Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[F-:12].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O>[CH3:11][O:10][C:8]([C:6]1[N:7]=[C:3]([CH2:2][F:12])[O:4][CH:5]=1)=[O:9]
Reactant: [F-]
Reactant: COC(=O)c1coc(CCl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: COC(=O)c1coc(CF)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-(chloromethyl)oxazole-4-carboxylate (CAS208465-72-9) (150 mg, 0.85 mmol) in acetonitrile (4.27 ml) was treated with tetra-n-butylammonium fluoride (2.56 ml, 2.56 mmol). The blue solution turned to orange and was left under stirring at room temperature overnight. For the workup, the reaction mixture was poured in water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated at reduced pressure. The crude material was purified by chromatography on a flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 50/50 as the eluent. The 2-fluoromethyl-oxazole-4-carboxylic acid methyl ester was obtained as a white solid (64 mg, 47% of theory). MS (ISP): m/z=160.1 [M+H]+. b) 2-Fluoromethyl-oxazole-4-carboxylic acid
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:24][CH2:25][N:20]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22]2)=[CH:9][N:8]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCN(CCc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.8 %

Procedure:
A suspension of 0.30 g (0.0019 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 20 ml of dimethylformamide was treated with 0.30 g (0.00157 mol) of 1-phenethyl-piperazine and 0.66 ml (0.0047 mol) of triethylamine and the mixture was stirred at room temperature under argon for 36 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with methanol as the eluent and recrystallized from toluene. 0.39 g (83%) of 2-methyl-5-(4-phenethyl-piperazin-1-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 162°-165°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:21]C(=O)C1C=CC=CC=1)=[N:9]2.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:18])([F:19])[F:20])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 65 °C
Yield: 11495.3 %

Procedure:
To a solution of N-((4aS,5S,7aS)-7a-(2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (250.2 g, 589 5 mmol) in methanol (1.25 L) was added K2CO3 (81.5 g, 590.0 mmol). The suspension was heated to 65° C. for 6 h. Upon cooling to ambient temperature, the solvent was evaporated under vacuum. To the resulting residue, was added 1.0 N aq NaOH (1.18 L) and THF (502 mL). The heterogeneous mixture was heated to 45° C. for 1 h. The mixture was cooled to ambient temperature, and EtOAc (1.38 L) was added. The aqueous layer was extracted with EtOAc (0.75 L). The organics were combined, washed with saturated aq. NaHCO3 (500 mL) and saturated aq. NaCl (500 mL). The organics were concentrated under vacuum to afford the title compound as a brown oil (184.1 g, 91.6% yield accounting for residual solvents). 1H NMR (500 MHz, DMSO) δ ppm 7.49-7.42 (m, 1H), 7.40-7.33 (m, 1H), 7.26-7.15 (m, 2H), 6.26 (s, 2H), 4.77-4.54 (m, 1H), 4.40 (d, J=8.0 Hz, 1H). 3.80 (dd, J=7.9, 2.3 Hz, 1H), 3.24-3.17 (m, 1H), 3.00 (dd, J=13.9, 3.2 Hz, 1H), 2.85 (dd, J=13.9, 3.9 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 159.75 (d, JCF=245.1 Hz), 149.51, 131.31 (d, JCF=3.9 Hz), 130.13 (d, JCF=8.8 Hz), 128.08 (d, JCF=10.4 Hz), 128.28 (q, JCF=282.1 Hz). 124.87 (d, JCF=3.0 Hz), 116.80 (d, J=23.8 Hz). 78.77, 76.80 (q, JCF=30.8 Hz), 66.31, 36.37, 23.27.
Reaction SMILES: [OH-:1].[K+].ClC1C=CC=CC=1C[C:7]1[CH:17]=[CH:16][CH:15]=[C:9]2[C:10](N[C:13](=[O:14])[C:8]=12)=[O:11].Cl.[OH2:23]>>[C:10]([OH:11])(=[O:23])[C:9]1[C:8](=[CH:7][CH:17]=[CH:16][CH:15]=1)[C:13]([OH:14])=[O:1]
Reactant: O=C1NC(=O)c2c(Cc3ccccc3Cl)cccc21
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 126.5 °C
Yield: 98 %

Procedure:
A 2 L, round-bottomed, 3-necked flask was charged with 830 g of 50% aqueous potassium hydroxide solution, and 333 g of 2-chlorobenzylphthalimide. The reaction mixture was then heated under reflux (pot temperature 125-128° C.) for 21 hours with stirring. It was then cooled in iced-water and allowed to settle in a separating funnel. The lower aqueous layer was drained, diluted with 2 L of water and acidified with 676 g of concentrated hydrochloric acid (with cooling). This caused the formation of a white precipitate, which was collected by filtration and dried in a vacuum oven overnight to yield 199.9 g of phthalic acid (98%). The organic layer was essentially pure (99.9% by GC) 2-chlorobenzylamine (163.4 g, 1.15 mol, 93.5%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23]([C:26]([C:28]6([CH2:31]O)[CH2:30][CH2:29]6)=[O:27])[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([N:36]([CH2:40][CH3:41])[CH:37]([CH3:39])C)(C)C.[CH3:42]S(OS(C)(=O)=O)(=O)=O>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23]([C:26]([C:28]6([CH2:31][N:36]7[CH2:37][CH2:39][CH2:42][CH2:41][CH2:40]7)[CH2:29][CH2:30]6)=[O:27])[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)C1(CO)CC1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)C1(CN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[4-(benzothiazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridin-1-yl}-(1-hydroxymethylcyclopropyl)-methanone (23.0 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) were added N,N-diisopropylethylamine (0.05 mL, 0.3 mmol) and methanesulfonic anhydride (11 mg, 0.06 mmol). The resulting mixture was stirred at rt overnight. LC-MS showed the reaction produced the desired product, but there was still 70% SM, another 1.2 eq. of methanesulfonic anhydride was added. 2 h later, LC-MS showed the reaction was complete. To the reaction mixture was added piperidine (0.05 mL, 0.5 mmol), and the resulting mixture was stirred at rt overnight. LC-MS showed the reaction was complete. The mixture was diluted with MeOH (1 mL) and purified by mass-directed purification to give the title compounds as an off-white solid. LC-MS (ES, Pos.): 514 [MH+]. 1H NMR (CD3OD, 400 MHz): δ=0.76 (s, 2H), 0.99 (s, 2H), 1.41-1.54 (m, 6H), 2.42-2.69 (m, 8H), 3.99 (m, 2H), 4.23 (m, 1H), 4.50 (m, 1H), 6.35 (s, 1H), 6.73 (s, 1H), 7.78 (dd, J=8.9 Hz, 2.1 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.74 (d, J=2.1 Hz, 1H), 9.12 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CN(C=O)C.Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>CCCCC>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:5]=1
Reactant: N#CCCCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: N#CCCCOc1cccnc1
Yield: 56 %

Procedure:
Sodium hydride (13.3 g., 0.32 mol, 57% oil dispersion) was washed with pentane to remove the oil and 26.1 g. (0.275 mol) of 3-hydroxypyridine in 300 ml. of anhydrous DMF was added with cooling in a cold water bath. The mixture was then stirred and heated at 60° for 1 hour. After cooling to 25°, 40.7 g. (0.275 mol) of 4-bromobutyronitrile in 40 ml. of anhydrous DMF was added dropwise over 1 hour with cooling to keep the reaction temperature below 30°. The reaction mixture was then stirred at 25° for 17 hours and the solvent was removed in vacuo. The residue was treated with 100 ml. of water and the product was extracted with CH2Cl2. After washing the extract with 1N NaOH and then with H2O, it was dried (MgSO4) and concentrated in vacuo to an oil which was distilled to yield 25.1 g., b.p. 133°-135°/0.4 mm, (56% yield), of 4-(3-pyridinyloxy)butyronitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.BrC1C=C(CC2C=C[C:42]([O:45]CC)=CC=2)C(Cl)=C(OC)C=1OC>>[Cl:1][C:2]1[C:3]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[C:6]([O:45][CH3:42])[C:7]=1[O:8][CH3:9]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Reactant: CCOc1ccc(Cc2cc(Br)c(OC)c(OC)c2Cl)cc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c(OC)c2Cl)cc1

Procedure:
Similar procedure with preparation of 75 proceeded except for using compound 160 to obtain the compound E151.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25]([CH:26]=O)=[CH:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:35]/[P:44](=[O:51])([O:45][CH2:46][CH3:47])[O:48][CH2:49][CH3:50])=[CH:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cn1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1)OCC
Reaction time: 15 h
Yield: 73.4 %

Procedure:
To a mixture of 3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.28 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-{3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.38 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])([CH3:20])[CH3:19]
Reactant: CC(C)N=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CC(C)NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 106.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.13 mg (0.131 mMol) isopropyl isocyanate, 21.9 mg of the title compound were recovered.
Reaction SMILES: OCC[C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27](C)=[O:28]>>[C:13]1([CH2:12][O:11][C:10]2[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=2)[O:6][CH2:26][CH2:27][OH:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: OCCc1c(O)cccc1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCOc1cccc(OCc2ccccc2)c1
Yield: 92 %

Procedure:
A slurry of 38.6 g (0.25 mole) of o-(2-hydroxyethyl)resorcinol (Lancaster), 44.3 g (0.35 mole) of benzyl chloride, and 55.2 g (0.40 mole) of potassium carbonate in 200 ml of acetone was stirred and heated at reflux for 72 hr. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crystalline residue was recrystallized from toluene/petroleum ether to give 56.3 g (92%) of the title compound as white flakes, mp 40.5°-43.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20](SC)=[CH:19][CH:18]=3)[N:14]=[C:13]([NH2:25])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[O:27][S:28]([O-:30])=O.[K+].OS([O-])(=O)=O.[K+].[CH3:38]C(C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:28]([CH3:38])(=[O:30])=[O:27])=[CH:19][CH:18]=3)[N:14]=[C:13]([NH2:25])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2cc(-c3ccc(SC)cc3)nc(N)n2)cc1Cl
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: COc1ccc(Nc2cc(-c3ccc(S(C)(=O)=O)cc3)nc(N)n2)cc1Cl

Procedure:
N4-(3-Chloro-4-methoxy-phenyl)-6-(4-methanesulfonyl-phenyl)-pyrimidine-2,4-diamine was prepared from compound N4-(3-chloro-4-methoxy-phenyl)-6-(4-methylsulfanyl-phenyl)-pyrimidine-2,4-diamine, in aqueous acetone (3:1) using oxone (2KHSO5.KHSO4.K2SO4) as an oxidizing agent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1C=C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[Cl:17])[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: C=Cc1ccccc1Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC(c2ccccc2Cl)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 32 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 2-chlorostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][OH:7].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH2:6][O:7][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCOc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of (S)-(tert-butoxycarbonylamino)-4-hydroxybutyric acid methyl ester (1.43 g; CAS 120042-11-7) in THF (4 ml) were added phenol (692 mg), triphenylphosphine (1.77 g) and diisopropyl azodicarboxylate (1.36 g). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→90:10) to give (S)-2-tert-butoxycarbonylamino-4-phenoxy-butyric acid methyl ester (1.16 g, 61%) as a light yellow oil. MS (ISP): 210.1 ([M+H-BOC]+)).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a 500 mL one-neck flask was added 4-fluorobenzophenone (35 g), piperazine (13 g), potassium carbonate (22 g) and dimethyl sulfoxide (100 mL). The reaction mixture was heated to 100° C. for 20 hours. The mixture was cooled to room temperature and poured into water (400 mL). The mixture was extracted with chloroform (200 mL) and the recovered bottom layer was dried over sodium sulfate. The solvent was removed and the product was dried in vacuum oven at 60° C. for 6 hours to afford 40 g of waxy 4-piperazinobenzophenone.
Reaction SMILES: NC1C2C=C(SC)C=C[C:4]=2[S:5]C=1C(OC)=O.C=O.Cl[C:20]1[C:28]2[C:27]([N:29]([CH3:31])[CH3:30])=[C:26]([C:32]([O:34][CH3:35])=[O:33])[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:30][N:29]([CH3:31])[C:27]1[C:28]2[CH:20]=[C:21]([S:5][CH3:4])[CH:22]=[CH:23][C:24]=2[S:25][C:26]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1sc2cccc(Cl)c2c1N(C)C
Reactant: COC(=O)c1sc2ccc(SC)cc2c1N
Agent: C=O
Product: COC(=O)c1sc2ccc(SC)cc2c1N(C)C
Yield: 71 %

Procedure:
Prepared from methyl 3-amino-5-(methylthio)-benzo[b]thiophene-2-carboxylate by alkylation with formaldehyde as described in the preparation of methyl 4-chloro-3-(dimethylamino)benzo[b]thiophene-2-carboxylate. Yield 71% after recrystallization from ether-petroleum ether; mp=63°-66° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:25][Si:26]([CH3:43])([CH3:42])[C:27]#[C:28][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[C:19]1([C:8]2[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]3[N:6]([C:2]([C:28]#[C:27][Si:26]([CH3:43])([CH3:42])[CH3:25])=[CH:3][N:4]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Temperature: 130 °C

Procedure:
400 mg 4-(3-bromo-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 11), 820 mg trimethyl[(tributylstannyl)ethynyl]silane and 60 mg Pd(PPh3)4 are suspended in 8 ml toluene under a nitrogen atmosphere. The mixture is heated (microwave) to 130° C. for 1 h. The solvent is evaporated and the crude product is purified by column chromatography (dichloromethane/methanol)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CN([C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl)S(C)(=O)=O
Temperature: 120 °C

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (95 mg, 0.27 mmol) in Isopropyl alcohol (4 mL) was added to 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (56 mg, 0.27 mmol) and 10-Camphorsulfonic acid (64 mg, 0.28 mmol) and was heated in a Microwave vial for 90 min at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. The material was taken up in DCM and was chromatographed (ISCO, 12 g silica gel, 50% EtOAc/Hex-non-retained) to afford the N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as off white solids (145 mg, 100%). mp=140-145° C.; LCMS: 521 (M+H); 1H-NMR, CDCl3: 7.92 (s, 1H), 7.68 (d, 1H, J=8.5 Hz), 7.46 (s, 1H), 7.39 (s, 1H), 7.11 (s, 1H), 6.89 (d, 1H, J=8.5 Hz), 5.69 (d, 1H, 7.8 Hz), 4.07 (m, 1H), 3.77 (m, 1H), 2.85 (s, 3H), 2.75 (s, 3H), 2.41 (t, 2H, J=7.0 Hz), 2.13 (m, 2H, J=7.0 Hz), 1.90 (m, 4H), 1.44 (s, 6H), 1.37 (m, 4H).
Reaction SMILES: C(C1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16]C=CC=3)[CH2:14][C@@H:13]2O)=[N:5]C(CC)=CN=1)C.Br[C:23]1[C:28]([CH2:29][CH3:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])=[C:25]([CH2:39][CH3:40])[N:24]=1.CC1C=C(C)N=C(N)C=1>>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:26]1[N:27]=[C:28]([CH2:29][CH3:30])[C:23]([NH:5][C:4]2[CH:16]=[C:15]([CH3:14])[CH:20]=[C:12]([CH3:13])[N:11]=2)=[N:24][C:25]=1[CH2:39][CH3:40]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Agent: Cc1cc(C)nc(N)c1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Nc1cc(C)cc(C)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and 4,6-dimethylpyridin-2-amine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.31, 1.38, 2.37, 2.46, 2.62, 2.90, 6.68, 7.31, 7.37, 7.52, 8.28; HRMS (ESI+) Calcd for C21H22Cl2N4 (M+H)+ 401.1299, found 401.1317.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2(OC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li]CCCC.C([O:27]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>C1COCC1.O>[C:11]1([C:6]2[C:7]3[C:3](=[C:2]([OH:27])[CH:10]=[CH:9][CH:8]=3)[CH2:4][CH:5]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COC1(c2ccccc2)CCc2c(Br)cccc21
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Oc1cccc2c1CC=C2c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 21.0 g (69.3 mmol) of 4-bromo-1-methoxy-1-phenylindane in 200 ml of THF, 27.7 ml of 2.5 M nBuLi (69.3 mmol) in hexanes was added with vigorous stirring for 1 hour at −78° C. Then, 24.0 ml (19.5 g, 104 mmol) of triisopropylborate was added at this temperature. The resulting mixture was slowly warmed to ambient temperature, and then 5.96 ml (6.25 g, 104 mmol) of glacial acetic acid was added. The resulting mixture was cooled to 0° C., and then 14.7 ml of 16% H2O2 was added. This mixture was stirred for ca. 30 min at room temperature, and then 300 ml of water was added. The product was extracted with 3×150 ml of CH2Cl2. The combined extract was dried over Na2SO4 and evaporated to dryness. The analytically pure product, 3-phenyl-1H-inden-7-ol, was obtained by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, l 350 mm, eluant: hexanes-CH2Cl2=4:1). Yield, 9.68 g (67%).