Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:34]([OH:36])[CH3:35]>C1COCC1>[OH:36][CH2:34][CH2:35][N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Reactant: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2CCO)cc1

Procedure:
6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (250 mg, 0.54 mmol) and Na2CO3 (2.0 g, 18.9 mmol) in THF (10 mL) is heated to reflux and bromoethanol (0.15 mL) is added every 45 min for 4 hours. The resulting mixture is then allowed to reflux overnight. After TLC suggested no starting material left, the THF is removed and after an aqueous work up, the desired product is isolated through chromatography (75 mg, 28%). MS (ESI): 504.0 (M+1)+1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:30][C:24]1[CH:23]=[C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.5 g; 23.28 mmol) and 4-bromo-2-chlorobenzonitrile (4 g; 18.48 mmol) were dissolved in THF (65 ml). To this mixture bis(triphenylphosphine)-palladium(II) chloride (0.65 g; 0.92 mmol), sodium carbonate (4.7 g; 44.3 mmol) and 18 ml of water were added and the reaction mixture was stirred at 35° C. for 2.5 h. The solvents were distilled to almost dryness and water (48 ml) was added. After 30 min of stirring the precipitated product was filtered and 32 ml of ethanol was added to the precipitation. The suspension was stirred for 15 min at RT and 30 min at −10° C. before filtering to give 3.7 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.63-1.54 (m, 3H), 1.84-1.80 (m, 1H), 1.97-1.94 (m, 1H), 2.39-2.35 (m, 1H), 3.63-3.57 (m, 1H), 3.99 (m, 1H), 5.32-5.27 (m, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (m, 1H), 7.92 (d, 1H), 8.14 (d, 1H).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)CC>[OH:1][CH:2]([CH2:17][NH:21][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: O=C1CCCc2c(cccc2OCC2CO2)N1
Solvent: CCCO
Product: CC(C)NCC(O)COc1cccc2c1CCCC(=O)N2
Yield: 40.3 %

Procedure:
3.3 g (0.014 mole) of 6-(2,3-epoxypropoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one are dissolved in 400 ml of n-propanol, 3 g of isopropylamine are added and the mixture is kept on a boiling waterbath for from 4 to 6 hours. The solvent and excess amine are then distilled off on a rotary evaporator and the residue is twice taken up in methanol, the solvent again being distilled off. The residue thus obtained is chromatographed on a silica gel column, using methanol as the mobile phase. 1.65 g (39.9% yield) of 6-(2-hydroxy-3-isopropylaminopropoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, of melting point 143°-145° C., are obtained.
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[CH:6]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[CH3:11][C:9]1[CH:10]=[C:5]([C:4](=[O:13])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([CH3:12])[N:8]=1
Reactant: BrCc1ccccc1
Reactant: CON(C)C(=O)c1cc(C)nc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Cc2ccccc2)cc(C)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
At −78° C., to a solution of N-methoxy-2,6,N-trimethyl-isonicotinamide (1 g) and benzyl bromide (0.73 mL) in THF (30 mL) was added n-BuLi (1.6M in hexane, 6.6 mL) dropwise. The reaction was stirred at −78° C. for 3 hours. A saturated aqueous solution of NH4Cl (200 mL) was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (EtOAc/n-heptane 1:2) yielded the title compound (1.8 g, 99%) as a colorless liquid, MS (ESI+): m/z=226.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH:27]=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH2:27][NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: O=Cc1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCC2)co1)NOCc1ccccc1
Yield: 52.2 %

Procedure:
Method and purification as for preparation 157 using (3R)-N-(benzyloxy)-6-cyclohexyl-3-(4-formyl-1,3-oxazol-2-yl)hexanamide (preparation 156) (200 mg, 0.50 mmol) and cyclopentylamine (50 μl, 0.50 mmol) as starting materials to afford the title compound as a colourless oil (122 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:36]#[CH:37])(C)C.C(N(CC)CC)C>O1CCCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:36]#[CH:37])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(I)c2)N1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.56 g, 1 mmol) prepared in example 192b in anhydrous tetrahydrofuran (30 mL) was added trimethylsilyl acetylene (0.1 g, 2.0 mmol) (Aldrich), CuI (0.38 g, 2.0 mmol) (Aldrich) and triethylamine (0.2 g, 2.0 mmol) was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium(0) (140 mg, 0.2 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added methanol (10 mL) and aqueous NaOH solution (1 N, 2 mL). The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified with chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.24 g, 52%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:28][CH2:29][CH3:30])=[C:22]([O:25][CH2:26][CH3:27])[CH:23]=3)[C@H:18]3[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[N:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>CO>[CH2:26]([O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:28][CH2:29][CH3:30])[C@H:18]1[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[N:12]=[C:11]2[C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)[CH3:27]
Reactant: CCOc1cc2c(cc1OCC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc2c(cc1OCC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.68 g of (+/-)-cis-6-(4-acetoxyphenyl)-8,9-diethoxy-1,2,3,4,4a,10b-hexahydrophenanthridine are dissolved in 15 ml of methanol, treated with 1.1 g of potassium hydroxide and the mixture is stirred at RT for 2 h. After removal of the solvent in vacuo, the residue is taken up in water, rendered neutral and extracted with ethyl acetate. The organic phase is dried using sodium sulfate and the solvent is removed in vacuo. 1.23 g (51.2% of theory) of the title compound of m.p. 232-234° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OCOC)[C:4]=1[C:13]1[C:18]([CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:17][C:16]([CH2:27][S:28]([NH2:31])(=[O:30])=[O:29])=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Na+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:27][S:28]([NH2:31])(=[O:30])=[O:29])=[CH:17][C:18]=3[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[O:26][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COCOc1cccc(OC)c1-c1ccc(CS(N)(=O)=O)cc1C(O)c1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1-c1ccc(CS(N)(=O)=O)cc1C(c1ccccn1)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (4-(2-methoxy-6-methoxymethoxyphenyl)-5-(1-hydroxy-1-(2-pyridyl)methyl)phenyl methanesulfonamide (0.030 g, 0.075 mmol), prepared according to the procedures of Examples 32A-F, in THF (1 mL) was treated with tributylphoshine (0.045 g, 0.23 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.057 g, 0.23 mmol), stirred for 4 hours at room temperature, and treated with saturated NaCl (10 mL) and ethyl acetate (10 mL) to provide two layers. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC with 20-100% CH3CN/water to provide the desired product. MS (ESI(−)Q1MS) m/z 381 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.53 (m, 1H), 8.31 (d, J=8 Hz, 1H), 7.79 (dt, J=8 Hz, 2 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.32 (m, 1H), 7.22 (m, 1H), 7.18 (d, J=8 Hz, 1H), 6.93 (d, J=2 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 6.21 (s, 1H), 3.90 (s, 3H), 3.00 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccc(OCc2ccccc2)cc1)C(F)(F)F

Procedure:
At 20° C., a solution of 15.7 g of sodium borohydride in 100 ml of water was added dropwise with cooling to a solution of 72.5 g of 4′-benzyloxy-2,2,2-trifluoroacetophenone in 900 ml of ethanol. The mixture was stirred under reflux for 3 hours and then concentrated, the residue was taken up in diethyl ether and water and made slightly acidic using dilute hydrochloric acid, and the organic phase was dried and concentrated to give the title product as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:38][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])=[O:30])[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)NS(=O)(=O)C5CC5)ccc4N3)c2)cc1
Yield: 20.1 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.48 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (130 mg, 0.72 mmol), 4-dimethylaminopyridine (88 mg, 0.72 mmol), cyclopropane sulfonic acid amide (170 mg, 1.44 mmol) in dichloromethane (20 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid {2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (50 mg, 20%) as a light yellow solid: MS (ESI) M+1=518.3.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:15]([O:17]C)=[O:16])[O:8][N:7]=1)([CH3:5])=[CH2:4]>O.CO>[C:3]([C:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:15]([OH:17])=[O:16])[O:8][N:7]=1)([CH3:5])=[CH2:4]
Reactant: C=C(C)c1noc(C(=O)OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)c1noc(C(=O)O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
At 0° C., a solution of 3.6 g (0.09 mol) of sodium hydroxide in 75 ml of water was dripped into 20.0 g (0.09 mol) of dimethyl 3-isopropenylisoxazole-4,5-dicarboxylate (from stage A.1) in 150 ml of methanol, and the mixture was stirred for 14 hours at room temperature. 250 ml of water was added, the pH was adjusted to 8, extraction was effected with 200 ml of dichloroethane, and the aqueous phase was adjusted to a pH of 1-2 with 6N hydrochloric acid and extracted three times, each time with 250 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Yield: 97%; 1H-NMR (in CDCl3): δ=2.12 ppm (s; 3H), 4.07 ppm (s; 3H), 5.41 ppm (m; 2H); 8.00 ppm (bs; 1H).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)([CH3:9])[CH:3]=[CH:4][Sn](C)(C)C.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21](I)=[C:20]([CH3:26])[N:19]=1.[Cl-].[Li+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH:4]=[CH:3][C:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)([CH3:9])[CH3:1])=[C:20]([CH3:26])[N:19]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: CC(C)(C=C[Sn](C)(C)C)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C=CC(C)(C)c1ccc(Cl)cc1
Temperature: 65 °C
Yield: 60 %

Procedure:
This compound is prepared in a manner analogous to that of Step E of Example 6, using 4.8 grams (0.014 mole) of 3-methyl-3-(4-chlorophenyl)-1-trimethylstannyl-1-butene, 2.7 grams (0.011 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine (prepared in Step B of Example 3), 2.8 grams (0.066 mole) of lithium chloride, 0.4 gram (5 mole %) of bis(triphenylphosphine)palladium(II) chloride, and about 0.05 gram (catalyst) of 2,6-di-tert-butyl-4-methylphenol in 25 mL of N,N-dimethylformamide. After heating at 65° C. for about 2.5 days, the reaction mixture is cooled and diluted with 100 mL of N,N-dimethylformamide. The mixture is filtered, and the filtrate is poured into 300 mL of water. The mixture then is extracted with two 200 mL portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is adsorbed onto silica gel and subjected to column chromatography, using 10% methanol in methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure to a residue. NMR analysis of the residue indicates that it is impure product. The residue is subjected to column chromatography on basic alumina (activity II), using 2%, 4%, and 6% methanol in methylene chloride as eluants. The product-containing fractions are combined and concentrated under reduced pressure, yielding about 2.0 grams of 2,4-diamino-6-methyl-5-[3-(4-chlorophenyl)-3-methyl-1-butenyl]pyrimidine, mp 195°-200° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:11]2=[O:33])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:41][C:42]#[N:43]>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:41][C:42]#[N:43])=[CH:17][CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:11]2=[O:33])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCN(C(C)=O)CC3)c2=O)cc1OC
Yield: 72.1 %

Procedure:
0.12 g of 1-(1-acetylpiperidin-4-yl)-3-(3,4-dimethoxybenzyl)-6-hydroxyquinazoline-2,4(1H,3H)-dione obtained in stage 2.2 and 0.172 g of Cs2CO3 in 3 ml of DMF are stirred for 15 min at AT. 0.038 g of bromoacetonitrile is added and the reaction mixture is subsequently irradiated under a microwave field at 100° C. for 15 min. It is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM mixture, (1/99, v/v) as far as (4/96, v/v), to give 0.094 g of the expected product.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][C:13]1[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=2)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:11][N:5]1[C:6](=[O:7])[CH:8]([C:28](=[O:29])[NH:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:14]3[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=3)=[CH:26][CH:25]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C=Nc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ncc(Cl)cc3Cl)cc2)C(=O)N(C)C1=O
Reaction time: 18 h

Procedure:
7.8 g (0.05 mol) of 1,3-dimethylbarbituric acid and 14 g (0.05 mol) of 4-(3,5-dichloropyrid-2-yloxy)phenylisocyanate are suspended in 50 ml of xylene. 1 g of triethylamine is added dropwise to the suspension and the temperature rises to 45°-50° C. After further addition of 50 ml of xylene the mixture is stirred for 18 hours at this temperature. Then 1/3 of the xylene is distilled off. After cooling, the precipitate is isolated by filtration, washed with xylene, suspended several times in HCl and the suspension is thoroughly washed with water and dried, affording 1,3-dimethyl-5-[4-(3,5-dichloropyrid-2-yloxy)phenylcarbamoyl]barbituric acid of the formula ##STR25## with a melting point of 234°-235° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:24][CH:25]=1>CN(C)C=O>[F:37][C:34]([F:35])([F:36])[C:30]1[CH:29]=[C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1cccc(C=Cc2nc(CCl)co2)c1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)c1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
26 mg (1.0 mmol) of 95% sodium hydride were given at 0° C. to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. 288 mg (1.00 mmol) 4-Chloromethyl-2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazole dissolved in 1.0 ml N,N-dimethylformamide were added at 0° C., stirring continued at 0° C. for 1 h and 12 h at room temperature thereafter. The mixture was quenched by 30 ml water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, three times with cold ether and drying at 40° C. in vacuo, 192 mg (41%) 1-[4-(4-{2-[2-(E)-(3-Trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[N:10]2[C:11]3[CH:12]=[C:13]([C:18]([O:20]CC)=[O:19])[CH:14]=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:23])[NH:7][CH2:6][CH2:5]1.Cl>C(O)C>[CH3:3][CH:4]1[N:10]2[C:11]3[CH:12]=[C:13]([C:18]([OH:20])=[O:19])[CH:14]=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:23])[NH:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)CCNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CCNC(=O)c2cc3ccc(C(=O)O)cc3n21
Yield: 93.6 %

Procedure:
1 NaOH solution (60 mL, 60 mmol) is added to a solution of ethyl 5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (7.0 g, 24 mmol) in ethanol (75 mL). The reaction mixture is refluxed for 1.5 h. Then the reaction mixture is acidified with 1M HCl and ethanol is removed under vacuum. The resulting solid is filtered, washed with water and dried to afford the title compound (5.8 g, 92%) as a solid.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[C:7]([CH3:19])=[CH:6][C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[CH3:19][C:7]1[C:8]2[C:9](=[O:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]=2[C:4]2[CH2:1][CH:2]([C:36]([OH:37])=[O:39])[O:20][C:5]=2[CH:6]=1
Reactant: C=CCc1c(O)cc(C)c2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc2c(c3oc4ccccc4c(=O)c13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
A mixture of 4-allyl-3-hydroxyl-1-methyl-9-oxo-9H-xanthene (3.0 g), m-chloroperbenzoic acid (8 g) and chloroform (500 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (5.5 g), water (25 ml) and concentrated sulfuric acid (8.5 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.5 g of 1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 231°-234° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 298.