Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[NH2:12].C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:12][C:18](=[O:17])[NH:19][C:6]2=[O:8]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c(=O)[nH]c(=O)[nH]c12
Reaction time: 2 h

Procedure:
3-Methoxyanthranilic acid (6 g, 0.036 mol) was suspended in water (200 ml, 35°) and glacial acetic acid (2.2 ml). A freshly prepared solution of potassium cyanate (3.7 g, 0.046 mol) in water (20 ml) was added dropwise to the stirred mixture. After 2 hours, sodium hydroxide (48.5 g 1.21 mol) was added in portions keeping the temperature below 40°. A clear solution was obtained momentarily before precipitating the hydrated sodium salt. After cooling, the precipitate was filtered off, dissolved in hot water which was acidified to pH 5, causing precipitation of 8-methoxy-2,4-quinazolinedione (4.6 g, 58%) m.p. 255°-257°.
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:26])[C:13]2[CH:14]([CH3:25])[C:15]3[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC1C=CC(C(C)C)=CC=1>[Pd].C(Cl)(Cl)Cl>[CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:26])[C:13]2[CH:14]([CH3:25])[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([CH3:24])=[CH:17][CH:16]=3)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)Oc1cc(C)ccc1C2C

Procedure:
A solution of 1.7 g. of 3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-1-hydroxy-6,9-dimethylxanthene in 70 ml. of p-cymene is added dropwise over one hour to a stirred suspension of 0.56 g. of 10% palladium-on-carbon in 70 ml. of refluxing p-cymene under a nitrogen atmosphere. The reaction mixture is refluxed for four hours, cooled and chloroform is added. The mixture is filtered and the filtrate is concentrated in vacuo to give a residue which is chromatographed on silica gel with 1:1 chloroform-cyclohexane as eluant to give the title compound, b.p. 208°-210° (0.004 mm.).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1>B(F)(F)F.CCOCC.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Yield: 77.1 %

Procedure:
In a 500-ml flask, 4-trifluoromethylaniline (80.6 g, 0.5 mol), methyl 3-oxopentanoate (65.1 g, 0.5 mol) and toluene 400 ml were placed. To this solution was added boron trifluoride etherate (1.42 g, 10 mmol), and the resulting mixture was heated under a reduced pressure of 8 kPa. The reaction mixture was heated for 5 hours under reflux, while water produced was removed out of the reaction system by using a Dean-Stark trap. Then, the heating was discontinued and nitrogen was leaked. After cooling, the solvent was removed by distillation by using a rotary evaporator. The residue was then distilled under reduced pressure to give 105.3 g of the title compound. The yield was 77.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[NH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([NH2:29])[CH:35]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 81 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-aminophenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[OH:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19](Cl)(=[O:21])=[O:20].CCOCC>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[O:9][S:19]([C:12]1[C:13]([CH3:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:23])(=[O:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(O)C(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)ON(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
A solution of 16 g. of N-t-butoxycarbonyl-N-methyl hydroxylamine and 23.8 g. of mesitylenesulfonyl chloride in 400 ml. of ether was cooled to 0° C. and treated with 15.4 ml. of triethylamine dropwise with stirring. Thirty minutes after the addition was complete, the mixture was filtered, and the filter cake was washed with 2 portions of ether. The filtrate and washings were evaporated to a heavy oil. The oil was dissolved in 40 ml. of benzene, filtered through diatomaceous earth and concentrated to dryness to give a crystalline residue of N-t-butoxycarbonyl-N-methyl mesitylenesulfonylhydroxylamine, which was used directly in the next step without characterization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:32]([C:34]1[CH:38]=[CH:37][S:36][C:35]=1B(O)O)=[O:33]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:35]2[S:36][CH:37]=[CH:38][C:34]=2[CH:32]=[O:33])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=Cc1ccsc1B(O)O
Product: COC(=O)c1cc(-c2sccc2C=O)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 70.6 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product of Example 89 and 343.2 mg (2.2 mmol) of 3-formylthiophene-2-boronic acid provided 379 mg (71%) of the desired product as a pale yellow solid. Electrospray Mass Spec 537 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16](O)[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][N:13]=2)[CH2:8][CH2:7]1.C(O)C.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>O>[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][N:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)Cc1cnc(N2CCOCC2)nc1O
Reactant: CCNCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cnc(N2CCOCC2)nc1N(CC)CC
Yield: 69.5 %

Procedure:
Phosphorus oxychloride (11.7 ml) was added to 3.35 g (12.5 mmoles) of ethyl 2-morpholino-4-hydroxypyrimidine-5-acetate, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and ice water were added. It was neutralized with sodium hydrogen carbonate. The methylene chloride layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the product were added 15 ml of ethanol and 7.0 g (95.7 mmoles) of diethylamine, and in an autoclave, the mixture was reacted at 120 ° C. for 7 hours. Water was added, and the mixture was extracted with methylene chloride. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 2.8 g (yield 56%) of the desired compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)#[N:2].[Br:10][CH2:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:10][CH2:11][CH2:12][CH2:13][S:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCCCBr
Reactant: N#Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(SCCCBr)cc1
Yield: 62.1 %

Procedure:
A mixture of 4-cyanothiophenol (20.8 g, 154 mmol), 1,3-dibromopropane (155 g, 0.77 mol) and K2CO3 (21.3 g, 154 mmol) in MeCN (300 mL) was refluxed overnight. Filtration and evaporation of the solvent gave a brown oil that crystallised when treated with EtOH. The crystals were isolated by filtration to give the sub-title compound (24.5 g, 62%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:14][CH:15](Cl)[C:16](=O)[CH3:17]>C1(C)C(C)=CC=CC=1>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[O:12][CH:17]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: CSc1ccc(C=CC(N)=O)cc1
Solvent: Cc1ccccc1C
Product: CSc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
2.00 g (10.3 mmol) 3-(4-methylsulfanyl-phenyl)-acrylamide, 2.63 g (22.0 mmol) dichloro acetone and 60.0 ml xylene were kept at reflux temperature for 3 h with continuous removal of water by use of a Dean-Stark trap (a water separator used in chemical reactions). After removal of solvents in vacuo, the residue was partitioned between ethyl acetate and water. The organic extracts were dried and the solvent was distilled off. The remaining residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:3). Yield: 1.50 g (55%) 4-Chloromethyl-2-[2-(4-methylsulfanyl-phenyl)-vinyl]-oxazole as a light yellow solid melting at 126-128° C.
Reaction SMILES: [CH:1]([C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].Br[C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1>>[OH:2][C@H:1]([C:17]1[S:18][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(-c2ccccc2)s1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1

Procedure:
(4R,5R)-5-[(1S)-Hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-phenyl-pyrrolidin-2-one was prepared from Intermediate Z and 2-bromo-5-phenylthiophene by a method analogous to that described for Example 6, then separated using the HPLC Separation B apparatus.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([O:15]C)=[O:14])=[C:6]2[S:17][CH3:18].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([OH:15])=[O:14])=[C:6]2[S:17][CH3:18]
Reactant: COC(=O)c1c(SC)c2cc(OC)ccc2n1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c(SC)c(C(=O)O)n2C
Temperature: 0 °C
Yield: 86.2 %

Procedure:
A suspension of methyl 5-methoxy-1-methyl-3-(methylthio)-1H-indole-2-carboxylate (3.2 g, 12 mmol) in 65 mL of methanol is treated with a solution of potassium hydroxide (2.5 g, 45 mmol) in 25 mL of water. The mixture is stirred at reflux for 2 hours, then cooled and added to 400 g of ice and water. After washing with dichloromethane, the aqueous layer is stirred with celite filter-aid and filtered. The filtrate is acidified with 4.0N HCl and the precipitated solid is filtered and washed with 10% methanol-water to yield 2.6 g (87%) of product. A sample recrystallized from hexane-ethyl acetate has mp 165° C.-dec.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Br-].[CH:14]1([Zn+])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1COCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: [Zn+]C1CCCCC1
Reactant: COC(=O)c1nc(Br)ccc1N
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2CCCCC2)ccc1N
Yield: 98 %

Procedure:
A solution of methyl 3-amino-6-bromopicolinate (1.0 equiv.), cyclohexyl zincbromide 0.5 M solution in THF (1.5 equiv.), and tetrakis(triphenylphosphine)-palladium(0) (0.05 equiv.) was stirred at 50° C. for 15 minutes. The reaction was filtered and washed with EtOAc. The organic was washed with H2O (100 mL), NaCl(sat.) (50 mL), dried over MgSO4, and the volatiles were removed in vacuo. The product was purified on silica utilizing the Isco 0-65% gradient of hexane/EtOAc to yield methyl 3-amino-6-cyclohexylpicolinate (98%). LCMS (m/z): 235.2 (MH+); LC Rt=1.89 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][NH2:12]>CO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:11][NH2:12])=[O:9]
Reactant: NN
Reactant: COC(=O)c1cnccn1
Solvent: CO
Product: NNC(=O)c1cnccn1
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 1 step c) (22 g, 159 mmol) in methanol (250 ml) was slowly added hydrazine monhydrate (36.6 ml, 710 mmol). The reaction mixture was stirred for 1.5 h. The precipitate produced was filtered, washed with diethyl ether and dried in the oven at 80° C. to give the required product (30 g). 1H NMR (250 MHz, DMSO) δ 4.66 (2H, broad peak), 8.66 (1H, m), 8.84 (1H, d, J=2.5 Hz), 9.13 (1H, d, J=2.5 Hz), 10.15 (1H, broad peak); MS (ES+) m/e 139 [MH+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH:11]1([CH:14]([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:15][C:16]#[N:17])[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>CCOC(C)=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[N:19][N:18]([CH:14]([CH:11]3[CH2:13][CH2:12]3)[CH2:15][C:16]#[N:17])[CH:22]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Reactant: COc1cnc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (from Aldrich Chemicals, 1.47 g, 0.00821 mol), 3-cyclopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (from example 177 step 1, 2.34 g, 0.00815 mol), tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.0005 mol), and potassium phosphate (5.2 g, 0.025 mol) in 1,4-dioxane (20 mL, 0.3 mol) and water (2 mL, 0.1 mol) was heated at 100° C. overnight. After cooling to room temperature, the mixture was dilute with AcOEt, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 60%, to give the desired product (580 mg, 23.43%). LCMS (M+H) 304.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:13])[CH:9]=1
Reactant: C[Mg]Br
Reactant: COc1c(C)cc(F)cc1C=O
Solvent: CCOCC
Product: COc1c(C)cc(F)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred solution of 5-Fluoro-2-methoxy-3-methylbenzaldehyde (1.2 g, 7.13 mmol) in dry diethyl ether (20 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in ether (6.0 mL, 17.83 mmol). The reaction mixture was brought to room temperature and was stirred for 30 min then refluxed for 3 h. It was then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-fluoro-2-methoxy-3-methylphenyl)ethanol (1.0 g, 76%): 1H NMR (400 MHz, CDCl3): δ 7.12 (dd, 1H), 6.83 (dd, 1H), 4.72 (m, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 1.47 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7]([CH:16]=[O:17])[C:6]([CH3:19])([CH3:18])[CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][CH2:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:20])[C:4]3[CH2:5][C:6]([CH3:19])([CH3:18])[N:7]([CH:16]=[O:17])[C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CC(C)(C)N2C=O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)C(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,2,4,7-tetramethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.90 g, 6.95 mmol) in dichloromethane (20 ml) and methanol (10 ml) were added calcium carbonate (0.90 g, 9.0 mmol) and benzyltrimethylammonium dichloroiodate (2.66 g, 7.64 mmol), and stirred for 15 minutes at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added a 5% aqueous solution of sodium hydrogen sulfite (15 ml), and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 2.40 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:15])=[O:14].FC1C=C(F)C=C2C=1CC/C/2=C\C(O)=O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:15])=[O:14]
Reactant: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Agent: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Product: O=C(Cl)/C=C1\CCc2c(F)cccc21

Procedure:
This compound was prepared in a similar manner to (E)-2-(4,6difluoro-1-indanylidene)acetyl chloride in Example 5f by substituting (E)-2-(4-fluoro-1-indanylidene)acetic acid (5.77 g, 0.03 mol) for (E)-2-(4,6-difluoro-1-indanylidene)acetic acid. The resulting solution was concentrated in vacuo, and the residue was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([F:7])[C:4](/[CH:8]=[N:9]/[NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:12])=[C:3]([F:19])[CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C1OC=NN1>>[F:19][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([F:7])[C:4]=1[CH:8]1[N:9]([C:20](=[O:22])[CH3:21])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[O:12]1
Reactant: O=C(N/N=C/c1c(F)cccc1F)c1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: C1=NNCO1
Product: CC(=O)N1N=C(c2ccncc2)OC1c1c(F)cccc1F
Yield: 31 %

Procedure:
The title compound was prepared from the isonicotinoylhydrazone of 2,6-difluorobenzaldehyde and acetic anhydride, using the General Structural Outline for Oxadiazoline Synthesis in 31% yield, mp 119-121° C.; IR ν 1673, 1624, 1594, 1554, 1334, 1312, 1295, 1209, 1092, 1062, 1008, 988, 974, 886, 825, 790, 730, 703, 663, 632 cm−1; NMR (300 Mhz) δ 8.75 (2H, □□br d, J=6 cps), 7.75 (2H, d, J=6 cps), 7.65-7.15 (4H, m from which emerges singlet at 7.5), 2.2 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[N:7]2[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CN1Cc2c(Br)cccc2NC1=O
Agent: [H-]
Agent: [Na+]
Product: CN1Cc2c(Br)cccc2N(Cc2cccc(F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
To a solution of 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one (132 mg, 0.55 mmol) in 5 ml anhydrous dimethylformanide was added sodium hydride (33 mg of a 60% suspension in mineral oil, 0.83 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial offgassing ended. 3-Fluorobenzyl bromide (0.08 ml, 0.65 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting residue was purified by flash chromatography to give 156 mg of 5-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one as a yellow solid (81%). MS: 349.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([CH3:21])(=[O:20])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@H:30]([OH:34])[C:31](O)=[O:32])=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C@H:30]([OH:34])[C:31]([N:15]2[CH2:16][CH2:17][N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13][CH2:14]2)=[O:32])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCNCC1
Reactant: O=C(O)[C@@H](O)Cc1ccc(Cl)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@@H](O)Cc2ccc(Cl)cc2)CC1
Reaction time: 18 h

Procedure:
To a 250-mL round bottomed-flask equipped with a magnetic stir bar and containing a solution of N-(cyclopropylmethyl)(methylsulfonyl)(2-piperazinyl-phenyl)amine (Step 2) (1.8 g, 5.8 mmol) and (2S)-3-(4-chlorophenyl)-2-hydroxypropanoic acid (Step 1) (1.2 g, 5.8 mmol) in CH2Cl2 (30 mL) and DMF (30 mL) at RT was added HOAT (Aldrich) (0.87 g, 6.4 mmol) followed by EDC (Aldrich) (1.3 g, 7.0 mmol). This was stirred for 18 h and diluted with CH2Cl2 (300 mL). The mixture was washed with H2O (3×100 mL), aq. NaHCO3 (1×100 mL) and brine (1×100 mL). It was dried (Na2SO4) and concentrated onto silica gel. Purification by chromatography (40 to 55% EtOAc/hexanes) afforded (2S)-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]-phenyl}-piperazinyl)-2-hydroxypropan-1-one as a slightly yellow oil (1.8 g). Analytically pure material was obtained by reverse phase preparative scale chromatography (Column: MetaChem Polaris C18-A 5 micron, flow: 20 mL/min, gradient: 5 to 100% CH3CN (0.1% TFA)/H2O (0.1% TFA). MS (ESI, pos. ion) m/z 492 (M+1). Calc'd for C24H30ClN3O4S: 491.16.