Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:31]#[N:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(N)c1ccc(C2(C#N)CCCCC2)cc1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CCCCC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (216 mg, 1.08 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclohexanecarbonitrile (246 mg, 1.08 mmol) prepared according to scheme 11, Et3N (328 mg, 3.24 mmol, 0.452 mL) and HATU (411 mg, 1.08 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (443 mg, 1.08 mmol, quantitative). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.22-1.36 (m, 1H) 1.39 (d, J=6.84 Hz, 3H) 1.53-1.68 (m, 2H) 1.68-1.77 (m, 1H) 1.77-1.89 (m, 4H) 1.98-2.08 (m, 2H) 4.88-5.02 (m, 1H) 5.24 (dd, J=24.61, 17.77 Hz, 2H) 7.35 (t, J=7.91 Hz, 1H) 7.40 (d, J=8.40 Hz, 2 H) 7.46 (d, J=8.40 Hz, 2H) 7.72 (d, J=7.62 Hz, 1H) 8.01 (dd, J=8.20, 0.78 Hz, 1H) 8.35 (s, 1 H) 8.85 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 412.0. found: 412.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[C:22]([F:34])=[C:23]([C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C1COCC1>[Cl:20][C:21]1[C:22]([F:34])=[C:23]([C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)[C:24]([N:12]=[C:6]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]1)=[O:25]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1c(C(F)(F)F)ccc(Cl)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)sc1=NC(=O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and 3-chloro-2-fluoro-6-trifluoromethyl benzoyl chloride (Alfa Aesar, 0.35 g, 13 mmol) in 5 mL THF was added dropwise via syringe. The mixture was allowed to stir at ambient temperature for 1 hour, then was warmed to reflux and was allowed to stir for 8 hours. The mixture was then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified via flash column chromatography (SiO2, 7:3 hexanes:EtOAc) to provide the title compound (0.20 g, 0.50 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.27 (s, 3H), 2.28 (s, 3H), 3.27 (s, 3H), 3.68 (t, J=4.7 Hz, 2H), 4.28-4.37 (m, 2H), 7.37-7.43 (m, 1H), 7.44-7.52 (m, 1H); MS (DCI/NH3) m/z 411 (M+H)+; Anal. calculated for C16H15ClF4N2O2S: C, 46.78; H, 3.68; N, 6.82. Found: C, 46.83; H, 3.30; N, 6.65.
Reaction SMILES: C([CH2:4][NH:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=O)(O)=O.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+].C(O[C:24](=[O:26])[CH3:25])(=O)C>>[C:24]([N:5]1[C:6]2=[N:14][CH:13]=[CH:12][CH:11]=[C:7]2[C:8]([O:17][C:15](=[O:18])[CH3:16])=[CH:4]1)(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNc1ncccc1C(=O)O
Agent: [Na+]
Product: CC(=O)Oc1cn(C(C)=O)c2ncccc12

Procedure:
Acetic acid 1-acetyl-1H-pyrrolo[2,3-b]pyridin-3-yl ester 502 is prepared by reacting 2-(Carboxymethyl-amino)-nicotinic acid 501 with sodium acetate in refluxing acetic anhydride for several hours, followed by purification and isolation by conventional means (e.g. recrystallization) (Su & Tsou; J. Am. Chem. Soc., 82, 1960, 1187).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1
Reactant: CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.9 %

Procedure:
To a solution of 4-chloro-1-ethyl-2-nitro-benzene (0.57 g, 3.08 mmol) in a mixture of ethyl acetate and ethanol (1/1, 30 mL) was added stannous chloride (1.7 g, 9.24 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and basified by addition of potassium carbonate until pH>10. The resulting mixture was extracted with dichloromethane; the organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 0.503 g of 5-chloro-2-ethyl-phenylamine as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:22])[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>N1C=CC=CC=1.C(Cl)Cl.C(OC(=O)C)C>[NH2:22][C:10]1[N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:12]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Cn1cc(-c2cccc(N)c2)nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccccc1Cn1cc(-c2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
55.1 A solution of 100 mg 4-(3-aminophenyl)-1-(2-methoxybenzyl)-1H-imidazole-2-ylamine (0.34 mmol, Example 51) in 3 mL pyridine was combined with 74 mg 4-isopropylbenzenesulfonic acid chloride at 0° C., then stirred for 18 hr at room temperature. The batch was then diluted with methylene chloride, extracted with 1 M NaOH and with water, and the organic phase was then dried (Na2SO4) and concentrated, and the residue thus obtained was stirred in acetic ethyl ester, suctioned off, and dried (130 mg target product).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:17][S@@](C(C)(C)C)=O)([CH3:16])[C:9]([F:15])([F:14])[C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([F:24])=[CH:4][CH:3]=1.[N:25]#[C:26]Br>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:16])[C:9]([F:14])([F:15])[C:10]([CH3:11])([CH3:12])[O:13][C:26]([NH2:25])=[N:17]2)[C:5]([F:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](C)(c1nc(Br)ccc1F)C(F)(F)C(C)(C)O
Reactant: N#CBr
Solvent: CCO
Product: CC1(C)OC(N)=N[C@](C)(c2nc(Br)ccc2F)C1(F)F
Temperature: 85 °C
Yield: 48.9 %

Procedure:
A solution of (R)-2-methyl-propane-2-sulfinic acid [(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-3-hydroxy-1,3-dimethyl-butyl]-amide (2.95 g, 6.84 mmol) and cyanogen bromide (2.24 g, 20.52 mmol) in dry ethanol (68 ml) was sealed with a glass stopper and heated at 85° C. for 9 hr. The reaction solution was evaporated in vacuo and the crude product was taken up with ethyl acetate and 2M aq. ammonia. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (2.74 g) was chromatographed over silica gel (toluene/ethyl acetate 6:4) to give the title compound as a colourless solid. 1.19 g (48.9% yield).
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](O)=[O:24])=[O:20])=[CH:13]2>C(OCC)(=O)C>[CH2:26]([CH:22]([NH:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)=[O:20])[C:23](=[O:24])[N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Piperidone monohydrate (2.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to procedure A (0-25° C. reaction temperature) substituting the following workup: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 2N NaOH and 2N HCl, the suspension filtered and the solids dried: Yield 111 mg, 26%; HPLC (60/40) 8.88 minutes (92%); PBMS 424/426 (MH+, 100%); mp 258-261° C.; PBMS 424/426 (MH+, 100%);
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[NH:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:2].C([Li])CCC.Cl[P:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[N:18][P:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCc1ccccc1NC(=N)c1ccc(C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: CCc1ccccc1NC(=NP(C(C)C)C(C)C)c1ccc(C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of N1-(2-ethylphenyl)-4-methylbenzamidine (Amidine VIII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.77 g, 100%).
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[C:12](OC(=O)C)(=[O:14])[CH3:13].[H][H]>[Pd]>[C:12]([NH:1][CH:3]([C:9]([CH3:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:14])[CH3:13]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Product: CCOC(=O)C(NC(C)=O)C(C)=O
Reaction time: 22 h
Yield: 92.3 %

Procedure:
A Parr flask was charged with 0.2 mol of ethyl 2-oximinoacetoacetate, 0.4 mol of acetic anhydride, 45 psi of hydrogen, and a mixture of 0.25 g of 5% palladium-on-carbon and 0.4 g of 10% palladium-on-carbon and shaken for about 22 hours. Work-up of the resultant reaction mixture provided a 92.3% yield of ethyl 2-acetamidoacetoacetate.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[PH2+]N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>ClCCl.O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: CN(C)[PH2+]On1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (102 mg, 0.34 mmol) in dichloromethane (10 mL) was treated with benzotriazol-1-yloxy-(dimethylamino)phosphonium hexafluorophosphate (BOP) reagent (223 mg, 0.51 mmol), triethylamine (0.14 mL, 0.52 mmol), and 2-aminothiazole (51 mg, 0.51 mmol) at 25° C. After the resulting brownish-orange solution was stirred 16 h at 25° C., it was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL), and brine (1×10 mL), then were dried over sodium sulfate and evaporated in vacuo. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to furnish rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (115 mg, 88% yield) as a white foam: EI-HRMS m/e calcd for C17H , H18Cl2O2N2S (M+) 384.0466, found 384.0469.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[C:10]1([S:16]([N:19]2[C:27]3[CH:26]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=[C:23]([NH2:32])[C:22]=3[CH:21]=[N:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:32][C:23]2[CH:24]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:26]=[C:27]3[C:22]=2[CH:21]=[N:20][N:19]3[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-1,3-thiazole-4-carbonyl chloride (350 mg) in DCM (4 ml) was added dropwise to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (300 mg) in DCM (15 ml) and pyridine (0.167 ml). The reaction was stirred at RT overnight. Saturated sodium bicarbonate (aq) (25 ml) was added and the reaction vigorously stirred for 15 min. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM and purified on a silica cartridge, preconditioned with cyclohexane, washing with cyclohexane followed by elution with ether. The ether was evaporated to give title compound, 373 mg.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1F)[C:13]([O:15]C)=[O:14])#[N:9].FC1C=CC(C=O)=CC=1C#N.[Li+].[OH-]>CN(C=O)C.C1COCC1.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:13]([OH:15])=[O:14])#[N:9]
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Reactant: CC1CCCCN1
Agent: N#Cc1cc(C=O)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Methylpiperidine (2.38 mL; 20.29 mmol) was added to a solution of methyl 3-cyano-4-fluorobenzoate, prepared as described in J. Med. Chem. 2004, 47, 1339-1350 from 2-fluoro-5-formylbenzonitrile (727 mg; 4.06 mmol) in DMF (4 mL). The resulting mixture was stirred at RT for 2 days. The solution was partitioned between EtOAc and water and the phases separated. The organic layer was washed with HCl (0.1 M) and brine, dried over MgSO4. Evaporation under reduced pressure afforded a greenish oil. The latter was taken up in THF (10 mL), LiOH (340 mg; 8.12 mmol) and water (10 mL) were added and the reaction mixture was stirred at RT for 16 hours. The resulting solution was diluted with water and washed with Et2O. The aqueous layer was made acidic (pH 2) by addition of HCl (1M) and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give a light yellow oil that precipitated upon trituration with a mixture of EtOAc and n-pentane to give the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 13 (br s, 1H), 8.08 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.8, 2.1 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 4.12-4.08 (m, 1H), 3.35-3.25 (m, 2H), 1.84-1.53 (m, 6H), 1.09 (d, J=6.6 Hz, 3H). LC/MS (Method B): 243.2 (M−H)−; 245.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH2:40]([Si:42](Cl)([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41].[CH3:48][Si](C)(C)[N-][Si](C)(C)C.[Li+].C(OCC)(=O)C>O1CCCC1>[CH3:38][C:37]1([O:39][Si:42]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:40][CH3:41])[CH2:48][CH:36]1[O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][CH:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC3CC3(C)O[Si](CC)(CC)CC)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.12 g) and triethylsilyl chloride (0.72 mL) in tetrahydrofuran (15 mL) was added dropwise lithium hexamethyldisilazide (1.1 M tetrahydrofuran solution, 2.9 mL) at −78° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in methylene chloride (5 mL), and the solution was added dropwise to a solution of diethylzinc (1 M hexane solution, 15 mL) and chloroiodomethane (1.09 mL) in methylene chloride (20 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.44 g, 31%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CC(C)=O>[CH3:15][O:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CN1CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)O
Temperature: 25 °C
Yield: 24 %

Procedure:
To solution of 5-chlorosulphonyl-2-methoxy-benzoic acid (0.5 g, 1.99 mmol) in acetone (5 ml) was added N-methylpiperazine (0.219 g, 2.19 mmol) and triethylamine (0.33 ml, 2.3 mmol) and the mixture stirred at RT. After 2 hours the reaction mixture was filtered and the collected solid washed with acetone, water and then diethylether to yield 2-methoxy-5-(4-methyl-piperazine-1-sulphonyl)-benzoic acid (150 mg, 24%). (LC/MS (acidic method): Rt 0.34, [M+H]+ 315).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12].[CH3:17][CH2:18]O>Cl>[CH2:17]([O:12][C:11](=[O:13])[CH:10]([C:3]1[C:4]([F:9])=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=1[F:1])[O:14][CH2:15][CH3:16])[CH3:18]
Reactant: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(OCC)c1c(F)ccc(O)c1F
Yield: 93 %

Procedure:
A solution of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid (14.8 g) in EtOH (200 ml) and 1.25 N HCl in EtOH (60 ml) was stirred over night at rt. The solvent was evaporated and the residue was purified by CC (AcOEt/Hept 1:1) to obtain 15.5 g (93%) of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester. Off-white solid. MS 258.9 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26](O)[CH2:27][CH3:28])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:13]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To THF solution of 0.409 g (2.4 mmol) methyl 3-hydroxyphenylacetate, 0.50 g (20.5 mmol) N-Boc-piperidin-4-yl-propanol and 0.645 g (24.6 mmol) triphenylphosphine was added diisopropyl azodicarboxylate at 0° C. slowly, then the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation, the residue was dissolved in 2 mL methylene chloride and was loaded on a silica gel column and, the product eluted with 80% hexane and 20% ethyl acetate. Methyl 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetate (0.5 g, 62%) was obtained. 1H NMR (500 MHz, CDCl3) δ 1.1 (m, 2H), 1.4 (m, 2H), 1.46 (s, 9H), 1.66 (d, 2H), 1.7 8(m, 2H), 2.67 (t, 2H), 3.58 (s, 2H), 3.68 (s, 3H), 4.05 (m, 2H), 6.75 (m, 3H), 7.18 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11](C2CCCCO2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[N:13]=2>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:13]2
Reactant: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Yield: 102.8 %

Procedure:
Trifluoroacetic acid (2.3 ml, 3.40 g, 29.9 mmol) was added to a stirred solution of 8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.479 g, 4.23 mmol) in methanol (25 ml). The resultant mixture was stirred for 66 hours under an atmosphere of nitrogen and then evaporated and dried in vacuo to give the title compound as a white solid (1.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:13]Br.OS([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:13][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1
Reactant: Clc1ccc(-n2cccn2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-n2cc(Br)cn2)cc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A solution of 1-(4-chlorophenyl)pyrazole (834 mg, 4.67 mmol) in acetic acid (10 mL) is treated with bromine (0.26 mL, 5.08 mmol). After stirring for 18 h, the solution is diluted with 40 mL water, and satd. aq. NaHSO3 solution is added until the bromine color had dissipated. Then, solid sodium bicarbonate is added until a neutral pH is obtained. This mixture is extracted with ethyl acetate (2×50 mL), and the extracts are washed with brine, combined, dried over MgSO4, filtered and evaporated. The solid residue is recrystallized from cyclohexane to afford pure product, 4-bromo-1-(4-chlorophenyl)-pyrazole (797 mg, 3.10 mmol, 66%). m.p. 75-76° C. (cyclohexane), 1H NMR (300 MHz, CDCl3): δ 7.89 (1H, s), 7.66 (1H, s), 7.57 (2H, d, J=9.0 Hz), 7.41 (2H, d, J=9.0 Hz). MS (ES+): m/e 261 (26), 259 (100), 257 (77).