Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:20]1)(=[O:18])=[O:17])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:7]=[C:6]([CH:13]([CH3:14])[CH3:15])[C:5]=1[S:16]([N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:30](=[O:31])[CH2:29][CH2:28][C:21]([C:22]=23)=[CH:20]1)(=[O:17])=[O:18])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc(CCC(=O)O)c3ccccc32)c(C(C)C)c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(=O)CC3)c(C(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
To a solution of 1-(2,4,6-triisopropylphenylsulfonyl)-indole-3-propionic acid (76.22 g) in chloroform (500 ml) was added dropwise thionyl chloride (28.9 ml) at room temperature taking about 10 minutes. The mixture was stirred for one hour at 60° C. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was again added chloroform, followed by concentration under reduced pressure. The concentrate was dissolved in dichloroethane (900 ml). To the solution was gradually added, under ice-cooling, crushed aluminum chloride (58.4 g). The mixture was stirred for 30 minutes, and was added to a mixture of 1N hydrochloric acid (1000 ml) and ice (200 g), followed by extraction with chloroform (900 ml). The extract solution was washed with water (900 ml), dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (eluted with ethyl acetate:n-hexane=1:4), followed by recrystallization from ethyl acetate-hexane to afford the title compound (43.86 g, m.p.124°-130° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Reactant: CC(C)(N)Cc1ccc(F)cc1F
Product: CC(C)(Cc1ccc(F)cc1F)NCC(O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
587 mg (2 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 555 mg (3 mmol) 2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamine are reacted and worked up as described for Example 1a). Yield: 220 mg (23%); mass spectroscopy [M+H]+=479.
Reaction SMILES: Cl.[CH:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12]COC)[CH2:5][CH2:4][CH2:3]1.CCOC(C)=O>CO>[CH:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:3][CH2:4][CH2:5]1
Reactant: COCOc1ccccc1C1CCC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccccc1C1CCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
After concentrated hydrochloric acid (3.1 mL) was added to a solution of 1-cyclobutyl-2-(methoxymethoxy)benzene (1.43 g) in MeOH (29 mL) at room temperature, the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, a standard buffer solution of pH 6.86 was added thereto, and EtOAc was added. Extraction was performed on the mixture using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure, whereby 2-cyclobutylphenol (1.1 g) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(CCCN)cc1
Reactant: O=CC(=O)c1cccc(Cl)c1
Product: Cc1ccc(CCCNCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 3-(4-methylphenyl)propanamine. Recrystallisation of the chromatographed material from ether gave the title compound, mp 115°-117.5°.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:30]I>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]([CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)[CH3:30])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(C)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of tert-butyl (6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (180 mg) in THF (4 mL) was added sodium hydride (32 mg, 60%) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. To the reaction mixture was added methyl iodide (0.107 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:2].[CH:33](=O)[CH3:34]>>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:33][CH3:34])[CH3:32]
Reactant: CC=O
Reactant: CCN(CC)CCCNCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CCN(CC)CCCN(CC)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 125 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 462. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1), 8.1 (m, 1), 8.0 (m, 2H), 7.5 (m, 2H), 71 (m, 3H), 6.7 (m, 2H), 4.9 (s, 1H), 3.8 (s, 1H), 3.6 (m, 3H), 3.0 (m, 6H), 2.8 (m, 3H), 2.6 (m, 4H), 1.8 (m, 2H), 1.2 (m, 9H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]([NH2:10])[C@@H:2]1[OH:11].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:11][C@@H:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:10][C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Temperature: 0 °C

Procedure:
(1S, 2R)-cis-1-Amino-2-indanol (XIV, 1.5 g) was dissolved with triethylamine (1.5 mL) in dry THF (45 mL), and cooled to 0° C. Butyryl chloride (XIII, 1.05 mL) was added by syringe, and the resultant solution stirred 0° C. for 20 min, whereupon the reaction mixture was partitioned between half-saturated NH4Cl (45 mL) and EtOAc (2×45 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give a solid, which was taken to the next reaction without further purification.
Reaction SMILES: C(OC([C@:6]1([CH:21]([CH3:23])[CH3:22])[C:19](=[O:20])[N:9]2[C@@H:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH2:12][C@@H:8]2[CH2:7]1)=O)C.[OH-].[Na+].C1(C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:21]([C@H:6]1[C:19](=[O:20])[N:9]2[C@@H:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH2:12][C@@H:8]2[CH2:7]1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)[C@@]1(C(C)C)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H]1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Temperature: 70 °C

Procedure:
A solution of 960 g of (3R,6R,7aS)-6-isopropyl-5-oxo-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazole-6-carboxylic acid ethyl ester in 8 L of tetrahydrofuran is treated with 3.33 L of a 2.0 M solution of sodium hydroxide at room temperature. The reaction mixture is stirred for 24 hours toluene (5.15 L) is added and the reaction pH adjusted to between 2-4 with a 10% solution of citric acid. The layers are separated and the aqueous layer saturated with sodium chloride. The aqueous layer is washed with 4 L of toluene and the organic layers combined and dried. The toluene solution is heated to reflux for 48 hours. Finally the solution is cooled to 70° C. and the toluene removed under a slight negative pressure to give (3R,6S,7aS)-6-isopropyl-3-phenyltetrahydro-pyrrolo[1,2-c]oxazol-5-one.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:29])/[CH:9]=[CH:10]/[C:11]1[N:12]([CH3:28])[C:13](=[O:27])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3][C:4](O)=[O:5]>C1(C)C=CC=CC=1.C(O)(=O)C>[OH:1][CH:2]1[CH2:7][CH:8](/[CH:9]=[CH:10]/[C:11]2[N:12]([CH3:28])[C:13](=[O:27])[C:14]3[C:19]([C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:29][C:4](=[O:5])[CH2:3]1
Reactant: Cn1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cn1c(/C=C/C2CC(O)CC(=O)O2)c(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A stirred mixture of a 2:1 mixture of the erythro- and threo-diastereoisomers of (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoic acid (0.1 g; prepared as described in Example 2) in dry toluene (10 ml) and glacial acetic acid (2 drops) was heated at reflux for 1 hour. Further quantities of toluene (15 ml) and glacial acetic acid (2 drops) were added and the mixture was heated at reflux for a further period of 3.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to half volume. The resulting white solid was filtered off and washed with petroleum ether (b.p. 40°-60° C.), to give (E)-4-hydroxy-6-[2-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethenyl]-3,4,5,6-tetrahydro-2H-pyran-2-one (0.07 g), m.p. 190°-193° C. [Elemental analysis: C, 71.1; H, 5.52; N, 3.52%; calculated for C23H21NO4 : 0.75 H2O: C, 71.0; H, 5.8; N, 3.6%].
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[CH:40]1(OC2C=CC=CC=2B(O)O)C[CH2:41]1>>[CH:39]1([O:38][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH3:32])[CH2:41][CH2:40]1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1OC1CC1
Product: CNc1cnccc1-c1ccccc1OC1CC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-cyclopropoxyphenylboronic acid after stirring at 90° C. for 18 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow oil (94%). MS (ESI): m/z=241.134 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.[NH2:23][NH2:24]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:23][NH2:24])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2NN)CC1
Yield: 36.5 %

Procedure:
A 500 mL 3-necked round bottom flask was charged with tert-butyl 4-(5-bromo-3-chloropyrazin-2-yl)piperazine-1-carboxylate (16.1 g, 42.6 mmol), hydrazine hydrate (4.2 mL, 85.2 mmol) and ethanol (200 mL). The resulting solution was refluxed overnight. TLC indicated an incomplete conversion. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether then 2% methanol in dichloromethane, to afford 5.8 g (47%) of the product as a yellow solid. MS m/z: 373 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCCN(Cc2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture of 1-benzyl-3-hydroxypiperidine (2.0 g, 10 mmoles), p-fluoro-nitrobenzene (1.06 ml, 12 mmoles) and sodium hydride (0.285 g, 12 mmoles) in DMF was stirred at room temperature for 3 hours, diluted with H2O and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by flash chromatography using as eluent 50% EtOAc/hexane to afford the title compound (3.0 g, 9.43 mmoles).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([N:32]2[CH2:33][CH:30]([OH:29])[CH2:31]2)=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: OC1CNC1
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N2CC(O)C2)C1(C)C

Procedure:
The product from Example 173 and 3-hydroxyazetidine hydrochloride (Oakwood) were processed using the method described in Example 178 to afford the title compound. 1H NMR δ 0.49-0.50 (m, 3H), 0.90 (t, J=7.2 Hz, 3H), 1.22 (s, 6H), 1.24-1.46 (m, 3H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.90-2.03 (m, 1H), 2.62-2.67 (m, 2H), 2.71-2.86 (m, 2H), 3.50-3.61 (m, 1H), 4.23-4.45 (m, 1H), 4.41 (br s, 1H), 3.83-4.09 (m, 2H), 3.50-3.61 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 450 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[O:22]=[C:16]1[CH:15]([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[C:5]2=[O:7])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 82.3 %

Procedure:
A stirred solution of 3-methylphthalic anhydride (2.96 g, 18.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (3.00 g, 18.2 mmol) and sodium acetate (1.57 g, 19.1 mmol) in acetic acid (30 mL) was heated at reflux for 23 hours. The solvent was removed in vacuo to give a solid which was stirred with water (40 mL) for 1 hour, filtered, washed with water (30 mL), and then heated with decolorizing charcoal (1 g) in acetone (2 L) at reflux temperature for 30 min. The suspension was filtered through a pad of Celite to give a clear solution. The solvent of filtrate was removed in vacuo to give 2-(2,6-dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione as a white solid (4.08 g, 82% yield); mp 290.0-292.0° C.; 1H NMR (DMSO-d6); δ2.03-2.09 (m, 1H, CHH), 2.50-2.60 (m, 2H, CH2), 2.63 (s, 3H, CH3), 2.83-2.95 (m, IH, CHH), 5.13 (dd, J=5.4,12.3 Hz, IH, NCH), 7.65-7.79 (m, 3H, Ar), 11.13 (br s, IH, NH); 13C NMR (DMSO-d6) δ17.04, 21.99, 30.93, 48.76, 121.05, 127.89, 131.63, 134.37, 136.91, 137.61, 167.04, 167.83, 169.87, 172.74; Anal Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.68; H, 4.37; N, 10.17.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[N:17]=[N:16][C:15]([N:18]([CH2:26][C:27]2([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:30][CH2:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1)#[N:11].[SH2:38]>CN1C(=O)CCC1>[C:10]([C:12]1[N:17]=[N:16][C:15]([N:18]([CH2:26][C:27]2([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:30][CH2:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1)(=[S:38])[NH2:11]
Reactant: S
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C#N)nn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C(N)=S)nn1

Procedure:
NMP (40 mL) and DIPEA (10 mL) were added to t-butyl 6-cyanopyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (3.9 g, 10 mmol), and hydrogen sulfide was bubbled through the reaction mixture for 2 h. The reaction was diluted with water, and the resultant yellow solid was filtered and dried under vacuum to give 2.1 g of t-butyl 6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][C:25]=4[CH3:26])[C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc(-c3ccc(F)cc3)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(-c3ccc(F)cc3)cc2C1=O
Yield: 10.9 %

Procedure:
Using analogous reaction conditions as described in example 1, 7-(4-fluoro-phenyl)-3,4-dihydro-2H-isoquinolin-1-one (100 mg, 0.4132 mmol) was reacted with 3-iodo-4-methyl-pyridine (108.5 mg, 0.4958 mmol), 1,4-dioxane (25 mL), copper iodide (2.8 mg, 0.01432 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (14.2 mg, 0.1239 mmol) and potassium phosphate (219.2 mg, 1.0330 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 15 mg of the product (11.1% yield).
Reaction SMILES: Cl[NH:2][C:3]1[N:8]=[C:7]([NH:9]Cl)[N:6]=[C:5]([NH:11]Cl)[N:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:2][C:3]1[N:8]=[C:7]([NH:9][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[N:6]=[C:5]([NH:11][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[N:4]=1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: ClNc1nc(NCl)nc(NCl)n1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCl)Nc1nc(NC(=O)CCCCl)nc(NC(=O)CCCCl)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 2.3 g N,N',N"-trichloromelamine, 20 ml carbon tetrachloride, 8.46 g 4-chlorobutyryl chloride and 30 mg N,N-dimethylaminopyridine was placed in a 100 ml flask fitted with a magnetic stirring bar, a reflux condenser and argon inlet. The reaction mixture was slowly heated in an oil bath to about 60° C. and was stirred at about 60° C. for 5 hours. It was allowed to cool down to room temperature and then diluted with 50 ml hexanes. The contents were stirred at room temperature for 30 minutes and then filtered. The residue was washed with hexane and dried under reduced pressure. It was characterized to be N,N',N"-tris(4-chlorobutyryl)melamine on the basis of NMR and mass spectroscopy (4.2 g; 95% yield):
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:27][C:28]1[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=1[C:30]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[CH3:27][C:28]1[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=1[C:30]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:38])=[CH:35][CH:34]=1)=[O:31]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A solution of 1.2 g of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate in 100 ml of methylene chloride is cooled to 0° C. and 10 ml of triethylamine added followed by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and concentrated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na2SO4 and concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 40% ethyl acetatehexane to give 1.0 g of the desired product as a solid; mass spectrum (M+ H)494.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1.O>[CH2:25]([O:24][C:22]([N:10]1[CH2:11][C@H:12]([CH3:14])[CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:9]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
((3R,5R)-5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (2.9 g, 13.53 mmol) was dissolved in 70 mL of a 1:1 mixture of dioxane and H2O and NaHCO3 (4.55 g, 54.13 mmol) was added. To the resulting suspension benzyl chloroformate (2.2 ml, 14.2 mmol) was added slowly. After 2 hours the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated. The remaining oil was purified by SiO2 chromatography (150 g SiO2, hexanes/EtOAc 0-20% EtOAc) to give 3.6 g of (3R,5R)-3-tert-butoxycarbonylamino-5-methyl-piperidine-1-carboxylic acid benzyl ester as a colorless oil (76% yield).