Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[C:23]([CH3:28])=[N:24][O:25][C:26]=3[CH3:27])=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:29]([O-])=O)(C)(C)[CH3:2]>C(O)C.C1COCC1>[CH3:28][C:23]1[C:22]([C:18]2[CH:17]=[C:16]3[C:21]([C:12]([NH:11][CH2:6][C:5]4[CH:1]=[CH:2][CH:8]=[CH:9][CH:10]=4)=[C:13]([NH2:29])[CH:14]=[N:15]3)=[CH:20][CH:19]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: Cc1noc(C)c1-c1ccc2c(Nc3ccccc3C(C)(C)C)c([N+](=O)[O-])cnc2c1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C)c1-c1ccc2c(NCc3ccccc3)c(N)cnc2c1
Yield: 100.6 %

Procedure:
To a solution of N-[2-(tert-butyl)phenyl]-7-(3,5-dimethyl-4-isoxazolyl)-3-nitro-4-quinolinamine (see Intermediate 19, 2.4 g, 5.77 mmol) in a mixture of ethanol (60 ml) and THF (20 ml), was added SnCl2,2H2O (7.81 g, 34.6 mmol). The reaction mixture was refluxed for 3 h and then concentrated to dryness. The resulting residue was poured into aqueous sodium hydroxide. The organic phase was extracted with EtOAc, washed with water, dried and concentrated to give the title compound as a yellow solid (2 g, 71%). [APCI-MS] m/z: 387 MH+, Rt 3.37 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)c1
Yield: 77 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 77%). 1H NMR (300 MHz, CDCl3): δ 3.28-3.31 (m, 4H), 3.74-3.77 (m, 4H), 3.80 (s, 3H), 4.15 (s, 3H), 6.46-6.58 (m, 2H), 7.18-7.28 (m, 4H), 7.40 (dd, J=9.3 and 2.7 Hz, 1H), 7.78-7.81 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[O:18][C:19]=1[CH3:20].C(OC)(C)(C)C>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Reactant: COc1cccc(-c2nc(CI)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.8 g of cis-3-allylcyclohexanol are dissolved in 20 ml of dimethyl-formamide, and 770 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 4 g of 4-iodomethyl-5-methyl-2-(3-methoxyphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour. 200 ml of methyl tert-butyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=10:1. This gives 750 mg of 4-(cis-3-allyl-cyclohexyloxymethyl)-2-(3-meLhoxpheny,”-5-methyloxazole as an Oil. C21H27NO3 (341.45), MS(ESI): 342 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[C@H:28]([CH3:39])[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[ClH:40]>>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][NH:29][C@H:28]([CH3:39])[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: C[C@@H]1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H]1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a reaction vial containing (R)-tert-butyl 4-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-1)]pyridazin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate (Example 36; 12 mg, 0.022 mmol) was added 0.5 mL 4 N HCl (dioxane) solution in one portion. After stirring at ambient temperature for 4 hours, the reaction was concentrated. The resulting solid residue was treated with ether and concentrated again to yield the final product salt form as a pale-yellowish powder. MS (apci) m/z=442.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[Cl:12])[CH:7]=O)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>C(Cl)Cl>[Cl:12][C:11]1[CH:10]=[CH:9][C:6](/[CH:7]=[C:21](/[N+:18]([O-:20])=[O:19])\[CH3:22])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: C/C(=C\c1ccc(Cl)c([N+](=O)[O-])c1)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A stirred mixture of 3-Nitro-4-chlorobenzaldehyde (10 g, 53.89 mmol), ammonium acetate (1.39 g, 18 mmol) and nitroethane (31.3 ml, 432 mmol) is heated at reflux (80° C.) overnight. After cooling to room temperature the reaction mixture is concentrated if vacuo to give a solid which is dissolved in DCM (200 ml) and washed with water (3×200 ml), followed by brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an orange solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1C(=O)[C@@H](Br)[C@H](O)COCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=[N+]=[N-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Br)[C@H](O)COCc1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NC(Cc2ccccc2)CO1
Temperature: 35 °C
Reaction time: 4 h

Procedure:
4(S)-3-[(2R, 3S)-2-Azido-4-benzyloxy-3-hydroxy-butyryl]-4-benzyl-oxazolidin-2-one. To a solution of 4(S)-benzyl-3-[(2S, 3R)-4-benzyloxy-2-bromo-3-hydroxy-butyryl]-oxazolidin-2-one (969 mg, 2.16 mmol) in dimethylformamide (9.0 mL) is added sodium azide (211 mg, 3.25 mmol) and the reaction mixture is stirred at 35° C. for 4 hr. The mixture is diluted with ethyl acetate and washed several times with water, brine and dried over Na2SO4. Filtration and removal of solvents under vacuo gives 4(S)-3-[(2R, 3R)-2-azido-4-benzyloxy-3-hydroxy-butyryl)]-4-benzyl-oxazolidin-2-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[CH:10]=[CH:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.1 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (250 mg/1.63 mmol) in 12 mL of DMF was added 676 mg (4.89 mmol) of potassium carbonate and the resulting mixture stirred at room temperature for 20 min. Benzylchloride (310 mg/2.45 mmol) was added and the new mixture stirred at room temperature for 24 h then filtered, concentrated and the residue purified by silica gel chromatography (3:1 hexanes/ethyl acetate) affording 318 mg (80%) of the title compound. LRMS: 244.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29].C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26]([Cl:33])=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2nccc(CN3CCc4c(C(=O)O)cccc4C3=O)c2cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2nccc(CN3CCc4c(C(=O)Cl)cccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 113.7 %

Procedure:
2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (126 mg, 0.321 mmol) was suspended in dichloromethane (4 mL) then added N,N-dimethylformamide (3-4 drops) and oxalyl chloride (0.442 mL, 0.643 mmol). The reaction mixture was stirred at room temperature for 4.5 hours. The mixture was concentrated under vacuum then dried under high vacuum overnight to afford 2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbonyl chloride (150 mg) as a light yellow solid. MS (ESI, pos. ion) m/z: 407.1 (M+1) for the methyl ester.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)=[O:26])[CH:6]=1)[CH2:3][OH:4].[NH3:34]>CO>[NH2:34][C:29](=[O:31])[C@@H:28]([NH:27][C:25]([C:7]1[CH:6]=[C:5]([C@H:2]([OH:1])[CH2:3][OH:4])[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)[N:8]=1)=[O:26])[CH3:33]
Reactant: COC(=O)[C@H](C)NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: N
Solvent: CO
Product: C[C@H](NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 87 %

Procedure:
To (S)-methyl 2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl) pyrimidine-4-carboxamido)propanoate (0.120 g, 0.263 mmol) was added MeOH (2.5 mL) and 7M NH3 in MeOH (2.5 mL, 17.5 mmol). The reaction was sealed, stirred overnight then evaporated in vacuo. MeOH was added and the reaction mixture evaporated again in vacuo. The resulting solid was triturated with 4 mL 20% EtOAc/hexanes, filtered, and rinsed once with 2 mL 20% EtOAc/hexanes. The material was dried under vacuum to give N-((S)-1-amino-1-oxopropan-2-yl)-6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (Compound Example No. 16) as a pale peach-colored powder (0.099 g, 0.23 mmol. 87% yield). 1H NMR (400 MHz, DMSO-d6): 8.99 (1 H, d, J=7.7 Hz), 8.55 (2 H, d, J=9.0 Hz), 8.01 (1 H, s), 7.60 (1 H, s), 7.33-7.25 (2 H, m), 7.24-7.17 (3 H, m), 7.14 (2 H, d, J=8.8 Hz), 5.83 (1 H, d, J=5.3 Hz), 4.83 (1 H, t, J=5.9 Hz), 4.70 (1 H, q, J=3.9 Hz), 4.50 (1 H, p, J=7.2 Hz), 3.84-3.77 (1 H, m), 3.71-3.63 (1 H, m), 1.41 (3 H, d, J=7.0 Hz); LC/MS: m/z=441.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:12]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCCC(=O)CBr
Solvent: CCO
Product: COC(=O)CCCc1csc(N)n1

Procedure:
Bromide 1-2 (3.45 g, 15.5 mmol) and thiourea (1.4 g, 18 mmol) were combined in 77 mL EtOH and heated to reflux. After disappearance of 1-2, the EtOH was removed by rotary evaporation and the residue was diluted with EtOAc, washed with water and brine, then dried (MgSO4), filtered and concentrated. The pH of the aqueous phase was adjusted to 7, and the solution was re-extracted with EtOAc (2×). These organic extracts were washed with brine, dried (MgSO4), filtered and concentrated, combined with the first organic residues, then purified by flash chromatography (silica, EtOAc) providing aminothiazole 1-3 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccccc1O
Yield: 88.6 %

Procedure:
A mixture of 4.64 g (14.1 mmol) of N-(tert-butoxycarbonyl)-3-[2-(benzyloxy)phenyl]propylamine, 1.0 g. of 5% palladium-on-carbon catalyst and 95 ml of ethanol was hydrogenated by shaking in a Parr apparatus using an initial pressure of 40 psi of hydrogen for 24 hours until hydrogen uptake was completed. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on a silica gel column which was eluted with a 5 to 20% gradient of ethyl acetate in hexane to give 3.14 g (88.7%) of the product as colorless crystals, mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][S:26][CH2:27]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:25][S:26][CH3:27])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Nc2c(Cl)ccc(O)c2C2(CCCCC2)N1
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCOc1ccc(Cl)c2c1C1(CCCCC1)NC(=O)N2
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 8′-chloro-5′-hydroxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one, which can be prepared according to processes disclosed in example 63 of PCT/EP02/03594 (6 g, 2.25 mmol) in dimethylformamide (6 mL) was added potassium carbonate (0.776 g, 5.6 mmol) and chloromethyl methyl sulfide (0.26 mL, 2.7 mmol). The mixture was stirred in a sealed tube at 100° C. for 3 days. Dimethylformamide was removed by evaporation in vacuo. Water was added to the residue and the aqueous layer was extracted twice with ethyl acetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].CO[C:15](OC)([CH3:17])[CH3:16]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][C:15]1([CH3:17])[O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=2[CH2:9][O:10]1
Reactant: COC(C)(C)OC
Reactant: OCc1ccc(CO)c(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)OCc2ccc(CO)cc2CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14357.5 %

Procedure:
5 g of (3,4-bis-hydroxymethylphenyl)methanol (29.7 mmol), 25 ml of 2,2-dimethoxypropane (21.2 g; 0.2 mmol) and 0.29 g of p-toluenesulfonic acid (1.5 mmol) are introduced into a flask. After stirring for 1 hour 10 minutes at room temperature, the solvent is evaporated under vacuum at 30° C. and the crude product is chromatographed on silica gel (dichloromethane/methanol/aqueous ammonia=98/2/0.1). 5.98 g of (7,7-dimethyl-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol are obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH2:31][N:33]5[CH2:40][CH2:39][CH2:38][C@H:34]5[C:35]([NH2:37])=[O:36])=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: NC(=O)[C@@H]1CCCN1
Product: NC(=O)[C@@H]1CCCN1Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde and L-prolinamide were reacted in an analogous manner to Example 10 to give the title compound; δH [2H6]-DMSO 9.85 (1H, b), 8.72 (1H, s), 8.50 (1H, s), 8.14 (1H, d), 7.79 (1H, d), 7.71 (2H, d), 7.54-7.31 (5H, m), 7.24 (1H, s), 7.17 (1H, s), 7.09 (2H, d), 7.02 (1H, d), 6.53 (1H, d), 5.15 (2H, s), 3.82 (2H, s), 3.42 (1H, b), 3.12 (2H, b), 1.85-1.67 (4H, m); m/z 520 (M+1)+.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[S:18])=[CH:12][CH:11]=1>ClCCl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH:20]([CH3:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[C:17]2=[S:18])=[CH:14][CH:15]=1
Reactant: CC(NC(=S)Nc1ccc(Br)cc1)C(C)(C)C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(Br)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Ethyl chlorooxoacetate (0.496 mL, 4.44 mmol) was added to a stirring solution of the above thiourea (0.70 g, 2.22 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.647 g (79%) of 1-(4-bromo-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 207.1–207.9° C.; 1H NMR (DMSO-d6): δ 7.74 (d, 1H), 7.32 (d, 2H), 4.81 (q, 1H), 1.48 (d, 3H), 0.99 (s, 9H); IR (KBr): 3500, 2970, 2230, 1770, 1500 cm−1; MS (m/z) 368 (M+).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-isohexyl-6-methylpiperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 70 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-isohexenyl-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 164.2-167.0° C.; 1H NMR (250 MHz) δ9.44 (s, 2H), 5.71 (s, 2H), 4.18 (s, 1H), 3.56 (s, 1H), 2.0-1.5 (m, 12H), 0.94 (dd, 6H); 13C NMR (62.7 MHz) δ135.7 (s), 123.6 (s), 4.84 (s), 47.9 (s), 36.9 (s), 28.9 (s), 28.4 (s), 28.2 (s), 22.5 (s), 22.1 (s), 17.6 (s), 17.2 (s) ppm. FT-IR (neat): 3429, 3165, 2940, 1620, 1550, 1478, 1400, 1354, 1097, 890. Elemental Analysis for C12H24NCl: C, 66.17%; H, 11.13%; N, 6.43%. Found: C, 66.25%; H, 11.05%; N, 6.50%.
Reaction SMILES: [OH:1][CH:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:3][CH3:4].Cl.N1C=CC=CC=1.Cl[O-].[Ca+2].Cl[O-]>ClCCl>[C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)(=[O:1])[CH2:3][CH3:4]
Reactant: CCC(O)c1cc(-c2ccccc2)no1
Agent: Cl
Agent: [Ca+2]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)c1cc(-c2ccccc2)no1

Procedure:
In 10 ml of dichloromethane, 1.0 g (5.0 mmol) of 5-(1-hydroxypropyl)-3-phenylisoxazole was dissolved. To the solution were added 100 mg (0.9 mmol) of pyridine hydrochloride, followed by the further addition of 1.4 g (9.9 mmol) of calcium hypochlorite. They were reacted at room temperature for 5 hours. After completion of the reaction, insoluble matter was filtered off and the organic layer wa washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was then recrystallized from ethanol, whereby the target compound, namely, 5-propiony-3-phenylisoxazole was obtained as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 82 g of 1-(4-methoxyphenyl)-2-propanone, 500 ml of acetic acid and 500 ml of aqueous hydrobromic acid is boiled under reflux for 2 hours and then evaporated in vacuo. The oily residue is extracted four times with 700 ml of hexane/ether (5:2) each time, the extract is evaporated and the residue is chromatographed over silica gel using hexanelethyl acetate (3:1). 1-(4-Hydroxyphenyl)-2-propanone is thus obtained with a melting point of 40-41°.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:2]([O:26][C:25]2[CH:20]=[CH:21][C:22]([CH3:27])=[CH:23][CH:24]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Br)CCCCCc1ccc(Cl)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)Oc1ccc(C)cc1

Procedure:
A mixture of 5.6 g (17 mmol) of ethyl 2-bromo-7-(4-chloro-phenyl)heptanoate, 1.82 g (17 mmol) of p-cresol, 7.0 g (50 mmol) of potassium carbonate and 70 ml of butanone is heated for 36 h at the refluxing temperature. Then the inorganic precipitate is removed on a suction filter and the filtrate is concentrated. The residue is taken up in ether, the solution washed twice with 0.5N caustic soda solution, dried and concentrated by evaporation. The residual oil is chromatographed with toluene on silica gel. 5.3 g (86% of theory) is obtained of ethyl 7-(4-chloro-phenyl)-2-(4-methylphenoxy)heptanoate, a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=3)[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3ccc(-c4ccc(F)cc4F)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K73) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (24 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](O)([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:12])=[CH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=C(C)c1ccc2c(c1)OCO2
Yield: 109.7 %

Procedure:
14.52 g of 2-(1,3-benzodioxol-5-yl)-2-propanol was dissolved in 200 ml of benzene, followed by the addition of a catalytic amount of p-toluenesulfonic acid monohydrate. The obtained mixture was heated under reflux in a short-neck Kieldahl flask fitted with a Dean-Stark reflux condenser for 2.5 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt successively, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain 14.33 g of the title compound as an oil.