Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:6]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:14][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[O:3][C:4]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-chloro-4-(3,4-dichlorophenyl)-5-oxazolepropionate (1.00 g), 2-methylimidazole (0.82 g), potassium carbonate (0.69 g) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 1 h. The reaction mixture was poured into iced water (100 mL) and the precipitated crystals were collected by filtration, washed with water and then with isopropyl ether and air-dried to give the title compound as crystals. Recrystallization from ethyl acetate-isopropyl ether gave pale-yellow prism crystals (0.82 g, 72%). melting point: 116-117° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:21]([OH:23])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CCCCCOCOCCOC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CCCCCOCOCCOC)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
1.5 ml of an aqueous solution containing 0.203 g of potassium hydroxide was added, whilst ice-cooling, to a solution of 1.029 g of diethyl 2-[5-(2-methoxyethoxy)methoxypentyl]malonate (prepared as described in Preparation 61) dissolved in 1.5 ml of ethanol. The reaction mixture was stirred at room temperature for 5 hours, after which it was washed with diethyl ether. The aqueous layer was adjusted to a pH value of 2 by adding 10% w/v aqueous hydrochloric acid, and it was then extracted four times with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue (0.94 g) was subjected to column chromatography through 20 g of silica gel, and 0.764 g of the title compound was obtained, as a colorless oil, from those fractions eluted with mixtures of hexane and ethyl acetate ranging from 2:1 to 1:1 by volume.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][CH:6]=[CH:5]2
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
53.0 g (236, mmol) of 6-bromo-isoquinoline 2-oxide (4) were heated in 400 ml of POCl3 under reflux conditions in two portions. After 4 h, the reaction was cooled to room temperature and poured carefully on ice with mechanical stirring. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated, which gave 42.8 g of the title compound, which was used without further purification. Rt=1.64 min (Method C). Detected mass: 242.1/244.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1>[CH2:1]([N:4]1[CH:5]([CH3:10])[C:6](=[O:8])[N:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[CH:13]=2)[C:20]1=[O:21])[C:2]#[CH:3]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: C#CCNC(C)C(=O)OC
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C1C
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of methyl 2-propargylaminopropionate (10 g, 0.07 mole) in toluene (100 mL) with 2 drops of stannous octonoate was added 3,5-dichlorophenylisocyanate (14.5 g, 0,077 mole) in small portions. The resulting mixture was heated at 100° C. for 3 hours. It was then washed with water twice and dried over sodium sulfate. Solvent was evaporated to give a thick, yellow oil. Material was further purified by passing it through a silica gel column using 30/70 ethyl acetate/hexane as eluent to give 18 grams of a light yellow oil which solidified on standing. The solids were triturated in boiling hexane and collected by suction filtration; mp 105°-106° C., NMR and elemental analysis confirmed the desired structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]([Cl:37])=[CH:34][CH2:35]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH2:4][C:5]([CH3:6])([O:25][CH2:35][CH:34]=[C:33]([Cl:37])[Cl:32])[CH:24]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(C)c1OCCCOc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1=C(OCCCOc2ccc(C(F)(F)F)cn2)C=CC(C)(OCC=C(Cl)Cl)C1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.7 g of 3-ethyl-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]phenol and 0.27 g of potassium carbonate, to which a solution of 0.34 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.6 g of 3-ethyl-1-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (65% yield), nD23.0 1.5188.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[C:20](O)(=O)C>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
The compound obtained in (1) above 73 gm was dissolved into 600 ml of acetic acid. To the solution were added 20 ml of 40% perchloric acid and 10% palladium-on-carbon to effect catalytic hydrogenation under 5 atm. After the evaporation of acetic acid and the addition of 100 ml of water, the residue was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated and 100 ml of dichloromethane, 74 gm of sodium carbonate, and 30 ml of thionyl chloride were added to the residue. The mixture was heated under reflux for 3 hours and then cooled to 0° C., and 150 ml of methanol was slowly added, followed by stirring for 12 hours at room temperature. After the addition of 300 ml of ethyl acetate, the resulting product was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 66.7 gm of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH:38]=[C:37]([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)[CH2:36][CH2:35]1>O1CCCC1.CN(C)C=O>[NH:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([C:37]2[CH2:38][CH2:39][N:34]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[C:24]=4[O:23][CH2:22][CH2:21][C:20]5=[O:25])[O:26][CH2:27]3)[CH2:35][CH:36]=2)=[CH:41]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4=O)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CCOc2c1ccc1c2OC(CN2CC=C(c3c[nH]c4ccccc34)CC2)CO1

Procedure:
To a mixture of [(2R)-7-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1.54 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethyl-formamide (20 mL) was added 0.91 g (4.61 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product. Evaporation of the product-containing fractions in vacuum gave 0.12 g (18%) of the (S)-enantiomer of the title compound as an off-white solid, m.p. 210° C.
Reaction SMILES: Cl[C:2]([CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[N:9]=[CH:8][C:7]=1[C:22]#[N:23])=[O:3].[CH2:24]([NH2:26])[CH3:25]>C(C(C)=O)C>[Cl:21][C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[N:10]1[C:6]([NH:5][CH2:4][C:2]([NH:26][CH2:24][CH3:25])=[O:3])=[C:7]([C:22]#[N:23])[CH:8]=[N:9]1
Reactant: CCN
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1NCC(=O)Cl
Solvent: CCC(C)=O
Product: CCNC(=O)CNc1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
A solution of 5-chlorocarbonylmethylamino-1-(2-chloro-4-trifluoromethylphenyl)-4-cyanopyrazole (4.72 g) in dry methyl ethyl ketone (25 ml) was added over 5 minutes to a stirred solution of ethylamine (20 ml) in methyl ethyl ketone (100 ml) at 0° C. (maintained by external cooling). The resulting suspension was stirred for 1 hour whilst the reaction mixture attained laboratory temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of diethyl ether (100 ml) and water (100 ml). After separation of the organic layer, the organic layer was washed successively with aqueous 2N hydrochloric acid (2×100 ml) and water (3×50 ml) and dried over anhydrous sodium sulphate. Evaporation of the solution to dryness gave a fawn coloured powder (3.6 g. m.p. 144°-145° C.) which was chromatographed using dichloromethane-ethyl acetate (4:1) as eluent. Evaporation of the eluate containing the major component gave a yellow oil which was crystallised from a mixture of toluene (5 ml) and hexane (40 ml) to give 1-(2-chloro-4-trifluoromethylphenyl)-4-cyano-5-ethylaminocarbonylmethylaminopyrazole, m.p. 150°-151° C. in the form of colourless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(#N)C.C(OCC)(=O)C>[Br:35][C:14]1[CH:13]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]=1[OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(Cc1ccc(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
402 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was dissolved in 5 ml acetonitrile, and 200 mg N-bromosuccimide was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate. The organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 433 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]2[NH:17][C:16]([C:18]3([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:14]=2)[CH:7]=1.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C(N(CC)CC)C>[CH2:28]([NH:30][C:31](=[O:32])[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][C:8]=1[C:13]1[NH:17][C:16]([C:18]2([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20][CH2:21][CH2:22]2)=[N:15][N:14]=1)[CH3:29]
Reactant: Cc1ccc(O)c(-c2nnc(C3(c4cccs4)CCCC3)[nH]2)c1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1ccc(C)cc1-c1nnc(C2(c3cccs3)CCCC2)[nH]1

Procedure:
A chloroform solution (2.7 ml) of 4-{4-methyl-[5-(1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenol (40 mg), triethylamine (103 μl), and ethyl isocyanate (57 μl) was heated at 60° C. for 5 hours. The solvent was removed by evaporation and a small amount of ethyl acetate was added to the residue. The resulting white solid was collected by filtration and washed with diethyl ether to obtain 4-{4-methyl-[5-(1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenyl ethylcarbamate (30 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.O.[OH-].[Na+]>[Cl-].[Na+].O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCCBr
Yield: 55.4 %

Procedure:
2,6-Dimethyl-4-nitrophenol (5.2 g) and 12.6 g of 1,3-dibromopropane were added to 19 mL of distilled water, the mixture was stirred, and 7.51 g of a 16.6% aqueous sodium hydroxide solution was then added thereto. Further, the mixture was heated under reflux while adding 2.46 g of a 30% aqueous sodium hydroxide solution for 5 hr. The reaction mixture was cooled, and ethyl acetate and brine were added thereto, followed by separation and washing with brine. The ethyl acetate layer was concentrated under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 4.97 g of 2-(3-bromopropoxy)-1,3-dimethyl-5-nitrobenzene. Next, 1.0 g of the product, 0.57 g of 4-trifluoromethylphenol, 2 mL of dimethylacetamide, and 0.36 g of potassium carbonate were mixed together, and the mixture was heated at 90 to 100° C. for one hr. The reaction solution was cooled and was then poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% aqueous sodium hydroxide solution and brine and was then concentrated under the reduced pressure to give 1.28 g of 1,3-dimethyl-5-nitro-2-(3-(4-trifluoromethylphenoxy)propoxy)benzene.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:38](Cl)(=[O:40])=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C>[CH2:30]([S:38]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:40])=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 341.8 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-octanesulfonyl chloride (Aldrich) (0.095 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0805 g, 34%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:20]5[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Yield: 4.3 %

Procedure:
A solution of 1.00 g (3.88 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.47 g (3.88 mmol) of p-fluorobenzonitrile, 0.54 g (3.88 mmol) of K2CO3 and 8 ml of dimethylsulfoxide are stirred at 80° C. for 3 days. The reaction mixture is allowed to cool and is diluted with water producing a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.06 g (4%) of the title compound as a pink solid: m.p.>275° C.; m/e 358.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=[O:7].[C:10]12([CH2:20][NH2:21])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>>[NH2:21][CH2:20][C:10]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][C:12]([OH:7])([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: O=[N+]([O-])O
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Product: NCC12CC3CC(CC(O)(C3)C1)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred mixture of concentrated sulfuric acid (22.7 mL) and 65% nitric acid (2.3 mL) at 0° C. was added C-adamantan-1-yl-methylamine (2.0 g, 12.12 mmol) dropwise. The reaction mixture was stirred for 2 h at 0° C., warmed to room temperature and stirred at that temperature for 24 h, cooled to 0° C. and slowly quenched with ice (10.8 g). The mixture was allowed to warm to ambient as ice melts overnight, cooled to 0° C. again and treated with sodium hydroxide (50 g) in small portions. The resulting brownish paste was filtered, and the filter cake was rinsed with DCM (200 mL). After separation, the organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated to give a white solid (1.09 g). (m/z): [M+H]+ calcd for C11H19N 182.2; found 182.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[OH:8][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[C:2]([OH:1])[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1nc(O)cc(O)n1
Product: CC(C)c1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
220 g of 4,6-dihydroxy-2-isopropyl-pyrimidine are added at 0°C to 500 ml of 100 % nitric acid and the mixture is stirred for 1 hour. Subsequently the nitration mixture is poured on ice water, filtered, washed with water, and dried in vacuo over P2O5, to yield 110 g of 4,6-dihydroxy-2-isopropyl-5-nitro-pyrimidine; mp. 300°C.
Reaction SMILES: F[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:10][C:9]2[N:4]([C:5](=[O:26])[C:6]([C:21]([O:23]CC)=[O:22])=[CH:7][C:8]=2NC)[CH:3]=1.[OH-].[Na+].[ClH:29]>C1COCC1>[ClH:29].[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:2]=[CH:3][N:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]3=[O:26])[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cc(NC)c2cc(N3CCN(C)CC3)c(F)cn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccn3c(=O)c(C(=O)O)ccc3c2)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 1 g (2.75 mmol)of ethyl 7-fluoro-1-methylamino-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 7, in 12 mL of THF and 16.5 mL of a 0.5N aqueous solution of sodium hydroxide is heated, with stirring, at 75° C. for 8 hours. The THF is removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 2.0 with 10.5 mL of 1N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to remove ~80% of the water and the concentrate is diluted with 50 mL of 95% ethyl alcohol. The solid is collected by filtration, washed with 2×5 mL of ethyl alcohol and dried in vacuo to afford the desired product.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:6][NH:7][C:8]=1[CH:9]([O:12][CH3:13])[O:10][CH3:11].I[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:6][N:7]([CH3:20])[C:8]=1[CH:9]([O:12][CH3:13])[O:10][CH3:11]
Reactant: COC(OC)c1[nH]nc(-c2nccs2)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1c(Br)c(-c2nccs2)nn1C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
Under a nitrogen atmosphere, sodium hydride 60% in oil (0.236 g, 5.92 mmol) was added portionwise to a solution of 2-[4-bromo-5-(dimethoxymethyl)-1H-pyrazol-3-yl]-1,3-thiazole (8c) (900 mg, 2.96 mmol) in dry dimethylformamide (5 mL). After 10 minutes stirring, iodomethane (0.28 mL, 4.44 mmol) was added and the reaction mixture was stirred at room temperature for 40 minutes. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). The organic layer was washed with brine (2×10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 100/0 to 95/5) to provide 2-[4-bromo-5-(dimethoxymethyl)-1-methyl-1H-pyrazol-3-yl]-1,3-thiazole (8d) (586 mg, 1.84 mmol, 62%) and the regioisomer 2-[4-bromo-3-(dimethoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,3-thiazole (199 mg, 0.62 mmol, 21%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:20].[CH2:21]([O:23]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:22]>>[C:21]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:20])(=[O:23])[CH3:22]
Reactant: Cc1cc2c(cc1C)C(=O)C(Cc1ccncc1Br)C2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: CC(=O)c1cnccc1CC1Cc2cc(C)c(C)cc2C1=O

Procedure:
The title compound 111 is prepared according to the procedure reported in Example 36.5 with compound 107 (235 mg, 0.71 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.24 mL, 0.71 mmol) as reactants. White solid. (Yield 125.0 mg, 60%).