Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:37]=[C:38]=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:38]([NH:37][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 73.3 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-octyl isocyanate (1.55 g; 10 mmole). Recrystallization from methanol/ethanol/water provided the title compound (3.1 g; 62% yield) as colorless crystals, m.p. 229°-230° C.
Reaction SMILES: CS[C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:5][N:4]=1.Cl[C:15]1C=C(C=CC=1)C(OO)=O.[S:25]([O-:28])(O)=[O:26].[Na+]>C(Cl)(Cl)Cl>[CH3:15][S:25]([C:3]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[S:5][N:4]=1)(=[O:28])=[O:26]
Reactant: CSc1nsc(C2CCCCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nsc(C2CCCCC2)n1
Reaction time: 7 h

Procedure:
370 mg of 3-methylthio-5-cyclohexyl-1,2,4-thiadiazole was dissolved in 8 ml of chloroform, 1.12 g of 3-chloroperoxybenzoic acid (content>65%) was added thereto, and the reaction mixture was stirred for 7 hours under ice-cooling. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 444 mg of 3-methylsulfonyl-5-cyclohexyl-1,2,4-thiadiazole.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis-(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluenetOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di- n-propylamino)-1,2,2a,3,4,5-hexahydzobenz[cd]indole, obtained in four crops, weighed 2.63 g. m.p. 103°-104° C.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])=[C:9]([CH3:23])[CH:8]=[C:7]([O:24][CH3:25])[C:6]=1[O:26][CH3:27])(=O)C.[O:28]1CCN(C2CCCCCCCCCCC=2)CC1.Cl.C(OC1C(OC)=C(OC)C=C(C)C=1CCCCCCCCCC([CH:73]1[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][C:74]1=[O:85])=O)(=O)C.[OH-].[Na+]>C(N(CC)CC)C>[O:21]=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1[C:9]([CH3:23])=[CH:8][C:7]([O:24][CH3:25])=[C:6]([O:26][CH3:27])[C:5]=1[OH:4])[CH2:73][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][C:74]([OH:85])=[O:28]
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)Cl)c(OC(C)=O)c1OC
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)C2CCCCCCCCCCC2=O)c(OC(C)=O)c1OC
Reactant: C1=C(N2CCOCC2)CCCCCCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COc1cc(C)c(CCCCCCCCCC(=O)CCCCCCCCCCCC(=O)O)c(O)c1OC
Yield: 73.2 %

Procedure:
In the presence of triethylamine (14.3 ml), 6-(9-chloroformylnonyl)-2,3-dimethoxy-5-methylphenyl acetate (36.9 g) is reacted with 1-morpholino-1-cyclododecene (24.3 g) as in the corresponding step of Reference Example 5. The reaction product is treated with 6N--HCl (47 ml) and the resultant 2-[10-(2-acetoxy-3,4-dimethoxy-6-methylphenyl)decanoyl]cyclododecanone (46.3 g) is hydrolyzed with a 6N-aqueous solution of sodium hydroxide to obtain 32.4 g of 13-oxo-22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid, m.p. 63°-64° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1
Reactant: CCCC1CCC(C2CCC(CC(O)c3c(C)cc(OCC)c(F)c3F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1

Procedure:
0.55 g of p-toluenesulfonic acid monohydrate was added to the compound (8) having been dissolved in 120 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 11.2 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethene (Compound 1-3-3-9) as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br-:9].[C:10]1([PH+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:9].[CH3:8][C:5]1[S:4][C:3]([CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CO)s1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 75 °C

Procedure:
2-Hydroxymethyl-5-methyl-thiophene (4.6 g.) was dissolved in 100 ml. of acetonitrile and 12.2 g. of triphenylphosphonium bromide were added. The reaction mixture was heated to 75° C. for 2.5 hours. After cooling the resulting precipitate was filtered off, washed with benene and dried at 80° C. under high vacuum. The resulting (5-methyl-2-thenyl)triphenylphosphonium bromide has a m.p. 262°-266° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1
Reactant: C1CSCCN1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCSCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and thiomorpholine are converted to the named compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[O:13]C(C)(C)CN=1)[CH3:2].CI.[OH-:21].[K+]>CS(C)=O.O>[CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]([OH:13])=[O:21])[CH3:2]
Reactant: CCc1c(C2=NCC(C)(C)O2)ccc(C)c1OC
Reactant: [OH-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CCc1c(C(=O)O)ccc(C)c1OC
Temperature: 0 °C

Procedure:
2-(2-Ethyl-3-methoxy-4-methylphenyl)-5,5-dimethyloxazoline, synthesized in like manner according to EXAMPLE 10, (2.7 g, 13.1 mmoles) and 2.2 mL (35.3 mmoles) of methyl iodide were dissolved in 4 mL of dimethyl sulfoxide. The resultant mixture was stirred for 18 hours at room temperature. A solution of 4.2 g of potassium hydroxide in 35 mL of water was added, and the mixture was heated at reflux for 8 hours. About 40 g ice was added, and the solution was extracted with ether. The aqueous layer was cooled on ice and acidified with 5% hydrochloric acid. The resulting precipitate was filtered and air-dried to yield 1.69 g of product. 1H NMR (200 MHz, CDCl3), δ=7.72 (1H, d, 8 Hz), 7.1 (1H, d, 8 Hz), 3.77 (3H, s), 3.06 (2H, q, 7 Hz), 2.36 (3H, s), 1.22 (3H, t, 7 Hz) ppm.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:20]=[N:19][CH:18]=[CH:17][C:9]=1[C:10]([OH:16])=[N:11]2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1.C(OCC)(=O)C>CC(N(C)C)=O>[F:38][C:37]([F:40])([F:39])[S:34]([O:16][C:10]1[C:9]2[CH:17]=[CH:18][N:19]=[CH:20][C:8]=2[C:7]2[C:12](=[CH:13][CH:14]=[N:15][C:6]=2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=1)(=[O:36])=[O:35]
Reactant: CCCCOc1nccc2nc(O)c3ccncc3c12
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccncc3c12
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
To a mixture of 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-ol (2 g, 7.43 mmol) and cesium carbonate (4.84 g, 14.85 mmol) in DMA (75 ml), N-phenyltrifluoromethanesulfonamide (5.31 g, 14.85 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 7 min. The reaction was then cooled to room temperature and added to ethyl acetate. The organic mixture was washed with aqueous sodium hydrogen carbonate (saturated), aqueous sodium carbonate (saturated), and brine. The organic extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.68 (s, 1H), 9.08 (d, 1H), 8.52 (d, 1H), 8.14 (d, 1H), 7.62 (d, 1H), 4.70 (t, 2H), 1.96 (m, 2H), 1.57 (m, 2H), 1.00 (t, 3H). LRMS (APCI) calc'd for (C16H15F3N3O4S) [M+H]+, 402.1; found 402.0.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:18]=[CH:17][C:13]([CH2:14][C:15]#N)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[OH2:19].[OH-:20].[K+]>CO>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:18]=[CH:17][C:13]([CH2:14][C:15]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: [OH-]
Reactant: O
Reactant: CCC[C@H]1CC[C@H](c2ccc(CC#N)cc2)CC1
Agent: [K+]
Solvent: CO
Product: CCC[C@H]1CC[C@H](c2ccc(CC(=O)O)cc2)CC1

Procedure:
106 g (0.44 mol) of 4-(trans-4'-propylcyclohexyl) benzyl cyanide, 40 g of water, 145 g (2.2 mol) of KOH and 440 cm3 of methanol were refluxed for 10 hours using a mantle heater. The ethanol was distilled off under reduced pressure. The residue was dissolved in 300 cm3 of water and poured into 300 cm3 of concentrated hydrochloric acid and 300 g of ice. The crystals deposited were filtered out and washed with cold water. The crystals were recrystallized from methanol to yield 112 g (0.43 mol) of 4-(trans-4'-propylcyclohexyl)phenyl acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:21]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[O:12][C:11]1[C:10]([Cl:24])=[CH:9][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[Cl:1])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a mixture of methyl 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)-benzoate (1.40 g, 3.37 mmol) in THF (10.0 mL) at 0° C. was added a solution of DIBAL-H (8.12 mL, 8.12 mmol, 1.0 M solution in THF). The reaction mixture was stirred at room temperature for 16 h, quenched with cold 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-(3′-iso-propyl-4′-methoxyphenoxy)-3,5-dichlorobenzyl alcohol as an off-white solid (0.94 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 7.54 (s, 2H), 6.81 (m, 2H), 6.40 (m, 1H), 5.51 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.75 (s, 3H), 3.21 (m, 1H), 1.13 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (17:3); Rf=0.27.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH2:15])([CH:12]([F:14])[F:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10].[C:17](Cl)(=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:16])[C:4]([CH:12]([F:14])[F:13])([NH:15][C:17](=[O:20])[CH2:18][CH3:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: COC(=O)C(N)(CCCNC(C)=O)C(F)F
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)NC(CCCNC(C)=O)(C(=O)OC)C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.47 g of 5-acetylamino-2-amino-2-difluoromethylpentanoic acid methylester in 10 ml of ether is added simultaneously at 0° C. 0.18 g of propionylchloride and 0.2 g of triethylamine. The reaction mixture is stirred at room temperature for 2 hours then extracted with ethylacetate. The organic phase is washed with a solution of sodium bicarbonate, water, then brine and dried over magnesium sulfate. Evaporation of the solvent gives 5-acetylamino-2-difluoromethyl-2-propionylaminopentanoic acid methylester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([CH:27]=[CH2:28])[C:20]=3[O:21][C:10]=2[CH:9]=1.CO.[H][H]>[Ni].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([CH2:27][CH3:28])[C:20]=3[O:21][C:10]=2[CH:9]=1
Reactant: C=Cc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 48.9 %

Procedure:
A solution of (863) (0.054 g, 0.167 mmol) prepared as described in example 444 in a methanol:tetrahydrofuran mixture (1:1, 4 mL) was hydrogenated over Raney nickel (100 mg) and hydrogen. The product was purified by column chromatography using a gradient of 0–100% ethyl acetate in dichloromethane to give (864) (0.032 g, 59%). 1H NMR δ [(CD3)2SO] 9.65 (s, 1H), 7.92 (m, 1H), 7.56 (d, J=3.0 Hz, 1H), 7.43 (m, 3H), 6.96 (d, J=2.5 Hz, 1H), 2.90 (q, 2H), 1.5 (t, 3H). MH−:392, 390.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(O)=O.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:41])([F:42])[F:30])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.080 g, 0.17 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.026 mL, 0.19 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. After, formic acid (5 mL) and concentrated HCl (0.5 mL) were added dropwise directly to the reaction mixture. Three major species were observed by LC-MS corresponding to AD71a, AD71b, and AD71c. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD71a (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), AD71b (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), and AD71c (ESI-MS m/z [M+H]+ found 670.5, calculated 670.2).
Reaction SMILES: [Mg].II.Br[CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8].[C:10]1([Si:16](Cl)([Cl:18])[Cl:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.CCCCCC>[CH3:9][C@@H:6]([CH2:7][CH3:8])[CH2:5][Si:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([Cl:18])[Cl:17]
Reactant: CC[C@H](C)CBr
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@H](C)C[Si](Cl)(Cl)c1ccccc1

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (5.7 g, 0.24 mol) and molecular sieves 4A which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. (S)-(+)-1-bromo-2-methylbutane (30 g, 0.20 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing phenyltrichlorosilane (50 g, 0.24 mol) in anhydrous tetrahydrofuran (50 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 40° C.-50° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[NH2:27]>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:33]3[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:26]([NH2:27])=[O:28])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(C(N)=O)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-carbamoylphenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 485.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[N:6][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[S:12][C:11]([C:13]3([OH:19])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:33]
Reactant: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1)Nc1cc(C(F)(F)F)ccc1F
Reaction time: 1 h

Procedure:
To a solution of Example 7B (0.042 mg, 0.151 mmol) in tetrahydrofuran (1 mL) was added 2-fluoro-5-trifluoromethylphenyl isocyanate (0.022 mL, 0.151 mmol). After 1 h, the mixture was concentrated under reduced pressure, the residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) to provide the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68 (br d, J=12.9 Hz, 2H), 2.07-2.17 (m, 2H), 3.68-3.80 (m 4H), 6.15 (s, 1H), 7.40-7.45 (m, 1H), 7.52 (m, 1H), 7.89 (m, 1H), 8.08 (m, 1H), 8.25 (s, 1H), 8.55-8.60 (m, 2H), 9.10 (s, 1H), 9.40 (s, 1H); MS (ESI) m/z 483 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19]1[C:20](=O)[C:21](=[O:26])[C:22]=1[O:23]CC)[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]1[C:22](=[O:23])[C:21](=[O:26])[C:20]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[O:9])[CH:3]=1)[CH3:17]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc(C(=O)N2CCC(O)C2)c1
Solvent: CCO
Product: CCOc1c(Nc2cccc(C(=O)N3CCC(O)C3)c2)c(=O)c1=O
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of the 30 ml of the solution of (3-aminophenyl)-(3-hydroxypyrrolidin-1-yl)methanone in ethanol and 6.81 g of 3,4-diethoxycyclobut-3-ene-1,2-dione (40.0 mmol, 2.5 eq) was heated at 60° C. overnight. The reaction medium was evaporated and the residue was chromatographed on silica gel eluted with heptane/ethyl acetate at 4/1, 2:1, then dichloromethane/methanol (6%). 3.03 g of 3-ethoxy-4-[3-(3-hydroxypyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione were obtained. Yield=63%.