Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9]C1CCNCC1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:33][CH2:34][CH3:35])[C:27]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1)[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:33][CH2:34][CH3:35])[C:27]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1)[CH2:23][N:4]1[CH2:5][CH2:6][CH:16]([C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:16][C:6]=2[C:7]([NH2:9])=[O:8])[CH2:2][CH2:3]1)[CH3:18]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(c3ncc(C)cc3C(N)=O)CC2)cc(OCC)c1-n1cccc1
Yield: 22 %

Procedure:
The title compound (10 mg, 22%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde. MS: 463.5 (MH+)
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:2][C:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=2)[O:16][CH2:15][CH2:14][O:3]1
Reactant: OCCO
Reactant: CCOC(=O)c1cc(C(C)=O)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2(C)OCCO2)on1
Yield: 100.1 %

Procedure:
A reaction mixture consisting of ethyl 5-acetylisoxazole-3-carboxylate (2.53 g, 13.8 mmol), ethylene glycol (1.29 g, 20.7 mmol) and p-TsOH (0.13 g, 0.69 mmol) in benzene (50 mL) was refluxed with the Dean-Stark adapter for 24 hours (scheme 59). Most of the solvent was removed under reduced pressure and the residue was partitioned between saturated NaHCO3 and EtOAc. Organic layer was collected, washed with brine, water, and dried over MgSO4. Evaporation of the dried extract under reduced pressure afforded the title compound as an oil (3.14 g, 100% yield), which was used for next step without further purification. 1H NMR (DMSO-d6) δ (ppm): 6.89 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.07-4.01 (m, 2H), 4.01-3.94 (m, 2H), 1.70 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS (m/z): 227.21 (calc) 228.1 (MH+) (found).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1nccnc1Br
Solvent: CCOC(C)=O
Product: COC(=O)c1nccnc1Nc1ccc(Cl)cc1
Reaction time: 96 h

Procedure:
A mixture of 21.7 g 3-bromo-pyrazine-2-carboxylic acid methyl ester and 25.5 g 4-chloroaniline in 150 ml ethyl acetate is boiled 4 days at reflux. The solution is washed with 4 N hydrochloric acid, water and then with 2 N sodium carbonate. The organic phase is dried over sodium sulphate and evaporated to give the heading compound (recrystallised from isopropanol) m.p. 135°-136°.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([Br:17])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccsc1C(=O)NCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a stirred solution of N-benzyl-3-methylthiophene-2-carboxamide (0.74 g, 3.18 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (0.57 g, 3.18 mmol). The reaction mixture was stirred for 16 h, and then concentrated in vacuo. The residue was purified by column chromatography eluting with 5-35% ethyl acetate in hexane to afford the title compound as a colorless solid (0.69 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 6.87 (s, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 310.1 (M+1), 312.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[Li+].[OH-]>O1CCOCC1>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=1)[C:3]([OH:23])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
N-Methyl-5-(2-oxo-pyrrolidin-1-yl)-N-propyl-isophthalamic acid methyl ester (D64) (0.40 g, 1.25 mmol) in dioxane (15 ml) was treated with 1M LiOH (2.5 ml, 2.5 mmol) and the reaction solution was stirred at room temperature for 2 h. It was then evaporated to dryness and the residue was partitioned between EtOAc and dil. NaHCO3 soln. The aqueous solution was separated and acidified to pH1 with 2M HCl. The product was extracted into EtOAc (×3) and the combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the title compound (D65) (0.30 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH3:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C([N:23](CC)CC)C.B.[NH4+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O1CCCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH3:17])[CH:9]([NH2:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: CCN(CC)CC
Agent: [Ti+4]
Agent: B
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(N)c1ccccc1
Temperature: 25 °C

Procedure:
In a reaction vessel that was vacuumed and then purged with argon, (R)-t-butyl[1-phenyl-1-oxopropan-2-yl]carbamate (0.75 g (3.0 mmol)) and ammonium chloride (0.24 g (4.5 mmol)) were placed. Then, dry tetrahydrofuran (15 mL) and triethylamine (0.63 mL (4.5 mmol)) was added to the reaction vessel, followed by titanium tetraisopropoxide (1.32 mL (4.5 mmol)). At room temperature, the reaction mixture was stirred for 8˜10 hrs. After addition of ammonium borane, the reaction mixture was again stirred for 8˜10 hrs.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Yield: 74 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-nitro-phenylamine provided the title compound (74% yield). 1H NMR (CD3OD) δ 2.41 (s, 3H, CH3), 6.42 (s, 1H, Ar), 7.39 (d, 1H, J=8.0 Hz, Ar), 7.67-7.70 (m, 2H, Ar), 8.14 (d, 2H, J=9.0 Hz, Ar), 8.31-8.34 (m, 2H, Ar).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Cl)C(C)CNCC2
Reaction time: 8 h
Yield: 109.3 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.399 g, 1.24 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.306 g of a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.05 (s, 1 H), 6.59 (s, 1 H), 3.80 (s, 3 H), 3.0−2.8 (m, 6 H), 2.62 (m, 1 H), 2.16 (bs, 1 H), 1.24 (d, J=7 Hz, 3 H). MS calculated for C12H16ClNO+H: 226, observed: 226.
Reaction SMILES: OS([O-])=O.[Na+].O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]2.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>O.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]2
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Reactant: CNCCO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2cc(N(C)CCO)ccc2c1
Yield: 73 %

Procedure:
A mixture of 4.15 g (55.5 mmol) NaHSO3, 8 mL of water, 0.78 g (4.19 mmol) of 1-(6-hydroxy-2-naphthyl)-1-ethanone (prepared as described in Example 1(b)), and 8 mL of 2-methylaminoethanol was heated and stirred in a steel bomb at 140° C. for 28 hours. After cooling, the mixture was distributed between ethyl acetate and water (500 mL and 200 mL, respectively). The organic layer was dried and evaporated to leave raw 1-(6-(2-hydroxyethyl-methylamino)-2-naphthyl)-1-ethanone (0.749 g, 73%) of which was further purified by radial chromatography (4 mm SiO3, CH2Cl2).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:43][CH:44]=1)[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-benzyl-N-methyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C32H29N3O3
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]4[O:26]C(C)(C)C(C)(C)[O:23]4)=[C:18]([CH:31]=O)[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl.O>CO>[CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]4[B:22]([OH:26])[O:23][CH2:31][C:18]=4[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OC4CCCC4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (2.0 g, 4.60 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.26 g, 6.90 mmol). After 1 h at rt, 2 M HCl was added to it at 0° C. until pH reached to 3˜4. The resulting mixture was stirred at 0° C. for 30 min and then sonicated to give white solid which was filtered and lyophilized to yield Z (0.85 g, 56%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1 H), 8.20 (d, J=8.2 Hz, 1 H), 7.77 (d, J=7.8 Hz, 1 H), 7.27 (d, J=1.2 Hz, 1 H), 7.18 (dd, J=8.2, 1.9 Hz, 1 H), 6.69 (d, J=8.2 Hz, 1 H), 4.97 (br. s., 3 H), 1.75-1.54 (m, 6 H), 1.52-1.33 (m, 2 H); MS (ES) m/z: 337 (M+1)+; HPLC purity 99.36% (Maxplot), 99.35% (220 nm); Elemental analysis for C18H17BN2O4.0.25 H2O: Calculated C=63.46%, H=5.18%, N=8.22%; Found C=63.34%, H=5.17%, N=8.34%.
Reaction SMILES: O=[C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][CH2:14][CH:3]12.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[OH:17][N:16]=[C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][CH:14]=[C:3]12
Reactant: O=C1C2=C(C=C3OCCC13)CCCO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1C2=CCOC2=CC2=C1OCCC2

Procedure:
27.4 g of 2,3,7,8-tetrahydro-4-oxofuro[2,3-g]benzopyran (see Preparation 1), 42 g of hydroxylamine hydrochloride and 41.9 g of sodium acetate in 288 ml of ethanol are heated at reflux for 1 hour. The solvent is evaporated off and the residue is taken up in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation and then recrystallisation from ethanol, 21.85 g of the desired compound are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:5]=[C:6]([I:10])[C:7]=1[O:8][CH3:9].Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[CH:23]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[O:18]=[C:12]1[NH:13][C:14](=[O:17])[CH:15]=[CH:16][N:11]1[C:4]1[CH:5]=[C:6]([I:10])[C:7]([O:8][CH3:9])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:24]=[CH:23]3)[CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Reactant: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2cc(NS(C)(=O)=O)ccc2c1
Yield: 11 %

Procedure:
A mixture of the product from Part B 1-(3,5-diiodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (118 mg, 0.25 mmol), the product from Example 2A, Part B (87 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride CH2Cl2 complex (10.21 mg, 0.013 mmol) and sodium carbonate (0.250 ml, 0.25 mmol) in toluene (1.0 ml) and ethanol (1.0 ml) was sparged with nitrogen for 5 min and microwaved at 100° C. for 30 min. The mixture was cooled and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/hexane (2:3 to 4:1) to give the title compound (16 mg, 11%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3H) 3.35 (s, 3H) 5.67 (d, J=8.09 Hz, 1H) 7.42 (dd, J=8.82, 2.21 Hz, 1H) 7.59 (d, J=2.57 Hz, 1H) 7.73 (m, 2H) 7.81 (d, J=8.09 Hz, 1H) 7.95 (m, 3H) 8.09 (s, 1H) 10.06 (s, 1H) 11.47 (s, 1H). MS (ESI−) m/z 562 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[CH:5][C:4]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(O)c(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(OC)c(OC)c1OC
Temperature: 25 °C
Yield: 82.3 %

Procedure:
Following the procedure by Tremblay et al.,17 17 (3.851 g, 20.9 mmol) was dissolved in dry acetone (90.0 ml), and K2CO3 (9.36 g, 67.7 mmol) was added followed by MeI (9.0 mL, 144 mmol). The reaction was heated under reflux for 26 h and monitored by TLC (1:9 EtOAc:hexanes) for completion. When complete the reaction was cooled to room temperature and filtered. The acetone was removed under reduced pressure and the residue was taken up in CH2Cl2 (50 mL). The suspension was filtered, dried over MgSO4, filtered again, and condensed. The crude product can be purified by flash chromatography (1:4 EtOAc:hexanes), however, recrystallization from Et2O/hexanes was sufficient to provide pure 18 (3.405 g, 17.2 mmol, 82%) as white needles.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[NH:9][CH:8]=[CH:7]2)[CH3:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccc2c(=O)[nH]ccc2c1
Product: CCOc1ccc2c(Cl)nccc2c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A suspension of 6-Ethoxy-2H-isoquinolin-1-one (896 mg, 4.74 mmol) in POCl3 (4 mL) was heated at 110° C. for 3 h (clear solution obtained upon heating). After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was poured into iced water (10 mL), pH was then adjusted to 10 with 3N NaOH and extracted with CHCl3 (3×25 mL). The combined CHCl3 layers were washed with brine and dried (MgSO4). The organic layer was then filtered and concentrated to give 1-chloro-6-ethoxy-isoquinoline (866 mg, 4.18 mmol, 88% yield, >90% pure) as tan solid. MS m/z 208 (M++H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[CH2:18]([O:25][N:26]1[CH2:30][CH:29]([CH3:31])[CH:28]([OH:32])[C:27]1=[O:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:18]([O:25][N:26]1[CH2:30][CH:29]([CH3:31])[C:28](=[O:32])[C:27]1=[O:33])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1CN(OCc2ccccc2)C(=O)C1O
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(OCc2ccccc2)C(=O)C1=O
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 79.1 %

Procedure:
Trifluoroacetic anhydride (30 ml, 44 g, 212 mmol) in dry dichlcromethane (100 ml) was added dropwise over 15 min to a stirred solution of dimethylsulphoxide (16 ml, 17.6 g, 259 mmol) in dry dichloromethane (500 ml) at -78° C. under nitrogen. After a further 10 min 1-benzyloxy-3-hydroxy-4-methylpyrrolidin-2-one (10 g, 45 mmol) in dichloromethane (80 ml) was added via cannula to the cloudy solution. After 30 min diisopropylethylamine (56 ml, 42 g, 330 mmol) was added dropwise over 5 min, and the reaction stirred for a further 35 min at -78° C. before being quenched at that temperature by the addition of methanol (20 ml). The mixture was then warmed to 0° C., washed with water (300 ml), and the water back extracted twice with dichloromethane. The combined organic layers were washed with brine, the brine extracted with dichloromethane, and the combined dichloromethane layers dried (Mg2SO4). After evaporation the product was purified by flash chromatography, eluting with dichloromethane: methanol (98:2 v/v) to give 1-benzyloxy-4-methylpyrrolidin-2,3-dione (7.8 g, 78%) as a white solid. In CDCl3 solution the ketone exists in its enol tautomeric form. 1H NMR (360 MHz, CDCl3) δ7.3-7.5 (5 H, m, Ph), 5.01 (2 H, s, OCH2), 3.61 (2 H, q, J=0.9 Hz, NCH2), 1.81 (3 H, t, J=0.9 Hz, CH3), m/z (CI, isobutane) 220 (M+ +H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O.C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1cccc(O)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cccc(O)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxybenzylamine (200 mg, 1.62 mmol) and Sodium hydrogen carbonate (273 mg, 3.25 mmol) suspended in water/DCM (4 ml, 1:1) is treated with phenyl chloroformate (0.204 ml, 1.62 mmol). After stirring at RT overnight, the reaction mixture is diluted with more DCM/water and the organic phase is separated. The organic portion is concentrated in vacuo to afford the titled compound. (MH+ 244)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C(Cl)Cl.O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:7]=1[CH2:15][CH2:14][C:13]2=[O:16]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C)c2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
180 mL CH2Cl2 and 36 g anhydrous AlCl3 (Carlo Erba) were charged in a 3-neck 0.5-L round bottomed flask equipped with magnetic stirring bar, 250-ml dropping funnel, thermometer and reflux condenser. A solution containing 31 ml p-xylene and 21 ml acryloylchloride (Aldrich) in 100 ml CH2Cl2 was placed in the dropping funnel. This solution was added dropwise over 4 hours to the flask, the content of which was kept under stirring at the temperature of 0° C. with a bath of water and ice. Evolution of HCl was observed and the reaction mixture turned dark brick-red. After addition was complete, the mixture was allowed to warm to room temperature and stirring was continued overnight (18 hours). The reaction mixture was poured in a flask containing 250 g ice and 250 ml HCl 37%, the organic phase was separated and the acqueous phase was extracted with Et2O (3 times). All organic fractions were combined and washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and the solvent was removed in vacuo. 38.25 g of light yellow-orange oil were obtained. This product was used without any further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:53])([F:52])[F:54])=[N:43][N:44]([CH2:47][C:48]([N:37]2[CH2:38][CH2:39][N:34]([C:27]3[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=3[Cl:25])[CH2:35][CH2:36]2)=[O:49])[C:45]=1[CH3:46]
Reactant: COc1ccc(Cl)c(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(Cl)c(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Chloro-5-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.31 (d, 1H), 6.65 (m, 2H), 5.37 (s, 2H), 3.73 (s, 3H), 3.62 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect=451.1, found=451.0.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[CH2:11][C:12]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:15]=[N:14][CH:13]=1>Cl>[O:2]=[C:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[CH2:11][C:12]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=[N:14][CH:13]=1
Reactant: CCCC1CC(=O)N(Cc2cncn2CC(=O)OCC)C1
Agent: Cl
Product: CCCC1CC(=O)N(Cc2cncn2CC(=O)O)C1
Temperature: 40 °C

Procedure:
In a 250 ml, three necked flask fitted with a magnetic stirrer, ethyl {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate hydrochloride x49 (5.19 g, 0.018 mol) is dissolved in 2M HCl (150 ml) and heated at 40° C. for 20 h. The reaction mixture is evaporated to dryness to afford the crude acid x50 (6.19 g) that is used as such in the next step.