Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10](=O)([O:19]N1C(=O)CCC1=O)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Yield: 191.6 %

Procedure:
A mixture of (R)-piperidine-3-carboxylic acid (3.0 g, 23 mmol), benzyl 2,5-dioxopyrrolidin-1-yl carbonate (5.79 g, 23.2 mmol) and Na2CO3 (6.15 g, 58.1 mmol) was stirred in water and 1,4-dioxane (1:1, 200 mL) at ambient temperature for about 96 h. The organic solvent was removed under reduced pressure. The aqueous layer was acidified with 1 N aqueous HCl and extracted with EtOAc (2×100 mL). The organic phase was washed with brine (150 mL), dried over anhydrous MgSO4 and concd under reduced pressure to yield crude (R)-1-(benzyloxycarbonyl)-piperidine-3-carboxylic acid (11.6 g, 191%) as a white solid: LC/MS (Table 1, Method a) Rt=1.80 min; MS m/z 264 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=3)[CH2:29]2)=[CH:23][CH:22]=1
Reactant: CNC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2cc(N3CC(Oc4ccc(F)cc4)C3)ncn2)c1
Temperature: 84 °C
Yield: 100 %

Procedure:
To 3-(6-chloropyrimidin-4-ylamino)-N-methylbenzamide (90.0 mg, 0.343 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (73.3 mg, 0.360 mmol) in a disposable sealed tube at RT was added 2-propanol (2 mL) followed by N,N-diisopropylethylamine (0.179 mL, 1.028 mmol). The resulting reaction mixture was heated to 84° C. for 51 h, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 65% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(6-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide (135.0 mg).
Reaction SMILES: C[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[C:18]([Cl:19])=[C:17]([Cl:20])[N:16]=[C:15]3[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][CH:8]=2)[C:3]=1[C:25]([O-:27])=[O:26]>CO.[OH-].[Na+].O>[CH2:21]([C:15]1[N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH:5]=[CH:6][CH:2]=[C:3]3[C:25]([OH:27])=[O:26])=[CH:8][CH:9]=2)[C:18]([Cl:19])=[C:17]([Cl:20])[N:16]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(Cl)c(Cl)n1Cc1ccc(-n2ccc(C)c2C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(Cl)n1Cc1ccc(-n2cccc2C(=O)O)cc1

Procedure:
A solution of 250 mg of the methyl ester from Example 1, Step (i) in 25 mL of methanol and 25 mL of sodium hydroxide in water (10%) was stirred at ambient temperature overnight. The methanol was removed in vacuo and the pH adjusted to 4 with hydrochloric acid which caused the acid to precipitate. The product was collected by filtration: m.p. 181°-182° C.; MS(FAB) m/e(rel. intensity 392 (60, M+H+), 200(100); HRMS. Calcd for M+H: 392.0933; found: 392.0967.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C@H:16]([S:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][N:14]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)=[O:39].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[N+:48]([C:45]1[CH:44]=[CH:43][C:42]([CH2:41][O:40][C:38]([N:14]2[CH2:15][C@@H:16]([S:18][C:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][C@H:13]2[CH:12]=[O:11])=[O:39])=[CH:47][CH:46]=1)([O-:50])=[O:49]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (1.06 ml, 14.9 mmol) was added to a solution of oxalyl chloride (0.648 ml, 7.43 mmol) in methylene chloride (40 ml) at -78° C. in a nitrogen stream over 2 minutes. The resulting reaction solution was stirred at the same temperature for 10 minutes. To this reaction solution, a solution of (2S,4S)-2-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (2.47 g, 4.45 mmol) in methylene chloride (10 ml) was added dropwise over 5 minutes. This reaction mixed solution was stirred for 10 minutes and then triethylamine (3.11 ml, 22.3 mmol) was added dropwise over 2 minutes. This reaction solution was reverted to room temperature over 30 minutes, brought together with saturated aqueous ammonium chloride to terminate the reaction, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to give a crude product of (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-4-tritylthioprolinal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH2:15])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(Cl)cc2)CC1
Yield: 71.7 %

Procedure:
To a solution of 4-(4-chlorophenyl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester (0.355 g, 1.107 mmol) in ethanol (20 ml) at room temperature was added Raney Nickel (Raney Nickel 2800, 1 ml) and the suspension stirred under 1 atmosphere of hydrogen for 20 hours. The suspension was filtered through celite and the filtrate concentrated to give the amine as an oil (0.258 g, 69%). LC/MS: (LCT) Rt 5.02 [M-But-NH2]+324.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH2:2][CH3:3].Br[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:18][C:19]([OH:21])=[O:20])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCNc1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 70B using 4-(propylamino)-2-(trifluoromethyl)benzonitrile and 1,1-dimethylethyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.7 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 6.71 (dd, J=8.8, 2.6 Hz, 1H), 4.18 (s, 2H), 3.41 (t, J=7.7 Hz, 2H), 1.68 (m, 2H), 0.98 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[OH:3].[OH-].[CH2:12]([N+:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>O.CC(O)C>[CH3:1][P:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[O-:4].[CH2:25]([N+:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][CH3:28]
Reactant: CP(=O)(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CP(=O)([O-])c1ccccc1

Procedure:
To a flask were added 2.0 g methylphenylphosphinic acid, 5.4 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 25 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, an oil was obtained.
Reaction SMILES: [C:1](#[N:3])[CH3:2].O1CCCC1.C([Li])CCC.[CH:14]([N:17]1[C:21]2[CH:22]=[C:23]([C:26](=O)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH2:34])([CH3:16])[CH3:15]>C(OCC)(=O)C.O>[CH:14]([N:17]1[C:21]2[CH:22]=[C:23]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:2][C:1]#[N:3])[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH2:34])([CH3:16])[CH3:15]
Reactant: CC#N
Reactant: CC(C)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(N)nc2ccc(C(=CC#N)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Forty millimoles (2.1 ml.) of dry acetonitrile were added to 30 ml. of tetrahydrofuran. A nitrogen blanket was applied and the temperature of the solution lowered to about -78° C. by means of an external acetone/dry ice bath. Twenty-five milliliters of a 1.6M solution of n-butyl lithium were added. After stirring at -78° C. for 30 minutes, a solution of 2.8 g. (10 mmoles) of 1-isopropyl-2-amino-6-benzoylbenzimidazole in 30 ml. of tetrahydrofuran was added. The reaction solution was allowed to warm to about -20° C. and was then stirred for 5 hours at -20° to -5° C. Water and ethyl acetate were then added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was dissolved in 100 ml. of 98% formic acid. After stirring on a hot water bath for 2.5 hours, the solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic solution was dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed over silica gel, eluting first with ethyl acetate to remove non-polar impurities, then with 10% methanol/90% ethyl acetate to elute the title product. The product was further purified by reverse phase chromatography, eluting with 60% aqueous methanol, followed by crystallization from methyl ethyl ketone, resulting in 350 mg. of the title product, M+ =302.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][C:12]#[N:13])[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>N.C(O)C.C(=O)([O-])O.[Na+].[Co]>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][CH2:12][NH:13][C:21](=[O:23])[CH3:22])[C:4]=2[CH2:3][CH2:2]1
Reactant: N#CCCc1nccc2c1CCO2
Reactant: CC(=O)Cl
Agent: [Co]
Agent: N
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NCCCc1nccc2c1CCO2
Temperature: 25 °C
Reaction time: 13 h
Yield: 33.9 %

Procedure:
3-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)propanenitrile (110 mg, 0.63 mmol) and Raney cobalt (200 mg) were suspended in 2M ammonia/ethanol solution (10 mL), and the suspension was stirred at room temperature for 13 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was evaporated under reduced pressure. This was dissolved in dichloromethane (5 mL), triethylamine (173 μL, 1.24 mmol) and acetyl chloride (52.8 μL, 0.743 mmol) were added, and the mixture was stirred at room temperature for 20 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→10/90) to give the title compound (47 mg, yield 35%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:21])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[C:16]([F:19])[CH:17]=2)[NH:12][CH:11]=1)(C)(C)C>Cl.CO>[Cl:20][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH2:9][C@@H:8]([NH2:7])[CH3:21])=[CH:11][NH:12]2)=[CH:17][C:16]=1[F:19]
Reactant: C[C@@H](Cc1c[nH]c2cc(Cl)c(F)cc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](N)Cc1c[nH]c2cc(Cl)c(F)cc12

Procedure:
A solution of [(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (200 mg, 0.6 mmol) in HCl/MeOH (10 mL) was stirred at room temperature. After TLC indicated the reaction was finished, the mixture was concentrated to remove the solvent. To the residue was added EtOAc (50 mL), and the mixture was neutralized with saturated NaHCO3 to pH 8˜9, and then extracted with EtOAc. The combined organic phases were dried with Na2SO4, filtered, concentrated to give a crude (S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-1-methyl-ethylamine which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1=[N:16][CH:17]=[CH:18][N:11]1[C:10]2([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH2:19][CH2:20][C:21]([N:23]1[CH:27]([CH3:28])[CH2:26][CH2:25][CH:24]1[CH3:29])=[O:22])(=O)=O.[CH3:39]B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:10]2([CH2:19][CH2:20][C:21]([N:23]3[CH:27]([CH3:28])[CH2:26][CH2:25][CH:24]3[CH3:29])=[O:22])[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([CH3:39])[CH:8]=3)[C:12]3=[N:16][CH:17]=[CH:18][N:11]23)=[CH:31][CH:32]=1
Reactant: CB(O)O
Reactant: CC1CCC(C)N1C(=O)CCC1(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-c2nccn21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(CCC(=O)N1C(C)CCC1C)(c1ccc(Cl)cc1)n1ccnc1-2
Temperature: 100 °C
Yield: 41.9 %

Procedure:
5-(4-chlorophenyl)-5-[3-(2,5-dimethylpyrrolidin-1-yl)-3-oxopropyl]-5H-imidazo[2,1-a]isoindol-7-yl trifluoromethanesulfonate (50 mg), methylboronic acid (8 mg), K2CO3 (37 mg), and PdCl2(dppf)-CH2Cl2 adduct (8 mg) were combined in 1,4-dioxane (400 μL):H2O (40.0 μL). The mixture was degassed (3× pump/N2) then heated to 100° C. After 3 h the mixture was cooled to room temperature and concentrated. The residue was taken up in DMF, filtered using a 0.45 μm PTFE syringe filter, then purified by preparative reversed-phase HPLC (21×100 mm Phenomenex Gemini (5-95% ACN/water containing 0.05% NH4OH over 20 min at 20 mL/min) to give a light grey solid (16 mg): 1H-NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.79 Hz, 1 H), 7.27 (m, 3 H), 7.19 (m, 1 H), 7.12 (dd, J=3.66 and 5.04 Hz, 2 H), 7.03 (bs, 1 H), 6.93 (dd, J=1.19 and 7.88 Hz, 1 H), 3.89 (m, 1 H), 3.41 (m, 1 H), 3.20-2.75 (m, 2 H), 2.34 (d, J=2.74 Hz, 3 H), 1.97-1.63 (m, 2 H), 1.50 (m, 4 H), 1.17 (dd, J=6.32 and 8.43 Hz, 3 H), 0.86 (dd, J=6.50 and 27.1 Hz, 3 H); HRMS (M+H)+ calculated 434.1994. found 434.1993.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].Cl>O1CCOCC1>[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH:20][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN1CCCC1CCN
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC1CCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared as in Example 81 with 4-chlorophenylsulfonyl chloride replacing 2-naphthalenesulfonyl chloride and with 2-(1-methyl-pyrrolidin-2-yl)-ethylamine replacing 2-pyrrolidin-1-yl-ethylamine. The hydrochloride salt was prepared by treatment with hydrogen chloride in 1,4-dioxan. 1H NMR (DMSO-d6) 8-7 (1H, br s), 7.82-7.77 (2H, m), 7.50-7.46 (2H, m), 3.10-3.01 (3H, m), 2.39 (1H, m), 2.28 (3H, s), 2.15-2.12 (1H, m), 1.82-1.42 (6H, m). Microanalysis found C 51.65 H 6.44 N 8.99. C13H19ClN2O2S requires C 51.56 H 6.32 N 9.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][SH:7])[NH2:5].[CH2:9](Br)[CH:10]=[C:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH3:17])[CH3:12]>N.CO>[CH3:1][O:2][C:3](=[O:8])[CH:4]([NH2:5])[CH2:6][S:7][CH2:9][CH:10]=[C:11]([CH3:12])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H](N)CS
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: N
Solvent: CO
Product: COC(=O)C(N)CSCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Into a 100 mL round bottomed flask at 0° C. is added L-Cysteine methyl ester (1.38 g, 10.2 mmols) in 60 mL of 7M NH3/MeOH. Neat farnesyl bromide (1b) (1.00 g 3.52 mmols) is then added and the solution is stirred at 0° C. for four hours. The reaction mixture is partitioned between ether and water and extracted 3× with ether, extracts are combined, dried over MgSO4 filtered and evaporated. Purification by flash chromatography (1% MeOH:CHCl3) yields 881 mg (74%) of a clear oil. Rf=0.22 in 5% MeOH in CHCl3. 1H NMR (CDCl3, 400 MHz): 5.24 (t, 1H, J=8 Hz), 5.10 (m, 2H), 3.75 (s, 3H), 3.64 (q, 1H), 3.10-3.25 (m, 2H), 2.86-2.91 (2d, 1H), 2.65-2.71 (2d, 1H), 2.04-2.10 (m, 6H), 2.04(m, 6H) 2.0 (t, 2H), 1.69 (s, 3H), 1.68 (s. 3H), 1.60 (s, 6H); 13C NMR (CDCl3, 50 MHz) 174.93, 139.91, 135.71, 131.62, 124.69, 124.11, 120.35, 54.64, 52.35, 39.93, 36.77, 30.15, 26.98, 26.67, 25.86, 17.86, 16.33, 16.21 MS: (ESI, +) (M−H+) 340
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12])[CH:2]=[CH2:3].CCN(CC)CC.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]2[C:5]=1[O:12][C:20](=[O:22])[CH:21]=[CH:7]2)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(C=O)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCc1cccc2ccc(=O)oc12
Temperature: 160 °C
Yield: 40 %

Procedure:
To a solution of 3-allylsalicylaldehyde (1.62 g, 10.0 mmol) in acetic anhydride (2 mL) in a 5 mL Emrys process vial was added Et3N (2.0 ml). The reaction was heated at 160° C. for 45 min in an Emrys Optimizer Microwave reactor then was cooled to RT. The reaction was diluted with 50 mL of ethyl acetate, the organic layer was washed with aqueous ammonium chloride, aqueous sodium chloride, dried (Na2SO4), and concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution: 5% to 30% Ethyl acetate/Hexanes) yielded the title compound (750 mg, 40%) as a colorless oil: MS (ES) m/e 186.9 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:23][CH:24]1[CH2:28][CH2:27][O:26][CH2:25]1>>[O:26]1[CH2:27][CH2:28][CH:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:25]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)n(C)n1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOC2)n(C)n1
Yield: 76 %

Procedure:
As described for example 86, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (60 mg, 0.2 mmol) was converted, using rac-3-aminotetrahydrofuran instead of isopropylamine, to the title compound (54 mg, 76%) which was obtained as a colorless oil. MS: m/e=363.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]2[CH:21]=1)=[O:5])[CH3:2].[Cl:22]N1C(=O)CCC1=O>O1CCCC1>[Cl:22][C:21]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]2=[N:8][C:7]=1[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCNC(=O)Nc1cn2ccc(-c3cccnc3)cc2n1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Ethyl-3-(7-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-urea (1) (196 mg, 0.70 mmol), prepared as in Example 1, was dissolved/suspended in tetrahydrofuran (80 mL) and cooled to 0° C., (ice/water). N-chlorosuccinimide (102 mg, 0.77 mmol) was added and the mixture stirred at 0° C. for 2 h. All solids had dissolved and the reaction was complete by LCMS after this time. The solvent was removed under reduced pressure to give a residue which was purified by chromatography on silica gel (2% methanol/dichloromethane), followed by recrystallization from ethyl acetate/methanol to afford 1-(3-chloro-7-pyridin-3-yl-imidazo[1,2-a]pyridin-2-yl)-3-ethyl-urea (2) as a solid (132 mg). HRMS (EI+) calcd C15H1435ClN5O (M+) 315.0887, found 315.0882; calcd C15H1437ClN5O (M+) 317.0857, found 317.0862.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][C:58]([N:61]=[C:62]=[O:63])=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=2)=[O:63])[CH2:48]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2ccc(F)cc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 79 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-4-isocyanatobenzene as the starting materials in 79% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([NH:15][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: CC(C)N
Product: CC(C)NS(C)(=O)=Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and isopropylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=291, 293 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH2:30][OH:31])(=[O:4])=[O:3].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:31][CH2:30][C@@H:6]1[CH2:7][C@@H:8]([S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])([CH3:40])([CH3:39])[CH3:38]
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O

Procedure:
Following Method A, (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol and tert-butyl bromoacetate gave (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-acetic acid tert-butyl ester, mp 98° C., slow dec., MS: 568 (MH+).