Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:34]3[C:29]([CH3:28])=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1ncccc1B(O)O
Product: Cc1ncccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (2-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.71 min, m/z=459.0 [M+H]+, m/z=547.2 [M−H]−.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (35 mg), potassium carbonate (37 mg), and piperidine (23 mg), and the mixture was stirred at 75° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 89%).
Reaction SMILES: C[O-].[Na+].C[Si](C)(C)[N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13].[CH3:16]S(OC)(=O)=O>COCCOC>[CH3:16][N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:13]
Reactant: C[Si](C)(C)N1CCCCCC1=O
Reactant: COS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.4 g (0.1 mol) of sodium methylate and 18.5 g (0.1 mol) of N-trimethylsilylcaprolactam are introduced successively into 150 ml of 1,2-dimethoxyethane, and the mixture is stirred at room temperature for 30 minutes. Then 11 g (0.1 mol) of methyl methanesulfonate are added dropwise. After the reaction mixture has been stirred at 50° C. for a further one hour, it is cooled, the sodium mesylate is removed by filtration with suction, and the filtrate is evaporated. The oily residue is distilled in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([I:21])[CH:14]=2)=[C:7]([Br:22])[CH:6]=1.B(Br)(Br)Br.O>ClCCl>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]=[C:7]([Br:22])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:21])[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(I)c2)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Temperature: -78 °C
Reaction time: 30 h
Yield: 89.8 %

Procedure:
Methyl[3,5-dibromo-4-(4-methoxy-3-iodophenoxy)phenyl]acetate (0.82 g, 1.5 mmol) was dissolved in dichloromethane (25 mL) and cooled down to −78° C. Boron tribromide (8.8 mL, 1 N in dichloromethane) was added and the reaction mixture was stirred at −20° C. for 30 hours. Water was added to the reaction mixture, the organic phase separated and concentrated. The residue was filtered on a short column (silica, dichloromethane/ethyl acetate 1:1), to give 0.73 g (90%) of methyl [3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)-phenyl]acetate as a beige solid mass.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C[O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:35])[C:14]2[O:20][C:19]3[C:21]([Cl:31])=[CH:22][C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:33])(=[O:32])[C:15]=2[CH:34]=1)=[O:10]>ClCCl.N1C=CC=CC=1>[Cl:31][C:21]1[C:19]2[O:20][C:14]3[C:13]([CH3:35])=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:34][C:15]=3[S:16](=[O:32])(=[O:33])[CH2:17][C:18]=2[CH:24]=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:29][CH2:30]2)[CH:22]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(C(=O)C4CC4)CC3)cc1CS2(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of cyclopropyl carbonyl chloride (0.22 mL, 2.4 mmol) in dichloromethane (2 mL) was added to a suspension of Example 104k (0.35 g, 0.8 mmol) in pyridine (3 mL)/dichloromethane (1 mL) at 10° C. The reaction mixture was stirred for 45 min, concentrated, treated with chilled water and dilute HCl to pH 6. The precipitated solid was filtered and dried to obtain the title compound. Yield: 0.372 g, (91.5%); 1H NMR (DMSO-d6): δ 0.76 (m, 4H, 2CH2); 2.06 (m, 1H, CH); 2.68 (s, 3H, CH3); 3.24 (s, 2H, CH2); 3.32 (s, 2H, CH2); 3.64 (s, 2H, CH2); 3.84 (s, 2H, CH2); 5.15 (s, 2H, CH2); 7.12 (d, 1H, Ar); 7.2 (d, 1H, Ar); 8.1 (s, 1H, Ar); 8.2 (s, 1H, Ar); 8.38 (s, 1H, OH). MS: m/e (ES+) 532 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[N:45]1([CH2:51][CH2:52][C:53](O)=[O:54])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.Cl>CCOCC.C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:53](=[O:54])[CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.12 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran, prepared according to the method of Example 6, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216° - 220°, J. Am. Chem. Soc. 73, 3168 (1951) are combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture is filtered and the methylene chloride removed using a rotary evaporator. The residue is treated with benzene and filtered to remove a small quantity of insoluble material. The benzene is evaporated and the dark, viscous residue is chromatographed using 100 g. of 60 - 100 mesh Florosil activated magnesium silicate and methanol/chloroform graded solvent mixtures. Chromatography yields an oil which is dissolved in ether and treated with a solution of ethereal HCl. The desired compound appears as crystals which are filtered and washed with additional ether to obtain the desired product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[C:17]([C:20]([NH2:22])=[O:21])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[C:5]([O:23][C@@H:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:4]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:26]1[CH2:27][CH2:28][C@@H:24]([O:23][C:5]2[CH:4]=[C:3]([F:2])[CH:8]=[CH:7][C:6]=2[NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[C:17]([C:20]([NH2:22])=[O:21])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:25]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCNC3)c12
Agent: Cl
Product: CC(=O)N1CC[C@@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 99.4 from 4-[4-fluoro-2-((R)-pyrrolidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide hydrochloride and acetic anhydride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(S)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
4-Fluoro-2-(trifluoromethyl)benzenesulphonyl chloride (2 g) was dissolved in 1,4-dioxane (12 mL) and water (3 mL) under a nitrogen atmosphere. Tris-(2-carboxylethyl)phosphine hydrochloride (8.73 g) was added and the mixture was stirred under reflux for 6 h. The reaction mixture was cooled to 25° C. and water (20 mL) was added. The product was extracted 3 times with CH2Cl2 (20 mL). The combined organic layers were dried over Na2SO4 filtrated and evaporated to dryness to yield the title compound (1.27 g, 85%) as a colorless liquid. MS (ESI): m/z=194.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.[NH3:23].CO>O1CCCC1>[NH2:23][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 14 g of 5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, A. D. Rudzik & B. V. Kamdar, J. Med. Chem., 1971, 14, 1078-1081) in 700 ml of tetrahydrofuran were added firstly 260 ml of 25% aqueous ammonia solution and then 50 ml of methanol. The solution was stirred at room temperature for 20 h. and then concentrated to about 25 ml in a vacuum. The crystalline precipitate was filtered off and recrystallized from dioxan. There were obtained 13.2 g of 2-amino-5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine of m.p. 222-224° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C[O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:35][CH2:34][O:33][C:26]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=3[C:24]([OH:37])=[O:23])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: c1coc(Cn2cc(C3CCNCC3)c3cccnc32)c1
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Product: COc1ccc(C(=O)O)c(OCCN2CCC(c3cn(Cc4ccco4)c4ncccc34)CC2)c1
Yield: 36 %

Procedure:
This compound was prepared following the procedure described in example 4, part E and F starting with 3.6 g (11 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 4.0 g (16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 36% (1.93 g).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11]Cl>>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: ClCCOc1ccccc1Br
Reactant: C1=CCNC1
Product: Brc1ccccc1OCCN1CC=CC1

Procedure:
The title compound was prepared from 3-pyrroline and 2-(2-bromophenoxy)ethyl chloride in a similar manner to Example 42 (b).
Reaction SMILES: N1([O:10][C:11](=[O:43])[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)C2C=CC=CC=2N=N1.[CH3:44][O-].[Na+]>CO.Cl>[CH3:44][O:10][C:11](=[O:43])[C:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH:36]3[S:40][C:39](=[O:41])[NH:38][C:37]3=[O:42])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[CH:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cc(C)cc(C)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 62 %

Procedure:
To a solution of 48 (240 mg, 0.4 mmol) in methanol (10 mL) was added sodium methoxide (0.5 N in methanol, 2 mL). After 10 min the mixture was diluted with 1N HCl (2 mL) and the product was extracted into ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography using hexanes:ethyl acetate (3:2) to yield 49 (122 mg, 62%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.71 (s, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.92 (s, 1H), 6.68 (s, 2H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.73 (s, 3H), 3.37 (dd, J=14.0 and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.12 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:34]1[C:35]2[C:31](=[CH:30][CH:29]=[C:28]([NH:27][C:2]3[N:3]=[C:4]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:5]4[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:36]=2)[CH:32]=[N:33]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: N#Cc1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CC3)c12
Temperature: 116 °C
Reaction time: 18 h
Yield: 6.5 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (109 mg, 0.28 mmol), 6-aminoindazole (75 mg, 0.56 mmol) and TMSCl (0.089 mL, 0.70 mmol) in nBuOH (4 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (6 mg). MS 331.1 (M+H); UV 246.2, 307.9 nm.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29](=[O:34])CCCC)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC1(C)C(C)(C)OB(C2C=[C:48]([CH2:52][NH:53][C:54](=[O:59])[CH2:55]CCC)[CH:49]=[CH:50][CH:51]=2)O1>>[C:54]([N:53]1[CH2:52][CH2:48][CH:49]([C:29]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:50][CH2:51]1)(=[O:59])[CH3:55]
Reactant: CCCCC(=O)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Reactant: CCCCC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)C5CCN(C(C)=O)CC5)c4)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide substituting 1-acetyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-4-piperidinecarboxamide (56 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][O:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26]>C1COCC1>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[C:23]=1[CH3:30])[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]1=[O:19]
Reactant: COc1cccc(C=O)c1C
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(C(O)C2CCCCC2=O)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of diisopropylamine (1.44 ml) in THF (8 ml) was added n-BuLi (1.56M solution in hexane, 70 ml) at −60° C. The mixture was warmed to 0° C., stirred for 10 minutes, and recooled to −60° C. To the mixture was added cyclohexanone (0.98 g) in THF (5 ml). After stirring for 1 hour, 3-methoxy-2-methylbenzaldehyde (1.5 g) was added and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was quenched with saturated NH4Cl solution, warmed to room temperature, extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 4:1 to 2:1) to give 2-[hydroxy-(3-methoxy-2-methylphenyl)methyl]cyclohexanone (1.86 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Temperature: 0 °C
Yield: 101.6 %

Procedure:
A stirred solution of 2-bromo-4-fluorobenzotrifluoride (1.0 g, 4.1 mmole) in concentrated sulphuric acid (10 ml) at 0° C. was treated portionwise with KNO3 (0.46 g, 4.6 mmole) and maintained at 0° C. for 0.5 hr before warming to room temp. over 2 hr. The mixture was added to well stirred ice/water (100 ml) and then extracted with ethyl acetate. The extract was dried and concentrated under vacuum to afford the title compound as a yellow solid (1.2 g, 100%). 1H NMR (400 MHz, CDCl3) δ: 7.75 (1H, d), 8.45 (1H, d).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:29]3([CH3:28])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC1(C(=O)O)CC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(C)CC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 1-methyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=361.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:32])=[CH:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSc1ccc(-c2cnc3c(C(=O)O)cnn3c2C2CCCCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2cnc3c(C(=O)O)cnn3c2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a cloudy solution of 14 mg (0.038 mmol) of 7-cyclohexyl-6-(4-methylsulfanyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in 2 mL of chloroform was added 9 mg (1.5 equiv) of m-chloroperoxybenzoic acid (mCPBA) and the cloudy solution became clear. Since after 5 min of stirring at rt TLC indicated disappearance of starting material, the mixture was concentrated to a residue which was purified via reverse-phase chromatography (using Gilson) to afford (after lyophilization) 10 mg (69% yield) of 7-cyclohexyl-6-(4-methanesulfinyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (491) as a solid as indicated by LC-MS—calcd for C20H21N3O3S [M++H]+: 384.13, found: 384.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[F:23][C:24]([F:38])([F:37])[C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Cl:16][C:12]1[CH:11]=[C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[C:25]([C:24]([F:38])([F:23])[F:37])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:32][CH2:33]3)[N:3]=[C:4]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1c(Cl)nc(N2CCOCC2)nc1-c1cccc(Cl)c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c(-c2cccc(Cl)c2)nc(N2CCOCC2)nc1N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
Dissolve 4-chloro-6-(3-chlorophenyl)-2-morpholinopyrimidine-5-carbonitrile (33.5 mg, 0.1 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (23 mg, 0.1 mmoles) in CH3CN (1.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (28 mg, 0.2 mmoles) to this mixture and heat at 80° C. for 24 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product Purify by flash column chromatography using 30% EtOAc/hexane to afford the title product as white solid. NMR (DMSO-D6) δ 3.30 (4H, s), 3.62 (4H, m), 3.80 (4H, s), 3.93 (4H, s), 7.19 (1H, m), 7.51 (1H, m), 7.59 (1H, m), 7.76 (1H, m), 7.83 (1H, s), 8.07 (1H, d, J=2.0), 8.52 (1H, d, J=1.2). Mass spec m/z=530.12.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[C:2]1([CH:1]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 89 %

Procedure:
7.05 g (0.05 mol) of benzoyl chloride, 6.5 g (0.0625 mol) of styrene, 8.65 g (0.05 mol) of tri-n-butylamine, 0.1122 g (0.0005 mol) of palladium acetate and 100 ml of p-xylene are introduced into a 250 ml flask and heated to 120° C., with stirring. A slight evolution of gas is observed. After the mixture has been stirred for 2 hours at 120° C., it is cooled and extracted by shaking with 2×25 ml portions of 2 N hydrochloric acid, and the organic phase is dried with magnesium sulfate. The p-xylene is distilled off and the residue is recrystallised from ethanol. 8.0 g (0.0445 mol) of stilbene are obtained as a colourless, crystalline compound, corresponding to a yield of 89% of theory; melting point 125° C.