Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]4[CH2:36][CH2:35]4)=[O:33])[N:30]=3)[CH:27]=2)[CH:37]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
3-(1-Cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (2.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (75 mg, 0.233 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and diisopropyl ether to give the title compound (40.8 mg, 35%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@@H:22]([O:25][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1

Procedure:
Combine 10.8 g (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one, 5.4 g tert-butyldimethylsilylchloride, and 2.7 g imidazole in 50 mL dry dimethylformamide and stir at ambient temperature over night. Pour into 300 mL brine and extract twice with 200 mL diethyl ether. Wash the combined extracts with brine, dry over magnesium sulfate and concentrate to dryness under vacuum. Purify by silica gel chromatography using 10-15% ethyl acetate in hexanes to recover 11.5 g of the product as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1noc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1noc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
1.0 g of benzo[d]isoxazole-3-carboxylic acid, 0.7 g of N,O-dimethylhydroxylamine hydrochloride, 2.3 g of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide) hydrochloride and 1 ml of pyridine in 40 ml of tetrahydrofuran are placed in a round-bottomed flask. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in 40 ml of ethyl acetate and 20 ml of water. The organic phase is washed with 20 ml of a 1N solution of sodium hydroxide and 20 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 1.1 g of compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[N:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=[C:35]=[O:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:37][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35](=[O:36])[O:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([N:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]([C:21]([F:23])([F:24])[F:22])=[N:10]3)=[CH:13][CH:14]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: OCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3nc(C(F)(F)F)cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-{4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethanol (step 1, 158 mg, 0.48 mmol) in dichloromethane (10 ml) was added p-toluenesulfonyl isocyanate (114 mg, 0.58 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture washed with water and the organic phase was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with toluene/ethanol (10:1) to afford 184 mg (73%) of the title compound as yellow solids: MS (ESI) m/z 530 [M+H]+, 528 [M−H]−, 1H-NMR (CDCl3) δ 7.87-7.80 (3H, m), 7.36-7.09 (10H, m), 6.75 (1H, s), 4.28 (2H, t, J=6.1 Hz), 2.91 (2H, t, J=6.9 Hz), 2.42 (3H, s).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@@H:6]1[C@H:12]([OH:13])[C@H:11]([CH3:14])[O:10][CH:8]([OH:9])[CH2:7]1)=[O:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][C@@H:6]1[C@:12]([S:18]([CH3:17])(=[O:20])=[O:19])([OH:13])[C@H:11]([CH3:14])[O:10][CH:8]([OH:9])[CH2:7]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1OC(O)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(O)C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)S(C)(=O)=O
Yield: 133.3 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy, 3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (504 mg, 1.41 mmol) in CH2Cl2 (7 ml) at 0° C. were added methanesulfonyl chloride (218 μl, 2.82 mmol) and triethylamine (590 μl, 4.2 mmol). After 2 hours the reaction mixture was worked up with CH2Cl2 and HCl 0.1N. The organic layer was washed with a solution of NaHCO3 and brine then dried over MgSO4. The solvent was evaporated to give 1-t-butyl dimethyl silyloxy, 3-trifluoroacetamido-2,3,6 trideoxy-4 methanesulfonyl-L-lyxohexopyranose (604 mg, 98%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=O.N1CCCCC1>C(Cl)(Cl)Cl>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:15]=1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)o1
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 1.85 g of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 0.40 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a-6]) as a yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:25])[CH3:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Sc2ccc(F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.19 g portion of this amine was dissolved in 50 ml of dichloromethane, cooled in an ice bath and treated with 1.52 g of triethylamine. The mixture was then treated dropwise with a solution of 1.18 g of acetyl chloride in 20 ml of dichloromethane over 20 minutes. This mixture was stirred at room temperature overnight, then the solution was washed successively with water, saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The residue was recrystallized from methanol-water, giving 2.26 g of the desired product as colorless crystals, mp 140°-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](O)=[O:43])=[CH:38][CH:37]=2)[S:30]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:43])=[CH:45][CH:46]=2)[S:30]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 84.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-trifluoromethylphenoxy)phenyl]-N-methylcarbamate (0.68 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.73 g), diethyl cyanophosphonate (0.49 g), triethylamine (0.30 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (0.97 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH3:14]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: COc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CN(Cc1ccccc1)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a solution of ethyl N-benzyl-glycinate (34.1 g, 176 mmol) and m-anisaldehyde (11.0 g, 80.8 mmol) in methanol (500 mL) was added acetic acid (12.1 mL, 202 mmol) followed by sodium cyanoborohydride (3.4 g, 54 mmol). The mixture was stirred at ambient temperature for 2.5 hours whereupon LCMS analysis showed completion of the reaction. The solvent was removed on a rotary evaporator and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate to neutrality. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (CH2Cl2) gave 21.5 g (85% of [benzyl-(3-methoxy-benzyl)-amino]-acetic acid ethyl ester as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (m, 4H), 7.25 (m, 2H), 6.93 (m, 2H), 6.82 (d, J=9 Hz, 1H), 4.10 (q, J=7 Hz, 2H), 3.74 (s, 3H), 3.70 (s, 2H), 3.32 (s, 2H), 3.24 (s, 2H), 1.18 (t, J=7 Hz, 3H; MS (m/e) 314 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2([CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[N:12]=[C:11]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH:10]=1>ClC1C=CC(Cl)=CC=1Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)[N:12]2[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14][C:13]=12
Reactant: COc1ccccc1C1=CC(N2CCN(Cc3ccc(C)cc3)CC2)=NC12C=CC(=O)C=C2
Solvent: ClCCl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: COc1ccccc1-c1cc(N2CCN(Cc3ccc(C)cc3)CC2)n2ccc(=O)ccc12
Yield: 64.3 %

Procedure:
A solution of 4-(2-methoxyphenyl)-2-[4-(4-methylbenzyl)-1-piperazinyl]-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (2.8 g) in 1,2,4-trichlorobenzene (80 cc) is heated for 4 hours at a temperature of about 210° C. After evaporation to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C., the residue obtained is dissolved in methylene chloride (50 cc) and the solution is poured into silica (60 g) contained in a column 2 cm in diameter. Elution is first performed with a mixture of methylene chloride and methanol (99:1 by volume) (200 cc); the corresponding eluates are rejected. Elution is then performed with a mixture of methylene chloride and methanol (99:1 by volume) (450 cc) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (75 cc), 1-(2-methoxyphenyl)-3-[4-(4-methylbenzyl)-1-piperazinyl]-7H-pyrrolo[1,2-a]azepin-7-one (1.8 g), m.p. 186° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:3]=1[C:4]([O:6]CCOC)=O.[CH3:18][NH2:19]>C[O-].[Na+]>[NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:3]=1[C:4]([NH:19][CH3:18])=[O:6]
Reactant: COCCOC(=O)c1cc(C#N)cc(C)c1N
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 97.9 %

Procedure:
The above-described method (Example 3) was repeated to stir 2-methoxyethyl 2-amino-5-cyano-3-methylbenzoate (200 mg, 0.81 mmol) with methylamine (5.40 g, 69.5 mmol, 40% in methanol) and one drop of sodium methoxide (30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and following purification by column chromatography, 2-amino-5-cyano-N,3-dimethylbenzamide (150 mg, 95.0% of theory, 97.8 area % LC) was obtained as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (83.5% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.97, 7.46-7.42, 7.39-7.29, 6.97, 4.07-4.01, 3.89-3.67, 3.58-3.51, 3.36-3.32, 1.53-147, 0.76-0.69, 0.48-0.42, 0.10-0.06. 13C NMR (75 MHz, CDCl3) 6166.7, 163.9, 162.8, 160.6, 159.9, 145.4, 129.6, 129.5, 127.0, 119.7, 119.4, 114.8, 114.7, 114.4, 114.38, 112.5, 44.4, 44.5, 44.3, 41.3, 39.6, 34.4, 8.6, 4.1. MS (ES+) m/z 466.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[CH3:23][N:24](CCI)[C:25](C1C=CC=CC=1)(C1C=CC=CC=1)[C:26]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:26][CH2:25][NH:24][CH3:23])[CH2:20][CH2:21]3)[C:6]=2[CH:22]=1
Reactant: CN(CCI)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CNCCN1CCC(=C2c3ccccc3CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(10,11-dihydro-3-fluoro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (5 g; 0.017 mol) and 2-[N-methyl-N-(triphenylmethyl)amino]ethyl iodide (7.3 g; 0.017 mol) in 30 ml of methyl isobutyl ketone (MiBk) is heated to the refluxing temperature. Potassium carbonate (4.7 g; 0.034 mol) is added in a single portion at this temperature, and the mixture is then heated to the refluxing temperature under an argon atmosphere for 10 h. The mixture is cooled, filtered and evaporated to dryness. The residual oil is then taken up with methylene chloride and the mixture is washed with water and with saline, dried over magnesium sulphate and then evaporated to dryness. 100 ml of 1N hydrochloric acid are added to the oil obtained, and the mixture is then stirred for 5 hours at room temperature. The tritylmethanol is separated off by filtration, the mother liquors are neutralized with 2N aqueous sodium hydroxide, the product is extracted using methylene chloride and the extract is dried over magnesium sulphate and evaporated. The oil obtained is used without further purification in the following stage.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1>CS(C)=O>[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:21])=[C:17]([NH:2][CH3:1])[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1
Reactant: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2cc1F
Reactant: CN
Solvent: CS(C)=O
Product: CNc1cc2c(cc1C)c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 40 °C
Reaction time: 72 h

Procedure:
Dimethyl sulfoxide (100 mg) and a 40% aqueous solution (50 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (30 mg), and the mixture was heated and stirred at 40° C. for 3 days. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. The mixture was left to stand for 3 days, and solids deposited were collected by filtration and washed with (ethanol and diethyl ether to obtain the title compound (11 mg) as a pale gray powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]#[N:35])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:36][Li].O.OO>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]([NH2:35])=[O:36])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]O
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Agent: OO
Solvent: CO
Solvent: O
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(4-benzylpiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (270 mg, 0.55 mmol, 1.00 equiv) in methanol (25 mL) were added LiOH.H2O (70 mg) and H2O2 (30%) (1.2 mL). The resulting solution was stirred for 4 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of Na2SO3 (sat.). The resulting solution was extracted with 6×50 mL of dichloromethane and the organic layers combined. After evaporation, the residue was purified by silica gel column with dichloromethane/methanol (4:1). This resulted in 90 mg (32%) of Compound I-122 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:6]=2[N:24]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:6]=2[N:24]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a solution of 0.60 g (0.0017 mole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-291) in 8 mL of dimethylformamide was added 0.83 g (0.0026 mole) of cesium carbonate, followed by 0.32 mL (0.0051 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water was added to the residue to give a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give 0.56 g of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 76 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3): δ 3.08-3.17 (m, 4H), 3.78-3.86 (m, 3H), 4.09-4.15 (m, 4H), 7.00-7.07 (m, 2H), 7.20-7.45 (m, 5H), 7.65-7.84 (m, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[C:23]([Br:24])=[CH:22][C:21]([CH2:25][CH2:26][C:27]([O:29]CC4C=CC=CC=4)=[O:28])=[CH:20][C:19]=2[Br:37])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.Br>O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:18]2[C:19]([Br:37])=[CH:20][C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:23]=2[Br:24])=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CCc1cc(Br)c(OC(=O)c2c3ccccc3nc3ccccc23)c(Br)c1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCc1cc(Br)c(OC(=O)c2c3ccccc3nc3ccccc23)c(Br)c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A mixture of 2,6-dibromo-4-(2-benzyloxycarbonylethyl)-phenyl acridine-9-carboxylate (191 mg, 0.309 mmol), glacial acetic acid (20 ml) and 48% hydrobromic acid (5 ml) was heated at 100° C. for 3 h and then cooled. The mixture was added to water (100 ml) and extracted with 20% methanol in chloroform (100 ml×4). The organic extracts were combined and evaporated and the residue was suspended in chloroform (50 ml) and neutralised with a slight excess of triethylamine. The mixture was washed with water (70 ml×3), and the organic layer was dried over sodium sulphate and evaporated to dryness. The residue was recrystallised from CHCl3 to give the desired product (115 mg, 74%.), mp 240–2° C. FAB-MS m/z 529 [M+, 75%], 511 [10], 486 [10], 207 [100].