Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH:6]1([C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=3)/[C:12]/2=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=O)[CH2:8][CH2:7]1>O>[S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[CH:6]1([C:9]2[C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[CH:17][C:18]=3[CH:19]=[C:20]3[N+:11]=2[CH2:12][CH2:25][C:26]2[CH:27]=[C:28]([O:34][CH3:35])[C:29]([O:32][CH3:33])=[CH:30][C:31]=23)[CH2:8][CH2:7]1
Reactant: COc1ccc(/C=C2/c3cc(OC)c(OC)cc3CCN2C(=O)C2CC2)cc1OC
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc3cc(OC)c(OC)cc3c(C3CC3)[n+]1CC2
Product: O=S(=O)([O-])O

Procedure:
To 10 parts of concentrated sulfuric acid, with vigorous agitation at 0°, is slowly added 1 part of (Z)-2-cyclopropylcarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy1-[(3,4-dimethoxyphenyl)methylene]isoquinoline. When the addition is complete, 90 parts of water is mixed in; and the yellow precipitate which forms is isolated by filtration and recrystallized from water, affording 8-cyclopropyl5,6-dihydro-2,3,10,11-tetramethoxydibenzo[a,g]quinolizinium hydrogen sulfate melting above 300°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH2:37]Cl)[O:34][N:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C)C.C(O)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:36]=[C:35]([CH2:37][N:18]3[CH2:17][CH2:16][N:15]([CH2:14][C@@H:13]([OH:21])[CH2:12][O:11][C:8]4[CH:9]=[CH:10][C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH:7]=4)[CH2:20][CH2:19]3)[O:34][N:33]=2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: CC(C)(C)c1ccc(-c2noc(CCl)n2)cc1
Agent: CN(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc(-c5ccc(C(C)(C)C)cc5)no4)CC3)ccc2s1
Reaction time: 8 h

Procedure:
A solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, a compound of formula (6) (75 mg, 0.14 mmol), and 3-(4-tert-butylphenyl)-5-chloromethyl-1,2,4-oxadiazole (40 mg, 0.16 mmol) in 10% trimethylamine/ethanol, was heated to 73° C. and allowed to stir overnight. The solvent was evaporated under reduced pressure, and the resulting residue chromatographed by preparative thin layer chromatography (PTLC) (3% methanol/methylene chloride). The resulting oil was diluted with methylene chloride and placed on the high Vac. overnight, to yield (2R)-3-[4-({3-[4-(tert-butyl)phenyl](1,2,4-oxadiazol-5-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol as a white solid.
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[O:33])[CH:28]=[CH:29][CH:30]=1>O1CCCC1>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:3]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[C:2]([CH3:12])[N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:35])([F:36])[F:23])[CH:26]=3)[C:32](=[O:33])[NH:34]2)=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1

Procedure:
A solution of diethyl (2-oxopropyl)phosphonate (250 mg, 1.29 mmol), 4-cyanobenzaldehyde (168.84 mg, 1.29 mmol), N-[3-(trifluoromethyl)phenyl]urea (263 mg, 1.29 mmol) and polyphosphoric acid ethyl ester (0.70 g) in tetrahydrofuran (5 ml) is refluxed overnight with stirring. The reaction solution is purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10). The fractions containing product are concentrated in vacuo and re-purified by flash chromatography on silica gel 60 with dichloromethane/methanol as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[P:12]([Cl:17])(Cl)(Cl)(Cl)[Cl:13].C(O)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:13][P:12]([Cl:17])([NH:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[CH3:1])=[O:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(C(N)=O)c(C)c1
Reactant: O=CO
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)NP(=O)(Cl)Cl)c(C)c1
Reaction time: 0.33 h

Procedure:
A suspension of 29 g (0.19 mole) of 2,4-dimethylbenzamide, 40.5 g (0.19 mole) of phosphorus pentachloride and 300 ml of AR carbon tetrachloride was heated at 70° for 30 min. The solution was cooled to 30° and 9.2 g (0.19 mole) of 97% formic acid added dropwise. Stirring was continued for another 20 min., then the product was collected by filtration, washed with AR carbon tetrachloride and air-dried to give 30.5 g, m.p. decomposes upon standing.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[CH:17]=[N:16][C:15]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)ncc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)ncc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (20 mg, 0.0389 mmol) in THF (2 mL) and water (2 mL) was added LiOH.H2O (3.2 mg, 0.078 mmol). The reaction was stirred at RT for 15 min, then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (5 mg, 26% yield) as a white solid. 1H NMR (CDCl3) δ: 8.20 (s, 1H), 7.74 (dd, J=11.1, 9.8, 5.7 Hz, 2H), 7.32 (t, J=8.1 Hz, 1H), 7.23-7.16 (m, 3H), 7.03 (t, J=2.1 Hz, 1H), 6.90 (dd, J=8.2, 1.5 Hz, 1H), 4.82 (s, 2H), 4.24 (t, J=6.2 Hz, 2H), 3.60 (d, J=13.0 Hz, 3H), 3.56 (d, J=5.6 Hz, 2H), 2.87 (s, 1H), 1.99-1.84 (m, 2H). LCMS: MH+ 486 and TR=3.024 min
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([NH:9][CH:10]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:11]([NH:13][CH2:14][C:15](=O)[CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=O)(=[O:8])[CH3:7]>C1(C)C(C)=CC=CC=1>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:10]([NH:9][C:6](=[O:8])[CH3:7])[C:11]2[NH:13][CH:14]=[C:15]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[N:5]=2)=[CH:25][CH:26]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.17 g, 79 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide (650 mg, 1.58 mmol) in xylene (10 mL). After stirring at 150° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded N-{2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[Cl:14].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:11])=[CH:7][C:6]=1[Cl:14]
Reactant: O=C(O)c1ccc(Oc2ccccc2Br)c(Cl)c1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3Br)c(Cl)c2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
4-(2-Bromophenoxy)-3-chlorobenzoic acid (174 mg, 0.53 mmol), 1-hydroxybenzotriazole (108 mg, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.8 mmol), triethylamine (0.4 mL, 2.88 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. To the mixture, water (20 mL) was added and the resultant mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(2-bromophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (190 mg, 78%). LRMS (M+H) m/z: calcd 460.02. found 460. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.44 (t, J=4.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.81-7.75 (m, 2H), 7.46-7.40 (m, 1H), 7.23-7.17 (m, 1H), 7.10 (dd, J=6.9 Hz, J=1.2 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 5.85 (s, 1H), 4.27 (d, J=4.5 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[C:30](O)=[O:31])=[CH:25][CH:24]=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:30](=[O:31])[C:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccc(F)cc2)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (500 mg, 1.70 mmol, as described in example 1, step 3) in CH2Cl2 (15 mL) was added under a nitrogen atmosphere at 0° C. (4-fluoro-phenyl)-oxo-acetic acid (300 mg, 1.78 mmol, commercially available) and EDC (342 mg, 1.78 mmol). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 15 mL) and water (15 mL), the combined aqueous layers were extracted with CH2Cl2 (3×15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (527 mg, 70%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)#[N:16].ClC1C=CC(NC(=O)C2C=CC(C#N)=CC=2)=CC=1C1C=CC=CN=1.CCN(C(C)C)C(C)C.Cl.[NH2:60][OH:61]>CCO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][C:17]([C:15](=[NH:16])[NH:60][OH:61])=[CH:18][CH:19]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: NO
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 60 °C

Procedure:
240 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 207 mg of 4-cyanobenzoic acid via Procedure G. To 445 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide and 2.5 mL of DIPEA in 10 mL of EtOH was added 793 mg Hydroxylamine Hydrochloride and heated to 60° C. until reaction was complete. The solvent was subsequently evaporated, extracted twice with water in Ethyl Acetate, dried with Magnesium Sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-hydroxycarbamimidoyl)benzamide. MS (Q1) 367.4 (M)+.
Reaction SMILES: [OH-:1].C([N+:6]([CH2:15]CCC)([CH2:11][CH2:12]CC)[CH2:7]CCC)CCC.[CH2:19]([OH:22])[CH2:20][OH:21]>C1(C)C=CC=CC=1>[CH3:15][N:6]([CH3:7])[C:11](=[O:1])[CH2:12][O:21][CH2:20][CH2:19][OH:22]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: OCCO
Reactant: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)COCCO
Yield: 35.5 %

Procedure:
The process according to Example 6 is followed with the difference that instead of ethylene glycol, toluene is used as solvent and 1 g tetrabutyl ammonium hydroxide is added to the reaction mixture. The yield is 5.22 g (35.5%) of the title compound having the purity higher than 98% as determined by gas chromatography.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][C:12]([O:14]C)=O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[NH3:16].Cl>CO.O>[NH2:16][C:12](=[O:14])[CH2:11][NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: N
Reactant: COC(=O)CNC(=O)c1nccnc1O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)CNC(=O)c1nccnc1O
Reaction time: 1 h

Procedure:
In 4 mL of methanol is suspended 0.19 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)carbonyl]-amino}acetate. The suspension is saturated with ammonia by introducing gaseous ammonia thereinto under ice-cooling for 30 minutes. The resulting mixture is stirred at the same temperature as above for 1 hour and then at ambient temperature for 15 hours. The solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in a mixture of 4 mL of water and 1 mL of methanol. To the resulting solution is added 0.9 mL of 1 mol/L hydrochloric acid. The deposited crystals are collected by filtration to obtain 0.16 g of N2-(2-amino-2-oxoethyl)-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH:38]([CH3:40])[CH3:39])[CH:36]=1)[CH:32]=O)([CH3:27])[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH:38]([O:37][C:35]1[CH:34]=[C:31]([CH:30]=[C:29]([O:28][CH:25]([CH3:27])[CH3:26])[CH:36]=1)[CH2:32][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:15]=[C:16]([O:18][CH2:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)([CH3:39])[CH3:40]
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Reactant: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 3-methoxy-N-piperidin-4-yl-5-(1H-tetrazol-5-ylmethoxy)-benzamide (example 170c) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 539.4 (MH+).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([Br:12])=[C:10]([CH3:13])[S:9][C:8]=2[CH:14]=1)(=O)C.[S].N1[CH2:21][CH2:20][O:19]CC1.[OH2:22]>>[Br:12][C:11]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:21][C:20]([OH:19])=[O:22])=[CH:14][C:8]=2[S:9][C:10]=1[CH3:13]
Reactant: O
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc2c(Br)c(C)sc2c1
Agent: [S]
Product: Cc1sc2cc(CC(=O)O)ccc2c1Br

Procedure:
A mixture of 6-acetyl-3-bromo-2-methylbenzo[b]-thiophene (12.0 g.), sulphur (3.0 g.) and morpholine (12 ml.) was heated under reflux for 6 hours. (This is the Willgerodt-Kindler reaction.) The mixture was poured into water and the resulting green solid was filtered off, washed with water and added to a solution of sodium hydroxide (12.0 g.) in methanol (250 ml.). The mixture was heated under reflux for 6.5 hours and then evaporated. The residue was dissolved in water and the solution was washed with ethyl acetate. The aqueous layer was acidified to give a solid which was filtered off, washed with water and dried to give 3-bromo-6-carboxymethyl-2-methylbenzo[b]thiophene (8.22 g.) pure enough for further reaction. A portion crystallized from toluene/petrol (b.p. 60°-80°) had m.p. 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nc2nccnc12
Reactant: Nc1ccncc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Cl)cc1-c1nc(Nc2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][N:20]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:53]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][N:20]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:53])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1Cc1cc(-c2ccccc2)on1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccccc2)on1

Procedure:
The methods described in Part I of Example 35 were used to treat 2-(ethoxymethyl)-1-[(5-phenylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline (0.650 g, 1.69 mmol) with mCPBA (0.455 g of 77% pure material, 2.0 mmol) followed by p-toluenesulfonyl chloride (0.355 g, 1.86 mmol) and concentrated ammonium hydroxide (15 mL) and purify the final product to provide 0.38 g of 2-(ethoxymethyl)-1-[(5-phenylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid, mp 221-223° C.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:35]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=5)[CH:26]=[CH:25][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (190 mg, 0.438 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (163 mg, 0.526 mmol) and K2CO3 (182 mg, 1.315 mmol) in dioxane (3 mL) and water (1 mL) was added Pd(Ph3P)4 (25.3 mg, 0.022 mmol). Upon completion of addition, the reaction mixture was heated to 100° C., where it stirred overnight. At the conclusion of this period, the reaction mixture was cooled to rt, diluted with water and then extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 1D as a white solid (166 mg, 0.310 mmol, 71% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.17 (2H, s), 7.62-7.65 (1H, m), 7.62 (1H, s), 7.40 (1H, dd, J=8.5, 1.9 Hz), 6.00-6.09 (1H, m), 5.42-5.49 (1H, m), 4.23 (2H, ddd, J=13.3, 6.7, 3.9 Hz), 4.05-4.13 (2H, m), 3.63-3.76 (4H, m), 2.53-2.61 (2H, m), 2.41 (2H, t, J=7.6 Hz), 2.14-2.23 (2H, m), 1.95 (2H, dddd, J=12.8, 8.5, 8.4, 3.9 Hz), 1.57-1.64 (2H, m), 1.51 (9H, s), 0.95 (3H, t, J=7.3 Hz).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>C1COCC1>[C:1]1([C:7]#[C:8][CH2:9][NH:10][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCC#Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCC#Cc4ccccc4)CC3)cc2o1

Procedure:
Condensation of 3-phenyl-prop-2-ynylamine (1.0 g, 7.6 mmol) and ketone 5 (1.7 g, 7.6 mmol), following the procedure described in Example 1, except THF was used as solvent gave compound 6-{trans-[4-(3-phenyl-prop-2-ynylamino)cyclohexyl]}-3H-benzoxazol-2-one (400 mg, 58%) as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.45-7.35 (m, 5H), 7.19 (s, 1H), 7.50-6.94 (m, 2H), 3.59 (s, 2H), 3.30 (m, 2H), 2.75-2.61 (m, 1H), 2.06-2.00 (m, 2H), 1.85-1.80 (m, 2H), 1.58-1.41 (m, 2H), 1.25-1.10 (m, 2H).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[C:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].CO[C:13]1C=CC(O)=C[CH:14]=1.C(=O)=O>>[C:5](=[O:8])([O:6][CH3:7])[O:10][CH2:1][CH:2]=[CH2:3].[C:5](=[O:10])([O:8][CH2:9][CH:13]=[CH2:14])[O:6][CH2:1][CH:2]=[CH2:3]
Reactant: COC(=O)OC
Reactant: COc1ccc(O)cc1
Reactant: C=CCCl
Agent: O=C=O
Product: C=CCOC(=O)OC
Product: C=CCOC(=O)OCC=C
Temperature: 25 °C
Yield: 2 %
Yield: 23.8 %

Procedure:
The procedure employed in Example 30 is substantially repeated employing polystyrene-bound benzyl-tri-n-butylphosphonium chloride (2 percent cross-linked with divinylbenzene) as the catalyst. Accordingly, 15 g of the polymeric catalyst, allyl chloride (76.5 g, 1.0 mole), dimethyl carbonate (90.0 g, 1.0 mole) and p-methoxyphenol (0.5 g, 0.004 mole) are combined in a reactor and heated for 6 hours at 150° C. under 600 psi carbon dioxide. The reactor is then cooled to room temperature and vented. After separating the catalyst by filtration, allyl methyl carbonate (23.8 percent yield) and diallyl carbonate (2.0 percent yield) are obtained by distillation.