Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])=[O:11].[OH-].[Na+]>CO.O>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:10](=[O:11])[CH:9]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(OC)c1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(38) To a solution of benzaldehyde (295 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hour at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 371 mg (49.9%) of white flakes: mp 125.5-126.6° C. (lit. mp 123-124° C., Kuck and Grutzmacher, Org. Mass. Spect., 1978, 13, 90-102). 1H NMR (250 MHz) δ 7.55-7.51 (m, 2 H), 7.39-7.30 (m, 5H), 7.00-6.94 (d, 1 H), 6.64-6.61 (d, 2 H), 3.79 (s, 6 H); 13C NMR (62.7 MHz) 213.8, 176.1, 163.9, 153.4, 149.4, 149.0, 147.4, 147.3, 147.0, 122.6, 74.5 ppm.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)C)[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.Cl.N[C@H]1CCN(C2C=CC(N3C[C@H](CN(C4C=CON=4)C(OCC(Cl)(Cl)Cl)=O)OC3=O)=CC=2F)C1.[CH3:65][S:66](Cl)(=[O:68])=[O:67]>>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25][S:66]([CH3:65])(=[O:68])=[O:67])[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Product: CS(=O)(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) and methanesulfonyl chloride gave the desired product (361 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cccc(F)c2)c1

Procedure:
By the procedure of Example 13, m-fluorothiophenol (3.0 g., 23.4 mmoles) was reacted with cuprous oxide (1.67 g., 11.7 mmoles) in 30 ml. of dimethylformamide and then reacted further with 5-bromofuran-3-carboxylic acid in 30 ml. of dimethylformamide. Isolation of crude solids (920 mg.) was according to Example 9. Recrystallization from methanol/water, which included decolorization with activated carbon, gave purified 5-(3-fluorophenylthio)furan-3-carboxylic acid (500 mg., m.p. 101°-103° C., m/e 238).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[C:5](=[O:19])[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]2=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CN1C(=O)c2cc(N)c(OC)cc2C1=O
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)c2cc(NS(C)(=O)=O)c(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A solution of methyl 2-(5-amino-6-methoxy-1,3-dioxoisoindolin-2-yl)acetate (0.202 g, 0.764 mmol) in pyridine (10 ml) was cooled to 0° C., and methanesulfonyl chloride (0.071 ml, 0.917 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. Additional methanesulfonyl chloride (0.090 ml, 1.146 mmol) was added over 30 hour, cooling to 0° C. and stirring at room temperature. The solvent was removed under vacuum, and the crude was partitioned between ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the crude was purified by chromatography on silica gel cartridge (petroleum ether:ethyl acetate from 6:4 to 100% ethyl acetate) affording methyl 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.584 mmol, 76% yield). MS/ESI+ 342.9 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20](F)=[C:19]([C:24]#[N:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:19]([C:24]#[N:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:26]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(N3CCOCC3)c(C#N)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Example 54a) (60.7 mg, 0.157 mmol) in acetonitrile (3 ml) is added potassium carbonate (43.3 mg, 0.314 mmol) followed by morpholine (27.6 μl, 0.314 mmol). The reaction mixture is stirred at room temperature for 2 hours and then filtered and concentrated in vacuo to yield the titled compound as an orange oil which is used crude in the next step. (MH+ 455).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20][S:21][CH2:22][CH2:23]Cl.O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[CH2:23][CH2:22][S:21][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reactant: CSCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCN(C)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.095 g, 0.32 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.015 g, 0.38 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then chloroethyl methyl sulfide (0.042 g, 0.38 mmol) was added in one portion as a solution in DMF (1 ml) and the reaction mixture was heated to 70° C. for 24 hours. After this time, the reaction mixture was cooled to RT and water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 70% hexane, 30% EtOAc) gave the title compound (0.021 g, 18% yield) as a white solid. δH (400 MHz, CDCl3), 7.73 (1H, d), 7.48 (1H, d), 7.13 (1 H, d), 5.41-5.29 (1H, m), 3.71 (2H, t), 3.18 (3H, s), 3.15 (3H, s), 2.73 (2H, t), 1.41 (6H, d).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC[C@H](C)CBr
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 3.01 g of (S)-(+)-1-acetoxy-3-bromo-2-methyl-propane (15.7 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. Stirring was continued for 2 h at 95-105° C. The dimethylformamide was removed by evaporation under reduce pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give the crude product as a brownish oil (5.81 g).
Reaction SMILES: Cl.O.[NH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[NH2:4].[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:25](=[O:37])[C:26](=[CH:33]N(C)C)[C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]2>CO>[CH:16]12[CH2:22][CH:20]3[CH2:19][CH:18]([CH2:23][CH:14]([CH2:21]3)[CH:15]1[NH:24][C:25]([C:26]1[CH:33]=[N:4][N:3]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=3)[C:27]=1[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:17]2
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C(C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
Hydrochloric acid (34.5% w/w, 15.88 g, 5.48 g @100.0%, 0.1504 mole, 1.0 mol. eq) and water (70 ml, 1.4 rel. vol) were added to a suspension of 4-hydrazinobenzoic acid (23.35 g, 22.88 g @100.0%, 0.1504 mole, 1.0 mol. eq) in methanol (1250 ml, 12.5 rel. vol). The resulting suspension was stirred for 30 min at 20 to 25° C. and a solution of N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4-dimethyl-3-oxo-pentanamide (intermediate #4) (53.47 g, 50.0 g @100.0%, 0.150 in 4 mole, 1.0 mol. eq) at 20-25° C. in methanol (250 ml, 5.0 rel. vol)] added over a period of 20 minutes followed by hydrochloric acid (34.5% w/w, 2.38 g, 0.82 g @100.0%, 0.02264 mole, 0.15 mol. eq) and water (70.0 ml, 1.4 rel. vol). The reaction mass temperature was increased to 62-65° C. and maintained for 90.0 min. For work up methanol solution was concentrated atmospherically until the residual volume 6.0 rel. vol (300.0 ml) remained. The resulting suspension was cooled to 20-25° C. and stirred for 1.0 hr. The product was filtered and washed with ethyl acetate (200.0 ml, 4.0 rel. vol) and sucked dry for 30 min. The product was dried under vacuum (100 mbar) at 50° C. for 8 hrs to give crude 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (47.0 g, 73.0%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:46])[C@H:42]([OH:45])[CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:46])[C@H:42]([OH:45])[CH2:43][NH:44][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([CH:18]([O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:31][CH:30]=1
Reactant: CC(C)CC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a mixture of 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (120 mg) in methylene chloride (3 mL) are added triethyl amine (0.12 mL, 0.87 mmol), DMAP (5 mg), 3-Amino-2(R)-hydroxy-propionic acid methyl ester (67.3 mg, 0.43 mmol) and EDCI (166 mg, 0.87 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4′-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R)-hydroxy-propionic acid methyl ester (60 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:34]1([NH2:41])[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1>CN1C(=O)CCC1.CO>[NH2:40][C@H:37]1[CH2:38][CH2:39][C@H:34]([NH:41][C:2]2[CH:3]=[C:4]([N:21]([CH:31]3[CH2:33][CH2:32]3)[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:35][CH2:36]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1

Procedure:
A solution of 6-chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (60 mg, 0.129 mmol) and (trans)-cyclohexane-1,4-diamine (147 mg, 1.285 mmol) in NMP (2 mL) was heated in a microwave reactor at 90° C. for 40 min. The reaction mixture was diluted with methanol and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)] to afford 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)CCC.[C:30](#[N:34])[CH2:31][CH2:32]C.C1(N)CC1>C1(C)C=CC=CC=1>[CH:30]1([NH:34][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:32][CH2:31]1
Reactant: CCCC#N
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Agent: NC1CC1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[α]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66A) and a solvent such as n-butanol, butyronitrile, glycol or toluene (3.0 vol) can be charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) can be added at temperature such as 15 to 30° C. under an inert atmosphere e.g. nitrogen. The contents can be heated to 40 to 105° C., in particular 40-80° C. and stirred at this temperature for 16 to 24 hours. Reaction completion can be determined by 1H NMR analysis. The reaction mixture can then be cooled to 10 to 20° C. The product can then be isolated by organic-aqueous extraction method as outlined above in Example 66A, or an alternative method of isolation may be employed such as the addition of an anti-solvent, for example n-heptanes, to the reaction mixture. This could allow the reaction product to precipitate with subsequent isolation by filtration. The solid can then be dried under vacuum at 35 to 45° C. to yield 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea. At this stage the solid can be purified by recrystallisation from an appropriate solvent, preferably a Class 2 or 3 solvent1. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. 1 Class 3 and Class 2 solvents are as outlined Q3C—Tables and List in Guidance for Industry Q3C Impurities: Residual Solvents (November 2003, CDER, CBER, FDA, ICH) and as further outlined in Impurities: Guideline for Residual Solvents (1997, ICH).
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]1[CH2:19][CH2:18][C@@:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]1)=[O:13].C1COCC1>C(N(CC)CC)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:28])[CH3:29])=[CH:26][CH:25]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)NC1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with cyclopentyl isocyanate (9 μL), (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (30 mg) and THF (2 mL). Triethylamine (11 μL) was added and the reaction mixture was shaken overnight at rt. After this time, the resulting solution concentrated and purified by preparative silica gel chromatography (100% EtOAc to 20% MeOH/CH2Cl2) to provide Example 511. MS found: (M+H)+=450.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:27]([NH:34][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)NCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a solution of 10.80 g (0.060 mole) of 3-(4-methoxyphenyl) propanoic acid and 6.57 g (0.065 mole of triethylamine in 25 ml dichloromethane at about 0.5° C., 6.84 g (0.063 mole) of ethyl chloroformate was added dropwise. The mixture was stirred for about 15 minutes at a temperature of about 5° to 10° C., then 6.96 g (0.065 mole) of benzylamine were added. The resulting mixture was stirred for about thirty minutes, and the solvent was evaporated. The residue was slurried in 5% aqueous sodium hydroxide. The solid was collected by filtration and rinsed with water until neutral. The washing process was repeated using 5% hydrochloric acid. The residue was dried under vacuum to give 11.0 g of the above-identified product, melting point 92°-94° C., which was suitable for use in step (b).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH:11]([NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(Cc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCC(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 2 g of 4-benzylcyclohexanone, the product of Example 1, Step 3, 16 g of ammonium acetate, 100 mL of methanol and 2.5 g of sodium cyanoborohydride was stirred for 5 days at room temperature. After cooling in an ice bath, the reaction was carefully quenched in an efficient fume hood by dropwise addition of 25 mL of 1N HCl. After stirring for 10 min, sodium hydroxide pellets were added to the cold solution until the pH (indicator paper) was about 10. The mixture was concentrated under reduced pressure, diluted with 100 mL of water, made basic by addition of more sodium hydroxide pellets and extracted into 4×100 mL portions of chloroform. After drying over magnesium sulfate, the extracts were concentrated under reduced pressure and then dried under vacuum overnight. Analysis by TLC (silica gel, elution with 90:10:1 chloroform:methanol:conc. ammonium hydroxide) indicated no 4-benzylcyclohexanone or 4-benzylcyclohexanol was present, only 2 new bands which correspond to a mixture of cis- and trans 4-benzyl-cyclohexylamine, which was an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cccnc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
3-Bromopyridine (5.4 g, 34.2 mmol) was dissolved in triethylamine (10 ml) and degassed under nitrogen. 4-Pentyn-1-ol (3.50 ml, 37.6 mmol) was added followed by bis(triphenylphosphine)palladium (II) chloride (0.245 g, 0.349 mmol) and copper(I)iodide (0.136 g, 0.714 mmol) and the resulting mixture was stirred and heated under reflux for 20 mins. when a dark brown sludge was obtained. The mixture was cooled to rt and partitioned between EtOAc (200 ml) and water (50 ml). The aqueous phase was extracted further with EtOAc (2×100 ml); the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The material was purified by column chromatography. The sample was loaded in dichloromethane and purified on silica (Si) 100 g using a gradient of 0-100% ethyl acetate in cyclohexane over 60 mins on the Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (4.99 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[OH:32][C@@H:31]([CH3:33])[C:30]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:23][CH:24]=4)[CH:14]=3)[N:9]=2)[CH2:2][CH2:3]1)=[O:34]
Reactant: c1cc(-c2ccc(Oc3ccc4nc(CN5CCNCC5)ccc4c3)cc2)[nH]n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O)C(=O)N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1
Reaction time: 72 h

Procedure:
A stirred suspension of intermediate F (35.0 mg, 0.076 mmol) in DCM (2.00 mL) is treated with L-(+)-lactic acid (17.2 mg, 0.191 mmol), triethylamine (53 mL, 0.382 mmol) and TBTU (30.7 mg, 0.095 mmol). After 72 h, the mixture is concentrated and purified using silica gel flash chromatography (0-10% MeOH in DCM) to afford the title compound (13).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=C([Cl:20])C=CC=1OC.COB(OC)OC>>[Cl:20][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1ccc(Cl)cc1Br
Agent: COB(OC)OC
Product: COc1ccc(Cl)cc1B(O)O
Yield: 77 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-chloroanisole (2.00 g, 9.0 mmol, 1.0 equivuiv), η-BuLi (2.5M in hexanes; 3.62 mL, 9.0 mmol, 1.0 equivuiv), and trimethylborate (3.0 mL, 26 mmol, 2.9 equivuiv) to afford 1.30 g (77%) of crude 5-chloro-2-methoxyphenylboronic acid as a white semi-solid. This compound was used in the next reaction with no further purification.