Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.Cl.[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.[Br:32][C:33]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O>[C:7]12([C:17]3[CH:23]=[CH:22][C:20]([NH:21][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:33]=4[Br:32])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:16]1)[CH2:8]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 300 mg of 4-(1-adamantyl)-2-methylaniline hydrochloride and 120 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 290 mg of 2-bromo-5-nitrobenzoylchloride was dropwise added under cooling with ice. After stirring for about 30 minutes, water was added thereto, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 310 mg of N-(4-(1-adamantyl)-2-methylphenyl)-2-bromo-5-nitrobenzamide (Compound No. 46) having a melting point of 229° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][CH3:19])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: COCc1cccc(-c2ocnc2C(=O)O)c1
Product: COCc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxymethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Se](=O)=[O:14].O1CCOCC1>O>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:14])[CH:8]=[CH:7]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2cccc(O)c2n1

Procedure:
8-hydroxy-2-methylquinoline (2 g, 12.4 mmol.), selenium dioxide (1.74 g, 15.8 mmol), 300 ml of pre-dried 1,4-dioxane, and 1.5 ml of water were mixed and stirred in a 1-L round bottom flask. The resulting solution was then refluxed for 24 h. The reaction was monitored until completion using TLC method. The reaction mixture was then filtered off, and the selenium metal was then washed with dichloromethane, and the combined filtrates were then evaporated off under reduced pressure. The crude product was then purified by sublimation under reduced pressure or by silica gel column chromatography to yield pure yellow needle crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:13][CH2:14][CH2:15][Cl:16])[C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>>[ClH:16].[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:13][CH2:14][CH2:15][N:23]([CH3:22])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C(=O)C2
Reactant: CNCCc1ccc(OC)c(OC)c1
Product: COc1ccc(CCN(C)CCCN2C(=O)Cc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione-3-yl)-3-chloro-propane with N-methyl-N[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dichloroaniline (8.87 g, 54.8 mmol) in ethanol (40 mL) was added to a solution of 2,4,6-trichloropyrimidine (10.0 g, 54.8 mmol) in ethanol (20 mL) followed by aqueous Na2CO3 (4.61 g, 43.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. The crude mixture was diluted with water (100 mL), and the resulting precipitate was filtered and dried (10.2 g, 61%). ESI-MS m/z: 307 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:26]([O:28]C)=O)[CH:21]=[C:22]([I:25])[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:31]>CC(O)C.CS(C)=O.O>[NH2:31][C:26]([C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[C:24]2[C:19]=1[N:18]=[CH:17][N:16]=[C:15]2[NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:28]
Reactant: COC(=O)c1cc(I)cc2c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(I)cc23)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dissolved methyl 4-{[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-6-iodoquinazoline-8-carboxylate (380.00 mg; 0.74 mmol; 1.00 eq.) in iPrOH (2.00 ml) and DMSO (2.00 ml) and then added ammonium hydroxide (5.00 ml). Stirred mixture at room temperature for 2.5 days. LCMS: M+1=498 major peak. Partially concentrated reaction. Diluted with water and filtered the resulting solids. Washed with water and dried to give an off-white solid (110 mg). LCMS: M+1=498.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.CC(C)(C)C([NH:28][NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=1)=O.[C:41](=[O:44])([O-])[OH:42].[Na+]>CC(O)C.C(OCC)(=O)C.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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:34]3[CH:33]=[CH:32][C:31]([C:30]([NH:29][NH:28][C:41]([O:42][C:6]([CH3:11])([CH3:7])[CH3:5])=[O:44])=[O:38])=[CH:36][CH:35]=3)[CH:7]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: CC(C)(C)C(=O)NNC(=O)c1ccc(Br)cc1
Reactant: O=C([O-])O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 90 °C

Procedure:
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 32) (3.27 g), 4-bromo-benzoic acid N′-(2,2-dimethyl-propionyl)-hydrazide (Intermediate 31) (3.39 g), tetrakis(triphenylphosphine)palladium (238 mg) and aqueous sodium hydrogen carbonate (1M, 21.6 ml) were mixed in propan-2-ol (20 ml) and heated at 90° C. under nitrogen for 18 hours. The cooled reaction mixture was reduced to dryness under vacuum, the residue partially dissolved in ethyl acetate and filtered. The filtrate was absorbed onto silica and purified by chromatography on silica biotage columns (2×100 g), eluting with ethyl acetate/cyclohexane (2:3). The product fractions were reduced to dryness under vacuum to give tert-butyl 2-({5′-[(cyclopropylamino)carbonyl]-3′-fluoro-2′-methyl-1,1′-biphenyl-4-yl}carbonyl)hydrazinecarboxylate.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:35]2([CH2:40][NH:39][CH2:38][CH2:37][N:36]2C(OC(C)(C)C)=O)[CH2:34]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][C:35]4([CH2:33][CH2:34]4)[NH:36][CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCNC3(CC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an off-white powder. HPLC (Condition 4) tR=4.44 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=475 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.27-0.54 (m, 4H) 2.82 (br. s, 2H) 2.96-3.20 (m, 5H) 6.64 (br. s, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.29 (br. s, 1H) 8.71 (br. s, 1H) 10.37 (br. s, 1H) 13.00 (br. s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[CH:7][C:8](=O)[NH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([Cl:27])=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1n[nH]c(=O)cc1-c1ccc(OC2CCCCC2)cc1
Product: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C

Procedure:
A suspension of the pyridazin-3-one (58.4 mmol, 19.1 g) in phosphorous oxychloride (292 mmol, 26.7 mL) was heated at 90° C. for 30 min with stirring during which period the starting material was fully consumed as judged by TLC. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 (3×100 mL), brine (100 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on a 330 g SiO2 cartridge eluating with 0-10% ethyl acetate in hexanes to afford 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=1[C:15]#[N:16]>>[C:15]([C:14]1[CH:17]=[C:18]([CH:19]=[CH:20][C:13]=1[F:12])[O:21][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])#[N:16]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: N#Cc1cc(O)ccc1F
Product: N#Cc1cc(Oc2ccc(C=O)cc2C#N)ccc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-fluoro-5-hydroxybenzonitrile.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.CN(C=O)C.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>O>[Si:1]([O:26][C:22]1[CH:21]=[C:20]([NH2:19])[CH:25]=[CH:24][CH:23]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 250 mL, three-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with tert-butyldimethylsilyl chloride (12.5 g, 82.8 mmol), imidazole (7.64 g, 112 mmol), and anhydrous DMF (60 mL). 3-aminophenol (10.0 g, 91.7 mmol) was added to the resulting solution. After stirring for 12 h at ambient temperature, the reaction mixture was poured into water (300 mL). The resulting suspension was extracted with hexanes (3×300 mL), and the extracts were combined, dried over sodium sulfate, and filtered. Concentration of the filtrate followed by column chromatography gave compound 122 as a light yellow oil. 1H NMR (DMSO-d6) δ (ppm), 6.84 (t, 1H, J=7.9 Hz), 6.16 (d, 1H, J=6.7 Hz), 6.10 (m, 1H), 5.97 (d, 1H, J=9.1 Hz), 4.98 (s, 2H), 0.95 (s, 9H), 0.16 (s, 6H); m/z=224 (M+H).
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]1[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:30]=1.ClC1C=CNC(=O)N=1>O1CCCC1>[CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:29]4[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]5[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=5)[N:30]=4)[CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)C1CCCCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: O=c1nc(Cl)cc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1)C1CCCCC1
Yield: 75.6 %

Procedure:
To a solution of (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)morpholine (4.47 g, 16.30 mmol) and triethylamine (3.1 ml, 22.2 mmol) in tetrahydrofuran (50 ml) was added 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (3.28 g, 14.82 mmol) portionwise. Upon disappearance of the chloropyrimidone, the reaction mixture was condensed under reduced pressure. The residue was partitioned between 1 N sodium hydroxide and dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow solid, which was recrystallized from ethanol to afford 2-((2S)-2-(4-(N-cyclohexyl-N-methylamino)-phenyl)morpholin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (5.15 g, 75.7%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1cc(-c2cc3c(O)cccc3o2)on1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)on1
Yield: 86.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 5-(4-hydroxybenzo(b)furan-2-yl)-3-methylisoxazole (2.6 g), (S)-glycidyl nosylate (3.1 g) and potassium carbonate (5.0 g), the title compound (2.8 g) was obtained as brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:26])([F:28])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=1)=[O:38]
Reactant: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: O=C=Nc1ccccc1Cl
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from {3-[3-(2-methylphenyl)-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chlorophenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 224-226° C.; MS (EI) m/z 532 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:5]=[C:4]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:36]1([CH2:35][O:34][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:27]=2[C:4]2[CH:5]=[C:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[C:7]3[CH2:8][N:9]([S:10]([CH3:13])(=[O:11])=[O:12])[C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)[CH2:37][CH2:38]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNS(C)(=O)=O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(S(C)(=O)=O)C(=O)N3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(methylsulfonyl)amino]methyl}-4-pyridinyl)-1-piperidinecarboxylate (0.050 g, 0.091 mmol) and triethylamine (0.077 mL, 0.549 mmol) in tetrahydrofuran (15 mL) was added to a solution of triphosgene (0.027 g, 0.091 mmol) in tetrahydrofuran(5 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs under an argon atmosphere. After quenched by water, the mixture was extracted with ethy acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was triturated with diisopropyl ether and collected by filtration to give tert-butyl 3-[7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(methylsulfonyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]-1-piperidinecarboxylate as a yellow solid (0.028 g, yield; 55%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH2:12][OH:13].[C:17]([O:21]C)(=[O:20])[CH:18]=[CH2:19].CC(C)([O-])C.[K+].O1CCCC1.C(O)(C)(C)C.Cl>>[CH2:12]([O:13][CH2:19][CH2:18][C:17]([OH:21])=[O:20])[CH:11]=[C:10]([CH2:9][CH2:8][CH:7]=[C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])[CH3:15])[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCOCCC(=O)O

Procedure:
All-trans-farnesol was reacted with methyl acrylate in the presence of one equivalent of 0.1 equivalent of potassium-tert butoxide/tetrahydorfuran/t-butanol for three hours at room temperature. The solution was acidified with 0.1N HCl, evaporated to dryness, and purified by thin layer chromatography on silica. The free acid was prepared by treatment of the ester with potassium hydroxide in methanol. The product showed the anticipated nmr and infrared spectra.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#N.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
A solution of 4-cyanobenzonitrile (20 g, 0.15 mol), 2,4-pentanedione (17 g, 0.17 mol), piperidine (130 mg, 1.5 mmol) and p-toluene sulfonic acid (260 mg, 1.5 mmol) in toluene (400 ml) is refluxed overnight with a Dean-Stark trap. The solution is concentrated in vacuo and purified over silica gel with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: O[C:2]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH:3]=[CH2:4].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[Cl:22][CH2:4][CH:3]=[C:2]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: C=CC(C)(O)c1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=CCCl)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 12.0 grams (0.056 mole) of 3-hydroxy-3-(2,5-dichlorophenyl)-1-butene and 4.7 grams (0.056 mole) of pyridine in 85 mL of methylene chloride is cooled in an ice-water bath, and 6.6 grams (0.056 mole) of thionyl chloride is added dropwise. Upon completion of addition, the reaction mixture is stirred for about one hour. After this time the reaction mixture is diluted with 50 mL of methylene chloride and about 50 grams of ice. The mixture is stirred until the ice melts, and then the organic layer is separated. The organic layer is washed in turn with two 50 mL portions of an aqueous 0.5M solution of hydrochloric acid, two 50 mL portions of an aqueous solution saturated with sodium bicarbonate, two 50 mL portions of water, and two 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 5.5 grams of 1-chloro-3-(2,5-dichlorophenyl)-2-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][C:41](Cl)=[O:42]>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:42]
Reactant: COc1ccc(CC(=O)Cl)c(OC)c1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)CN3C(=O)C(c4ccccc4)(c4ccccc4)N=C3C)cc2)c(OC)c1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and (2,4-dimethoxy-phenyl)-acetyl chloride to yield 2-(2,4-dimethoxy-phenyl)-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide. LC/MS at 254 nm; [M+H] 562; Rt 3.533 min.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1Cl)=[O:9])[CH3:6].Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1[O:1][CH2:2][CH3:3])=[O:9])[CH3:6]
Reactant: CC[O-]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(Cl)cc1OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium ethoxide (1.16 g, 17 mmol) is added to a stirred solution of 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (3.73 g, 17 mmol) in THF (45 mL) cooled to 0° C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (20 mL). The resulting solution is then neutralized with saturated NaHCO3. EtOAc (20 mL) is added and the layers are separated. The aqueous layer is extracted twice with EtOAc (20 mL) and the combined extracts are washed with brine (25 mL), dried (Na2SO4), and evaporated. The residue is then purified by flash column chromatography (silica gel, eluted with 2:1 Hexane, EtOAc) to give the title product as a white solid. H1 NMR δ (CDCl3) 7.02 (s, 1H), 4.47 (q, 2H, J=7.2 Hz), 4.19 (q, 2H, J=7.2 Hz), 1.50 (t, 3H, J=7.2 Hz), 1.41 (t, 3H, J=7.2 Hz).