Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[N:3]=1
Reactant: Cc1ccccc1CN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: Cc1ccccc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-methylbenzylamine in DME. ES-MS m/e (%:306 (M+H+, 100).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=1[Cl:20])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCCCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5 g (19.0 mmol) of methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate from Example 26 in 10 ml DMF is added 3.0 g (22.8 mmol) of N-chlorosuccinimide in a single portion at room temperature. The resulting solution is allowed to stir 24 hours at room temperature. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered, concentrated and subjected to flash chromatography (20% EtOAc/hexanes) to yield methyl 6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate. This is used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[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]([C:41]2[CH:42]=[N:43][C:44]([N:47]([CH3:49])[CH3:48])=[CH:45][CH:46]=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]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[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]([C:41]2[CH:42]=[N:43][C:44]([N:47]([CH3:49])[CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CN(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K28) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (409 mg, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18](=[O:20])[CH2:17][C:16]3=[O:21])[C:7]=2[CH:22]=1)#[N:2].[BH4-].[Na+].O>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH:18]([OH:20])[CH2:17][C:16]3=[O:21])[C:7]=2[CH:22]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(=O)CC2=O)[C@@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(O)CC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2,4-dioxo-1-pyrrolidinyl)-2H-1-benzopyran -3-ol (0. g) in dry DMSO under N2, was added NaBH4 (0.11 g). The reaction was stirred for 3 h at room temperature. Water (100 mL) was added add the aqueous phase extracted with EtOAc. The organic layer was washed with H2O add brine, dried over MgSO4, filtered and evaporated to give the crude product (0.5 g) as an orange solid. This mixture was chromatographed (chromatotron CHCl3 →CHCl3 -10% MeOH gradient elution; 2 mm silica gel) to give two fractions.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COc1ccc(Br)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-chlorophenol (7.0 g, 33.0 mmol, 1 eq), N,N-dimethylformamide (50 mL) and cesium carbonate (8.5 g, 42.0 mmol, 1.2 eq) was stirred at room temperature then iodomethane (2.5 mL, 1.2 eq) was added. The mixture was heated to 50° C. overnight, cooled to room temperature and treated with water (500 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane. 7.5 g of clean product in a quantitative yield.
Reaction SMILES: C[N:2](C)[C:3]([CH3:24])=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:24][C:3]1[CH:4]=[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)[N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:2]=1
Reactant: CC(=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O)N(C)C
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
A solution of 3-[3-(dimethylamino)but-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.270 g, 0.77 mmol) and phenyl hydrazine (0.200 mL, 2.0 mmol) in acetic acid (5.0 mL) was heated under microwave conditions at 120° C. for 10 min. After this time, the reaction was cooled to room temperature and concentrated onto silica gel. The crude product purified by column chromatography (silica gel, 50:50 ethyl acetate/hexanes to ethyl acetate) to separate the two isomers, followed by preparative reverse phase HPLC and crystallization from diethyl ether to give 3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.048 g, 16%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H), 6.73 (d, J=7.9 Hz, 1H), 6.99 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (br s, 1H), 7.21 (s, 1H), 7.30-7.49 (m, 6H), 7.55 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H); APCI MS m/z 397 [M+H]+; mp 167-168° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][CH:12]1[NH:16][N:15]=[CH:14][CH2:13]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([N:16]2[CH:12]([CH3:11])[CH2:13][CH:14]=[N:15]2)=[O:9])[CH:4]=1
Reactant: CC1CC=NN1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CC=NN1C(=O)c1cccnc1

Procedure:
Hydrochloride of nicotinic acid chloride (4 g) was suspended in 20 ml of chloroform followed by addition of a mixture of 1.7 g of 5-methyl-2-pyrazoline and 4 g of triethylamine, washing with water and concentration. The product was purified by chromatography on a silica gel column (chloroform/methanol=100/1). Yield; 3.4 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCN3CCOCC3)CC2)nc1N

Procedure:
To a stirred solution of 3-chloro-propane-1-sulfonic acid [4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-amide (104 mg, 0.20 mmol, Example 293) in tetrahydrofuran (5 mL), morpholine (100 mg, 1.15 mmol, Aldrich) was added and the mixture was heated at reflux for 24 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×5 mL). The extracts were combined and dried with sodium sulfate and concentrated. The residue was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 57 mg, 50%. MS (ES) MH+=569. CDK4 IC50=0.015 μM; CDK1 IC50=0.008 μM; CDK2 IC50=0.005 μM; HCT 116 IC90=0.374 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[F:15][C:16]([F:46])([F:45])[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:33](OC2C=CC([N+]([O-])=O)=CC=2)=[O:34])=[CH:19][CH:18]=1.O>C1COCC1>[CH3:9][N:8]([CH3:10])[C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH:1][C:33]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]2[C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:45])([F:15])[F:46])=[CH:18][CH:19]=2)=[O:34])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N,N-dimethylbenzamide (74 mg, 452 μmol) in THF (0.5 mL) was added sodium hydride, 60% dispersion in mineral oil (19 μL, 452 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 5 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added slowly and the mixture was extracted with EtOAc (2×1 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in DMSO (1.0 mL) and the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired compound, which was dissolved in MeOH (1.0 mL). Then, the solution was washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as light brown solid. MS (ESI, positive ion) m/z: 468 (M+H).
Reaction SMILES: [CH:1](C([O-])=O)([C:10]([O-:12])=[O:11])[CH:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].[Na+].[Na+].Cl.C(=O)=O>O>[CH2:3]([C:4]([OH:6])=[O:5])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:1]\[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])CC(C(=O)[O-])C(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)/C=C(\CC(=O)O)C(=O)O

Procedure:
Nine grams of the product as prepared in Example 19, i.e. tetrasodium propane-1,1,2,3-tetracarboxylate, is dissolved in 100 mls water and acidified with dilute HCl (10%). Liberation of CO2 is instantaneous. The residue, after evaporation of water, is extracted with acetone. The acetone is evaporated to leave a residue consisting of a 1:1 by weight mixture of cis:trans aconitric acid. The structure of the product is confirmed by NMR analysis (D2O):
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[CH2:28]1)=[O:26])[CH3:23]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28][CH:29]2[CH3:33])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CCOC(=O)N1CCNC(C)C1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C(C)C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethoxycarbonyl-3-methyl-piperazine, and dimethyl sulfoxide was stirred at 150° C. for 2 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-ethoxycarbonyl-2-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 220°-225° C.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C>>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][OH:2])[CH2:5][CH2:6]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: N#Cc1ccc(F)cc1
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCC(CO)CC2)cc1

Procedure:
A solution of 12.2 g of 4-hydroxymethyl-piperidine-hydrochloride, 9.8 g of 4-fluorobenzonitrile and 28.3 ml of N-ethyl-diisopropylamine is heated to 140° C. for 4 hours. After cooling, it is chromatographed over silica gel using methylene chloride and methylene chloride/ethyl acetate (1:1) as eluant. After the solvent has been removed under reduced pressure the residue remaining is triturated with petroleum ether and suction filtered. Yield: 5.1 g (29% of theory), Melting point: 148°-150° C.
Reaction SMILES: [C:1](C([O-])=O)([C:10]([O-:12])=[O:11])=[C:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].[Na+].[Na+].Cl.C(=O)=O>O>[CH2:3]([C:4]([OH:6])=[O:5])/[C:2](/[C:7]([OH:9])=[O:8])=[CH:1]\[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])CC(C(=O)[O-])=C(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)/C=C(\CC(=O)O)C(=O)O

Procedure:
Nine grams of the product as prepared in Example XXIII, i.e. tetrasodium propene-1,1,2,3-tetracarboxylate, is dissolved in 100 mls water and acidified with dilute HCl (10%). Liberation of CO2 is instantaneous. The residue, after evaporation of water, is extracted with acetone. The acetone is evaporated to leave a residue consisting of a 1:1 by weight mixture of cis-trans aconitic acid. The structure of the product is confirmed by NMR analysis (D2O): ##STR74##
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+]>O>[CH2:18]([O:24][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To dimethylformamide solution (91 ml) containing 2-chloro-5-nitrobenzonitrile (18.2 g) and n-hexanol (11.2 g) was added sodium hydride (60% content, 4.8 g) under ice-cooling and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give 2-n-hexyloxy-5-nitrobenzonitrile (16.2 g). Then, ammonium chloride (0.2 g) and iron powder (1.6 g) were added to a mixed solvent of water (6.3 ml) and ethanol (17 ml), and the mixture was heated to 65° C. Then, the obtained ethanol solution (4 ml) containing 5-nitro-2-n-hexyloxybenzonitrile (16.2 g) was added dropwise thereto, and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated and the solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (6.0 g).
Reaction SMILES: [C:1]1([CH:7]2[N:15]3[C:10]([S:11][CH2:12][CH2:13][CH2:14]3)=[N:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=[O:17]>[OH-].[Na+]>[SH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]1=[O:17]
Reactant: O=C=O
Reactant: c1ccc(C2CN=C3SCCCN32)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCC(c2ccccc2)N1CCCS

Procedure:
A mixture of 55.0 g of 3-phenyl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b][1,3]thiazine and 540 ml of 0.5N sodium hydroxide solution is stirred and refluxed under nitrogen for thirty hours. The solution is cooled, neutralized to pH 8 with carbon dioxide and extracted with methylene chloride. The organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo to yield a colorless solid. Recrystallization from isopropyl acetate yields the product of this example, 53.8 g, m.p. 97°-99° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCCC2)c2ccccc12
Reaction time: 0.25 h

Procedure:
1-Cyano-4-fluoronaphthalene (2.0 g, 11.7 mmol) was transferred to a 25 mL flask and pyrrolidine (4.0 mL) was added. The reaction mixture was stirred for 15 min where after the product precipitated out. The reaction mixture was concentrated in vacuo. The solid was then re-crystallized with MeOH and the crystals washed with EtOH. Yield: 1.6 g (62%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>ClCCl.C(OCC)(=O)C>[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][NH:17][C:18]([NH:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: NCc1ccco1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=S)NCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Furan-2-ylmethylamine (0.58 g) was dissolved in dichloromethane (50 ml) and to the solution was added 4-t-butylbenzylisothiocyanate (1.23 g), followed by stirring at room temperature for 8 hours. Then, the resulting mixture was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by column-chromatography (dichloromethane) to yield the compound 16-2 (1.57 g, 87%) as a liquid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([O:7][C:8](=[O:11])[CH:9]=[CH2:10])C.[O:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>>[C:8]([CH:9]1[CH2:10][CH:13]2[O:12][CH:16]1[CH:15]=[CH:14]2)([O:7][CH3:5])=[O:11]
Reactant: c1ccoc1
Reactant: C=CC(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1CC2C=CC1O2
Reaction time: 1 h

Procedure:
4.5 g (0,033 Mol) AlCl3 are added to 100 g (1 Mol) ethylacrylate and dissolved with stirring. 68 g (1 Mol) furane is then added drop-wise, during cooling to 20° to 25° C. After one hour, the exothermic reaction is terminated, followed by stirring for one hour at 25° C. and 30 g water is added. The organic phase is separated. First, the non-converted furane and ethylacrylate is distilled off under a pressure of 10 Torr. The 2-carbomethoxy-7-oxabicyclo(2.2.1)hept-5-ene boils at 60° C. and is obtained in a yield of 67.2 g (40% theoretical).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1COCC1.C(O)C>[CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCN
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of benzaldehyde (1.0 ml, 10.0 mmol) in THF (50 ml) was added with heating at reflux to a solution of 1,6-diaminohexane (5.81 g, 50.0 mmol) and p-toluene sulfonic acid (9.5 1 g, 50.0 mmol) in ethanol (50 ml) and then it was heated to reflux for 3 h under a nitrogen atmosphere. After cooling to room temperature, sodium borohydride (1.13 g, 30.0 mmol) was added to the solution and it was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue dissolved in chloroform. The chloroform phase was washed with water, and dried over magnesium sulphate, the solvent was removed under reduced pressure. The residue was washed with water (25 ml), and it dissolved in chloroform and washed again with water (2×50 ml). Then dried over magnesium sulphate, and the solvent removed under reduced pressure to yield a yellow oil (1.61 g, 78%).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3Cc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of Example 1 (0.25 g, 0.82 mmol) in dichloromethane (2 mL) was added 4-picolyl chloride hydrochloride (0.13 g, 0.79 mmol) and triethylamine (0.29 mL, 2.08 mmol). The resulting mixture was stirred at ambient temperature overnight. The crude product was extracted into dichloromethane and washed with water followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.11 g, 45%); 1H NMR (400 MHz, CDCl3); δ 1.70-1.81 (m, 3H), 2.03 (m, 1H), 2.27 (m, 1H), 2.94-3.03 (m, 2H), 3.49 (d, J=14.4 Hz, 1H), 3.86 (m, 1H), 3.92 (s, 2H), 3.94 (m, 1H), 4.19 (d, J=14.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 3H), 7.26-7.29 (m, 4H), 8.51 (m, 2H); MS (m/z) 359.5 (M+1); LC (99.7%); HPLC (91.6%)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:24]([CH2:23][Cl:22])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Cl)c2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Yield: 56.9 %

Procedure:
9.8 g (32 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime were stirred in 60 ml of N,N-dimethylformamide with 7 g (41 mmol) of chloroacetic anhydride at room temperature for 1 hour and at 105° for 4 hours. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 6.63 g (65%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one.