Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>CC#N>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:12][C:13]=1[Br:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1Br
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of [4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 29 mg, 0.10 mmol) in CH3CN (1 mL), NBS (19.5 mg, 0.100 mmol) was added. The resulting mixture was stirred overnight and concentrated to half the volume. The resulting precipitate was collected by filtration to obtain the title compound (12 mg, 32%): Mass spectrum (ESI, m/z): Calcd. for C15H20BrN3O3, 370.0 and 372.0 (M+H), found 370.1 and 372.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)c(O)cc2o1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cc2oc(=O)[nH]c2cc1Cl)(C(C)C)C(C)C
Yield: 84.8 %

Procedure:
5-chloro-6-hydroxy-1,3-benzoxazol-2(3H)-one (0.93 g, 5 mmol) and imidazole (1.00 g, 15 mmol) were dissolved in dimethylformamide (10 mL) with stirring under inert atmosphere. Triisopropylsilylchloride (1.15 g, 6 mmol) was added and the resulting solution was stirred for 3 days. The reaction mixture was partitioned between water and heptane. The organic layer was washed with water and dried over magnesium sulphate, filtrated and concentrated, to give 1.45 g (85%) of the subtitled compound as a grey solid.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([OH:28])=[O:27])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture stirred at 40° C. overnight. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[Acetyl-(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylbutanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2N=N1.NC1C=CC=CC=1.Cl>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([NH:27][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: COc1cc(-c2noc(C)n2)c(C(=O)Nc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 730.2 %

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (500 mg), benzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate (1.15 g), 1-hydroxybenzotriazole (20 mg), methylene chloride (3 mL) and N,N-dimethylformamide (3 mL) were added aniline (0.2 mL) and triethylamine (0.62 mL). After stirring at room temperature for 4 hours, ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with a 2 mol/L aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (449 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][CH:9](Cl)[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH:9]([CH2:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Sc1ccccc1Cl
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(CCC(Cn2ccnc2)Sc2ccccc2Cl)s1

Procedure:
A mixture of 850 mg of 1-[4-(5-chloro-2-thienyl)-2-chloro-n-butyl]imidazole, 670 mg of 2-chlorothiophenol and 500 mg of potassium carbonate in 40 ml of acetone is stirred and refluxed for 4 hours. The solvent is evaporated under vacuum and 50 ml of water is added. The resulting mixture is extracted with ether and the ether extract is washed with water, dried and evaporated to afford 1-[2-(2-chlorophenylthio)-4-(5-chloro-2-thienyl)-n-butyl]imidazole as an oil. This material is converted to the nitrate salt by treatment with nitric acid, which salt is recrystallized from acetone/ethyl acetate as colorless flakes, mp 121°-122°.
Reaction SMILES: [CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
N-butyl-N-(2,3-dimethoxybenzyl)-3-(4-hydroxyphenyl)propanamide (50 mg, 0.13 mmol) and methyl 2-(bromomethyl)benzoate (0.034 g, 0.15 mmol) was dissolved in acetonitrile (10 ml) and potassium carbonate (37 mg, 0.27 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off and solvent was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with three portions of water. After drying the crude (MgSO4), the solvent had been removed by evaporation. The residue was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 15 mg of methyl 2-[(4-{3-[butyl(2,3-dimethoxybenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (21.4%).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a suspension of sodium theobromine (2.22 g, 11.0 mmol) in dimethylsulfoxide (25 mL) was added 12-tridecenyl bromide and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (80 mL) and extracted with dichloromethane (3×50 mL). The combined organic portions were washed with water (3×100 mL), dried using magnesium sulfate, and evaporated to give a gummy residue. Purification by column chromatography using an ethyl acetate/hexane eluant yields 1.89 g (50% yield) 1-(12-Tridecenyl)-3,7-dimethylxanthine (inventive compound no. 2555) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[CH:12]=[CH:13][N:14]([CH2:15][CH:16]([F:18])[F:17])[C:9]2=[CH:8][C:7]=1[Cl:19])=[O:5])C.[OH-].[Na+]>C1COCC1>[Cl:19][C:7]1[CH:8]=[C:9]2[N:14]([CH2:15][CH:16]([F:17])[F:18])[CH:13]=[CH:12][C:10]2=[N:11][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2ccn(CC(F)F)c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccn(CC(F)F)c2cc1Cl
Temperature: 65 °C
Reaction time: 4.5 h

Procedure:
To a solution of 6-chloro-1-(2,2-difluoro-ethyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.520 mmol) in THF (10 ml) was added 1N aq. sodium hydroxide (0.624 ml, 0.624 mmol) and mixture was stirred at 65° C. for 4.5 h. The solvents were evaporated, the residue was dissolved in water, acidified with 2N aq. HCl and the mixture extracted with EtOAc. The combined organic layers were dried with Na2SO4 and evaporated to provide the title compound as light orange solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][N:26]1[CH2:27][CH2:28][CH:24]([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:25]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ncc[nH]2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.4 %

Procedure:
3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 5.81 mmol), 1H-2-imidazolecarbaldehyde (77 mg, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10) as mobile phase to give 1-[1-(1H-2-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 83%). 1H NMR (DMSO-d6) δ 2.33 (m, 2H), 2.81 (m, 4H), 3.15 (m, 1H), 3.69 (s, 2H), 5.38 (m, 1H), 6.90 (s, 2H), 7.15 (m, 5H), 7.44 (m, 2H), 7.66 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+453.4, Rt=2.17 min.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[N:23][CH:22]=4)[CH:20]=3)[N:12]=[C:11]([CH3:36])[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:35][O:34][C:31]1[N:30]=[CH:29][C:28]([NH:27][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:36])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[N:23][CH:22]=3)=[CH:18][N:17]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccnnc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(-c3ccnnc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 11.2 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(pyridazin-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (140 mg, 0.223 mmol) was treated with TFA (10 mL) and fitted with a reflux condenser and heated at 80° C. for 15 h. The TFA was removed in vacuo and the residue was pipetted into an ice-cooled saturated solution of NaHCO3 resulting in a yellow suspension which was collected by filtration on a sintered glass frit. The resulting yellow solid was washed with water and MeOH dry-packed on silica gel and attempted purification on the ISCO (12 g column, 1-40% MeOH in DCM (also tried 25% 2M NH3 in MeOH in DCM)) could not liberate the desired product from silica gel. The silica gel was washed with DMSO (20 mL) and filtered through 0.45 μm acrodiscs and the DMSO removed in a Genevac over the weekend to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(pyridazin-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (9.5 mg, 0.025 mmol, 10.99% yield) as a bright yellow amorphous solid. m/z (ESI, +ve ion) 388.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.99 (1H, s); 9.66 (1H, s); 9.25 (1H, s); 9.21 (1H, d, J=2.3 Hz); 8.91 (1H, d, J=2.3 Hz); 8.55 (1H, d, J=2.7 Hz); 8.16-8.20 (1H, m); 7.98-8.02 (1H, m); 7.92 (1H, s); 7.81 (1H, s); 6.88 (1H, d, J=8.8 Hz); 3.87 (3H, s); 2.54 (3H, s).
Reaction SMILES: C([N:5]([CH2:9][CH2:10][O:11][NH:12][C:13]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]2[CH2:22][N:16]1[C:17](=[O:28])[N:18]2[O:23][S:24]([OH:27])(=[O:26])=[O:25])=[O:14])C(=O)[O-])(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O.C([O-])(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl.C(OCC)C>[NH2:5][CH2:9][CH2:10][O:11][NH:12][C:13]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]2[CH2:22][N:16]1[C:17](=[O:28])[N:18]2[O:23][S:24]([OH:27])(=[O:26])=[O:25])=[O:14]
Reactant: CC(C)(C)N(CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)C(=O)[O-]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 73.5 %

Procedure:
A solution of tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (68.9 g, 104 mmol) in methylene chloride (170 mL) solution was cooled to −20° C., and trifluoroacetic acid (170 mL) was added at −15° C. or less over 20 min., followed by stirring at 0° C. for 35 min. To the reaction solution was added diethyl ether (510 mL), and followed by stirring at 0° C. for 40 min. The precipitated solid was filtered through Kiriyama funnel, and washed with diethyl ether (450 mL), subsequently dried under vacuo to afford a crude product (39.5 g). This was added to 0.5M sodium acetate/acetic acid buffer (400 mL, pH 5.6), and further pH was adjusted to pH 5.6 with 5M sodium hydroxide aqueous solution, and then was purified by octadecyl silica gel column chromatography (water) to afford 24.8 g of the title compound (yield 74%). Instrumental data were consistent with those of Example 59.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].O1[CH2:20][CH2:19][CH2:18][CH2:17]1>[Zn].BrCC1C=CC(C#N)=CC=1>[CH2:1]([C:5]1[CH:14]=[C:13]([CH2:17][C:18]2[CH:3]=[CH:2][C:1]([C:5]#[N:6])=[CH:20][CH:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)c2ccccc2n1
Reactant: C1CCOC1
Agent: N#Cc1ccc(CBr)cc1
Agent: [Zn]
Product: CCCCc1cc(Cc2ccc(C#N)cc2)c2ccccc2n1

Procedure:
Using the procedure of Step G of Example 1, 0.614 g of 4-chloro-2-butyl quinoline of Step D, 0.8 ml of tetrahydrofuran, 0.323 g of tetrakis triphenylphosphine palladium and 10 ml of a 0.5 M 4-bromomethyl benzonitrile zinc solution in tetrahydrofuran were reacted to obtain after chromatography on silica (eluant: hexane - ethyl acetate (8-2)) 0.781 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]2[C:6]3[CH:16]4[NH:17][CH:13]([CH2:14][CH2:15]4)[CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Na+].[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([C:2]2[CH:3]=[C:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]3[C:6]4[CH:16]5[NH:17][CH:13]([CH2:14][CH2:15]5)[CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)cc(Br)cc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)cc(S(=O)(=O)c4ccccc4)cc31)C1CCC(C2)N1
Yield: 35 %

Procedure:
Prepared from the product of step B and benzene sulfinic acid sodium salt according to the procedure of Example 27, step C. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) provided tert-butyl 3-phenylsulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (53 mg, 35%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.95 (m, 3H), 7.52 (m, 5H), 5.21 (m, 1H), 4.68 (m, 1H), 3.67 (s, 3H), 3.39 (m, 1H), 2.53 (d, J=17.0 Hz, 1H), 2.32 (m, 2H), 2.17 (m, 1H), 1.88 (t, J=10.1 Hz, 1H), 1.37 (brs, 9H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1>CN(C=O)C>[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1
Reactant: Fc1cnc(Cl)c([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL), then dried (Na2SO4) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68% yield). MS (apci) m/z=390.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:17].Br[CH2:19][CH2:20][CH2:21][Cl:22].C(O)(=O)C>C(O)C>[Cl:22][CH2:21][CH2:20][CH2:19][S:17][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: ClCCCBr
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(SCCCCl)nnc1-c1ccc(C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
To 4-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.63 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.23 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.394 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].ClCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[C:32]([C:33]#[N:34])=[CH:31][NH:30][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[N:30]=[CH:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1Cl
Reactant: N#Cc1c[nH]nc1N
Agent: O=C(CCl)c1ccccc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccccc3Cl)nc12
Yield: 22.6 %

Procedure:
Reaction of 1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 2-chloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (73 mg, 23%). MS (ISP) 323.1 [(M+H)+]; mp 169° C.