]3[CH2:31][C:30]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:39])=[CH:29][C:28]3=[O:40])[CH2:23][CH:24]([CH3:26])[CH3:25])=[N:16]2)[CH2:12][O:11]C1(C)C)=O)(C)(C)C>C(OCC)C>[NH2:9][C@@H:13]([CH2:12][OH:11])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:41])[C@@H:22]([N:27]2[CH2:31][C:30]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:29][C:28]2=[O:40])[CH2:23][CH:24]([CH3:26])[CH3:25])=[N:16]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](N)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
Hydrochloric acid gas was bubbled into a stirred solution of (R)-4-(3-{(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidin-3-carboxylic acid t-butyl ester (1.00 g, 16.63 mmol) in diethyl ether (20 mL) for 30 seconds. The reaction mixture was then stirred at room temperature for 30 min during which a white solid precipitates out of solution. The diethyl ether was decanted off and the solid washed with three portions of diethyl ether. The crude product was purified via supercritical fluid chromatography on a DAICEL AD column, 25% methanol, 70 mL/min to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2-amino-3-hydroxy-propyl)-1H-pyrazol-3-yl]-amide (362 mg, 47%) as a white solid: LR-ES-MS m/z calculated for C22H28ClN5O4 [M]+ 461, observed 462 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.34-1.85 (m, 5H), 3.00 (br. s., 1H), 3.22 (br. s., 2H), 3.80 (dd, J=13.4, 6.9 Hz, 1H), 4.02 (dd, J=13.4, 5.0 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.61 (d, J=18.4 Hz, 1H), 4.65-4.75 (m, 1H), 4.79 (s, 1H), 4.89 (dd, J=9.8, 4.1 Hz, 1H) H), 6.42 (s, 1H), 7.31-7.42 (m, 1H), 7.42-7.55 (m, 2H), 7.57 (br. s., 1H), 7.65 (d, J=7.2 Hz, 1H), 10.79 (br. s., 1H).
Reaction SMILES: [C:1]([C:9]1[C:10]([CH2:33]Br)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>>[C:1]([C:9]1[C:10]([CH2:33][C:36]2[NH:35][CH:39]=[CH:38][N:37]=2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(-c2c(C(=O)c3ccccc3)c(Cc3ncc[nH]3)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 3, 3-benzoyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline was reacted with imidazole to give 3-benzoyl-4-(3,4-dimethoxyphenyl)-2-(1-imidazolylmethyl)-6,7-dimethoxyquinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 214°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH3:18])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=6[NH:7][C:8]5=[O:19])[CH:13]([CH3:18])[CH2:14]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1C)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1C)C(=O)N2

Procedure:
60 mg (0.21 mmol) 7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.29 mmol) TEA were stirred overnight in 1 mL DMF at RT. Then the reaction mixture was combined with 2 mL MeOH, the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.