Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:19]1([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[N:19]1([C:24]2[CH:25]=[C:26]([C:2]3[N:6]4[CH:7]=[C:8]([NH:11][CH:12]5[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]5)[CH:9]=[CH:10][C:5]4=[N:4][CH:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Product: OC1CCCC(Nc2ccc3ncc(-c4cccc(-n5cccn5)c4)n3c2)C1

Procedure:
This compound is prepared from (1RS,3RS)-3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate J [step 1]) and 3-(1H-pyrazol-1-yl)-phenylboronic acid analogously to Example 2.1 (step 2)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1CCNC1
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCCN4CCCC4)c23)ccc1OCc1ccccn1
Yield: 39 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 17) and pyrrolidine to give the title compound in 39% yield; NMR Spectrum: 1.66 (br s, 4H), 1.95-2.01 (m, 2H), 2.42 (br s, 4H), 2.53 (t, 2H), 4.35 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.35-7.38 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.89 (m, 2H), 8.27 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 480 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24]Br)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.[NH3:26]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[C:22]([CH3:23])=[N:21][N:20]=[C:19]3[CH2:24][N:26]=[C:7]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])[C:6]=2[CH:17]=1
Reactant: N
Reactant: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 10, 5-chloro-2',6'-difluoro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with a saturated solution of ammonia in methanol to give 8-chloro-1-methyl-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 126°-127° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:3]=1.[N+:22]([O-])([O-:24])=[O:23].[K+].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:22]([O-:24])=[O:23])[C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1CN1CCOCC1)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Yield: 83 %

Procedure:
To a mixture of N-[4-chloro-2-(morpholin-4-ylmethyl)phenyl]-2,2,2-trifluoroacetamide (3.8 g, 11.8 mmol) in concentrated sulfuric acid (35 mL) cooled to 0° C. is added potassium nitrate (1.4 g, 14.1 mmol). The reaction is slowly warmed to room temperature over a period of 2 h and is then poured into ice water. The mixture is neutralized with saturated aqueous K2CO3 and the resulting solid is isolated by filtration to afford the title compound (3.6 g, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1I.[C:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)#[N:11].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O.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>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: Clc1nccc(I)c1Br
Reactant: N#Cc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccnc(Cl)c2Br)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.7 %

Procedure:
A suspension of impure 3-bromo-2-chloro-4-iodopyridine (2.23 g), 4-cyanophenylboronic acid (1.62 g, 11.0 mmol), 2 M aqueous Na2CO3 solution (6 mL, 12 mmol), and toluene (40 mL) was purged with argon, then (Ph3P)4Pd (1.1 g, 0.95 mmol) was added in one portion. The resulting yellow mixture was vigorously stirred under argon at 100° C. for 4 h. Analysis by HPLC/MS indicated the reaction was not complete, and additional 4-cyanophenylboronic acid (0.82 g, 5.57 mmol), 2 M aqueous Na2CO3 solution (3.5 mL) and (Ph3P)4Pd (850 mg) were added. The reaction mixture was stirred at 100° C. for 12 h more. Additional (Ph3P)4Pd (1.0 g) was added, and the reaction mixture was stirred for another 20 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (80 g) eluted with a gradient of EtOAc (0-60%) in hexanes to obtain 590 mg (29%) of the title compound as an off-white solid. HPLC/MS: retention time=3.11 min, [M+H]+=292.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:23]2[C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 90 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-nitrobenzaldehyde as described in Example 11. 1-Nitro-5-(p-nitrophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is obtained. M.p.: 190°-191° C. Yield: 90%.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:4]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution containing 600.0 mg (2.25 mmol) of 2,3-dihydro-6-(2-trimethylsilylethynyl)-(4H)-1-benzothiopyran-4-one and 100.0 mg (0.72 mmol) K2CO3 in 15 ml MeOH was stirred at room temperature for 20 hours. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as an orange solid. 1H NMR (CDCl3): δ 8.17 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=1.8, 8.2 Hz), 7.19 (1H, d, J=8.2 Hz), 3.22 (2H, t, J=6.3 Hz), 3.08 (1H, s) 2.94 (2H, t, J=6.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])=[CH2:8])[CH3:2].II.I[CH2:27]I>CCOCC.CCOC(C)=O.[Cu].[Zn]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:6][C:7]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[CH2:27][CH2:8]1)([OH:22])[C:18]([F:19])([F:20])[F:21])[CH3:2]
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cc(F)ccc1OC
Reactant: ICI
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)(CC1(c2cc(F)ccc2OC)CC1)C(F)(F)F
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of 620 mg (1.84 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester, 475 mg zinc copper couple, and an iodine crystal in anhydrous ether in a sealed tube warmed to 55° C. was added dropwise 500 μL (6.20 mmol) of diiodomethane. The reaction was monitored by TLC in dichloromethane-hexanes (1:1) or ether-hexanes (2:8). After 18 hours, the mixture was cooled, diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with three 10 mL portions of 1 N aqueous HCl, 10 mL of brine, three 10 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The crude material was adsorbed onto silica gel and chromatographed on silica gel using ether-hexanes (0:100, then 1:99, then 2:98) to afford 494 mg (76%) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]#[N:20]>O1CCCC1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:18][C:19]#[N:20])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
18.4 g of 4-benzylphenol was dissolved in 100 ml of anhydrous tetrahydrofuran and 4.0 g of sodium hydride (60 % oil dispersion) was gradually added to the solution with ice cooling :n nitrogen stream. The solution was stirred for 1 hour at room temperature and 12.0 g of bromoacetonitrile was added thereto under ice cooling, followed by refluxing with heating for 3 hours. After being left for cooling, the reaction mixture was concentrated under reduced pressure and to the residue was added 100 ml of water, followed by extracting twice with 100 ml of chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. The residue was chromatographed on a silica gel column (eluting solvent hexane : acetone=3 : 1 (v/v)) to obtain 19.1 g of (4-benzylphenoxy)acetonitrile.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](O[Si](C(C)(C)C)(C)C)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][CH:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:35][CH:34]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(COc2ccc(F)cc2)O1
Reactant: O=S(=O)(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfinic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 Mz CDCl3): δ1.90-3.0 (m, 4H), 3.85-5.0 (m, 4H), 6.70-7.05 (mn, 4H), 7.45-7.72(m, 3H), 7.77-8.0 (n,2H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:32])([F:31])[S:9]([C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21]Br)[CH:15]=[C:14]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[C:13]=1[OH:30])(=[O:11])=[O:10].Cl>C1COCC1>[F:28][C:26]([F:27])([F:29])[S:23]([C:14]1[CH:15]=[C:16]([CH2:18][CH2:19][CH:20]=[CH2:21])[CH:17]=[C:12]([S:9]([C:8]([F:32])([F:31])[F:7])(=[O:11])=[O:10])[C:13]=1[OH:30])(=[O:25])=[O:24]
Reactant: O=S(=O)(c1cc(CCCCBr)cc(S(=O)(=O)C(F)(F)F)c1O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCc1cc(S(=O)(=O)C(F)(F)F)c(O)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.6 g of potassium t-butoxide was dissolved in 200 ml of anhydrous THF under nitrogen. The solution was cooled with a dry ice bath to keep the inside temperature at -30° C. 4.9 g of compound (10) in 20 ml of THF was dropped into the solution and the mixture was stirred for 1 hour followed by warming to the room temperature. Then the reaction mixture was poused into ice, acidified with diluted hydrochloric acid and extracted with ether. After washing, drying and the solvent removal 3.5 g of liquid product was collected. MNR (CDCl3): δ 2.8 (m, 2H), 3.5 (t, 2H), 4.7-5.0 (m, 2H), 5.5-6.2 m, 1H), 7.2 (s, 1H), 8.1 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:24]([O:26][CH2:27][CH3:28])=[CH2:25])CCC>O1CCOCC1.O.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>[CH2:27]([O:26][C:24]([C:7]1[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)=[CH2:25])[CH3:28]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(OCC)c1nc(C(=O)OC)cn1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
Methyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (10 g, 29.9 mmol) was dissolved in dioxane (200 ml). Tributyl(1-ethoxy-vinyl)stannane (16.2 g, 44.8 mmol) was added to the solution. The resulting mixture was degassed and purged with argon for 20 min. Then Pd(PPh3)4 (3.45 g, 2.99 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to RT and diluted with cold water. The mixture was extracted with EtOAc and washed with aqueous KF solution. The organic layer was concentrated to give the desired product. Yield 12.1 g. LC-MS: [M+1]=327.78.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([OH:43])=O)=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:43])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cc(OC)ccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 65) (210 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[C:6]([NH2:10])=[N:7][NH:8][CH:9]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:18][C:19](OCC)=[O:20]>C(O)(=O)C>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[CH:9]=[N:8][N:7]2[C:19]([OH:20])=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:10][C:6]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Cc1cccc(Cc2c[nH]nc2N)c1C
Solvent: CC(=O)O
Product: Cc1cccc(Cc2cnn3c(O)cc(-c4ccncc4)nc23)c1C
Reaction time: 2 h

Procedure:
To a solution of 4-(2,3-dimethylbenzyl)-1H-pyrazol-3-amine (189 mg, 0.93 mmol) in acetic acid (2.0 mL) was added ethyl 3-oxo-3-(4-pyridinyl)propanoate (185 mg, 0.96 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 140° C. for 60 minutes. The reaction mixture was cooled and stood for 2 hours. Precipitate was observed, filtered. Solid was washed with acetic acid (1 mL), then ethanol (1 mL×2). Solid was dried. The titled compound was obtained. (107 mg, 34%); LC/MS: MS (ES+) m/e 331 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.26 (s, 3H) 4.02 (s, 2H) 6.12 (s, 1H) 6.98-7.06 (m, 3H) 7.56 (s, 1H) 7.82 (br. s., 1H) 7.81 (d, J=5.31 Hz, 1H) 8.80 (dd, J=4.55, 1.52 Hz, 2H) 12.37 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22](Br)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])[CH2:32][CH2:31]1>CN(C=O)C>[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22]([S:11][C:8]1[S:9][C:10]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=1)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH3:38])[CH2:32][CH2:31]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Reactant: Sc1nc2cccc(Cl)c2s1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-Chloro-2-mercaptobenzothiazole (0.020 g, 0.097 mmol) in DMF (2.0 mL) was added (CH3)3COK (0.011 g, 0.97 mmol) at room temperature and stirring continued for 30 min. To the above reaction mixture tert-butyl ((1S)-2-{4-[2-(6-amino-8-bromo-9H-purin-9-yl)ethyl]piperidin-1-yl}-1-methyl-2-oxoethyl)carbamate (0.040 g, 0.081 mmol) in (1 mL) of DMF was added at room temperature. The reaction mixture was heated to 130° C. for 6 h, at the end of this period solvent was evaporated and crude was purified by preparative HPLC [X-Terra prep-RP18 10 um, 19×250 mm (waters), Mobile phase: solvent A: Water HPLC grade containing 0.01% TFA, and solvent B: acetonitrile containing 0.01% TFA, general eluting gradient—solvent B 15% to 80 over 15 to 25 minutes run time]. After lyophilization of HPLC fractions to afford title product. 1H NMR 6 (CD3OD), 8.35 (s, 1H), 7.85-7.82 (m, 1H), 7.50-7.40 (m, 2H), 4.40 (t, J=7.2 Hz, 2H), 4.00-3.90 (m, 2H), 1.80-1.70 (m, 4H), 1.21-1.15 (m, 6H), 1.15 (s, 9H), 1.10 (s, 3H); LC-MS [M+H]+ 617.1
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[F:22].Cl[CH2:24][CH:25]([OH:28])[CH2:26]Cl>N1C=CC=CC=1>[CH:13]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:1]4[CH2:26][CH:25]([OH:28])[CH2:24]4)[C:11]=3[F:12])[C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: OC(CCl)CCl
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Yield: 54.9 %

Procedure:
A solution of 0.8 g (2.60 mmoles) of ethyl 7-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.33 g (2.60 mmoles) of 1,3-dichloro-2-propanol and 25 ml of pyridine is agitated for 3 days, protected from light at ambient temperature; then left refluxing for 3 days and more. The solution is concentrated almost to dryness, poured onto water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum, yielding 0.52 g (55%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate. Its melting point and spectroscopic data are identical to those of the derivative obtained according to method A.
Reaction SMILES: CO[C:3](=[O:27])[C:4]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.CCCCCC>[N+](C1C=CC=CC=1)([O-])=O>[CH3:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[CH3:24])[C:17]([C:4]1[C:3](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[NH:6][CH:5]=1)=[O:26]
Reactant: COC(=O)C(=CNc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(C)c(C)c1
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(C(=O)c2c[nH]c3ccc(C(F)(F)F)cc3c2=O)cc1C
Yield: 83.3 %

Procedure:
2-(3,4-dimethyl-benzoyl)-3-(4-trifluoromethyl-phenylamino)-acrylic acid methyl ester 2c (151 mg, 0.40 mmol) was refluxed in 5 mL of nitrobenzene for 3 h, then cooled down and to it was added 10 mL of hexane. The crude product precipitated out of solution and was isolated by filtration. The crude product was washed with hexane to give 115 mg of 3-(3,4-dimethyl-benzoyl)-6-trifluoromethyl-1H-quinolin-4-one as off-white crystals 3b: LC-MSD, m/z for C19H14F3NO2, [M+H]+=346.4,; HPLC retention time: 2.3 min.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10](=[S:13])[S:9][C:8]=2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].C(OO)(=[O:20])C>C(Cl)(Cl)Cl>[N+:1]([C:4]1[C:12]2[S:11][C:10](=[S:13]=[O:20])[S:9][C:8]=2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2sc(=S)sc12
Solvent: ClC(Cl)Cl
Product: O=S=c1sc2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1

Procedure:
To a stirred solution of 7.35 g., (24.7 mmoles) of 4-nitro-6-trifluoromethyl-1,3-benzodithiole-2-thione in 150 ml. of chloroform was added dropwise a solution of 5.17 g., (24.7 mmoles) of 40% peracetic acid in 50 ml. of chloroform over a period of 20 minutes, the temperature being maintained at 8°-12° C.