Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[O:9][C:8](=O)[NH:7][C:6](=[O:12])[C:5]=2[CH2:4][CH2:3]1.[OH-].[NH4+:20]>>[CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[NH:20][C:8](=[O:9])[NH:7][C:6](=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(c2ccccc2)CCc2c1oc(=O)[nH]c2=O
Reactant: [NH4+]
Agent: [OH-]
Product: CC1(c2ccccc2)CCc2c1[nH]c(=O)[nH]c2=O
Temperature: 80 °C
Yield: 70 %

Procedure:
To solid 7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (420 mg, 1.727 mmol) was added concentrated Ammonium Hydroxide (4706 μL, 121 mmol) in a sealed tube. The tube was heated for 4 h at 80° C. Cooled to rt. Removed the solvent under a stream of N2. Loaded the residue onto Silica gel and eluted with an EtOAc/Hexane gradient to afford 7-methyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (293 mg, 1.209 mmol, 70.0% yield). LC-MS (M+H)+=243.1.
Reaction SMILES: CC1(C)CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)C2C(=CC(OC)=CC=2)N1.[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=2)[C:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH:32]=2)[NH:27]1>>[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:18]([F:21])([F:20])[F:19])=[CH:38][CH:37]=2)[C:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH:32]=2)[NH:27]1
Reactant: COc1ccc2c(c1)NC(C)(C)CC2c1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(c1)NC(C)(C)CC2c1ccc(Cl)cc1
Product: COc1ccc2c(c1)NC(C)(C)CC2c1ccc(C(F)(F)F)cc1

Procedure:
2,2-dimethyl-7-methoxy-4-(3-trifluoromethylphenyl)dihydroquinoline; and 2,2-dimethyl-7-methoxy-4-(4-chlorophenyl)dihydroquinoline.
Reaction SMILES: O[CH:2]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:13]([OH:19])(=[O:18])[C:14](C)(C)C.[CH3:20]C(C)(C)C([O-])([O-])[O-]>CO>[O:12]=[C:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:13]([O:19][CH3:20])=[O:18])[C:7]1=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)C(=O)O
Reactant: CCCCC(O)C1=CCCC1=O
Reactant: CC(C)(C)C([O-])([O-])[O-]
Solvent: CO
Product: CCCCC=C1C(=O)CCC1CC(=O)OC
Yield: 88 %

Procedure:
A mixture of 2-(1-hydroxypentyl)-2-cyclopenten-1-one (720 mg, 4.2 mmol) and pivalic acid (100 mg, 0.98 mmol) in trimethylorthoacetate (5 ml, 39.3 mmol) was heated at 115° C. for 3 hours with distillation of MeOH. The concentrated reaction mixture was bulb-to-bulb distilled to afford the title compound in 88% yield and in the form of a 66:34 (Z)/(E) mixture.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH3:23])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[O:24]=[C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27](O)=[CH:26]1>C(Cl)Cl>[O:24]=[C:25]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:27]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([O:14][CH3:15])[CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:26]1
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Reactant: O=C1C=C(O)C12CCCCC2
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C12CCCCC2
Reaction time: 48 h
Yield: 93.4 %

Procedure:
To a solution of methyl (2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (0.80 g, 2.5 mmol) in DCM (10 ml) at room temperature was added 1-keto-3-hydroxyspiro[3,5]-non-2-ene (0.38 g, 2.5 mmol) and the mixture stirred for 48 h. Volatiles were removed in vacuo and the residue purified by column chromatography (SiO2, EtOAc) to give the title compound as a white solid (1.05 g, 92%). δH (CDCl3): 7.32-7.26 (3H, m), 7.12 (2H, d, J 8.2 Hz), 6.92 (2H, d, J 8.3 Hz), 5.90 (1H, br d, J 8.2 Hz), 4.60 (1H, s), 4.33 (1H, br), 3.86 (3H, s), 3.73 (6H, s), 3.30 (1H, dd, J 13.9, 5.3 Hz), 3.13 (1H, dd, J 13.9, 6.3 Hz), 1.82-1.33 (10H, m); m/z (ES+, 70V) 450.1 (MH+).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>O>[Br:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: ClCc1cc(Br)ccc1Sc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1cc(Br)ccc1Sc1ccccc1

Procedure:
136.5 g of potassium cyanide in 183 ml of water are heated under reflux for 10 hours under a nitrogen atmosphere with 470 g of 3-bromo-6-(phenylthio)-benzyl chloride. The ethanol is distilled off under reduced pressure, the residue diluted with water and extracted with ether. The extracts are washed with water, dried over magnesium sulphate and evaporated. There is obtained 3-bromo-6-(phenylthio)-phenylacetonitrile as a brown oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:28]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:12]=[O:28])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: C=CC(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc(COC(C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 77 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3R/S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (14a) (4.0 g, 10.2 mmol) dissolved in 100 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.69 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 3.1 g (77% yield) of the title compound (14b) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (13b).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[O:45]([CH2:52][CH2:53][CH2:54]Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:54][CH2:53][CH2:52][O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCCCOc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 3-phenoxy-1-bromopropane (487 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (245 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21]C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CC)[C@@H:33](C1C=CC=C(OC)C=1)[OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:34][CH3:33])[CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC[C@H](N)[C@H](O)c1cccc(OC)c1
Agent: Cl
Product: CC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
was synthesised in the same way as (91a) from (1R,2S)-2-amino-1-(3-methoxyphenyl)butan-1-ol hydrochloride (97b, 50 mg, 0.22 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:34]2[CH:38]=[CH:37][N:36]([CH2:39][CH2:40][NH2:41])[N:35]=2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32].C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:34]2[CH:38]=[CH:37][N:36]([CH2:39][CH2:40][NH:41][C:7]([C:5]3[CH:6]=[C:2]([CH3:1])[NH:3][N:4]=3)=[O:9])[N:35]=2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: COc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccn(CCNC(=O)c3cc(C)[nH]n3)n2)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
3-Methylpyrazole-5-carboxylic acid (70.0 mg, 0.555 mmol), HOBt (85 mg, 0.629 mmol) and PS-carbodiimide (672 mg) were weighed in a glass vial. DCM (4 ml) and DMF (0.4 ml) were added. The mixture was stirred for 10 minutes. 2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine (97 mg, 0.370 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off. PS-Trisamine (616 mg, 1.849 mmol) was added to the filtrate. The mixture was stirred for 2 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 46 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 2.35 (s, 3H), 3.92, (m, 2H), 4.05, (s, 3H), 4.40, (t, 2H), 6.57 (s, 1H), 6.61 (d, 1H), 7.31 (s, 1H), 7.40-7.43 (m, 1H), 7.47 (d, 1H), 7.62 (d, 1H), 7.96 (d, 1H), 9.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.[CH3:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: CN
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (267.9 mg, 0.890 mmol) in methanol (5 mL) was added a 2M solution of methylamine in methanol (0.890 mL, 1.779 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (184.6 mg, 0.624 mmol, 70.2% yield) as brown solid. LC-MS (M+H)+=296.1.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[C:7](=[O:11])[CH:6]=[CH:5][C:4](=[O:12])[C:3]=2[O:2]1.[CH2:13]=[CH:14][C:15]([Cl:17])=[CH2:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[Cl:17][C:15]1[CH:16]=[C:5]2[C:6](=[CH:13][CH:14]=1)[C:7](=[O:11])[C:8]1[O:9][CH2:10][CH2:1][O:2][C:3]=1[C:4]2=[O:12]
Reactant: O=C1C=CC(=O)C2=C1OCCO2
Reactant: C=CC(=C)Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 90 h
Yield: 71.2 %

Procedure:
A mixture of 2,3-ethylenedioxy-1,4-benzoquinone (17 g) and freshly distilled chloroprene (13 g) in glacial acetic acid (100 mL) was stirred at ambient temperature for 90 hours. The mixture was then diluted with additional acetic acid (500 mL) followed by the addition of a solution of sodium dichromate (40 g) and sulfuric acid (2 mL) in water (25 mL). The mixture was heated at 60° -70°C. for 2 hours, then cooled and diluted with water (500 mL). The resulting bright orange precipitate was collected and dried to yield 18.25 g of 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone, mp 279°-80° C.
Reaction SMILES: C1COCC1.CO.[OH-].[Na+].[Cl:10][C:11]1[C:12]([NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([CH3:37])[CH:28]=2)=[O:26])=[CH:13][C:14]([F:23])=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:16]=1>Cl>[Cl:10][C:11]1[C:12]([NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([CH3:37])[CH:28]=2)=[O:26])=[CH:13][C:14]([F:23])=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3ccc(F)cc23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)Nc2cc(F)c(CC(=O)O)cc2Cl)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.2 %

Procedure:
THF/methanol (1/1, 60 ml) and 0.25N NaOH (43 ml, 10.6 mmol) were added to ethyl (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetate (865 mmol, 2.13 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured in 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was solidified with methanol/chloroform/hexane. The crystals thus precipitated were collected by filtration under reduced pressure and dried under reduced pressure to give (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetic acid (736 mg, 91%) as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:25]>ClCCl>[CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([NH:25][NH:24][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:9]
Reactant: Cc1scnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1scnc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methyl-1,3-thiazole-4-carboxylic acid (500 mg, 3.49 mmol) in dry dichloromethane (DCM) (17.500 ml) was stirred at room temperature under an atmosphere of argon. EDC (736 mg, 3.84 mmol) and HOBt (267 mg, 1.746 mmol) were added to the stirred solution and the resulting solution was stirred at room temperature for ½ hour. After this time, 1,1-dimethylethyl hydrazinecarboxylate (554 mg, 4.19 mmol) was added and the solution was stirred for a further 16 hours (overnight) at room temperature. The solution was diluted with DCM (approx. 50 ml) and washed with water (2× approx. 25 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oily solid. The residue was chromatographed [SiO2, MeOH in DCM 0-5%] to give a pale yellow coloured solid of desired material in 544 mg.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[ClH:25].[OH:8][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:26][CH2:27][CH2:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:11][CH2:10]1)([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(O)(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(O)(c2ccccc2)C2CCN(CCCC(=O)c3ccccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 12 g (0.0372 mole) of α-phenyl-α-(p-tert-butylphenyl)-4-piperidinemethanol, 7.85 g (0.042 mole) of 4-chlorobutyrophenone, 13.8 g (0.1 mole) of potassium carbonate, and 0.1 g of potassium iodide in 100 ml of toluene is refluxed with stirring for 64 hours. Upon cooling to room temperature the mixture is filtered, and to the filtrate is added an equal volume of ether followed by treatment with ethereal HCl. The resulting precipitate is recrystallized from isopropyl alcohol and from methanolbutanone to give 4-[4-[α-hydroxy-α-(p-tert-butylphenyl)benzyl]piperidino]butyrophenone hydrochloride, M.P. 228°- 230°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].[N:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])=[C:19]=[S:20]>C(O)C>[OH:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:19]([NH:18][C:21]1[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27])=[S:20]
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(NC(=S)Nc2cccc([N+](=O)[O-])c2O)c(C)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a mixture containing 0.10 g (0.65 mmol) of 2-amino-6-nitrophenol and 0.14 g (1.3 mmol) of sodium carbonate in ethanol was added 0.14 g (0.78 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The reaction was heated at reflux overnight. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.17 g (80%) of product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.NC1C=CC=CC=1.[SH2]=N.[CH3:35][S:36]([CH3:38])=O>C(N(CC)CC)C.C(Cl)Cl>[CH3:35][S:36][CH2:38][C:6]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[C:4]=1[NH2:5]
Reactant: CS(C)=O
Reactant: Nc1ccccc1C(F)(F)F
Agent: N=[SH2]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: CSCc1cccc(C(F)(F)F)c1N
Reaction time: 3 h

Procedure:
In a 2-liter flask with stirrer is placed 147 g o-(trifluoromethyl)aniline, 250 g P2O5 and 1 liter CH2Cl2. With vigorous stirring simultaneously and separately, 250 mL dimethyl sulfoxide and 200 g triethyl amine were added dropwise at such a rate as to create gentle reflux; addition time ca 1 hour with reflux at 41°-42° C., and final temp 52° C. Fifteen minutes after completion of addition, temperature was still 51° C., but external heat was applied for 3 hours, then let stand overnight. Monitoring the reaction by glc was only partially successful; there was decrease in starting aniline and an increase in product peak (sulfilimine decomposing on column to ortho-rearranged product). After reaction, 10% caustic was added to fill flask, then layers separated. Caustic layer washed once with more CH2Cl2, then combined organic layers washed with water (salt added). The organic layer was stripped of solvent, heated (in kugelrohr) to ca 140°-150° C. for ca 1/2 hour. The material was distilled through 6" vigreux to give 100 g distillate, bp 60°-100° C. (0.3 mm). A more viscous oil 9.2 g was collected bp 140° C. (0.25-0.45 mm). A second distillation gave 80 g of 2-methylthiomethyl-6-trifluoromethyl aniline, bp 68°-78° C. (0.1 mm Hg).
Reaction SMILES: [Na].CO[C:4](=[O:6])[CH3:5].C(O[C:11](=[O:19])[CH:12]=[C:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])(C)C.[CH2:20](O)C>>[CH3:18][C:13]1([C:14]([F:15])([F:16])[F:17])[CH2:5][C:4](=[O:6])[CH2:20][C:11](=[O:19])[CH2:12]1
Reactant: CCO
Reactant: CC(=CC(=O)OC(C)C)C(F)(F)F
Reactant: COC(C)=O
Agent: [Na]
Product: CC1(C(F)(F)F)CC(=O)CC(=O)C1

Procedure:
0.64 g of sodium is introduced into 40 ml of ethanol, 3.23 ml of acetic acid methyl ester and 4.9 g of 4,4,4-trifluoro-3-methyl-but-2-enoic acid isopropyl ester are incorporated and the mixture is heated at boiling temperature for 18 hours. After extraction with dilute hydrochloric acid against ethyl acetate, concentration by evaporation is carried out. The non-purified 2-methyl-4,6-dioxo-2-trifluoromethyl-cyclohexanecarboxylic acid methyl ester that remains behind is esterified in the presence of 9.1 g of sodium hydroxide in a mixture of methanol and water at boiling temperature. The mixture is then acidified with hydrochloric acid and extracted with fresh ethyl acetate. After recrystallisation (ethyl acetate), pure 5-methyl-5-trifluoromethyl-cyclohexane-1,3-dione having a melting point of 150-152° C. is obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](Cl)(=[O:26])=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:30]>>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](=[O:26])(=[O:25])[NH2:30])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1-c1ccccc1

Procedure:
3-Benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml) while stirring at 10°-12° C. After additional stirring at room temperature for about 18 hours, the resulting solution is dropwise added to an excess of icecold 4 N hydrochloric acid. The resulting precipitate is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3-benzylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a melting point of 221°-222° C.
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][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].CCN(C(C)C)C(C)C.[C:34]([C:38]1[O:42][N:41]=[C:40]([NH:43][C:44](=O)[O:45]C2C=CC=CC=2)[CH:39]=1)([CH3:37])([CH3:36])[CH3:35].O>C1COCC1.CN(C1C=CN=CC=1)C>[C:34]([C:38]1[O:42][N:41]=[C:40]([NH:43][C:44]([NH:21][C:20]2[CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[C:17]([F:24])=[CH:18][C:19]=2[F:23])=[O:45])[CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)C)on4)c(F)cc3F)c2cc1OC
Temperature: 70 °C
Yield: 25.1 %

Procedure:
To a solution of 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmol) in THF (10 mL), DIEA (58 mg, 0.45 mmol), DMAP (20 mg, 0.16 mmol), and phenyl 5-tert-butylisoxazol-3-ylcarbamate (117 mg, 0.32 mmol) were added and the mixture heated overnight at 70° C. The mixture was poured into water and extracted with EtOAc three times. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel chromatography eluting with EtOAc/Hexane (3-80%). The appropriate fractions were concentrated to afford 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea (37.56 mg, 25% yield). 1H NMR (300 MHz, CDCl3) δ 1.35 (s, 9H), 4.05 (s, 6H), 6.09 (s, 1H), 6.85 (s, 1H), 7.28 (s, 1H), 7.35 (s, 1H), 8.28 (m, 1H), 8.70 (s, 1H), 9.50 (s, 1H). LC-MS (ESI) m/z 500 (M+H)+