Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]4[NH:27][N:26]=[CH:25][CH:24]=4)=[CH:18][C:17]=3[Cl:28])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[OH:31][C:32]([CH3:39])([CH3:38])/[CH:33]=[CH:34]/B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.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>[Cl:28][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2](/[CH:34]=[CH:33]/[C:32]([OH:31])([CH3:39])[CH3:38])[CH:30]=[CH:29][C:5]=2[N:6]=1
Reactant: CC(C)(O)/C=C/B(O)O
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)/C=C/c1ccc2nc(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)c3cc[nH]c(=O)c3c2c1
Temperature: 80 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1H-pyrazol-5-yl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (Example 100, Step 4) (125 mg, 0.25 mmol) in THF (4 mL) was added [(1E)-3-hydroxy-3-methylbut-1-en-1-yl]boronic acid (65 mg, 0.45 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol) and sodium carbonate (0.125 mL, 0.25 mmol, 2M in water). The reaction was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF and methanol, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][O:16][CH3:17])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][O:32][CH2:31]1)(=O)(=O)C>C(#N)C>[O:32]1[CH2:33][CH2:34][CH2:35][CH:30]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][O:16][CH3:17])[N:9]=3)=[CH:6][CH:7]=2)[CH2:31]1
Reactant: COCCn1nc(-c2ccc(O)cc2)oc1=O
Reactant: CS(=O)(=O)OCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCn1nc(-c2ccc(OCC3CCCOC3)cc2)oc1=O
Yield: 24.7 %

Procedure:
2 g of 5-(4-hydroxyphenyl)-3-methoxyethyl-1,3,4-oxadiazol-2(3H)-one are dissolved in acetonitrile, followed by addition of 2.92 g of potassium carbonate and a solution of 3.12 g of 3-tetrahydropyranylmethyl mesylate in acetonitrile. The mixture is heated to reflux for 5 h and then filtered, diluted with ethyl acetate and washed with three times 50 ml of 2N sodium hydroxide. The organic phase is then washed with water until neutral, dried over sodium sulphate and filtered, and the solvent is then evaporated off. After two recrystallizations in diisopropyl ether, 0.7 g of product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.OS(O)(=O)=O.O.[Br:18]N1C(=O)CCC1=O>[OH-].[Na+]>[Br:18][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2c(Br)cccc2n1
Temperature: 35 °C
Reaction time: 38 h
Yield: 5.3 %

Procedure:
To a solution of 2-Chloroquinoline (8) (1.0 g, 6.11 mmol) in 1:1 H2SO4 : H2O (30 ml) was added N-Bromosuccinimide (1.7 g, 9.55 mmol). The mixture was stirred at 35° C. for 38 h and then cooled. The solution was diluted with enough 50% NaOH (aq) to maintain pH<1 and the mixture was extracted with CH2Cl2. The combined organic layers were washed with sat. NaHCO3 (aq) and dried (MgSO4). Concentration of the solvent afforded a dark brown oil (0.078 g, 79%) which was sequentially purified by flash chromatography (85:15 Hexane:CH2Cl2) and MPLC (85:15 Hexane:CH2Cl2) to afford 9 (0.22 g, 15%) as a white amorphous solid (m.p. 71° -72° C.). 1H NMR d (ppm): 7.39 d (CH arom), 7.51 dd (CH arom), 7.74 d (CH arom), 7.91 d (CH atom), 8.37 d (CH arom).
Reaction SMILES: [C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:16]=3[C:17](O)=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:17]([C:16]1[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:13][C:12]=1[CH2:11][C:1]12[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2)=[O:18]
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccccc1N
Product: COC(=O)c1ccccc1NC(=O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Yield: 33.1 %

Procedure:
2-Adamantan-1-ylmethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (Example 1, step c) (335 mg, 1.00 mmol) was reacted with 2-amino-benzoic acid methyl ester (1.51 mg, 1.00 mmol) according to the procedure of Example 1, step d to afford the product as a pale yellow solid (155 mg, 33%). 1H NMR (300 MHz, d6-DMSO) 11.32 (1H, s), 11.24 (1H, s), 8.67 (1H, d), 8.00 (1H, d) 7.60 (3H, m), 7.40 (2H, m), 7.25 (1H, t), 7.12 (1H, t), 6.83 (1H, s), 3.92 (3H, s), 2.86 (2H, s), 1.88 (3H, s), 1.55 (12H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:15]([NH:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:16])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:25](OC=O)(=[O:27])C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:15]([N:17]([CH:25]=[O:27])[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:16])[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCC[C@@H](C(=O)O)[C@H](C)NOC2CCCCO2)cc1
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: Cc1ccc(CCC[C@@H](C(=O)O)[C@H](C)N(C=O)OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of (2R,3S)-2-(3-(4-methylphenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (114 mg, 0.34 mmol) in pyridine (2 mL) at 0° C. is added formic acetic anhydride (0.3 mL). The resulting solution is allowed to warm to 25° C., stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-methylphenyl)-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (120 mg, 97% yield).
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:7]([CH2:12][CH2:13][CH2:14][CH:15]=C)[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH3:6].CC[O:19]CC.O>C(O)(=O)C.[Zn]>[CH:15]([CH2:14][CH2:13][CH2:12][CH:7]([CH2:4][CH2:5][CH3:6])[C:8]([O:10][CH3:11])=[O:9])=[O:19]
Reactant: CCOCC
Reactant: C=CCCCC(CCC)C(=O)OC
Agent: O=[O+][O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(CCCC=O)C(=O)OC

Procedure:
Ozone stream was bubled into a solution of methyl 2-propyl-6-heptenoate (2 g) in glacial acetic acid (80 ml) for 55 minutes at room temperature. Ether (100 ml) was added to the resulting mixture, followed by the portionwise addition of zinc powder (10 g) and water (1.1 ml) under cooling. The mixture was heated under reflux until KI-starch test became negative. After cooling, ether (100 ml) was added to the mixture, which was then filtered. The organic layer was separated, washed with water, dried and concentrated. The resulting residue was purified by silica gel column chromatography to give oil of methyl 5-formyl-2-propylpentanoate (1.1 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([OH:27])([CH3:34])[CH3:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)(O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (65 mg, 61%), MS (ISP) m/z=429.4 [(M+H)+], mp 168° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-hydroxy-3-methyl-butyric acid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:38](=[O:41])[CH2:39][CH2:40][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1C(=O)CCS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (500 mg, 0.953 mmol) in butanone (9.5 ml) was added acryloyl chloride (0.077 ml, 0.953 mmol). The reaction was stirred at ambient temperature for 10 min followed by 50° C. for 2 h. The reaction was cooled to 40° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow oil. The oil was recrystallized with diethyl ether/hexanes to provide the title compound as a light yellow solid (125 mg, 0.217 mmol, 23%): mp 118° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.16 (s, 1H), 7.85-7.75 (m, 4H), 7.46-7.36 (m, 4H), 7.33-7.26 (m, 1H), 7.10 (d, J=7.6 Hz, 1H), 3.26-3.14 (m, 4H), 2.81 (heptet, J=6.9 Hz, 1H), 1.21 (t, J=7.2 Hz, 6H); ESIMS m/z 580 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:26][CH2:27]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cc3ccccc3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(Cc3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-benzyl-1-chloro-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-yl-methyl)piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](Cl)([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21].[Cl-].C([NH+](CC)CC)C>O1CCCC1>[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cc1C(F)(F)F

Procedure:
A mixture of 2-amino-5-chlorobenzotrifluoride (14.4 ml, 0.1 mol) and triethylamine (14.0 ml, 0.1 mol) was dissolved in dry tetrahydrofuran, THF (250 ml). To this solution was added with stirring a solution of ethoxalyl chloride in THF (50 ml). After completion of the addition (30 min.) the mixture was stirred at ambient temperature for 3 h, whereafter the precipitated triethylammonium chloride was filtered off, and the filtrate was evaporated in vacuo. This left the crude title compound (24 g) as pale crystals. M.p. 55°-58° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23]C(OC(C)(C)C)=O)[N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:38])[C:20]=3[CH2:22][NH2:23])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: NCc1c(Cl)ccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reaction time: 48 h
Yield: 51.5 %

Procedure:
To a stirred solution of tert-butyl 1′-benzyl-4-((tert-butoxycarbonylamino)methyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (115 mg, 0.227 mmol) in DCM (2 mL) was added 1-chloropyrrolidine-2,5-dione (NCS) (66 mg, 0.50 mmol). The reaction mixture was stirred at about room temperature for 48 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was dissolved in DCM (2 mL) and treated with 4N HCl in dioxane (0.5 mL) overnight. The solvents were evaporated. The residue was taken up in DCM and basidified with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated to give (1′-benzyl-5-chlorospiro[indoline-3,4′-piperidine]-4-yl)methanamine (40 mg, 52%) as an oil, which was used in the next step without further purification. LCMS (APCI+) m/z 342, 344 [M+H]+; Rt=1.71 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 37.2 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 297a (195 mg, 0.66 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 199e (315 mg, 0.66 mmol), PdCl2(dppf) (40 mg, 0.050 mmol), K3PO4 (250 mg, 1.2 mmol), sodium acetate (100 mg, 1.20 mmol), acetonitrile (8 mL), and water (1 mL). The system was evacuated and then refilled with N2. It was then heated at 100° C. for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 297b as a yellow solid (150 mg, 38%). MS-ESI: [M+H]+ 612.3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([F:19])([F:18])[C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([N:15]2[CH:16]=[CH:17][C:13]([C:12]([F:19])([F:18])[F:11])=[N:14]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Temperature: 110 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of 2-chloro-4-fluorobenzaldehyde (5.0 g, 31.5 mmol), 3-(trifluoromethyl)-pyrazole (4.28 g, 31.5 mmol) and potassium carbonate (6.53 g, 47.3 mmol) in anhydrous N,N-dimethylformamide (40 mL) was stirred for 2 h at 110° C. The reaction mixture was cooled to 0° C., poured into ice water (500 mL) and stirred for 15 min. The precipitate formed was filtered and dried under reduced pressure to afford the title compound (8.1 g), which was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([OH:13])[CH:12]=1.Br[CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([CH:12]=1)[O:13][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (0.4 g) in DMF (5 ml) was dropwise added, under ice-cooling, a DMF (5 ml) solution of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenol (3.3 g), and the mixture was stirred for 10 minutes. To the solution was added diethyl bromomalonate (2.1 ml), and the mixture stirred at 70° C. for 30 minutes. Then, to the reaction mixture was added water (10 ml), and the mixture extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=5/1) to give 3.0 g of the title compound (colorless oil). Also, 0.7 g of the phenol derivative of the starting material was recovered.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
To a solution of 0.688 mole (219 g.) of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in 657 ml. of benzene is added 1.376M. (100.4 ml.) of thionyl chloride slowly over 1 hour while heating to about 60° C. The mixture is then heated at reflux for about 8 hours, then evaporated to provide the desired product, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride as a residue. The structure is verified by means of infrared spectral analysis.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pt]=O>[NH2:1][CH2:4][C@@H:5]1[C@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Agent: O=[Pt]
Solvent: CCO
Product: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Yield: 99.9 %

Procedure:
(3R,4S)-3-Azidomethyl-1-benzyl-4-fluoropyrrolidine (215 mg) was dissolved in ethanol (3 mL). To this solution, platinum oxide (IV) (30.0 mg) was added and the mixture was stirred at room temperature for 5 hours in a stream of hydrogen (provided from a balloon). Subsequently, the catalyst was removed from the reaction mixture by filtration through a Celite pad. The removed catalyst and the Celite pad were washed with ethanol. The filtrate and the washing solution were combined and the combined organic layer was concentrated under reduced pressure to obtain 191 mg of (3S,4S)-3-aminomethyl-1-benzyl-4-fluoropyrrolidine as a brown oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCCC(=O)O

Procedure:
The title compound was prepared from ethyl 8-bromooctanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 2.18 (t, 2H), 1.66 (m, 2H), 1.54-1.40 (m, 4H), 1.36-1.24 (m, 4H); MS (ESI): 494.9.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][CH:10]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:11]([N:13]2[CH:17]([C:18](=[O:29])[NH:19][C:20]3([C:25]([O:27]C)=[O:26])[CH2:22][CH:21]3[CH:23]=[CH2:24])[CH2:16][CH:15]([O:30][C:31]([N:33]3[CH2:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][C:39]=4[F:42])[CH2:34]3)=[O:32])[CH2:14]2)=[O:12])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1.CO.O>[C:25]([C:20]1([NH:19][C:18]([CH:17]2[N:13]([C:11](=[O:12])[CH:10]([NH:9][C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:14][CH:15]([O:30][C:31]([N:33]3[CH2:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][C:39]=4[F:42])[CH2:34]3)=[O:32])[CH2:16]2)=[O:29])[CH2:22][CH:21]1[CH:23]=[CH2:24])([OH:27])=[O:26]
Reactant: C=CC1CC1(NC(=O)C1CC(OC(=O)N2Cc3cccc(F)c3C2)CN1C(=O)C(NC(=O)OC1CCCC1)C(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)N2Cc3cccc(F)c3C2)CN1C(=O)C(NC(=O)OC1CCCC1)C(C)(C)C)C(=O)O

Procedure:
4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 1-(2-cyclopentyloxycarbonylamino-3,3-dimethyl-butyryl)-5-(1-methoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester (550 mg, 0.86 mmol) was dissolved in THF:MeOH:H2O (1:1:1 8.7 mL) and treated with lithium hydroxide (180 mg, 4.28 mmol). The reaction was judged complete by complete consumption of starting material after approximately 2 h, at which time the reaction was neutralized with 1N aqueous HCl. The organic phase was extracted with EtOAc then washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 5-(1-carboxy-2-vinyl-cyclopropylcarbamoyl)-1-(2-cyclopentyloxycarbonylamino-3,3-dimethyl-butyryl)-pyrrolidin-3-yl ester was obtained (540 mg, 0.86 mmol), which was used in the next reaction without further purification.