Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].[CH3:3][C:4]([C:7]1[N:12]=[C:11](Cl)[C:10]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=1)([CH3:6])[CH3:5].C1OCCOCCOCCOCCOCCOC1.O>S1(CCCC1)(=O)=O>[CH3:3][C:4]([C:7]1[N:12]=[C:11]([F:1])[C:10]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(c1cnc(C(C)(C)C)nc1Cl)C(C)C
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1F)C(C)C
Temperature: 150 °C
Yield: 45 %

Procedure:
A stirred suspension of dry potassium fluoride (1.41 g) and ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-chloropyrimidin-5-yl]-3-methylbutyrate (1.88 g) in dry sulpholane (14 cm3) in the presence of 18-crown-6 (0.38 g) was heated to 150° C. for a period of 24 hours, under an atmosphere of dry nitrogen. After cooling to the ambient temperature (ca. 22° C.), the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was washed with water and brine, dried and the solvent evaporated under reduced pressure. The residual brown liquid was purified by column chromatography on silica gel, using dichloromethame as eluent, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-fluoropyrimidin-5-yl]-3-methylbutyrate (0.8 g) as an orange liquid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])[O:11][C:10]2=O)=[CH:5][CH:4]=1.[O:21]=[C:22]1[N:26](CO)[C:25](=[O:29])[CH2:24][N:23]1[CH2:30][C:31]#[CH:32]>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:13]([CH:14]([CH3:15])[CH3:16])[C:12]([O:11][CH2:10][N:26]2[C:25](=[O:29])[CH2:24][N:23]([CH2:30][C:31]#[CH:32])[C:22]2=[O:21])=[O:17])=[CH:7][CH:8]=1
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2)C(C)C)C1=O

Procedure:
In the same way, 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol to give (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:17])[CH:23]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2ccc(OC3CN4CCC3CC4)cc2)c1
Temperature: 25 °C

Procedure:
The product of Example 1A (330 mg, 1 mmol) in toluene (8 mL) was treated with 3-amino-phenylboronic acid (Lancaster, 276 mg, 2 mmol), Pd2(dba)3 (Strem Chemicals, 18.3 mg, 0.02 mmol), 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride, 95%, 26.9 mg, 0.06 mmol), and Na2CO3 (aqueous, 2M, 2 mL, 4 mmol) at 110° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (20 mL), and washed with brine (2×5 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as oil (230 mg, yield, 78%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40-1.53 (m, 1H), 1.62-1.85 (m, 2H), 1.96-2.20 (m, 2H), 2.80-2.94 (m, 5H), 3.28-3.40 (m, 1H), 4.52-4.60 (m, 1H), 6.66 (ddd, J=7.8, 2.3, 1.0 Hz, 1H), 6.89 (ddd, J=7.3, 1.6, 1.0 Hz, 1H), 6.92-6.96 (m, 3H), 7.13 (t, J=7.8, Hz, 1H), 7.48 (dt, J=8.8, 2.1 Hz, 2H) ppm. MS (DCl/NH3) m/z 295 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]4[CH:29]=[C:30]([F:34])[C:31]([Cl:33])=[CH:32][C:26]=4[N:25]=3)=[CH:20][C:19]=2[Cl:35])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCN(CCCOC2C=CC(C=O)=CC=2Cl)CC1)=O)(C)(C)C.ClC1C=C(N)C(N)=CC=1F>>[Cl:33][C:31]1[C:30]([F:34])=[CH:29][C:27]2[NH:28][C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:19]([Cl:35])[CH:20]=3)=[N:25][C:26]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(-c3nc4cc(Cl)c(F)cc4[nH]3)cc2Cl)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2Cl)CC1
Agent: Nc1cc(F)c(Cl)cc1N
Product: Fc1cc2[nH]c(-c3ccc(OCCCN4CCNCC4)c(Cl)c3)nc2cc1Cl
Yield: 15 %

Procedure:
4-{3-[2-Chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester. This compound was prepared by the method described in Example 1, using 4-[3-(2-chloro-4-formyl-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.6 mmol, 1.0 equiv), 4-chloro-5-fluoro-benzene-1,2-diamine (421 mg, 2.6 mmol, 1.0 equiv), and Na2S2O5 (648 mg, 3.4 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 256 mg (15%) of the title compound. MS (electrospray): mass calculated for C25H29Cl2FN4O3, 522.16. m/z found, 545.3 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[C:9](=[O:20])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:11][C:5]2=[CH:4][N:3]=1>NC1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:11][C:5]3[C:6](=[N:7][C:2]([NH:10][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3][CH:4]=3)[N:8]([CH3:21])[C:9]2=[O:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N(C)C2=O)cc1
Solvent: Nc1ccccc1
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C)C2=O)cc1
Temperature: 120 °C

Procedure:
The mixture of 7-chloro-3-(4-methoxy-phenyl)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-one (65 mg, 0.21 mmol) in aniline (1.0 mL) (Aldrich) was heated to 120° C. for 1 hour. After cooling, the reaction mixture was washed with hexanes (100 mL×4) and the crude product was re-crystallized from ethyl acetate-hexanes to give 3-(4-methoxy-phenyl)-1-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-one as an off-white solid. (Yield 76.0 mg, 98.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14](COC(=O)C(C)(C)C)[CH:15]=[N:16]2)=[C:11]([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[NH:14][CH:15]=[N:16]2)=[C:11]([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude tert-butyl (2R)-2-{[(7-(benzyloxy)-3-{[(2,2-dimethylpropanoyl)oxy]-methyl}4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (assumed 18 g) was dissolved in 7N ammonia in methanol and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography using 0-10% methanol in DCM as eluent to give a mixture of two products. The mixture was dissolved in DCM, washed with 20% aqueous sodium hydroxide solution (2×) and then dried (MgSO4) and concentrated in vacuo to leave tert-butyl (2R)-2-({[7-(benzyloxy)-4-oxo-3,4-dihydroquinazolin-5-yl]oxy}methyl)pyrrolidine-1-carboxylate as a beige foam (6.8 g, 48% for the two steps); Mass spectrum MH+ 452.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1)(=O)=O.[CH3:36][NH2:37]>CO>[CH3:36][NH:37][CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(COS(C)(=O)=O)c3ccccc32)cc1
Reactant: CN
Solvent: CO
Product: CNCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 100 °C

Procedure:
To 5-methanesulfonyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is added a 30% solution of methylamine in methanol (50 ml), and the mixture is heated at 100° C. for 3 hours in a sealed tube. After cooling, the reaction solution is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol:aqueous ammonia=100:10:1) to give 5-methylaminomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.07 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[C:9]([Br:12])[C:10]=1[OH:11])[CH:5]=[N:6][OH:7].N1(C2CCCCCCC2)CCCCCCN1.[CH3:30][N:31]=[C:32]=[O:33]>CS(C)=O>[CH3:30][NH:31][C:32](=[O:7])[OH:33].[CH3:30][NH:31][C:32](=[O:7])[OH:33].[CH3:30][NH:31][C:32](=[O:7])[OH:33].[OH:13][C:3]1[C:2]([Br:1])=[C:10]([OH:11])[C:9]([Br:12])=[CH:8][C:4]=1[CH:5]=[N:6][OH:7]
Reactant: CN=C=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Agent: ON=Cc1cc(Br)c(O)c(Br)c1O
Solvent: CS(C)=O
Product: CNC(=O)O
Temperature: 0 °C

Procedure:
6 g of 3,5-dibromo-2,4-dihydroxy-benzaldoxime were dissolved in 50 ml of dimethylsulfoxide and a little diazabicyclooctane was added. 4 ml of methyl isocyanate were now added with cooling (<20° C.) and stirring and the mixture was then stirred thoroughly at room temperature for 12 hours. The reaction mixture was poured into ice-water and salted out. The suspension was filtered with suction, the residue was washed with water and dissolved in a little dimethylformamide and active charcoal was added to the solution.
Reaction SMILES: COCN[C:5]([C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[OH:17][C:16]1[C:7]([C:5](=[O:6])[CH3:18])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COCNC(=O)c1cc2ccccc2cc1O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc2ccccc2cc1O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid methoxymethylamide (600 mg) was dissolved in tetrahydrofuran (36 ml) to prepare a solution. A solution (9.8 ml) of 0.93 M methylmagnesium bromide in tetrahydrofuran was added thereto at −78° C., temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hr. A saturated aqueous ammonium chloride solution was added to stop the reaction, water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with an aqueous potassium carbonate solution, was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 1-(3-hydroxynaphthalen-2-yl)-ethanone (378 mg, yield 78%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:21]=[C:20]([C:22]([N:24]2[CH2:29][CH2:28][C:27]3([CH2:38][C:37](=[O:39])[C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:40]5[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=5)[CH:35]=4)[O:30]3)[CH2:26][CH2:25]2)=[O:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[CH:46]1[CH2:48][CH2:47]1)(=O)=O.[NH:51]1[CH2:56][CH2:55][CH:54]([C:57]([O:59][CH2:60]C)=[O:58])[CH2:53][CH2:52]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:46]1([N:17]2[C:18]3[C:14](=[C:13]([N:51]4[CH2:56][CH2:55][CH:54]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH2:52]4)[CH:21]=[C:20]([C:22]([N:24]4[CH2:25][CH2:26][C:27]5([CH2:38][C:37](=[O:39])[C:36]6[C:31](=[CH:32][CH:33]=[C:34]([C:40]7[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=7)[CH:35]=6)[O:30]5)[CH2:28][CH2:29]4)=[O:23])[CH:19]=3)[CH:15]=[CH:16]2)[CH2:47][CH2:48]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc3c2ccn3C2CC2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (261 mg, 0.800 mmol), Pd(OAc)2 (8.98 mg, 0.040 mmol), 1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl trifluoromethanesulfonate (251 mg, 0.4 mmol), ethyl 4-piperidinecarboxylate (94.0 mg, 0.600 mmol) and biphenyl-2-yl(di-tert-butyl)phosphine (11.9 mg, 0.0400 mmol) were suspended in 1,4-dioxane (3 ml) and the mixture was stirred at 100° C. overnight. The mixture was filtered through celite pad, washing with CHCl3, and the solvent was evaporated under reduced pressure. The residue was purified by silicagel column chromatography (CHCl3/MeOH), then preparative-TLC (CHCl3/MeOH) to give intended compound as brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[O:22][CH2:23][O:24][CH3:25])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[CH3:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:8]=3[N:9]=2)=[C:13]([O:22][CH2:23][O:24][CH3:25])[CH:14]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
A mixture of 6 (612 mg, 1.5 mmol), 2-(aminomethyl)pyridine (1.08 g, 10 mmol), and Na2CO3 (excess) in CH3CN (30 mL) was stirred overnight at room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. Water (20 mL) was added to the residue, which was extracted with ethyl acetate (20 mL) three times. The combined organic layer was washed with brine and water, dried over MgSO4, and evaporated. The resulting oily material was purified by silica gel column chromatography (CHCl3-ethyl acetate) to afford 7 as pale yellow oil (112 mg, 17%): 1H-NMR (500 MHz, CDCl3) δ3.56 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.02 (s, 2H), 4.30 (s, 2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.15 (dd, 1H, J=7.5, 5.0 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.55 (d, 1H, J=5.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6′-bromo-1′-(1,1-dimethylethylsulfinamido)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (6) (62.8 mg, 0.129 mmol) in MeOH (5 mL) was added a 4 M HCl solution in dioxane (2 mL). The resulting mixture was stirred for 30 min. Solvent was removed under reduced pressure, and the residue 7 was used for next step without further purification. MS ESI+ve m/z 382 (M+H)30.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C(O)=O.C([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CN1CCCCC1
Reactant: Cc1ccsc1C=O
Agent: Cl
Solvent: O
Solvent: O=CO
Product: Cc1ccsc1CN1CCCCC1

Procedure:
A mixture of 3-methyl-2-thiophenecarboxaldehyde (20 g), formic acid (6 ml) and N-formyl piperidine (44.4 ml) was heated under reflux for 12 h. Water (50 ml) and 2 M hydrochloric acid (30 ml) were added; and the aqueous solution was washed with ether. The solution was basified to pH 10 with 2 M sodium hydroxide (30 ml) and extracted with ether. The organic extract was evaporated to give a brown oil which was distilled to afford the title compound as a colourless oil (11.8 g) b.p. 70°/0.4 mm. NMR (CDCl3) 2.9,d, (1H); 3.27,d, (1H); 6.48,s, (2H); 7.6,m, (4H); 7.83,s, (3H); ca. 8.5,m, (>6H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([C:12](Cl)=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[CH2:17]([OH:19])[CH3:18].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([C:12]([O:19][CH2:17][CH3:18])=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: CC1(C)OC(C(=O)Cl)Oc2ccc(Cl)cc21
Reactant: CCO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1Oc2ccc(Cl)cc2C(C)(C)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
A solution of 9.4 g of 6-chloro-4,4-dimethyl-[4H]-1,3-benzodioxin-2-carboxylic acid chloride in 50 ml of anhydrous benzene was added dropwise at room temperature with stirring to a mixture of 2.3 g of ethanol, 30 ml of anhydrous benzene and 3.03 g of triethylamine and the solution was stirred for 6 hours at room temperature and was vacuum filtered. The filtrate was washed with 70 ml of an aqueous saturated sodium bicarbonate solution and twice with 70 ml of water, was dried over magnesium sulfate, treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the 8.4 g of residue were chromatographed over silica gel H. Fractional elution with methylene chloride and evaporation of the solvent yielded 5.3 g of ethyl 6-chloro-4,4-dimethyl-[4H]-1,3-benzodioxin-2-carboxylate in the form of an oil which crystallized at less than 50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:12][C:7]1[CH:6]=[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
1-Fluoro-4-(methylsulfonyl)benzene (5.0 g, 28.7 mmol) in conc. sulfuric acid (30 mL) was cooled to 0° C. To this solution was added N-bromosuccinimide (5.62 g, 31.6 mmol). The reaction mixture was stirred at room temperature for 6 hours and then poured into ice-water. The resulting solid was collected by filtration, washed with cold water three times, and dried in a vacuum oven overnight to give the title compound (6.95 g, 27.5 mmol, 96% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@@H:31]2[CH3:36])[CH2:29][CH2:28]1>>[CH:27]1([N:30]2[CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32][C@@H:31]2[CH3:36])[CH2:29][CH2:28]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C[C@H]1CNCCN1C1CC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C4CC4)[C@@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropyl-2-methylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09-0.71 (m, 4H) 0.87-1.23 (m, 3H) 3.43 (br. s., 1H) 2.36 (s, 3H) 2.48-2.65 (m, 1H) 2.72-3.14 (m, 3H) 3.43 (br. s., 2H) 4.05 (br. s., 1H) 7.59 (d, J=7.64 Hz, 1H) 7.66 (s, 1H) 7.70 (br. s., 1H) 8.00 (d, J=8.08 Hz, 1H) 8.09 (br. s., 1H) 8.34 (br. s., 1H) 8.44-8.50 (m, 1H); ESI-MS m/z [M+H]+ 443.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:31]([O:26][C@@H:20]([C:3]1[C:4]([CH3:19])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]=2[CH3:11])[C:2]=1[Cl:1])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@@H](O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 2.5 h
Yield: 56.6 %

Procedure:
A solution of (S)-ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (3.08 g, 7.81 mmol) in CH2Cl2 (130 ml) was treated with tert-butyl acetate (73.9 ml, 547 mmol) and perchloric acid (2.014 ml, 23.44 mmol), and the reaction was stoppered. The reaction was stirred for 2.5 hrs, then diluted with CH2Cl2 (130 ml) and carefully quenched with sat. NaHCO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give a light amber mobile oil. The crude product was purified by flash silica gel column chromatography, eluting with 10%-30% EtOAc in hexanes, to afford the product, (S)-ethyl 2-(tert-butoxy)-2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (2.05 g, 4.42 mmol, 56.5% yield) as a viscous oil, which began to crystallize upon standing. 1H NMR (500 MHz, CDCl3) δ: 7.87 (t, J=1.5 Hz, 1H), 7.74 (dt, J=7.3, 1.5 Hz, 1H), 7.46-7.36 (m, 2H), 5.63 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 2.68 (s, 3H), 2.51 (s, 3H), 1.26 (s, 9H), 1.21 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>C(Cl)Cl>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:31]
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)c1ccc2occ(CCN)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2occ(CCNC(=O)c3ccco3)c2c1
Reaction time: 0.33 h

Procedure:
1 mmol of the compound obtained in Step A is introduced into 30 ml of anhydrous CH2Cl2. The temperature is lowered with the aid of an ice bath, and 1.5 mmol of triethylamine and then 1.5 mmol of 2-furoic acid chloride are added dropwise in succession. The mixture is stirred for 20 minutes, and the organic phase is then washed with water, dried over MgSO4 and evaporated. The residue is purified by chromatography on a silica gel column and the title product is recrystallised.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(Cl)Cl.[F:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([OH:26])=[CH:21][C:20]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:25][C:23]2[CH:24]=[C:19]([F:18])[C:20]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:21][C:22]=2[O:26]1
Reactant: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Reactant: Clc1ccccc1C(Cl)(Cl)c1ccccc1Cl
Product: O=C(c1cc2c(cc1F)OC(c1ccccc1Cl)(c1ccccc1Cl)O2)N1CCOCC1
Temperature: 150 °C
Yield: 4.5 %

Procedure:
A mixture of bis-(2-chlorophenyl)dichloromethane (Example 182, 258 mg, 0.84 mmol, 2.6 eq.) and (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b, 72 mg, 0.32 mmol) were heated 5 h at 150° C. in a sealed glass tube. Purification by flash chromatography afforded the title compound (6.8 mg, 4.5%) as an off-white solid, m.p.: 98° C.