Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C(O)=O)CCSC.CS(O)(=O)=O.[O:15]1[C@@H:27]2[C@@:28]34[CH2:30][CH2:31][N:32]([CH3:33])[C@@H:22]([C@:23]3([OH:35])[CH2:24][CH2:25][C:26]2=[O:34])[CH2:21][C:20]2=[C:29]4[C:16]1=[C:17]([O:36]C)[CH:18]=[CH:19]2>C1CCCCC1>[O:15]1[C@@H:27]2[C@@:28]34[CH2:30][CH2:31][N:32]([CH3:33])[C@@H:22]([C@:23]3([OH:35])[CH2:24][CH2:25][C:26]2=[O:34])[CH2:21][C:20]2=[C:29]4[C:16]1=[C:17]([OH:36])[CH:18]=[CH:19]2
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: C1CCCCC1
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 17.5 °C
Reaction time: 0.5 h

Procedure:
30 kg of DL-Methionine was added to a solution of methane sulphonic acid (390 kg) maintained at 15-20° C. and stirred for 30 minutes. To this solution, 4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one (40 kg) was added at 20° C. and the reaction mass was heated to 50-55° C. the reaction mixture was maintained at 50-55° C. for 12.0 hrs. After reaction completion, it was quenched in a mixture of methanol (400 L) and water (800 L) and the pH of the resultant solution was adjusted to 9-9.2 with aqueous ammonia at below 20° C. The product was extracted with methylene dichloride and concentrated to obtain the product which was isolated with cyclohexane. Yield: 33.4 kg
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:5].[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)=[O:20].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:25]([C:24]1[CH:28]=[CH:29][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: COc1cccc(CCNC(=O)CCN)c1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCC(=O)NCCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-N-(3-methoxyphenethyl)propanamide (60 mg, 0.27 mmol) was added 4-(methoxycarbonyl)benzoic acid (49 mg, 0.27 mmol), hydroxybenzotriazole (3.7 mg, 0.027 mmol), triethylamine (42 μL, 0.30 mmol) and dimethyformamide (2.7 mL). Lastly, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57 mg, 0.30 mmol) was added and the solution was allowed to stir overnight at room temperature in a capped vial. Upon completion of the reaction an aqueous workup is performed to give the crude product which was purified using flash chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[O:28][CH:29]=1>>[F:41][C:38]([F:39])([F:40])[C:35]1[CH:36]=[CH:37][C:32](/[CH:31]=[CH:30]/[C:27]2[O:28][CH:29]=[C:25]([CH2:24][O:1][C:2]3[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[C:12]4[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=3)[N:26]=2)=[CH:33][CH:34]=1
Reactant: OCC(O)Cc1nccn1CCCc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCc1cccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)c1
Yield: 68.9 %

Procedure:
Using 3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (194 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (212 mg), the same reaction as Example 2 was carried out to yield the titled compound (255 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:21][CH2:22][C:23]([N:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:24]
Reactant: CC(C)CNc1ccc(F)cc1Cl
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(C(=O)CCl)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A solution of the above amine (15.0 g, 74 mmol) and triethylamine (12.0 g, 119 mmol) in dichloromethane (200 ml) was cooled to -10° C. and chloroacetyl chloride (11.3 g, 113 mmol) was carefully added while the temperature was kept below 10° C. The mixture was then stirred at ambient temperature for 1 h. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (2×100 ml). The organic phase was washed with 4N hydrochloric acid (2×50 ml), water (100 ml) and saturated aqueous sodium hydrogencarbonate (50 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 13.6 g of 2-chloro-N-(2-chloro-4-fluorophenyl)-N-(2-methyl-1-propyl)acetamide.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH2:9].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1>O1CCOCC1>[F:35][C:30]1[CH:29]=[C:28]([C:22]2[C:21]([CH2:20][O:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:9][CH2:8][CH2:7][O:6][CH3:5])=[O:11])=[CH:14][N:15]=3)=[C:25]([CH2:26][OH:27])[O:24][N:23]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: COCCN
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: COCCNC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 12.4 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.80 mL, 1.60 mmol) was added to a solution of 2-methoxyethylamine (93.3 μL, 1.06 mmol) in dioxane (4 mL). The mixture was stirred for 45 min at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (4 mL) was added and the reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:3 to 1:0) to afford the title compound (14 mg, 13%) as a white solid. MS: m/e=418.2 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1>O1CCCC1>[CH3:15][C:13]1[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: CN1CCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCN(C)CC2)nc1-c1ccc(C)cc1
Yield: 73 %

Procedure:
Methyl 2-(4-methyl-2-(4-methylpiperazin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from 1-methylpiperazine (0.132 mL; 1.18 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.098 g; 0.235 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of methanol (0-6%) in dichloromethane furnished 68 mg (74%) of the title compound as an oil. ESI/APCI(+): 397 (M+H)a). ESI/APCI(−): 395 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[CH:9]=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:11][C:2]1([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[CH2:9][OH:10]
Reactant: CC1CCC(C=O)C(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1CCC(CO)C(C)(C)C1
Yield: 91.6 %

Procedure:
The procedure described in the above Example 3 was repeated, using 20 g (0.13 mole) of 2,2,4-trimethyl-1-cyclohexanecarbaldehyde and 1.7 g (45 mmole) of LiAlH4 in 200 ml of diethyl ether. Distillation at 50°/0.5 hPa afforded 18.6 g (92%) of pure product, composed of about 90% of trans and 10% of cis-isomer.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH3:23][O:22][C:18](=[O:21])[CH2:19][O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[NH:8][C:6]1[C:5]([Cl:17])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COC(=O)CO
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a suspension of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol (0.300 g, 1.09 mmol), Methyl Glycolate (0.118 g, 1.31 mmol), and Triphenylphosphine (0.459 g, 1.75 mmol) in Methylene chloride (10 mL) cooled to 0° C. on an ice bath was slowly added Di-tert-butyl azodicarboxylate (0.403 g, 1.75 mmol), at which time a solution formed. The reaction mixture was stirred at rt overnight. The reaction did not go to completion, so one additional equivalent of Methyl Glycolate and Triphenylphosphine were added to the reaction mixture, which was then cooled to 0° C. and one equivalent of Di-tert-butyl azodicarboxylate was also added. The reaction was stirred at rt for an hour. The reaction mixture was concentrated and dissolved in minimal amounts of DCM. It was then purified by silica gel chromatography in 0-50% ethyl acetate solvent to afford [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenoxy]-acetic acid methyl ester as a clear oil (0.30 g, 79%). 1H-NMR (DMSO): 9.26 (s, 1H), 8.37 (s, 1H), 7.34 (m, 1H), 6.98 (m, 2H), 4.83 (s, 2H), 3.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[S:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)cs1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.01 ml (0.22 mmol) of bromine is provided in 1 ml of acetic acid, and 58.0 mg (0.22 mmol) of the compound from Example 13A, dissolved in 1 ml of acetic acid, are added dropwise. The mixture is stirred at 60° C. overnight. 0.01 ml (0.22 mmol) of bromine is a subsequently added, and the mixture is stirred at 60° C. for another 24 hours. Water is added to the reaction mixture, and the resulting precipitate is collected by suction filtration, washed with water and dried under high vacuum. 43.0 mg (54% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)[C:3]=1[CH:16]=[O:17].OO.[O-:20]Cl=O.[Na+]>C(#N)C.[O-]S([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[C:3]=1[C:16]([OH:20])=[O:17]
Reactant: Cc1cc(C)cc(-c2cccc(C)c2C=O)c1
Reactant: [O-][Cl+][O-]
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(C)cc(-c2cccc(C)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 106.8 %

Procedure:
The aldehyde 51 (2.75 g, 11.5 mmol) was dissolved in acetonitrile (18 ml, technical grade). NaH2PO4 (0.453 g, dissolved in 5.5 ml H2O) and H2O2 (1.93 ml of a 30% solution) was added. The reaction mixture was cooled to 0° C. (with ice/water) and NaClO2 (2.2 g, dissolved in 19 ml water) was added within 60 min via a syringe. The solution was allowed to warm to ambient temperature and was stirred for additional 3.5 h. Then Na2SO3 (100 mg) was added, stirred for 5 min. After treatment with HCl (50 ml of a 10% solution) the reaction mixture was extracted with ether (3×75 ml). The combined organic phase was extracted with NaOH (4×75 ml, 1 N). The combined NaOH layers were acidified with HCl to pH 1 and extracted again with Et2O. The combined organic layers were dried over MgSO4 and the volatiles removed in vacuo to afford 52 (2.95 g, quant.) as a colorless oil. The product was used without any further purification.
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[C:7]([C:13]#[C:14]CO)[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4](C)[C:3]=1[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:10]1[CH:9]=[CH:8][C:7]([C:13]#[CH:14])=[C:6]2[C:11]=1[CH:2]=[C:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=[N:5]2
Reactant: CCCCc1c(C)nc2c(C#CCO)ccc(F)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1ccc(F)c2cc(CCCC)cnc12
Temperature: 120 °C
Yield: 71.6 %

Procedure:
Dimethylhydroxymethyl-5-fluoro-3-butyl-8-quinolylacetylene (788 mg, 2.76 mmol) and NaOH (121 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98% article, 3.03 mmol) were placed in a 30 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 18.0 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture, and then the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 449 mg of 5-fluoro-3-butyl-8-quinolylethyne as a yellow solid. This was immediately dissolved in 11.0 mL of ethanol, under an argon atmosphere, in a 30 mL Schlenk tube, and Au(PPh3)Cl (290 mg, 0.587 mmol) was added thereto, and then sodium ethoxide (243 μl, 0.620 mmol: 2.55 mol/L (liter) in ethanol solution) was added dropwise thereto, followed by stirring of the mixture at room temperature for 15 hours. After completion of the reaction, the resulting white precipitate was filtered and successively washed with 5 mL of water four times and 5 mL of ethanol twice, followed by drying under vacuum to give 751 mg of the desired compound as a pale yellow powder (yield: 39.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:35][CH2:34][C:21]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>ClCCl>[CH2:22]1[C:21]2([CH2:34][CH2:35][CH:18]([NH:17][C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=4)[N:4]=3)[CH2:19][CH2:20]2)[CH2:26][CH2:25][NH:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCCn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (500 mg, 0.99 mmol) in dichloromethane (20 mL) was added a solution of HCl in EtOAc (5 mL, 20 mmol). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in methanol (2 mL) and adjust to pH=7-8 with the solution of NaHCO3 and extracted with DCM (100 mL×3) The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified with a silica gel column chromatography (MeOH/DCM (v/v)=1/10 to 1/7) to give the product as a light yellow solid (340 mg, 84.77%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:18]1[C:23]([O:24][CH2:25][C@@H:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:28][CH:26]4[O:27][C:18]5=[N:19][CH:20]=[CH:21][CH:22]=[C:23]5[O:24][CH2:25]4)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: Brc1ncccc1OC[C@@H]1CO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(C3=CCN(CC4COc5cccnc5O4)CC3)c[nH]c2c1
Temperature: 25 °C
Yield: 12 %

Procedure:
6-Fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.87 g, 8.65 mmole) and 2-bromo-3-[(2S)oxiranylmethoxy]pyridine (1.00 g, 4.34 mmole) were combined in DMSO (45 mL). This solution was heated at 75–80° C. under nitrogen for 5 hours. After completion, the reaction was cooled to room temperature and partitioned between 250 mL each of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride as eluant to remove impurities and then 3% methanol in methylene chloride to elute the product, which was a yellow solid (0.30 g, 15%). The intermediate (0.30 g, 0.67 mmole) was then cyclized in toluene (40 mL) in the presence of palladium (II) acetate (0.010 g, 0.044 mmole), (S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.030 g, 0.044 mmole), and potassium carbonate (0.11 g, 0.80 mmole). The heterogeneous mixture was heated at 100° C. for a period of 24 hours. After the mixture cooled to room temperature, the catalysts were removed by filtration and the filtrate was concentrated in vacuum. The resulting crude brown oil was then column chromatographed on silica gel with 3% methanol in methylene chloride to give the desired product as a brown oil (0.19 g, 79%). The oil was crystallized from ethanol with the addition of a solution of oxalic acid in hot ethanol to give 0.070 g of the (S)-enantiomer of the title compound as beige solid dioxalate, m.p. 120° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[K+].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O.C(Cl)Cl.[Cl-].[Na+]>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:2][CH2:3][C:4]([NH2:6])=[O:5])=[CH:12][CH:11]=1
Reactant: NCC(N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)CNCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To glycinamide hydrochloride (1B2) (129 mmol, 15.4 g) in methanol (343 ml) was added potassium hydroxide (9.27 mmol, 0.520 g) followed by 4-bromobenzaldehyde (1B1) (93 mmol, 17.15 g) and the mixture stirred for 15 minutes at 0° C. Sodium triacetoxyborohydride (278 mmol, 58.9 g) was added and stirring continued for 1 h. The reaction was diluted with water (75 ml), DCM (300 ml) and saturated sodium chloride solution (100 ml) and the phases separated. The aqueous layer was washed twice with DCM (100 ml) before addition of sodium hydroxide solution to ˜pH10 and the resulting precipitate was collected by filtration to give 2-(4-bromobenzylamino)acetamide (1B3) 13.2 g (58.5%); 1H NMR (400 MHz, DMSOd6) δ 7.50 (d, 2H) 7.31 (d, 2H) 7.08 (bs, NH2) 3.65 (s, 2H) 3.01 (s, 2H) 2.58 (bs, NH).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][O:5][CH2:6][CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.O>[CH2:6]([O:5][CH2:4][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][NH:1][C:23](=[O:24])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOCC(CN)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (1-amino-3-ethoxypropan-2-yl)carbamate (0.45 g, 2.6 mol) and sodium carbonate (0.29 g, 3.2 mol) in THF (5 mL) and water (3 mL) was added dropwise benzyl chloroformate (0.58 g, 3.4 mol) at 0° C. and then the reaction mixture was allowed to warm to ambient temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give benzyl tert-butyl (3-ethoxypropane-1,2-diyl)biscarbamate. MS ESI calc'd. for C18H29N2O5 [M+H]+ 353. found 353. 1H NMR (400 MHz, CD3OD) δ 7.36-7.35 (m, 5H), 5.09 (s, 2H), 3.52-3.49 (m, 1H), 3.42-3.32 (m, 6H), 1.45 (s, 9H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[C:6]([CH2:10][Cl:11])([F:9])([F:8])[F:7].[Cl-].[K+].[F-].[K+]>CN1CCCC1=O.O>[C:6]([CH2:10][Cl:11])([F:9])([F:8])[F:7].[C:6]([CH2:10][O:3][C:1]([CH3:2])=[O:4])([F:9])([F:8])[F:7]
Reactant: CC(=O)[O-]
Agent: FC(F)(F)CCl
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)OCC(F)(F)F
Temperature: 140 °C
Reaction time: 6.1 h

Procedure:
A pressure vessel containing 8009 g of powdered potassium acetate was heated to 140° C. and evacuated to a pressure of 0.4 mm Hg for 4 hrs. removing 87 grams of water and acetic acid. To the remaining potassium acetate (7922 g, 80.7 mols) 11,800 g of N-methyl-2-pyrrolidone (NMP) containing 10 parts per million water was added. Then 95 mols of CF3CH2Cl containing 62 parts per million water was also added. As the mixture was heated to 180° C., the pressure rose to about 200 pounds per square inch (psig). For the next 4.3 hours, as the pressure dropped, CF3CH2Cl was added as necessary to keep the pressure near 200 psig. A total of 14,350 g (121.1 mols) of CF3CH2Cl was added to the reactor. After another 6.1 hours at 180° C., the reaction pressure had fallen to 173 psig and appeared to be no longer dropping appreciably. The reaction vessel was cooled to near room temperature and filtered with the filtrate entering a still. The remaining liquid products were washed from the salts on the filter into the still with an additional 65.6 mols of CF3CH2Cl leaving behind 69.3 mols of potassium chloride (85.9% conversion of the potassium acetate) and 0.50 mol of potassium fluoride (0.24% loss based on the reacted CF3CH2Cl). The distillation yielded 111.5 mols of unreacted CF3CH2Cl and 66.1 mols of the CF3CH2O2CCH3 leaving behind 11,655 g of dry NMP to be reused.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:21][C@H:19]([OH:20])[CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[S:2]([O:16][C:15](=[O:17])[C@@H:14]1[CH2:18][C@@H:19]([OH:20])[CH2:21][N:13]1[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (2 eq) was slowly added at 0° C. to a DCM solution of N-(tert-butoxycarbonyl)-hydroxyproline N,O-dimethylhydroxamide and TEA (2 eq). The reaction mixture was stirred for an additional 10 minutes and allowed to aftain room temperature with continued stirring for an additional 45 minutes. The solvent was then evaporated and residue taken in water. It was extracted with ethyl acetate (twice) and the combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated and residue dried under vacuum to give O-mesyl N-(tert-butoxycarbonyl)-hydroxyproline N,O-dimethylhydroxamide. The yield from this reaction approached 100%. To a suspension of sodium hydride (2 eq) in DMF was added an aromatic alcohol (2 eq) taken in DMF under vigorous stirring. After completion of the hydrogen release, the solution was added to the DMF solution of O-mesyl N-(tert-butoxycarbonyl)-hydroxyproline N,O-dimethylhydroxamide and stirred for 16 hours. The reaction temperature then was raised to 90° C. with continued stirring for 24-48 hours. After cooling, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layer was washed with water (twice), brine (once), and dried over sodium sulfate. The solvent was evaporated and product purified as described in Example 7, Method A.