Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[CH2:10]([Cl:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Cl-:17].[CH2:10]([N+:6]1[C:5]([CH3:9])=[C:4]([CH2:3][CH2:2][OH:1])[S:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ncsc1CCO
Solvent: CC#N
Product: Cc1c(CCO)sc[n+]1Cc1ccccc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
71.6 g (500 millimoles) of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole), 63.3 g (500 millimoles) of freshly distilled benzyl chloride and 250 ml of absolute acetonitrile are refluxed for 24 hours in a 500 ml round-bottomed flask. The stirred reaction mixture is slowly cooled to room temperature, and the precipitate is filtered off under suction, washed colorless with dry acetonitrile, predried and then dried at 90° C. under reduced pressure from a water pump.
Reaction SMILES: C([Mg]Br)C.C[CH2:6][O:7]CC.[C:10]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[OH:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1>[C:10]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH:6]=[O:7])[C:20]=1[OH:26])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11]
Reactant: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCOCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
Ethylmagnesium bromide 21.0 ml (an ether solution, 3.0N, 63.1 mmol) and THF 40 ml were charged in a 500 ml reactor purged with nitrogen, 20 ml of a THF solution containing 2-cumyl-4-methylphenol 13.61 g (60.1 mmol) was added dropwise to the reactor at 0° C. in 1 hour and after that, the temperature was gradually raised to a room temperature and the resultant mixture was stirred for 30 minutes at a room temperature, in which toluene 220 ml was added, and then heated to 100° C. and about 50 ml of the mixed solvents of ether and THF were evaporated off to obtain a slightly opaque slurry. After the slurry was cooled to 24° C., p-formaldehyde 4.37 g (145.5 mmol) and triethylamine 12.0 ml (86.0 mmol) were added and the resultant mixture was stirred at 90° C. for 1 hour. After being cooled to a room temperature, the mixture was quenched with 42 ml of 18% hydrochloric acid and an organic layer was concentrated and the obtained liquid was purified by silica gel column chromatography to obtain 3-cumyl-5-methylsalicylaldehyde 14.13 g (yield 92%).
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.C[O:23][C:24]([C:26]1[C:27]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])=[CH:28][CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)=[O:25]>>[Cl:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH3:43])=[C:35]([C:27]2[C:26]([C:24]([OH:25])=[O:23])=[CH:31][C:30]([N+:32]([O-:34])=[O:33])=[CH:29][CH:28]=2)[CH:40]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(Cl)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 93.8 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate (0.83 g, 2.6 mmol) to afford 0.75 g (95%) of 5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid as a yellow solid. Data for (5'-chloro-2'-methoxy-4-nitro-2-biphenyl)carboxylic acid: 1 H NMR (400 MHz, acetone-d6) 8.69 (d, J=2.5, 1H); 8.46 (dd, J=8.3, 2.6, 1H); 7.68 (d, J=8.5, 1); 7.41 (dd, J =8.9, 2.7, 1H); 7.33 (d, J=2.8, 1H); 7.08 (d, J=8.6, 1H); 3.75 (s, 3H).
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:28]1([N:7]2[CH2:6][C@@H:3]3[C@@H:2]([N:1]([C:9]4[CH:14]=[CH:13][C:12]([C:15]5[CH:20]=[CH:19][C:18]([N:21]6[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]6)=[CH:17][CH:16]=5)=[CH:11][CH:10]=4)[CH2:5][CH2:4]3)[CH2:8]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCC1
Reactant: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CN(C5CCC5)C[C@@H]43)cc2)cc1

Procedure:
The product from Example 85B (0.033 g, 0.092 mmol), cyclobutanone (8.00 μL, 0.101 mmol), and sodium triacetoxyborohydride (0.025 g, 0.0.120 mmol) were processed as described in Example 85C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (d, J=1.7 Hz, 1H), 7.63 (s, 4H), 7.50 (d, J=8.5 Hz, 2H), 7.23 (d, J=3.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.5 Hz, 2H), 4.13-4.24 (m, 1H), 3.52 (q, 1H), 3.32 (q, J=7.3 Hz, 1H), 2.74-3.04 (m, 3H), 2.63 (t, 1H), 2.46 (dd, J=9.3, 2.2 Hz, 1H), 2.35 (dd, J=8.8, 4.4 Hz, 1H), 2.06-2.23 (m, 1H), 1.82-2.05 (m, 4H), 1.60-1.80 (m, 3H). MS (ESI+) m/z 413 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(C=O)cc1
Yield: 97.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (732 mg, 6 mmol) in anhydrous DMF (13 ml), under nitrogen atmosphere, K2CO3 (1658 mg, 12 mmol), and, after 10 minutes, iododecane (1785 mg, 7.2 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried with Na2SO4. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 11/1) and 1530 mg (yield 97%) of the pure product of the title were obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:22][C:23](OC(C)=O)=[O:24].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[CH3:22])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OCc2ccccc2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(OCc2ccccc2)nc1
Yield: 94.5 %

Procedure:
To a solution of 6-[(phenylmethyl)oxy]-3-pyridinamine (0.213 g, 1.07 mmol; step B above) in CH2Cl2 (5 mL) at rt was added pyridine (0.17 mL, 2.14 mmol), DMAP (0.0065 g, 0.050 mmol) and Ac2O (0.12 mL, 1.28 mmol). After 5 min the mixture was poured into water and extracted with CH2Cl2 (×3). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.245 g of the title compound as a colorless solid: MS (ESI) m/z 243 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=3)[NH2:19])=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:23]([C:25]1([CH2:32][CH3:33])[CH2:30][C:29](=[O:31])[O:28][C:26]1=[O:27])[CH3:24]>N1C=CC=CC=1>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([NH:19][C:29](=[O:31])[CH2:30][C:25]([CH2:32][CH3:33])([CH2:23][CH3:24])[C:26]([OH:28])=[O:27])[CH:20]=[CH:21][CH:22]=3)=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCC1(CC)CC(=O)OC1=O
Reactant: CC(=O)c1ccc2ccc(COc3cccc(N)c3)nc2c1
Solvent: c1ccncc1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(C(C)=O)cc3n2)c1)C(=O)O
Reaction time: 0.5 h

Procedure:
0.36 g of 3-(7-acetyl-2-quinolinylmethoxy)aniline and 0.385 g of 2,2-diethylsuccinic acid anhydride are stirred in 5 ml of pyridine for 72 hours at 20° and concentrated by evaporation. The residue is suspended in 5 ml of 2N aqueous hydrochloric acid, the suspension is stirred for 30 min. at 20° and filtered and the residue retained on the filter is dried in vacuo at 20°. The crude product obtained is chromatographed on 50 g of silica gel. The product-containing fractions (eluted with toluene/ethyl acetate 1:1 and with ethyl acetate) are combined and concentrated by evaporation and the evaporation residue is recrystallised from a CH2Cl2 /methanol/acetone mixture to give the title compound in the form of crystals of m.p. 164°. IR (Nujol): inter alia 3600-2100, 3350, 1675, 1600 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1)=[N+:29]=[N-:30]
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(N)c3)c2cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3cccc(N=[N+]=[N-])c3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
Dissolved 643 mg (2.00 mmol) 4-(3-amino-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile in 25 ml 80% acetic acid in water. Chilled to 0° C. and added 152 mg (2.21 mmol) sodium nitrite in 2.2 ml water. After 10 minutes, added 144 mg (2.21 mmol) sodium azide in 2.2 ml water. At 1.5 hours stripped solvent and dissolved residue in hot ethyl acetate. Washed with saturated sodium bicarbonate, water and brine and dried with sodium sulfate. Stripped solvent and redissolved in 60% ethyl acetate/methylene chloride and filtered through a pad of silica gel. Stripped solvent and dried in vacuo, giving 526 mg of brown solid: mass spectrum (electrospray m/e): M+H=347.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][O:28][CH2:27]4)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Yield: 67.9 %

Procedure:
To a 150-mL sealed tube containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.72 g, 2.0 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.33 g, 2.2 mmol) in ethanol (20 mL) was added triethylamine (1.0 mL, 2.2 mmol). The mixture was heated with a heat gun until all solid material was dissolved, then mixture was allowed to cool, at which time a precipitate was formed. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a pale yellow solid (0.59 g, 68%). MS (ES+): 435.0 (M+H)+
Reaction SMILES: N[C@H](C1C=CC=CC=1)CC(OC)=O.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1Cl)([O-])=O.NC1C=CC=CC=1C(NC1C=CC2N=C[N:38]([CH:41]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:42][C:43]([OH:45])=[O:44])[C:37]=2C=1)=O>>[N+:23]([C:21]1[CH:20]=[CH:19][C:18]2[N:38]([C@H:41]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:42][C:43]([OH:45])=[O:44])[CH:37]=[N:14][C:17]=2[CH:22]=1)([O-:25])=[O:24]
Reactant: Nc1ccccc1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: COC(=O)C[C@H](N)c1ccccc1
Product: O=C(O)C[C@@H](c1ccccc1)n1cnc2cc([N+](=O)[O-])ccc21

Procedure:
Using a similar procedure to that described in Preparation 45, the title compound (19 mg) was prepared from methyl (3S)-3-amino-3-phenylpropanoate and 2,4-dinitrochlorobenzene, and liberated as the free acid using a procedure similar to that described in Preparation II. [LCMS (Method C, Mobile Phase I) RT=2.60 min, MH+ 312].
Reaction SMILES: CO.[BH4-].[Na+].[CH:5]1([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.O>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(C=NC2CCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CNC2CCCC2)cc1
Yield: 93.7 %

Procedure:
160 ml of methanol are added to 18.2 g of sodium borohydride. 90.7 g of 4-fluorobenzaldehyde-cyclopentylimide are added dropwise at 10°-15° C., while cooling with ice and stirring, and the mixture was then stirred for 1.5 hours at room temperature. 120 ml of H2O and 150 ml of methylene chloride were then added, the methylene chloride phase was separated off, and the aqueous phase was further extracted twice with CH2Cl2. The combined methylene chloride phases were washed with water and dried with Na2SO4, and the solvent was stripped off in vacuo. Distillation of the residue under a medium vacuum gave 85.9 g of N-4-fluorobenzyl-N-cyclopentylamine of boiling point 106° C. 0.25 bar.
Reaction SMILES: Br[C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:15][O:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[C:10]([C:8]1[CH:9]=[C:2]([C:22]2[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]([OH:14])=[C:4]([CH:7]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1O
Yield: 77.4 %

Procedure:
step 1—A sealed tube containing 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde E-1b (R1═OH, R4=tert-Bu, 858 mg, 3.339 mmol), 37 (766 mg, 5.008 mmol), Pd(PPh3)4 (240 mg, 0.208 mmol), and Na2CO3 (891 mg, 8.406 mmol) in a mixture of MeOH (10 mL) and DCM (2 mL) was irradiated in a microwave reactor at 115° C. for 30 min. The organic volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (3 to 5% EtOAc) to afford 737 mg (77%) of 5-tert-butyl-2-hydroxy-3-(2-methoxy-pyridin-3-yl)-benzaldehyde (48) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(Cl)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Clc1cccc(CN2CCNCC2)c1

Procedure:
Synthesized according to General Procedure A: 3-chlorobenzyl chloride (4{8}, 5 mL, 39.3 mmol, 1 equiv.), piperazine (20.3 g, 235.7 mmol, 6 equiv.), THF (85.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{8} (5.41 g, 65%) as a light yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.28 (br s, 1H) 7.19-7.12 (m, 3H), 3.39 (s, 2H), 2.82 (t, 4H, J=5.6 Hz), 2.34 (br s, 4H), 1.54 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 140.2, 133.9, 129.2, 128.8, 127.0, 126.9, 62.8, 54.3, 45.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2cscc21
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3cc(Cl)ccc3Nc3cscc32)CC1

Procedure:
A solution of 0.9 g. of 7-chloro-10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine in 4.5 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled and made alkaline with concentrated ammonium hydroxide. The sticky precipitate is collected and dissolved in chloroform. The dried chloroform solution is concentrated under reduced pressure to give 7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5] benzodiazepine as an oil. An ethanolic solution of the oil is treated with 70% perchloric acid and diluted with water. The precipitate is recrystallized from methanol to give yellow crystals, m.p. 268°-270°C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH3:20][O:19][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:8][CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: COC(OC)c1ccc(C(=O)Cc2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(OC)c1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1

Procedure:
5 g 1-[4-(dimethoxymethyl)phenyl]-2-phenylethanone and 4.43 g N,N-dimethylformamide dimethylacetal were stirred for 18 h at 100° C. in DMF. The solvent was removed and the crude product used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]2[O:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.I[C:16]1[CH:17]=[C:18](C)[C:19]([NH2:22])=[N:20][CH:21]=1>>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([N:8]2[C:7](=[O:11])[C:6]3[CH:12]=[C:2]([F:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(I)cnc1N
Reactant: CNc1cc2c(cc1F)C(=O)NCO2
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Yield: 13.6 %

Procedure:
Analogous to the procedure described in Ex. 40, 6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.100 g, 0.51 mmol) and 5-iodo-3-methylpyridin-2-amine (0.119 g, 0.53 mmol) were coupled to yield pure 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.020 g, 13%) after reverse phase HPLC purification. ES-MS (M+H)+=303.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13].[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(OCC)(=O)C>[C:17]1([N:23]2[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=3[F:13])[CH2:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: O=C(/C=C/c1ccc(F)cc1F)C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccc(C2CC(C(F)(F)F)=NN2c2ccccc2)c(F)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
In a 50 mL beaker are introduced (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-buten-2-one(2.66 g, 11.2 mmol), monohydrated p-toluensulphonic acid (2.1 g, 11.2 mmol) and phenylhydrazine chlorhydrate (1.33 g, 12.3 mmol) and heated to 110° C. A small amount of ethyl alcohol can be used to facilitate the initial mixture. After approximately 2 h (control by CCF) the mixture is allowed to cool and it is diluted with ethyl acetate. It is then washed with a saturated solution of NaHCO3, dried with MgSO4, filtered and the solvent evaporated at low pressure. The crude thus obtained (3.9 g) is recrystallised with methanol (2 mL) to precipitate 3.67 g (65%) of the pyrazoline (±)-5: pf=83–84° C.; IR (KBr) μ max (cm−1) 1600, 1505, 1326; 1H-RMN (CDCl3) δ (ppm): 7.28–6.72 (m, 8H), 5.64 (dd, J=13 Hz, J=7.5 Hz, 1H), 3.8–3.6 (m, 1H), 2.94 (dd, J=17.2 Hz, J=7 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH:11]([CH3:21])[CH2:12][N:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:14])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][I:25]>ClCCCl>[I-:25].[CH:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH:11]([CH3:21])[CH2:12][N+:13]([CH3:24])([CH3:14])[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(CN(C)C1CCCCC1)OC(=O)c1ccc(C(C)C)cc1
Reactant: CI
Solvent: ClCCCl
Product: CC(C[N+](C)(C)C1CCCCC1)OC(=O)c1ccc(C(C)C)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(cyclohexyl(methyl)amino)propan-2-yl 4-isopropylbenzoate (0.5 g, 1.57 mmol) in DCE (5 mL, methyl iodide (0.2 mL, 3.15 mmol) was added. The resultant reaction mixture was stirred at rt for 16 hours. The solvent was evaporated, and the crude product was purified by column chromatography. The product isolated was re-crystallized from methanol/ether. Yield: 134.9 mg (18.65%). 1H NMR (400 MHz, DMSO-d6) δ 7.94-7.92 (d, J=8 Hz, 2H), 7.43-7.41 (d, J=8 Hz, 2H), 5.54-5.50 (m, 1H), 3.95-3.89 (m, 1H), 3.61-3.58 (d, J=14 Hz, 1H), 3.40-3.34 (m, 1H), 3.03-2.95 (m, 7H), 2.22-2.20 (d, J=11 Hz, 1H), 2.10-2.07 (d, J=11 Hz, 1H), 1.86-1.83 (m, 2H), 1.57-1.43 (m, 3H), 1.36-1.35 (d, J=6 Hz, 3H), 1.16-1.11 (m, 9H). LCMS: m/z=331.8 [M+], RT=3.08 min (Column: Y, Program: P1). UPLC: 99.65% (200 nm), RT 3.09 min (Mobile phase: A. ACN, B. 0.05% HCOOH in water, Column: Gemini® NX C18 (50*4.6 mm) 3μ.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:19]#[C:20][CH2:21][N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.C(O)C>[Pd].C(OCC)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14]1
Reactant: CC1(C)CC(c2ccc(C#CCN3CCCCCC3)cc2Cl)CC(C)(C)C1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CC(c2ccc(CCCN3CCCCCC3)cc2Cl)CC(C)(C)C1
Yield: 59 %

Procedure:
3.6 g of the compound of EXAMPLE 1 are hydrogenated in the presence of 0.36 g of 10% palladium on charcoal and 50 ml of ethanol. The reaction mixture is filtered, and the filtrate is evaporated off under reduced pressure. The oily residue obtained is taken up in diethyl ether and hydrochloric acid is bubbled through. The precipitate obtained is filtered off and dried; yield=59%; m.p.=215° C. (HCl).