Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([C:14]3[CH2:18][CH2:17][CH2:16][CH:15]=3)[CH:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([C:14]3[CH2:18][CH2:17][CH2:16][CH:15]=3)[CH:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2]
Reactant: COC(=O)c1ccc2c(c1)OCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1=CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2=CCCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To a solution of methyl 2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate (125 mg, 0.30 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1M aqueous sodium hydroxide (2 mL). The solution was stirred for 20 hours at ambient temperature. The resulting slurry was concentrated to half volume, acidified to pH=2 with 1M hydrochloric acid and collected by vacuum filtration (yellow solid, 66 mg, 55% yield). The title compound was largely present as (±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. Reversed-phase HPLC on 4.6×50 mm C-18 column, tR=2.92 minutes (10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254 nm, at 20° C.); HRMS Calculated for C24H21N3O3: 400.1656 (M+H)+. Found: 400.1678. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.87 (m, 2H), 2.03-2.13 (m, 2H), 2.17 (br. s., 2H), 2.39 (s, 3H), 3.83-3.91 (m, 1H), 3.97-4.06 (m, 1H), 4.65 (dd, J=10.20, 5.91 Hz, 1H), 5.44 (d, J=10.47 Hz, 1H), 5.60 (br. s., 1H), 6.86 (br. s., 1H), 7.11 (br. s., 1H), 7.42 (d, J=1.34 Hz, 1H), 7.53 (d, J=8.59 Hz, 1H), 7.56 (dd, J=8.19, 1.48 Hz, 1H), 7.90 (d, J=8.06 Hz, 1H), 13.12 (br. s., 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCCl>[CH:25]1([NH:31][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(F)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)c1c(NC2CCCCC2)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Yield: 116 %

Procedure:
Ethyl 5-methyl 2-fluoro-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (14 mg, 0.042 mmol) was dissolved in DCE (1 mL). Cyclohexylamine (9.67 ul, 0.085 mmol) and triethylamine (5.89 ul, 0.042 mmol) were added and the reaction was heated at reflux 18 hours. The mixture was concentrated, diluted with ethyl acetate and brine, extracted with ethyl acetate, dried over sodium sulfate, and concentrated to afford the title compound (20 mg) that was used without further purification: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08-7.15 (m, 2 H) 6.97-7.07 (m, 2 H) 4.04-4.19 (m, 1 H) 3.75-3.88 (m, 2 H) 3.41 (s, 3 H) 2.43 (s, 3 H) 2.35 (s, 3 H) 1.96-2.17 (m, 2 H) 1.55-1.93 (m, 4 H) 1.36-1.53 (m, 2 H) 1.17-1.37 (m, 2 H) 0.56-0.71 (m, 3 H); LCMS (m/z) ES+=411 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([N-:31][S:32](N1C=CC(=[N+](C)C)C=C1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])(=[O:33])=[O:34])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
To a solution of (5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methanamine (788 mg, 2.44 mmol) (described in WO 2011/074560) in DCM (10 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (737 mg, 2.44 mmol) (Winum, J.-Y. et al., Org. Lett., 3(14):2241-2243 (2001)) and the reaction mixture stirred at rt for 3 days. The mixture was diluted with satd. NH4Cl and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-100% EtOAc/DCM to give Compound 46a (1.16 g, 95% yield) as a brown oil. LCMS=0.99 min using analytical method (M), 502.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J=8.4, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.44-7.36 (m, 1H), 6.96 (br. s., 1H), 5.26 (br. s., 2H), 4.79 (s, 2H), 4.63 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][OH:8].[Cl:9][CH2:10][CH:11]1[CH2:13]O1>>[Cl:9][CH2:10][CH:11]1[O:8][CH2:7][CH:2]2[CH2:3][O:4][CH2:5][CH2:6][N:1]2[CH2:13]1
Reactant: OC[C@@H]1COCCN1
Reactant: ClCC1CO1
Product: ClCC1CN2CCOCC2CO1
Temperature: 170 °C
Yield: 35.4 %

Procedure:
A solution of (3R)-morpholin-3-ylmethanol (4.21 g, 36.0 mmol) in 2-(chloromethyl)oxirane (28.2 mL, 0.360 mol) was heated to 40° C. for 3 h and then the solution was concentrated in vacuo. The intermediate was cooled in an ice bath and treated with 30.0 mL of concentrated sulfuric acid. The mixture was heated to 170° C. for 2 h and then allowed to cool to room temperature. The mixture was poured into ice-water and solid sodium bicarbonate was carefully added until the solution was basic. 10% methanol in ethyl acetate was added and the biphasic mixture was filtered. The layers were separated and the aqueous layer was extracted (3×100 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 2:5 hexanes:ethyl acetate) provided 3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine 2.44 g (35%) as two separated diastereomers. (3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: (0.886 g, 13% yield): 1H NMR (400 MHz, CDCl3): 3.91 (m, 3H), 3.82 (m, 1H), 3.68 (dt, 1H), 3.61 (dd, 1H), 3.47 (dd, 1H), 3.35 (t, 1H), 3.19 (t, 1H), 2.80 (d, 1H), 2.54 (m, 2H), 2.40 (m, 2H); MS (EI) for C8H14NO2Cl: 192 (MH+). (3S,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: (1.55 g, 22% yield): 1H NMR (400 MHz, CDCl3): 3.85 (m, 2H), 3.73 (m, 3H), 3.50 (m, 2H), 3.29 (t, 1H), 3.18 (t, 1H), 2.85 (dd, 1H), 2.64 (dd, 1H), 2.40 (m, 2H), 2.17 (t, 1H); MS (EI) for C8H14NO2Cl: 192 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH3:10]>>[NH2:10][C:7]1[CH:6]=[C:5]([Cl:9])[N:4]=[N:3][C:2]=1[Cl:1]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: N
Product: Nc1cc(Cl)nnc1Cl

Procedure:
A suspension of 3,4,6-trichloropyridazine (prepared by the method of B. Kasnar et al, Nucleosides and Nucleotides, 1994, 13, 459) (10.0 g) in conc. aqueous ammonia (1 L) was heated at 75° C. for 16 h. The mixture was concentrated to a small volume and extracted several times with ethyl acetate. The extracts were washed with brine, dried and evaporated. The crude product was recrystallised from ethyl acetate to give the product (5.03 g).
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([OH:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][N:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[CH2:26]([O:25][C:23]([N:22]([CH2:28][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])[CH3:21])=[O:24])[CH3:27]
Reactant: CCOC(=O)N(C)CCl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)COC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Temperature: 0 °C

Procedure:
725 mg (2.5 mM) of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 50 ml of dimethyl formamide is treated at room temperature with 375 mg (2.5 mM) of N-chloromethyl-N-methylurethane for one hour. The mixture is carefully poured into ice water and the precipitated solid is removed by filtration and washed with water. The solid is dissolved in ethylacetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate filtered and evaporated to dryness in vacuo to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-ethoxycarbonyl-N-methylaminomethyl ester.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: C[C@H](O)C(=O)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:16]=3)[OH:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[Mn+4].[O-2].ClCCl>[C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1)=[O:14]
Reactant: OC(c1cccc(-c2ccccc2)n1)c1cccc(-c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1cccc(-c2ccccc2)n1)c1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Manganese (IV) oxide (2.8 g, purity 90%, 29.5 mmol) was added to a dichloromethane (20 ml) solution of 1,1-bis(6-phenylpyridine-2-yl)methanol (1.0 g, 3.0 mmol) obtained by Example 19, and this reaction mixture was stirred for 1 hour at room temperature. The obtained reaction mixture was filtered by silica gel, the solvent of the filtrate was distilled off, and the residue was purified by recrystallization, thereby obtaining 920 mg of 2,2′-carbonylbis(6-phenylpyridine) as white powder. Yield: 92.7%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of 4-trifluoromethyl-2-nitrophenol (1.0 g, 4.8 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol (150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (708 mg, 83%). 1H NMR (CD3OD): δ6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[C:8]([CH:22]=[CH2:23])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH2:22]([C:8]1[CH:9]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:11]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:7]=1)[CH3:23]
Reactant: C=Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 83.8 %

Procedure:
0.12 g (0.00036 Mol) 4-(2-Pyrrolidin-1-yl-6-vinyl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethanol (36 ml) and hydrogenated under an atmosphere of H2 -gas with a catalytic amount of Pd/C (10%) at ambiente temperature for 3 h. After filtration and evaporation of the solvent the residue was chromatographed on SiO2 with ethyl acetate hexane 1:2. After drying in a high vacuum it was obtained 0.10 g (83%) 4-(2-ethyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as an offwhite solid; mp.: 154-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1)=[O:20].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:22]=1)=[O:20]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCOCC3)c2)c1)c1ccnc(N2CCOCC2)c1
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 21, N-[2-chloro-5-(2-chloropyrid-4-ylcarbonylamino)phenyl]-2-chloropyridine-4-carboxamide was reacted with morpholine to give the title compound in 84% yield; NMR Spectrum: (DMSOd6) 3.52 (m, 8H), 3.73 (m, 8H), 7.12 (m, 2H), 7.26 (d, 2H), 7.55 (d, 1H), 7.73 (d, 1H), 8.3 (m, 2H), 10.21 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 523.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=1[NH:1][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccc(N)c(C(N)=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)Nc1ccc(OC)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of 2-amino-5-methoxybenzamide (1.50 g, 9.03 mmol) and triethylamine (1.00 g, 9.93 mmol) in THF (40 mL) was added dropwise ethyl chloroglyoxylate (1.36 g, 9.93 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the precipitated insoluble material was collected by filtration. The filtered cake was washed with water and ethanol to give ethyl ((2-(aminocarbonyl)-4-methoxyphenyl)amino)(oxo)acetate as a pale-yellow powder (2.42 g, 100%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN>>[NH2:3][CH:12]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(COc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Product: CC(C)(C)OC(=O)NCC(N)COc1ccccc1

Procedure:
1.08 g of rac-tert-butyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenoxypropyl]carbamate (2.72 mmol, 1 equivalent) were initially charged in 5 ml of 40% strength aqueous methylamine solution and reacted in a microwave at 100° C. for 2 h. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane/methanol gradient). This gave 200 mg (27% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH2:38][CH2:39][N:40]([C:13]([CH:5]2[CH2:4][N:3]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:28])[F:27])(=[O:18])=[O:17])[C:2](=[O:1])[N:6]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:14])[CH2:41][CH2:42]1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4C(F)(F)F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
Steps 4 and 5: In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using sodium hydroxide solution to give (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid. Finally, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 586.8 ([M+H]+)
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH2:18][CH2:19][CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([N:32]2[CH:33]=[C:29]([C:2]3[C:3]([O:17][CH2:18][CH2:19][CH3:20])=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:30]=[N:31]2)[CH2:39][CH2:38]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1c(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc2c1CC[C@H](C)N2C(=O)OC
Temperature: 100 °C
Yield: 100.3 %

Procedure:
A mixture of (S)-methyl 6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate (0.060 g, 0.175 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.066 g, 0.175 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (0.014 g, 0.018 mmol), and cesium carbonate (0.171 g, 0.526 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate (0.090 g, 100%) as a colorless oil. MS (ESI, pos. ion) m/z 513 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([OH:19])[CH2:15][CH2:16][C:17]#[CH:18]>>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:19]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: C#CCCCO
Product: COc1ccc2nccc(CCCCC=O)c2n1
Yield: 50 %

Procedure:
This intermediate was prepared starting from 8-bromo-2-methoxy-[1,5]naphthyridine (2 g, 8.3 mmol) and 4-pentyn-1-ol (1 mL, 1.3 eq.) and following the procedures of Example 29 step 29.i and Example 33, steps 33.i and 33.ii. The title aldehyde was isolated as a yellow oil (1.1 g, 50% yield over 3 steps).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[N+](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-]>C(Cl)Cl.CCOC(C)=O.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:1][CH:2]1[CH2:3][CH:4]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1)[CH3:28]
Reactant: O=C(OCc1ccccc1)N1C2COCC1CC(O)C2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)COC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of benzyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate O (200 mg, 0.72 mmol) in DCM (4 mL) was added ethyl 2-diazoacetate (202 mg, 1.44 mmol) and Rhodium(II) acetate (319 mg, 0.72 mmol) at 0° C. The resulting mixture was stirred at room temperature for overnight, and then diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried (Na2SO4). The organic solvent was removed in vacuo to give the crude product, which was purified by column chromatography to give the intermediate benzyl 7-(2-ethoxy-2-oxo-ethoxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (144 mg, 55%). LC/MS: calc'd 364 (MH+), exp 364 (MH+).