Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:28]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccsc1C(=O)NCCCSc1ccncc1
Yield: 84.5 %

Procedure:
In 100 ml of benzene was suspended 3.00 g (21.1 mmol) of 3-methyl-2-thiophenecarboxylic acid, oxalyl chloride [7.36 ml (84.4 mmol)] was added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off to obtain 3.40 g of 3-methylthenoyl chloride (yield: quant.). To a solution of 1.50 g (6.23 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.61 ml (18.7 mmol) of triethylamine in 60 ml of methylene chloride, 1.20 ml (7.48 mmol) of the 3-methylthenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.54 g of the desired compound (yield: 84.5%, pale yellow powder). mp: 104.0°-105.0° C.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[NH2:20].C>[OH-].[Na+]>[Cl:19][C:14]1[CH:15]=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)cc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)cc(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
5-Chloro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.64 g, 18.1 mmol) and 1,2-diamino-3-chloro-5-fluorobenzene (290 mg, 1.81 mmol) was heated to reflux under N2 for 10 h. The reaction was allowed to cool to room temperature and the shiny yellow-brown crystals collected by vacuum filtration and rinsed with EtOH (10 mL) and air dried to give 164.1 mg (42%). A portion of this solid was taken and dissolved in 10 mL 1N NaOH. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=6). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O and further dried under vacuum (0.1 torr, 78° C.) to yield 67.8 of powdery pale yellow crystals. mp 306°-308° C. (dec), 1H NMR (d6 -DMSO) δ7.28 (s, 1H, ArH), 7.56 (s, 1H, ArH), 11.7 (br s, 2H, NH), EIMS m/z 216 (M+2,34, 214 (M+, bp), 188 (21), 186 (68), 123 (61), 131 (62). EIHRMS calc. for C8H4ClFN2O2 213.9945, found 213.9961.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[C:45]([CH2:46][N:47]([CH3:49])[CH3:48])=[CH:44][N:43]=[N:42]2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[C:45]([CH2:46][N:47]([CH3:49])[CH3:48])=[CH:44][N:43]=[N:42]2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K8) (172 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (179 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:31][CH3:32])=[N:16]2)=[CH:11][CH:10]=1.C(OC([NH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.CN(C)C=O>C([O-])(O)=O.[Na+]>[NH2:40][C:41]([CH3:46])([CH3:45])[C:42]([N:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[N:17]4[N:16]=3)=[C:20]([O:31][CH3:32])[CH:21]=2)[CH2:26][CH2:27]1)=[O:43]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(C(=O)C(C)(C)N)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (80.00 mg, 0.186 mmol), 2-tert-butoxycarbonylamino-2-methyl-propionic acid (0.045 g, 0.22 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.043 g, 0.22 mmol) and N,N-dimethylformamide (1.54 mL, 20.0 mmol) were combined in a round-bottom flask and stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NaHCO3 and the resulting precipitate was collected by filtration and was washed twice with water, then dried under vacuum and used in the next step without further purification. Following the experimental procedure described in Example 787b), this precipitate was converted to 2-amino-1-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-2-methyl-propan-1-one as a yellow solid (58 mg, 61%). MP: 81-89° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.99 (dd, J=7.6; 1.6 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.7 Hz, 1H), 6.70 (m, 2H), 4.84 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.88 (m, 2H), 2.72 (m, 1H), 1.90 (m, 2H), 1.63 (m, 4H), 1.45 (s, 6H); LC/MS (ESI+): 515.0 (M+H).
Reaction SMILES: [CH:1]([N:4]([CH3:17])[C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[H][H]>[Pd].CCO.C1COCC1>[CH:1]([N:4]([CH3:17])[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)N(C)c1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2ccc(N)cc2s1
Yield: 89.5 %

Procedure:
Combine isopropyl-methyl-(6-nitro-benzothiazol-2-yl)-amine (1.32 g, 5.25 mmol) and 5% palladium on carbon (3.00 g) in EtOH (50 mL) and THF (25 mL). Shake on a Parr shaker at 60 psi hydrogen at room temperature for 7 h. Filter with filter paper, washing with EtOH (20 mL), and concentrate in vacuo to afford the title compound (1.04 g, 90%). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=8.4 Hz), 6.93 (d, 1H, J=2.2 Hz), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 4.31 (m, 1H), 3.62 (s, 2H), 2.99 (s, 3H), 1.25 (d, 6H, J=6.6 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]=[CH2:25]>>[CH2:25]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH:24]=[CH2:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: C=CCBr
Product: C=CCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 131 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-bromoprop-1-ene and conditions outlined in procedure V. M.p.=166-168° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.9 (d, 1H), 7.75 (s, 2H), 7.55 (s, 1H), 5.8 (m, 1H), 5.2-5.1 (m, 2H), 3.1 (s, 2H), 3.0 (d, 2H), 2.7 (d, 2H), 2.3 (t, 2H), 1.95 (d, 2H), 1.8 (t, 2H); LCMS: 328 [M+H].
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([OH:29])[C:27]=1[I:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:29][C:26]1[CH:25]=[C:19]([CH:18]=[C:17]([O:16][CH2:14][CH3:15])[C:27]=1[I:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(O)c(I)c(OCC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c(I)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Benzyl bromide (2.95 mL) was added to a DMF (200 mL) suspension of ethyl 3-ethoxy-5-hydroxy-4-iodobenzoate (7.59 g) and potassium carbonate (4.68 g), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.09 g).
Reaction SMILES: [OH2:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][CH2:20]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21](=[O:1])[CH2:20]3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=C1CSCN1CCCCN1CCN(c2ccc(F)cc2)CC1
Reactant: O
Solvent: C1CCOC1
Product: O=C1CS(=O)CN1CCCCN1CCN(c2ccc(F)cc2)CC1

Procedure:
A second run using NaIO4 (1.41 g), H2O (13 ml), 1 (2.02 g) and THF (20 ml) was conducted in a similar manner yielding 0.910 g of product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.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.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(-c2ccc(Cn3nc(C(C)C)c(O)c(C(=O)NCC(=O)O)c3=O)c(F)c2)cc1
Yield: 5.9 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 75 mg, 0.17 mmol), [4-(methylthio)phenyl]boronic acid (34 mg, 0.20 mmol), potassium carbonate (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by low pressure reverse phase c18 (ODS silica, gradient 15-95% acetonitrile/water) to afford the title compound (5 mg, 0.010 mmol, 6% yield) as an off white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.92 (s, 1H), 12.95 (s, 1H), 10.16 (t, J=5.43 Hz, 1H), 7.65 (d, J=8.34 Hz, 2H), 7.54 (dd, J=11.62, 1.52 Hz, 1H), 7.48 (dd, J=7.96, 1.64 Hz, 1H), 7.30-7.38 (m, 3H), 5.33 (s, 2H), 4.10 (d, J=5.81 Hz, 2 H), 3.31-3.34 (m, 3H), 3.18 (m, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 486 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH:25]=[O:26])=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:34])(=O)=O.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH3:37][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH:25]=[O:26])=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:34]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 85.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (176 mg, 0.336 mmol) was dissolved in dimethoxyethane (8.8 mL), and the solution was treated with trimethylboroxine (0.140 mL, 1.01 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (32.9 mg, 0.0403 mmol), potassium carbonate (231 mg, 1.68 mmol) and water (0.121 mL), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=4/1) to obtain 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (112 mg, yield 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 72 h
Yield: 96.7 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (25 g; 0.159 mol) in DMF (600 ml) under argon was treated at room temperature with Na2CO3 (33.7 g; 0.318 mol). The mixture was stirred and treated dropwise with benzyl bromide (32.6 g; 0.19 mol). Stirring was continued for 3 days when the mixture was poured into water and extracted with Et2O. The organic phase was washed with water, brine and dried over MgSO4. Evaporation gave 4-benzyloxy-2-fluoronitrobenzene as a yellow solid (38 g).
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][NH2:20])=[CH:13][CH:12]=1.O>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][N:20]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:15][CH:16]=1
Reactant: NCCCc1ccc(Cl)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)/C(Cl)=C(/Cl)C(O)=NCCCc1ccc(Cl)cc1
Temperature: 20 °C
Yield: 77.5 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 17.0 g (0.1 mol) of 3-(4-chlorophenyl)-propylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 50 ml of water are added and the mixture is cooled to 20° C. The product is filtered off with suction and dried. 26.1 g (82% of theory) of dichloromaleic acid N-[3-(4-chlorophenyl)-propyl]-imide of melting point 72°-73° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:25])C(=O)C(F)(F)F)[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:44]>>[F:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:29]2[CH:28]=[CH:27][C:26]([C:4]3[C:3]([C:1]([NH2:2])=[O:44])=[C:7]4[NH:8][CH2:9][CH2:10][CH:11]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[NH:18][CH3:25])[N:6]4[N:5]=3)=[CH:31][CH:30]=2)=[CH:38][CH:37]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: CN(C(=O)C(F)(F)F)c1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21
Product: CNc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21

Procedure:
The desired product was prepared form N-(2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, CD3OD-d4) δ 7.39 (d, J=8.8 Hz, 2H), 7.09-6.90 (m, 7H), 6.58 (d, J=8.0 Hz, 1H), 6.51 (t, J=7.2 Hz, 1H), 6.30 (d, J=7.2 Hz, 1H), 5.52-5.48 (m, 1H), 3.27-3.24 (m, 1H), 3.11-3.02 (m, 1H), 2.76 (s, 3H), 2.32-2.10 (m, 2H). MS (ESI) m/e [M+1]+ 457.9.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[S:8]1)=[O:4]
Reactant: CN=C=O
Reactant: CCCCOc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 17.5 g of 3-hydroxy-5-n-butoxy-1,2,4-thiadiazole in 125 ml of tetrahydrofuran containing 0.5 ml of triethylamine and after stirring for 2 hours at 20° C, the mixture was evaporated to dryness. The residue was empasted with isopropyl ether and was vacuum filtered and dried to obtain 21 g of 2-(N-methylcarbamoyl)-5-n-butoxy-1,2,4-thiadiazole-3-one melting at 108° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:10])[C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:7][CH2:6][C:5]([CH3:9])([N:4]([CH3:10])[CH3:3])[CH3:8]
Reactant: CN(C)C(C)(C)CO
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)CCOCC(C)(C)N(C)C
Temperature: 70 °C
Yield: 27 %

Procedure:
To toluene (100 ml), sodium hydroxide (16.7 g, 418 mmol) and 2-dimethylamino-2-methyl-1-propanol (23.4 g, 200 mmol) were added and the mixture was heated at reflux for 2 hours. After cooling to 70° C., β-dimethylaminoethyl chloride hydrochloride (28.8 g, 200 mmol) was added. Then, the mixture was heated at reflux for 5.5 hours. After cooling to room temperature, insolubles were separated by filtration and the organic phase was concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 10.3 g (in a yield of 27%) of the objective compound as a colorless liquid.
Reaction SMILES: [CH3:1][CH:2]([N:19]1[CH2:26][C:24](=[O:25])[N:23](CN2CCOCC2)[C:21](=[O:22])[CH2:20]1)[CH2:3][N:4]1[CH2:11][C:9](=[O:10])[N:8]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:6](=[O:7])[CH2:5]1>O>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][N:8]2[C:9](=[O:10])[CH2:11][N:4]([CH2:3][CH:2]([N:19]3[CH2:20][C:21](=[O:22])[NH:23][C:24](=[O:25])[CH2:26]3)[CH3:1])[CH2:5][C:6]2=[O:7])[CH2:14][CH2:15]1
Reactant: CC(CN1CC(=O)N(CN2CCOCC2)C(=O)C1)N1CC(=O)N(CN2CCOCC2)C(=O)C1
Solvent: O
Product: CC(CN1CC(=O)N(CN2CCOCC2)C(=O)C1)N1CC(=O)NC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
Water (200 ml) was added to dl-1,2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)-propane (4.0 g) obtained in Example 1 and the mixture was stirred at room temperature for 0.5 hours. Then, the mixture was filtered and the filtrate was stirred at room temperature for further 3 hours. The reaction mixture was freezed on a dry ice-acetone bath and the freezed mixture was allowed to stand at room temperature to give an aqueous suspension. Colorless solids, which precipitated in the aqueous suspension, were collected by filtration and dried over phosphorus pentaoxide under a reduced pressure to give the titled compound (1.22 g; yield 40%).
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.CC(C[AlH]CC(C)C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:15]2[CH2:16][C:13](=[C:4]([C:5]3[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=3)[CH2:3][OH:2])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.11 g (4.45 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 40 mL of hexanes and 40 mL of CH2Cl2 was added a solution of 26.7 mL (26.7 mmol) of DIBAL-H (1M solution in THF followed by stirring for 1 h at −78° C. Then the reaction mixture was warmed to rt for 1.5 h and 8 g of sodium sulfate decahydrate was added to quench the reaction followed by stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as white solid. 1NMR (CDCl3) δ 3.99 (s, 2H), 4.03 (s, 2H), 4.35 (s, 2H), 4.54 (s, 1H), 6.70-6.80 (m, 3H), 7.30-6-7.40 (m, 8H). Mass Spectrum: m/e=446 (M+1 35Cl, 35Cl) and 448 (M+1 35Cl, 37Cl).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=1[C:8]=23>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]=[C:9]3[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=1[C:8]=23
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ncco4)c(c23)C1
Yield: 37.1 %

Procedure:
A solution of 0.65 g (2.0 mmol) of (-)(2aR,4S)-6-(2-oxazolyl)-4-(di--propylamino)-1,2,2a, 3,4,5-hexahydrobenz[cd]indole in 30 ml of CH2Cl2 was sonicated (50-55 KHz) in the presence of 2.5 g of MnO2 for 5 hours. The oxidant was removed by filtration through celite. The crude product obtained after filtering and removing the solvent was chromatographed over 15 g of silica gel using 1:9 EtOAc/toluene, then crystallized from isooctane to provide 0.24 g of title compound.