Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-(4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1.7 g, 3.7 mmol) was dissolved in anhydrous MeOH(MeOH) (110 mL) followed by addition of 2 M of hydrogen chloride in MeOH (9.2 mL). Reaction was stirred at 70° C. for 4 hrs. After concentration in vacuo the sample was loaded onto 120 g ISCO cartridge eluting with EtOAc/hexane. Fractions were combined and evaporated to yield desired product as an off-white powder. (1.12 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ: 7.96 (dd, J=6.8, 2.3 Hz, 1H), 7.66 (m, 1H), 7.64 (m, 1H), 5.95 (s, 1H), 4.85 (s, 2H); MF=CHH6ClFN4O4; LCMS calculated for C11H7ClFN4O4(M+H)+: m/z=313.014.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].CO[C:19]([CH3:21])=[CH2:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:20][CH:19]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:21]
Reactant: COC(=O)c1sc(-c2ccncc2)cc1N
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1sc(-c2ccncc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of methyl 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylate (0.469 g, 2.00 mmol), 2-methoxypropene (0.29 mL, 3.0 mmol) and acetic acid (0.114 mL, 2.00 mmol) in dichloromethane (6 mL) was added sodium triacetoxyborohydride (0.636 g, 3.00 mmol), and the reaction was stirred at room temperature overnight. Then, the reaction mixture was poured into sat. NaHCO3 (70 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography (Combiflash, silica gel, hexanes to ethyl acetate) to give the title compound (0.256 g, 46%) as a yellow solid:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3C=CC=[CH:19][C:14]=3[N:13](C)[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30](C(C)(C)C)=[CH:29][CH:28]=1)[CH:23]1[O:25][CH2:24]1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:13]([CH:14]([CH3:15])[CH3:19])[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[O:25]1[CH:23]([CH2:22][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24]1
Reactant: Cn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: CC(C)(C)c1ccc(OCC2CO2)cc1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 4-tert-butylphenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)#[N:8]>C(Cl)Cl>[CH3:26][C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([CH3:27])[CH:23]=1)[O:19][C:12]1[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:14][C:13]=1[S:15]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:17])=[O:16]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reaction time: 74 h
Yield: 58.5 %

Procedure:
To a solution of piperazine (16.144 g, 186.4 mmol) in CH2Cl2 (80 mL) stirred in an ice-brine bath was added dropwise of a solution of compound 23 (3.009 g, 9.35 mmol) in CH2Cl2 (270 mL) over the course of two days. The reaction was then stirred for 74 hrs, whereupon the starting material was consumed (TLC, 5% MeOH in CH2Cl2). The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was then washed with saturated sodium chloride solution and dried over anhydrous MgSO4. The organic layer was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield an light yellow oil. The oil was then triturated with CH2Cl2/diisopropyl ether and vacuum filtered to afford compound 24 as a white powder (2.032 g, 58.5% yield, 95.5% HPLC purity). 1H NMR (500 MHz, DMSO-d6): δ 8.21 (d, J=2 Hz, 1H), 8.03 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.01 (m, 1H), 6.96 (d, J=11 Hz, 1H), 6.80 (d, J=9 Hz, 2H), 3.19 (m, 2H), 3.11 (m, 2H), 2.70 (m, 2H), 2.46 (m, 2H), 2.30 (s, 1H), 2.27 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.ClC(OCC(C)C)=O.Cl.[CH3:24][NH:25][O:26][CH3:27]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([N:25]([O:26][CH3:27])[CH3:24])=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1cccc2c(Br)cccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc2c(Br)cccc12
Reaction time: 0.42 h
Yield: 30 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1 H, d, J=8.6 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.86-7.93 (3 H, m), 7.74 (1 H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1 H, m), 7.40 (1 H, dd, J=8.5, 7.6 Hz), 7.25 (2 H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:14][C:13]=2[CH:21]=1.C(=O)(O)[O-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:14][C:13]=2[CH:21]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 36 h
Yield: 38.1 %

Procedure:
To a solution of ethyl bromoacetate (1.2 ml, 11 mmol) and 6-hydroxy-2-sulfamoylbenzo[b]thiophene (2.29 g, 10 mmol) in DMSO (10 ml) was added dropwise a solution of potassium bicarbonate (1.0 g, 10 mmol) and potassium carbonate (0.13 g, 1 mmol) in water (7 ml). The mixture was stirred for 1-2 days, then diluted with water. The precipitated product was collected dissolved in ethyl acetate, dried (Na2SO4) and evaporated to dryness. The residue was recrystallized from hot ethyl acetate, boiling off solvent until crystallization began, to give 1.2 g of product, m.p. 182°-184° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2Cl)([O-:3])=[O:2].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[Cl:28]>C(O)(C)C>[Cl:28][C:22]1[CH:23]=[C:24]([NH:25][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:26]=[CH:27][C:21]=1[O:20][CH2:19][C:18]1[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Yield: 67 %

Procedure:
In a flask equipped with a reflux condenser, 6-nitro-4-chloro-quinazoline 1.20 g (5.7 mmol) and 4-(3-fluorobenzyloxy)-3-chloroaniline 1.37 g (5.6 mmol) were dissolved into 80 mL of isopropanol, and the solution was refluxed for 3 h. Then a lot of yellow solid was deposited, which was filtered, dried under vacuum, and identified as the title compound. Yield: 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH:8]([OH:22])[CH2:9][N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:22][CH:8]([CH2:9][N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)CN(CC(O)COc1ccc(Cl)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CN(CC(COc1ccc(Cl)cc1)OC(C)=O)c1ccccc1
Reaction time: 20 h
Yield: 82.9 %

Procedure:
After 5.5 g (0.0157 moles) of 1-(p-chlorophenoxy)-3-(N-carbomethoxymethyl-N-phenylamino)-2-propanol and 6.0 g (0.059 moles) of acetic anhydride were dissolved in 30 ml of pyridine and left to stand at the room temperature for 20 hr, the reaction mixture was concentrated. The resulting residue was poured into iced water to afford precipitates. The precipitates were collected by filtration, washed with water and dried. Recrystallization from isopropanol gave 5.1 g (83%) of the crystals, m.p. 82-83.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([C:10]([NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl

Procedure:
To a stirred solution of 1 kg of 2,5-dichloroaniline in 2500 ml of pyridine is added 840 ml of pivaloyl chloride and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is poured into water. The solid is filtered, washed with water and air dried to yield N-tert-butylcarbonyl-2,5-dichloroaniline, melting at 74°-76°.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:2]([C:7]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[C:27]4[C:28]5[C:20](=[CH:21][NH:22][C:23]=5[CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl-].C[CH:39]=[N+:40]=[CH:41]C.[CH2:43](Cl)Cl>O>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:2]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:16]3[C:27]4[C:28]5[C:20](=[C:21]([CH2:39][N:40]([CH3:41])[CH3:43])[NH:22][C:23]=5[CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:29][CH:30]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=[N+]=CC
Reactant: ClCCl
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3c[nH]c4cccc2c34)cc1)c1ccccc1-c1ccccc1
Agent: [Cl-]
Solvent: O
Product: CN(C)Cc1[nH]c2cccc3c2c1CCCN3C(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 10 (0.10 g, 0.2 mmol), N, N-dimethylmethyleneammonium chloride (0.10 g, 5.3 eq) and CH2Cl2 (25 mL) was stirred under argon for about 2 h and diluted with water (5 mL). The layers were separated and the organic layer was washed with water (5 mL), dried (sodium sulfate) and evaporated to give 17 (clear glass). 1H NMR (DMSO-d6) 2.1 (m, 2 H), 2.22 (s, 6 H), 3.0 (m, 2 H), 3.3 (m, 1 H), 4.0 (m, 1 H), 4.79 (s, 2 H), 6.2 (d, J=7, 1 H), 6.8 (t, J=7, 1 (d, J=8, 2 H), 7.2-7.6 (m, 13 H), 10.31 (s, 1 H). MS m/e 529.65 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([OH:10])([C:8]#[N:9])[CH2:5][C:4]([CH3:12])([CH3:11])[NH:3]1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].S(=O)(=O)(O)[OH:20]>C(O)(=O)C>[CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([OH:10])([C:8](=[O:20])[NH:9][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][C:4]([CH3:12])([CH3:11])[NH:3]1
Reactant: CC(C)(C)O
Reactant: O=S(=O)(O)O
Reactant: CC1(C)CC(O)(C#N)CC(C)(C)N1
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)C1(O)CC(C)(C)NC(C)(C)C1
Reaction time: 2 h

Procedure:
54.6 g 2,2,6,6-Tetramethyl-4-hydroxy-4-cyanopiperidine together with 45 g tert.-butanol in 200 ml glacial acetic acid are introduced into the reactor. Subsequently, 60 g concentrated sulfuric acid are added dropwise with agitation, and agitation is continued for 2 hours at 70° C., thus forming a precipitate which is filtered off and dissolved in water. On alkalization with NaOH, the product precipitates, it is suction-filtered and recrystallized from ethyl acetate. Yield 44 g, m.p. 134°-136° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[NH2:9][C:10]([NH2:12])=[S:11]>O>[ClH:1].[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:11][C:10](=[NH:9])[NH2:12])#[N:8]
Reactant: N#CCCCCCCl
Reactant: NC(N)=S
Solvent: O
Product: Cl
Product: N#CCCCCCSC(=N)N
Reaction time: 1 h

Procedure:
The 6-chlorohexanenitrile (6.36 g, 48.3 mmol) and thiourea (4.04 g, 53.1 mmol) are mixed in 40 ml of water. The mixture is heated to reflux for 3 to 4 hours. The reaction mixture is evaporated and 20 ml of ethanol is added and then evaporated as well. This is repeated three times. After that, 10 ml of methanol and 30 ml of acetone are added and the mixture is stirred for one hour. The crystalline material is filtered and the product is dried under high vacuum overnight to yield S-(5-cyanopentyl)isothiourea hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C(C)=CC=CC=1C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>O1CCCC1>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)=[O:26]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: Cc1nc2cc(NC(=O)c3ccco3)ccc2o1
Temperature: 3 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
5-Amino-2-methylbenzoxazole (14.8 g, 0.100 mol) and 2,6-lutidine (12.0 g, 0.111 mol) were combined with 100 mL of tetrahydrofuran (THF) and the solution was cooled to 3° C. in an ice-bath under nitrogen. 2-Furoyl chloride (13.7 g, 0.105 mol) in 20 ml of THF was added dropwise so as to keep the temperature below 10° C. After addition the ice-bath was removed and after stirring for 1 hr the mixture was poured into 300 mL of water. The solid was collected and washed with water and dried. This afforded 21.1 g (87% yield) of product; m.p. 156°-158° C.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OC1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)OC1CCC(O)CC1
Yield: 25 %

Procedure:
1,4-cyclohexanediol (20.0 g, 172.4 mmol) was dissolved in dichloromethane (200 mL). Cinnamoyl chloride (7.2 g, 43.1 mmol) dissolved in 50 ml dichloromethane was then slowly added. After 2 h of mixing, triethyl amine (5.3 g, 52 mmol) was added slowly. After 48 h of mixing, the solution was washed three times with dilute HCl (1 M) and two more times with H2O before it was dried over MgSO4 and filtered. The product was then dissolved in methanol which resulted in precipitation of the byproduct. After filteration and evaporating the solvents from the filtrate, the product was a obtained as yellow-orange viscous liquid, which was used without further purification. Yield: 25-40%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]1([C:27](Cl)=[O:28])[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1>ClCCl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:4]2[CH:3]=[C:2]([NH:1][C:27]([C:14]3[C:26]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]=4[CH:17]=[CH:16][CH:15]=3)=[O:28])[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cccnc2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a suspension of 3-pyridin-3-yl)aniline (0.17 g) and pyridine (0.24 ml) in dichloromethane (3 ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.23 g) in dichloromethane (2 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyridin-3-yl)phenyl)-9H-fluorene-1-carboxamide (0.317 g, 87.6%).
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27].C(O)C.C>CO>[ClH:23].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:27][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: Cc1ccc(N)cc1Cl
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(Nc2ccc(C)c(Cl)c2)c2c(ccc3nc[nH]c32)n1
Reaction time: 8 h

Procedure:
A 500 ml., 3-neck, r.b. flask fitted with stirrer, condenser, and thermometer was charged with a mixture of the compound of Example I, C. (21.7 g., 0.1 mole), 3-chloro-4-methylaniline (14.2 g., 0.1 mole) and ethanol (300 ml.). The mixture was heated at reflux, while stirring, overnight. The near solution was concentrated to dryness by rotary evaporator and the residue was collected and dried to yield 35 g. (97.5%), m.p. 352°-364°C (dec). A 10 g. sample was dissolved in methanol (200 ml.), treated with charcoal and filtered while hot. Ether (ca 750 ml.) was added until the filtrate remained turbid and was then chilled. The crystals were collected by filtration and dried to yield 3.4 g. yellow crystals, m.p. 362°-370°C (dec). After two recrystallizations a m.p. 368°-372°C (dec) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:15])[N:7]2[CH2:12][CH:13]=O.[C:16]([O:20][C:21](=[O:40])[N:22]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:16]([O:20][C:21](=[O:40])[N:22]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][N:7]2[C:8]3[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:15])[CH2:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=CCn1c(=O)ccc2c(Br)cccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Br)cccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To 25 mL of a chloroform solution containing 520 mg of (5-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde and 705 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 112 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 629 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 890 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([C:15]2[C:16]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: Brc1cccc2ccccc12
Reactant: Br[Mg]C1CC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc2c(C3CC3)cccc2c1
Temperature: 0 °C
Yield: 76 %

Procedure:
Cyclopropylmagnesium bromide (150 mL, 0.5 M in tetrahydrofuran) was slowly added to a solution of 1-bromo-naphthalene (10 g, 50 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) in tetrahydrofuran (10 mL) stirred at 0° C. The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under reduced pressure. EtOAc and ammonium chloride in water were added. After extraction, the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-cyclopropyl-naphthalene (6.4 g, 76%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[N:12]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Agent: [Na]
Product: CCn1ncc2c1ncc1c(=O)n(CCN3CCOCC3)c3cc(C)nn3c12
Reaction time: 24 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) and 0.3 g. of sodium are refluxed for 1 hour in 30 ml. of diethylene glycoldimethylether with stirring. The temperature is lowered to 90° and 2 g. of 1-chloro-2-morpholinoethane are added and stirring is continued for 24 hours. The inorganic precipitate is filtered off, the solvent removed in vacuo and the crystalline product, 8-ethyl-2-methyl-4-(2-morpholino)ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one is recrystallized from ethyl acetate, yield 3.1 g. (81%); m.p. 140°-141°.