Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(I)cc1
Reaction time: 64 h

Procedure:
N-(3-bromopropyl)phthalimide (1 eq., Aldrich), 4-iodophenol (1 eq., Aldrich) and potassium carbonate (2 eq.) were stirred in acetonitrile. The mixture was heated at reflux. After 64 hours, the reaction mixture was concentrated to a thick mixture which was slurried in water. A white solid was collected, washed with water and vacuum dried to provide 1-(4-iodophenoxy)-3-(phthalimido)propane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[Cl:11][C:12]1[CH:32]=[CH:31][C:15]2[C:16](=[O:30])[C:17]3[C:24]([C:25](OCC)=[O:26])=[N:23][NH:22][C:18]=3[C:19](=[O:21])[NH:20][C:14]=2[CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:32]=[CH:31][C:15]2[C:16](=[O:30])[C:17]3[C:24]([C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:26])=[N:23][NH:22][C:18]=3[C:19](=[O:21])[NH:20][C:14]=2[CH:13]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: C1COCCN1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12)N1CCOCC1
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
Morpholine (268 μL, 3.06 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (365 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (0.760 mL). The resulting solution was stirred for 4 hours at room temperature and then quenched with aqueous hydrochloric acid (1.88 mL, 1N) and water (50 mL). The aqueous layer was extracted with chloroforrn (7×50 mL) and ethyl acetate (3×50 mL). The combined organic layers were concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-80:20) to give the title compound (89.9 mg, 80% yield, m.p. 347° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:16]#[N:17].CN1C(=O)CCC1>[NH4+].[OH-]>[CH:9]1([O:8][C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[N:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ccc(OC2CCCCC2)cn1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(OC2CCCCC2)cn1
Temperature: 180 °C
Yield: 57.1 %

Procedure:
Under a nitrogen atmosphere, add 6-chloro-3-cyclohexyloxy-pyridine (1.5 g, 7.1 mmol) and copper(I) cyanide (1.89 g, 21 mmol) to NMP (15 mL). Heat the mixture at 180° C. overnight. Cool the mixture to room temperature and add copper(I) cyanide (0.63 g, 7.1 mmol). Heat the mixture at 180° C. for 6 h. Cool the mixture to room temperature, dilute with 5N aqueous NH4OH and extract with DCM. Separate the layers and extract the aqueous phase with additional DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the residue by chromatography on silica gel (500 g) eluting with hexane/EtOAc (20:1) to obtain the desired intermediate (820 mg, 57%). MS (ES+) m/z: 203 (M+H)+.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([N:18]([CH2:22][CH2:23][CH2:24][S:25][CH3:26])[CH2:19][CH2:20][CH3:21])[CH2:13]2>CN(C)C=O>[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([N:18]([CH2:22][CH2:23][CH2:24][S:25][CH3:26])[CH2:19][CH2:20][CH3:21])[CH2:13]2
Reactant: CCCN(CCCSC)C1CCc2c(cccc2OC)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCCN(CCCSC)C1CCc2c(O)cccc2C1
Reaction time: 20 h

Procedure:
1 g sodium hydride in 40 g dimethylformamide is treated at 0° with 3.3 ml ethylmercaptan. 4.5 g 1,2,3,4-tetrahydro-5-methoxy-2-[N-(3-methylthiopropyl)-N-propylamino]-naphthalene in 30 ml dimethylformamide are added. The reaction mixture is stirred for 20 hours at 120°, cooled, concentrated and partitioned between ether and 2 N hydrochloric acid. The aqueous phase is adjusted to pH 11 at 5° and extracted with methylene chloride. The organic phase is dried, filtered and concentrated to give the crude title compound, which is converted into the hydrogen fumarate in isopropanol/pentane. M.pt. sintering from 70° (from ethanol/ether). The starting material may be obtained as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][NH:33][C:34]([NH:36][OH:37])=[NH:35].[ClH:38]>C(O)C>[ClH:38].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:32][NH:33][C:34](=[NH:35])[NH:36][OH:37])[CH2:10]1
Reactant: Cc1ccc(C)c(C2CC(=O)c3c(C)ccnc3C2)c1
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(C2CC(=NNC(=N)NO)c3c(C)ccnc3C2)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (100 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (131 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (2 ml) was stirred at 85° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (20 ml), tetrahydrofuran (12 ml) and 0.2 N sodium hydroxide (10 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (5 ml) and water (5 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.5 ml), and the mixture was concentrated under reduced pressure. The residue was washed with a mixture of ether (4 ml) and ethanol (2 ml), and dried to give 7-(2,5-dimethylphenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 94) (121 mg) as yellow crystals.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[N:32][CH:33]=1>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>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:6]2[N:10]3[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]3=[N:8][CH:7]=2)=[CH:33][N:32]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cn1

Procedure:
To a degassed solution of 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was added 5-bromo-2-fluoropyridine (0.128 ml, 1.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol) and the mixture heated at reflux for 5 h. The crude reaction was washed with water and extracted with ethyl acetate. After adding isohexane a dark solid was collected by suction filtration. The solid was adsorbed onto silica and purified by chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (20-60%), to give 3-(2-fluoropyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (150 mg) as a dark solid: δH (500 MHz, CDCl3) 7.12 (1H, m), 7.30 (1H, d, J 7), 7.99-8.02 (1H, m), 8.10 (1H, s), 8.46 (1H, s), 8.72 (1H, d, J 7); m/z (ES+) 282, 283 (M++H).
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:18][CH:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH2:16]3)[CH2:11]2)=[CH:6][CH:5]=1.[Cl-:19].[Cl-].[Cl-].[Cl-].[Zr+4:23]>C(OCC)C>[Cl-:19].[Cl-:19].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:18][CH:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH2:16]3)[CH:11]2[Zr+2:23][CH:11]2[C:12]3[CH:17]([CH2:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][CH:10]2[C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=2)=[CH:8][CH:9]=1
Reactant: [Zr+4]
Reactant: Brc1ccc(C2CC3=CC=CCC3C2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Product: Brc1ccc(C2CC3CC=CC=C3C2[Zr+2]C2C3=CC=CCC3CC2c2ccc(Br)cc2)cc1

Procedure:
Again the procedure of Example I was used but in this case 0.677 mmol of potassium hydride was used in place of the n-butyllithium and the starting material was 2-(para-bromophenyl) tetrahydroindene in the amount of 0.615 mmol in 8 ml of diethylether. The procedure employed 0.31 mmol of the zirconium tetrachloride. The resulting product was purified and identified as bis(2-(para-bromophenyl) tetrahydroindenyl) zirconium dichloride.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClC(Cl)C>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[CH:19]([C:20]([CH:19]([C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(C(c1ccccc1)c1cc(O)ccc1O)C(c1ccccc1)c1cc(O)ccc1O
Yield: 23.7 %

Procedure:
22 g (0.2 mole) of hydroquinone were dissolved in 60 ml of dichloroethane and 26.8 g (0.2 mole) of anhydrous aluminum chloride were added to the solution. To the obtained complex 30.8 g (0.2 mole) of phenyl-acetyl chloride in 30 ml of dichloroethane were added. Further the procedure of Example 1 was followed. 10.1 g of 2,5-dihydroxy-phenyl-benzyl-ketone were obtained, m.p.: 118°-120° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:15]1[C:19]2[CH:20]=[C:21]([CH2:24][NH2:25])[CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16]1>>[O:15]1[C:19]2[CH:20]=[C:21]([CH2:24][NH:25][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccc2ccoc2c1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3ccoc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and benzofuran-6-ylmethanamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1Cl

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-chloro-4-fluoroaniline were reacted to yield N2-(3-chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.75 (bd, 1H), 7.70 (bd, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.90 (m, 2H), 6.75 (m, 1H), 4.20 (bs, 4H); LCMS: ret. time: 25.04 min.; purity: 99%; MS (m/e): 392 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH:21]=O)[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][NH:27][CH:24]2[CH2:26][CH2:25]2)[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)CC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CNC2CC2)c1)CC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (4.30 g, 12.4 mmol) and cyclopropylamine (1.77 mL, 12.4 mmol) in MeOH (125 mL) was stirred for 2 h at rt. Cyclopropylamine (0.44 mL, 6.2 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt. NaBH4 (935 mg, 24.7 mmol) was added in portions. The mixture was stirred for 1 h. The solvents were removed under reduced pressure, and the residue was taken in EtOAc (800 mL). The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (3.53 g, 73%). LC-MS: tR=0.83 min; ES+: 389.52.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([N+]([O-])=O)[CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[CH:13]=1
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)n1
Reactant: Cc1ccc(Cl)c(O)c1F
Product: Cc1ccc(Cl)c(Oc2cc(Cl)nc(C#N)c2)c1F
Yield: 88.2 %

Procedure:
The title compound was prepared in a similar manner to that described herein using 6-chloro-2-fluoro-3-methylphenol (0.60 g, 3.74 mmol) and 6-chloro-4-nitro-2-pyridinecarbonitrile (0.69 g, 3.74 mmol) to give the title compound as a white solid (0.98 g, 88%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.24 (1H, m) 7.16 (1H, d) 7.14 (1H, d) 6.98 (1H, d) 2.33 (3H, d). LCMS: m/z 297 (M+1).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with morpholine and pyridine in chloroform. [α]D20=+43.1° (c=1.05, CHCl3), ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:66]2[CH2:67][CH2:68][CH2:69][C@@H:64]([CH2:63][N:58]3[CH2:59][CH2:60][CH2:61][CH2:62]3)[CH2:65]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: C1CNC[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CCC[C@@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-[5-(2,6-difluoro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (236 mg), HATU (1.2 eq.), (R)-3-pyrrolidin-1-ylmethyl-piperidine (2×) in DMF (2.5 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 120 mg of the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[N:9](C)[N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:21]=1.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(OCCO)C>[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH:26][C:10]1[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[CH:21][C:6]=2[CH:7]=[N:8][N:9]=1
Reactant: COC(CN)OC
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Solvent: CCOCCO
Product: COC(CNC1=NN=Cc2ccccc2N1)OC

Procedure:
A mixture of 2.66 grams (8.42 m moles) of 7-chloro-3-methyl-2-(methylthio)-5-phenyl-3H-1,3,4-benzotriazepine, 1.0 grams (9.32 m moles) of aminoacetaldehyde dimethyl acetal (98%), and 10 ml of 2-ethoxyethanol was stirred and refluxed under nitrogen for about 18 hours. The solvent was removed in vacuo on a rotary evaporator, and the residue was dissolved in diethyl ether. The resulting solution was washed in water, dried with magnesium sulfate and concentrated in vacuo. The dark residue was found to be a mixture and was chromatographed on a column containing 170 grams of alumina. The column was washed with benzene. The desired dimethoxyethylamino-1,3,4-benzotriazepine intermediate was obtained on elution with successive portions of methylene chloride and chloroform. The reactions were combined and evaporated to yield a red viscous oil.
Reaction SMILES: [N:1](OC(C)(C)C)=O.[CH3:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH:16]C(C)=O>C1(C)C=CC=CC=1>[Br:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][N:1]=[CH:8]2
Reactant: CC(=O)Nc1ccc(Br)cc1C
Reactant: CC(C)(C)ON=O
Solvent: Cc1ccccc1
Product: Brc1ccc2[nH]ncc2c1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 38.8 %

Procedure:
tert-Butyl nitrite (8.34 g, 0.081 mol) was added dropwise, over 30 minutes, to a suspension of 4-bromo-2-methylacetanilide (12.3 g) in toluene (300 ml) at 65° C. and the mixture was stirred at 65° C. for 45 minutes and then at 90° C. for 3 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 diethyl ether:hexane to give 5-bromoindazole (4.12 g), as a sand-coloured solid.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.Cl[C:15]1[CH:16]=[C:17]([NH:21][NH2:22])[CH:18]=[CH:19][CH:20]=1>C(O)(=O)C>[C:17]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=3)=[N:22]2)[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
A mixture of ethyl trifluoroacetoacetate (5 g, 27.2 mmol), 3-chlorophenylhydrazine hydrochloride (4.86 g, 27.2 mmol) and acetic acid (50 mL) was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo, CH2Cl2 (80 mL) and hexane (40 mL) were added to the residue and the solid which formed was collected by filtration to afford 3.11 g of 2,4-dihydro-2-(3-chlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =3-Cl--Ph; R2 =CF3 ; R3 =H).
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+].Cl>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: OCc1ccccc1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 mL). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 N HCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:13][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(F)cc1
Product: Cc1cc2ncc(C#Cc3ccc(F)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-4-fluoro-benzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CCOC(=O)CC(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
14.4 g (0.05 mole) β-chloro-β,β-diphenyl-propionic acid ethyl ester (prepared from β-hydroxy-β,β-diphenyl-propionic acid ethyl ester, Ber. 40, 4538, by treatment with phosphorus pentachloride) are heated in 100 ml acetonitrile with 10 g imidazole at boiling temperature for 16 hours. The solvent is distilled off in a vacuum, the residue treated with 50 ml of water and extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum. The β-imidazolyl-β,β-diphenyl-propionic acid ethyl ester is thus obtained in the form of crystals of m.p. 75° C.