Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:13]O)[CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[Cl:16][CH2:17][C:18]([OH:20])=[O:19].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[Cl:16][CH2:17][C:18]([O:20][CH:3]([N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])[C:2]([CH3:15])([CH3:13])[CH3:1])=[O:19]
Reactant: CC1=C(C)C(=O)N(CC(C)(C)CO)C1=O
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(=O)N(C(OC(=O)CCl)C(C)(C)C)C1=O
Yield: 84.1 %

Procedure:
A mixture of 105.6 g (0.5 mole) of N-(2,2-dimethyl-3-hydroxypropyl)dimethylmaleimide, 56.7 g (0.6 mole) of chloroacetic acid, 5.9 g of concentrated sulfuric acid and 400 ml of toluene are heated as described in Example 1 until the formation of water (9 ml) has ceased. The reaction solution is worked up as in Example 1, affording 121 g of a colourless liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].I[CH2:17][CH2:18][CH3:19].O>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH2:17]([CH:8]([C:9]([CH3:11])=[O:10])[C:7]([O:13][CH2:14][CH3:15])=[O:12])[CH2:18][CH3:19]
Reactant: CCCI
Reactant: CCOC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCC(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Keto ester 9 was synthesized according to the method of Barbry et. al. [71]. A mixture of potassium carbonate (14 g, 0.10 mol), ethyl acetoacetate (4.3 g, 33 mmol), 1-iodopropane (5.7 g, 33.7 mmol), tetrabutylammonium chloride hydrate (10 g), water (50 mL) and chloroform (50 mL) was stirred at room temperature for 40 h. The aqueous layer was then separated, acidified with 5M hydrochloric acid and extracted with ether. The organic portions were combined, concentrated and the residual tetrabutylammonium chloride was precipitated by addition of ether. After filtration, the ethereal filtrate was dried: (MgSO4) and evaporated to give a yellow liquid which was fractionated by distillation. The fraction which boiled at 93° C. at ˜15 mmHg (Lit. [72] 106-107° C., 22 mmHg) was collected (2.13 g) and 1H NMR has indicated that this colorless liquid contained about 5% of ethyl acetoacetate and 95% of 9; δH (270 MHz, CDCl3) 0.93 (3H, t, J=7.3 Hz, CH3), 1.28 (5H, m, —CH2CH2CH3 and CH3), 1.83 (2H, m, —CH2CH2CH3), 2.23 (3H, s, CH3CO), 3.42,(1H, t, J=7.3 Hz, —CH) and 4.20 (2H, q, J=7.3 Hz, COOCH2CH3); MS (EI) m/z (rel. intensity) 172.1(25, M+), 143.1[50, (M−Et)+], 130.1[28, (M+H—CH3CO)+], 115.1(23),101.1(40), 85.0(20), 69.0(30), 55.0(30), 43.0[100, (CH3CO)+]. This crude 9 was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20]C)=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+]>Br.O>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1

Procedure:
Heat and stir a mixture of 0.850 g (0.0028 moles) of the product of step D in 12 ml of 48% hydrobromic acid at 100° C. for 16 hours. Dilute with 75 ml of water and heat on a steam bath to dissolve. Adjust to about pH 8 with solid sodium bicarbonate, filter, and wash the .resulting precipitate with water. Recrystallize from ethanol to obtain analytically pure (S)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 188°-189° C., [α]D26 =+44.8° (c=1, dimethylformamide).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].[BrH:13]>>[BrH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1
Reactant: NCCS
Reactant: ClCc1ccon1
Agent: Br
Agent: Cl
Product: NCCSCc1ccon1

Procedure:
A solution of 3-chloromethylisoxazole (5.8 g.) and cysteamine hydrochloride (6.25 g.) in aqueous hydrobromic acid (48%, 100 ml) was heated under reflux for 6 hours. Concentration in the presence of water and subsequently n-propanol, followed by recrystallisation of the residue from isopropyl alcohol-ethanol afforded 3-[(2-aminoethyl)thiomethyl]isoxazole hydrobromide, m.p. 131°-133°. (Found: Br, 33.6; S, 13.7. C6H10N2O S. H Br requires: Br, 33.4; S, 13.4).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.CN1CCOCC1>CCO.[Pd]>[OH:1][C:2]1[C:7]([NH:8][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [Pd]
Solvent: CCO
Solvent: CN1CCOCC1
Product: O=C(Nc1cccnc1O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A sample of 10% Pd on C (0.40 g) was added to a solution of 2-hydroxy-3-nitropyridine (3.52 g, 25.0 mmol, 1 equiv) in EtOH. The reaction mixture was stirred at room temperature under H2 atmosphere (balloon) overnight and then was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH3CN (100 mL), cooled to 0° C., and cyclopentanecarbonyl chloride (25 mmol, 3.04 mL, 1 equiv) and NMM (2.75 mL, 25 mmol, 1 equiv) were added sequentially. The resulting mixture was stirred at 0° C. for 20 min, then was partitioned between water (400 mL) and 10% CH3OH in CH2Cl2 (2×400 mL). The organic layers were dried over Na2SO4, concentrated, and the resulting residue recrystallized from CH2Cl2/hexanes to afford the title intermediate as a off-white solid (3.36 g, 65%); mp=242-243° C.; IR (cm−1) 3263, 1644, 1605, 1521, 1199; 1H NMR (DMSO-d6) δ 1.51-1.57 (m, 2H), 1.60-1.72 (m, 4H), 1.79-1.88 (m, 2H), 2.98-3.08 (m, 1H), 6.20 (t, 1H, J=6.9), 7.08 (d, 1H, J=6.6), 8.23 (d, 1H, J=7.5), 9.02 (s, br. 1H), 11.95 (s, br. 1H); Anal. C11H14N2O2: C, H, N.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>CO.C(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1
Yield: 62.8 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 10. Reaction of 2-chlorosulfonyl-5-(4-methylphenyl)thiophene (100 mg, 0.37 mmol) with 5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, after column chromatography using 10% MeOH/CHCl3, 96 mg final product as a pale yellow solid, (63% yield, m.p. 175° C.).
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[C:20]4[C:19]5[CH:21]=[C:22]([NH:25][C:26]([C:28]6[C:33]([Cl:34])=[CH:32][CH:31]=[C:30](Cl)[N:29]=6)=[O:27])[CH:23]=[CH:24][C:18]=5[CH2:17][CH2:16][C:15]=4[C:14]([C:36]([NH2:38])=[O:37])=[N:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1>CC(N(C)C)=O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[C:20]4[C:19]5[CH:21]=[C:22]([NH:25][C:26]([C:28]6[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([NH:2][CH3:1])[N:29]=6)=[O:27])[CH:23]=[CH:24][C:18]=5[CH2:17][CH2:16][C:15]=4[C:14]([C:36]([NH2:38])=[O:37])=[N:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(Cl)ccc3Cl)cc1-2
Reactant: CN
Solvent: CC(=O)N(C)C
Product: CNc1ccc(Cl)c(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc4c(c2)OCO4)CC3)n1
Reaction time: 120 h

Procedure:
The title compound was synthesized from N-methylamine (6 mL of 33 w % solution in EtOH) and the compound of Example 216 (1.04 g) by the same procedure used for Example 207 except that 1 mL of DMA was added. The reaction was carried out at 82° C. for 5 days. The title compound, isolated by preparative HPLC, is a white solid (0.29 g, 52%), M.p. 269–270° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (d6-DMSO): δ 2.76 (d, 3H, J=5.5 Hz), 2.84–3.99 (m, 4H), 6.16 (s, 2H), 6.57 (d, 1H, J=9 Hz), 6.91–7.04 (m, 3H), 7.12 (d, 1H, J=1 Hz), 7.22–7.34 (m, 3H), 7.46–7.54 (m, 3H), 10.19 (s, 1H). ESI mass spectrum for C26H22ClN6O4+: 517 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:14]=[C:13]([NH:23]CC3C=CC(OC)=CC=3)[N:12]=2)=[N:5]1)([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1>[NH2:23][C:13]1[N:12]=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:15][CH:14]=1
Reactant: COc1ccc(CNc2cnc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)n2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)n1nc(-c2nc(N)cnc2-c2ccccc2)ccc1=O
Yield: 47.1 %

Procedure:
A suspension of 2-isopropyl-6-{6-[(4-methoxybenzyl)amino]-3-phenyl-2-pyrazinyl}-3(2H)-pyridazinone (2.01 g) in a mixture of toluene (1 ml) and conc. HCl (6 ml) was refluxed for 4 hours. After cooling, an organic layer was removed and an aqueous layer was adjusted to pH 8 with 8N aq. NaOH to yield a precipitate. The precipitate was collected by filtration and dried under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give 6-(6-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (680 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>C(O)(C)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:32][C@H:33]4[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1

Procedure:
1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (50.0 g, 148 mmol) was suspended in isopropanol (400 mL) and DIPEA (35.0 mL, 207 mmol) was added, followed by trans-4-aminocyclohexanol (18.7 g, 163 mmol). The mixture was heated at reflux for 2 hours, then cooled and concentrated under vacuum. The residue was dissolved in dichloromethane and washed with water (added 1 N HCl to bring pH to 6-7). The organic layer was dried (Na2SO4) and concentrated under vacuum. The residual foam was taken up in ethanol and the resulting precipitate collected to give 65.0 g (quant) of crude trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 9.03 (d, 1H), 8.19 (dd, 2H), 7.62 (m, 2H), 7.52 (m, 2H), 6.71 (d, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 3.78-3.67 (m, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.59 (m, 1H), 1.54 (m, 4H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([Cl:30])=[N:25][N:24]=[C:23]3Cl)=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[O:34]1CCOCC1.Cl>O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([Cl:30])=[N:25][NH:24][C:23]3=[O:34])=[O:19])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C1COCCO1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (322 mg, 0.683 mmol), 2N NaOH (3.4 mL, 6.83 mmol) and dioxane (5 mL) was heated to 50° C. for 1 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (49 mg) as a yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 2.99 (m, 4H), 3.80 (m, 4H), 7.41 (d, 1H), 7.56 (dd, 1H), 8.18 (d, 1H), 8.28 (s, 1H), 8.51 (dd, 1H), 8.80 (d, 1H), 10.23 (s, 1H), 13.05 (s, 1H) ppm; m/z (M+1) 452.96; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (40 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 2.99 (m, 4H), 3.80 (m, 4H), 7.41 (d, 1H), 7.58 (dd, 1H), 8.29 (s, 1H), 8.43 (s, 2H), 8.46 (s, 1H), 10.23 (s, 1H), 13.02 (s, 1H) ppm; m/z (M+1) 452.96.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:58]1[C:62]2[CH:63]=[CH:64][C:65]([C:67](=[O:70])[CH2:68]Br)=[CH:66][C:61]=2[O:60][CH2:59]1.CCN(CC)CC>CC(C)=O.C(Cl)Cl.O>[O:58]1[C:62]2[CH:63]=[CH:64][C:65]([C:67](=[O:70])[CH2:68][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C@@H:9]3[C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:66][C:61]=2[O:60][CH2:59]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl (4-{(2R,3R)-1-(4-chlorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (Method 27) (0.70 g, 1.22 mmol) was dissolved in acetone (30 mL) at room temperature, then water (10 mL) and triphenyl phosphine (0.32 g, 1.22 mmol) was added. The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure to afford the crude thiol as a brown oil. This crude thiol was immediately dissolved in CH2Cl2 (30 mL) and 1-benzo[1,3]dioxol-5-yl-2-bromo-ethanone (0.59 g, 2.44 mmol) was added, followed by Et3N (0.34 mL, 2.44 mmol). The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash-chromatography (Heptane:EtOAc 7:3 and then 2:1). The resulting product (0.90 g) was dissolved in 15 ml formic acid and stirred at room temperature for 3 hours. Concentration under reduced pressure and purification by flash-chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CCNCC
Solvent: O
Product: CCN(CC)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A sealed tube with 3-chloro-4-fluorobenzonitrile (0.366 g, 2.4 mmol) and diethylamine (0.6 mL, 5.8 mmol) was heated to 100° C. for 8 hours. The reaction was allowed to cool to room temperature and water (5 mL) was added. The solution was extracted with dichloromethane (2×5 mL), dried over magnesium sulfate and concentrated in vacuo to afford 3-chloro-4-diethylaminobenzonitrile as an oil (0.38 g). This was reacted as described in Methods A-C (Examples 1-3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.89 (dd, 1H), 8.26 (d, 1H), 8.11 (ddd, 1H), 7.97 (dd, 2.2 Hz, 1H), 7.53 (d, 1H), 7.27 (dd, 1H), 7.15 (d, 1H), 3.86 (b, 2H), 3.20 (q, 4H), 3.03 (t, 2H), 1.91 (quint, 2H), 1.08 (t, 6H); MS (m/e) calculated for C21H26ClN5 383, found 384.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred solution of methyl 5-chloro-2-fluoro-4-methylbenzoate (Preparation 12, 340 mg, 1.68 mmol) in dioxane/water (5:1, 12 mL) was added a sodium hydroxide solution (5 M, 1.63 mL, 8.39 mmol). The reaction mixture was stirred at room temperature for 18 hours and then evaporated in vacuo. The resulting residue was suspended in water and extracted with diethyl ether (3×20 mL). The aqueous layer was separated, cooled in an ice bath, acidified with aqueous hydrochloric acid (6 M) and then extracted with EtOAc (30 mL). The combined organics were washed with brine (2×20 mL), dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound as a white solid (266 mg, 84%).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.CSC>O>[OH:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of triethyl phosphonoacetate (0.89 mL) in tetrahydrofuran (30 mL) was added potassium tert-butoxide (0.50 g), and the mixture was stirred at room temperature for 15 minutes. A solution of 4-(2-benzyloxybenzyl)benzaldehyde (1.0 g) in tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. To the resulting mixture was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give ethyl (E)-3-[4-(2-benzyl-oxybenzyl)phenyl]acrylate (0.86 g). To the obtained ethyl (E)-3-[4-(2-benzyloxybenzyl)phenyl]acrylate (0.86 g) were added trifluoroacetic acid (9.5 mL), water (0.5 mL) and dimethyl sulfide (1.0 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give ethyl (E)-3-[4-(2-hydroxybenzyl)phenyl]acrylate (0.51 g).
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[N:4].[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[CH:8]=1.[OH-].[Na+].Cl>CS(C)=O>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[C:8]=1[CH:2]([CH3:5])[C:3]#[N:4]
Reactant: CC(Cl)C#N
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
A mixture of 2-chloropropanenitrile (0.2 mol) and 1,3-dichloro-5-nitrobenzene (0.2 mol) in DMSO (50 ml) was added dropwise at RT to a solution of NaOH (1 mol) in DMSO (150 ml) while the temperature was kept below 30° C. The mixture was stirred at RT for 1 hour, then poured out on ice and acidified with HCl. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 70/30). The pure fractions were collected and the solvent was evaporated, yielding 19.5 g (40%) of (±)-2,6-dichloro-α-methyl-4-nitrobenzeneacetonitrile (interm. 1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:21]1[N:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (41 mg, 49%), MS (ISP) m/z=335.5 [(M+H)+], mp 280° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].P(=O)(O)(O)O.COC1C(=O)C=CC(=O)C=1>C1C2C(=CC=CC=2)CCC1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:8]([N:20]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: CC(=O)[O-]
Agent: COC1=CC(=O)C=CC1=O
Agent: O=P(O)(O)O
Solvent: c1ccc2c(c1)CCCC2
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 210 °C
Reaction time: 2 h

Procedure:
The same reactor as used in Example 7 was adopted. In this reactor, a solution of 120 g of maleic anhydride in 360 g of tetrahydronaphthalene was placed. Then, a solution of 220 g of dodecylamine and 1760 g of tetrahydronaphthalene was added thereto at 40° C. over a period of 120 minutes. After the addition was completed, the resultant mixture and 65.4 g of ortho-phosphoric acid (purity 89% by weight), 1.344 g of methoxybenzoquinone, and 0.1 g of zinc acetate added thereto were heated at 210° C. for one hour to effect reaction. Thereafter, the resultant reaction mixture was cooled to 30° C. and separated into a water layer and a tetrahydronaphthalene layer. The tetrahydronaphthalene layer was distilled to expel tetrahydronaphthalene. Consequently, there was obtained 285 g of slightly impure N-dodecyl maleimide. It was found to have purity of 92.3% by weight, indicating the yield thereof to be 83.5 mol% based on dodecylamine.
Reaction SMILES: [CH3:1][CH:2]1CC[N:6]2[C:9](=[O:21])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4][CH2:3]1.[CH2:22]([O:24][C:25](C1C2=NC3SC4CCCCC=4C=3C(=O)N2CCC1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([CH:4]1[C:5]2=[N:12][C:11]3[S:13][C:14]4[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]=3[C:9](=[O:21])[N:6]2[CH2:1][CH2:2][CH2:3]1)=[O:26])[CH3:23]
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Reactant: CCOC(=O)C1CCCn2c1nc1sc3c(c1c2=O)CCCC3
Product: CCOC(=O)C1CCCn2c1nc1sc3c(c1c2=O)CCCC3=O

Procedure:
Compound 18 was synthesized by the method described for compound 17 using compound 15 as a starting material.