Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OCC)=[O:15])[N:6]=1.CO.O.[NH2:26][NH2:27]>C1COCC1>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH:26][NH2:27])=[O:15])[N:6]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Temperature: 65 °C
Reaction time: 10 h

Procedure:
150 mg (0.50 mmol) of ethyl 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carboxylate from example 7A are introduced into a mixture of 1 ml of methanol and 0.5 ml of THF, and 503 mg (10.1 mmol) of hydrazine hydrate are added. The mixture is heated firstly at 65° C. for 4 h and then at 90° C. for 10 h. It is then concentrated to dryness. The resulting crude product (157 mg, quantitative) is reacted without further purification.
Reaction SMILES: C([O:4][CH:5](OC(C)C)[C:6]([CH3:27])([CH3:26])[C:7](=[O:25])[C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[O:25]=[C:7]([C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])[C:6]([CH3:27])([CH3:26])[CH:5]=[O:4]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O

Procedure:
A mixture of (4R,5S,6S)-1,1-diisopropoxy-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonen-3-one (4.58 g) and p-toluenesulfonic acid monohydrate (0.45 g) in 100 mL of 3:1 THF/water is heated at reflux for 7 hours. The mixture is cooled and poured into sat. aq. NaHCO3, then extracted with ethyl acetate. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (3% ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[C:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[C:24]1([C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: O=C(O)C1=CCCCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3=CCCCC3)cc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.48 mmol), cyclohex-1-enecarboxylic acid (73 mg, 0.58 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.2 mmol,) in dichloromethane (5 mL) was added phosphorus oxychloride (0.06 mL, 0.58 mmol) via syringe below 0° C. The mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(cyclohex-1-enecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 130 mg, yield: 60%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[O:5]1[C:6]2=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]2[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c2n(c3ccccc13)CCCO2
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Method C A mixture of methyl 2-(3-chloropropoxy)-indole-3-carboxylate (100 g, 0.37 mol), aqueous sodium hydroxide solution (38 ml, 10.8M, 0.41 mol), water (38 ml) and tetrabutylammonium bromide (6.0 g, 0.019 mol) in toluene (1000 ml) was stirred at 50-60° C. for about one hour. Water (120 ml) was added and the aqueous layer was removed. The organic layer was washed with water (120 ml) and dried by azeotropic distillation of toluene (250 m) giving a dry solution of methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate in toluene. This solution was cooled to ambient temperature and treated sequentially with a solution of 1-butyl-4-piperidinylmethylamine (66.8 g, 0.39 mol) in toluene (200 ml) followed by a solution of trimethylaluminium in toluene (196 ml, 2.0M, 0.39 mol). The mixture was heated to reflux and stirred for three hours. The reaction was quenched by cautious addition of aqueous sodium hydroxide solution (460 ml, 10% w/v) and then washed once with aqueous sodium hydroxide solution (460 ml, 10% w/v) and twice with water (275 ml each wash) while maintaining the temperature at about 70° C. Toluene (200 ml) was added and the resulting solution was dried by azeotropic distillation of toluene (200 ml) at about 55° C. under reduced pressure. Hexane (1400 ml) was added and the resulting slurry cooled to about 0-5° C. for about one hour. The solid was isolated by filtration and dried in vacuo to give the product, N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide, (114.7 g, 83%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([I:11])[CH:10]=1)[NH2:6].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[I:11][C:9]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(I)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(I)ccc1NS(C)(=O)=O
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a solution of 5-iodoanthranilic acid methyl ester (1.00 g) and triethylamine (1.01 mL) in CH2Cl2 (25 mL) is added methanesulfonyl chloride (0.59 mL) at 0° C. The ice bath is removed and after 3 h at room temperature the solution is poured into water (20 mL) and extracted with CH2Cl2 (2×20 mL). The organic layers are combined, dried over MgSO4 and the solvent removed in vacuo. The resulting residue is dissolved in CH3OH (20 mL) and sodium methoxide (20 mL) is added. After 45 min, the solvent is removed in vacuo. The residue is diluted with Et2O (20 mL) and washed with water (20 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude black liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc ) to afford 0.58g (46%) of the title compound as a brown solid. Physical characteristics: m.p. 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 10.41, 8.36, 7.82, 7.52, 3.94, 3.06; IR (diffuse reflectance) 1700, 1682, 1483, 1385, 1335, 1328, 1307, 1249, 1213, 1159, 1147, 1093, 1086, 978, 971 cm−1; MS (FAB) m/z 356 (MH+); HRMS (FAB) m/z 355.9447 (C9H10INO4S+H). Anal. Found: C, 30.49; H, 2.88; N, 3.96.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[O:41][N:40]=[C:39]([C:42]2[N:43]=[C:44]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[S:45][CH:46]=2)[CH2:38]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[O:41][N:40]=[C:39]([C:42]2[N:43]=[C:44]([CH:47]3[CH2:52][CH2:51][N:50]([C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:49][CH2:48]3)[S:45][CH:46]=2)[CH2:38]1
Reactant: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: CC(CC(=O)O)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,4-trifluoro-3-methyl-butanoic acid (64 mg, 0.408 mmol) in dichloromethane (3 mL) was added 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate, 0.5 mL). After stirring for 5 minutes, 4-[4-[5-(2-fluorophenyl)-4,5-dihydro-3-isoxazolyl)-2-thiazolyl]piperidine hydrochloride (i.e. the product of Step C) (150 mg, 0.408 mmol), triethylamine (0.1 mL) and 4-dimethylaminopyridine (5 mg) were sequentially added The reaction mixture was stirred for 3 h, and then concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel to provide the title compound, a compound of the present invention, as an oil (151 mg).
Reaction SMILES: [CH2:1]([C:4]1O[C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl.C(O)CO.O>[CH2:15]([N:22]1[C:8](=[O:10])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]1[CH2:1][CH2:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCCc1nc2ccccc2c(=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1nc2ccccc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 2-propyl-4H-3,1-benzoxazin-4-one (1—1, 2.84 g, 15.0 mmol, 1 equiv.) and benzylamine(1.77 g, 16.5 mmol, 1.10 equiv.) in chloroform (10 mL) was heated at reflux for 4 hours. The reaction mixture was concentrated and the residue was heated in a mixture of NaOH (60 mg, 1.5 mmol, 0.1 equiv.) in ethylene glycol (10 mL) at 135° C. for 5 hours. The reaction mixture was cooled and diluted with water. The pH of the resulting mixture was adjusted to 7 by the addition of 6 N HCl. The insoluble solid was collected by filtration and recrystallized from acetone/water to give 3-benzyl-2-propylquinazolin-4(3H)-one (1–2) as cream-colored crystals. 1H NMR (500 MHz,CDCl3)δ8.31 (d, J=8 Hz, 1H), 7.74 (t, J=7 Hz, 1H),7.66 (d,J=8 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 7.32 (m, 2H), 7.26 (m, 1H), 7.18 (d, J=7 Hz, 2H), 2.72 (t, J=7 Hz, 2H), 1.80 (m, 2H), 0.99 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[C:20]([SH:22])[CH:21]=1>CS(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[NH:23][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[C:5]=1[S:22]2
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccc(Cl)cc1S
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Cl)cc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (2.6 g, 13.1 mmole) and 5-chloro-2-aminobenzenethiol, 6 (X=Cl, 2.0 g, 13.1 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from EtOH and proves to be identical. An analytical sample of 4f, (R=Cl), mp 229-230° C. occurs as light orange crystals; yield: 2.05 g (49.4%).
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([BH3-])#N.[Na+].[CH2:17]([O:19][C:20]1[C:21]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:22][C:23]2[CH2:24][CH2:25][C@@H:26]3[C@@H:35]([C:36]=2[CH:37]=1)[CH2:34][CH2:33][C@@:31]1([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]1=O)[CH3:18]>ClCCCl.C(Cl)Cl.CCCCCC.C(Cl)Cl.CCCCCC>[CH2:17]([O:19][C:20]1[C:21]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:22][C:23]2[CH2:24][CH2:25][C@@H:26]3[C@@H:35]([C:36]=2[CH:37]=1)[CH2:34][CH2:33][C@@:31]1([CH3:32])[C@H:27]3[CH2:28][CH2:29][C@@H:30]1[NH:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:18]
Reactant: CCOc1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCCCCC
Product: CCOc1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccccc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
Glacial acetic acid (0.8 mL), benzylamine (1.6 mL, 15 mmol), and sodium cyanoborohydride (0.9 g, 14 mmol) were added under an argon atmosphere to a solution of 17-keto derivative (18) (2 g, 5 mmol) in anhydrous 1,2-dichloroethane (30 mL). The resulting mixture was stirred at room temperature for 72 h. Additional amounts of anhydrous benzylamine (0.4 mL), acetic acid (0.2 mL), and sodium cyanoborohydride (0.25 g) were added to the mixture, and stirring was continued for 24 h. The solvent was removed under reduced pressure, the residue was diluted with water (50 mL), and extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with water (100 mL), sodium bicarbonate solution (100 mL), brine (100 mL), and dried over anhydrous sodium suleate. The organic layer on evaporation under reduced pressure gave crude product (3.1 g) which was subjected to column chromatography on silica gel using hexane, followed by hexane-CH2Cl2 (1:1), and finally CH2Cl2. Appropriate fractions were combined and evaporated under reduced pressure to give pure amine derivative (19) (2.2 G, 89%). The mp for aminederivative (19) could not be determined as it was a sticky solid which was used without any further purification: IR (KBr) 2921, 1608, 1508, 1453, 1264, 1209, 1119, 1019, 729 cm-1 ; 1H NMR (CDCl3) δ 7.52-7.25 (m, 11 H), 6.85 (s, 1 H), 6.65 (s, 1 H), 4.20 (q, J=8.5 Hz, J=8.5 Hz, 2 H), 3.80 (s, 2 H) 2.75 (m, 1 H) 2.65 (t, J=8.5 Hz, 1 H), 2.35-2.12 (m, 4 H), 2.10 (s, 2 H), 1.85 (m, 4 H), 1.75-1.52 (m, 6 H), 1.40 (t, J=8.5, 3 H), 0.78 (s, 3 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1I)(=[O:3])[CH3:2].[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C.O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:30]#[C:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)c(I)c1NC(C)=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(-c2ccccc2)c(C#Cc2ccccc2)c1NC(C)=O
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 74.6 %

Procedure:
Nitrogen was bubbled through a mixture of ethyl 2-(5-acetamido-4-iodo-3-phenyl-pyrazol-1-yl)acetate (18.6 g, 45 mmol), phenyl acetylene (9.2 g, 90 mmol), copper iodide (860 mg, 4.5 mmol), triethylamine (200 mL) and DMF (75 mL) for 15 min. Bis(triphenylphosphine)palladium(II) dichloride (1.6 g, 2.25 mmol) was added and the reaction mixture was stirred at 90° C. under nitrogen for 4.5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was partially purified by column chromatography (silica gel, CH2Cl2, then isohexane/ethyl acetate 1:1 followed by CH2Cl2/ethyl acetate 9:1 to 8:2), then triturated with diethyl ether to provide the title compound as a solid (13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[C:16]([C:10]1[NH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:15])=[C:12]([C:13]#[N:14])[CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)cc1-c1[nH]ccc1C#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(-c2cc(Cl)ccc2C)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a mixture of 2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carbonitrile (900 mg, 4.14 mmol) in DCM (20 mL) was added acetyl chloride (0.468 mL, 6.57 mmol) at room temperature, under nitrogen. The resulting mixture was cooled to 0° C. and anhydrous aluminum trichloride (1.31 g, 9.9 mmol) was added in small portions during a period of 10 min, keeping the internal temperature below 5° C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 30 min. Then, the mixture was slowly poured in a solution of ice-cooled 1 M HCl (9 mL). The aqueous layer was separated and extracted twice with DCM (20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (10 to 20% EtOAc/hexane) to afford the title compound (1.0 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.N#N.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[N:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[N:3][C:4]2=[CH:10][CH:9]=1
Reactant: Clc1ccn2nccc2n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [C-]#N
Product: N#Cc1ccn2nccc2n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-chloropyrazolo[1,5-a]pyrimidine (2-1) (1.0 g, 6.45 mmol) and Zn(CN)2 (770 mg, 6.58 mmol) in dried DMF (20 mL) exchanged by N2 was added Pd(PPh3)4 (400 mg, 3.46 mmol). The reaction mixture was stirred at 110° C. overnight. After cooled to the room temperature, the solution was concentrated and purified by chromatography on silica gel to afford the title compound (620 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH2:11](Br)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]#[N:6]
Reactant: CC(C)CBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(C#N)cc1F
Temperature: 110 °C

Procedure:
A reaction mixture solution prepared by suspending 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate in 1 mL of dimethylformamide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile. (2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and 24.5 mg of imidazole to the crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspending the above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.[NH3:37]>ClCCl.CN(C=O)C.O1CCOCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH2:37])=[O:28])=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed with 1:1 water:methanol to yield 70 mg of an off-white powder as the desired product.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:19])[O:17][CH3:18]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:18][O:17][C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)=[O:19]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
From 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and methyl chlorocarbonate in a mixture of dioxane and toluene, 4,9-dihydro-4-methoxycarbonyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>ClCCl.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:5][CH2:6]1)=[O:11]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCN1CCN(C=O)CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCN1CCN(C=O)CC1
Yield: 43.7 %

Procedure:
117.9 g (0.75 mol) of N-2-aminoethyl-N'-formylpiperazine, 85.8 g (0.85 mol) of triethylamine and 100 mg of 2,6-di-tert.-butyl-4-methylphenol were reacted in 230 ml of dichloromethane with 78.4 g (0.75 mol) of methacryloyl chloride as described in Example 1 and the mixture was worked up. 73.9 g (44% of theory) of N-formyl-N'-(methacryloylaminoethyl)piperazine were obtained in this manner as a colorless oil.