Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C@@H:25]([OH:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:39][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C@@H:25]([OH:31])[CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1
Reactant: CCC(CC)[C@H](O)CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)[C@H](O)CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 96.1 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(S)-hydroxypentylthio}pregna-5,7,16-triene (55.3 mg, 0.0802 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=9:1, developed once) to give the title compound as a white solid (35.5 mg, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH3:14][CH:13]([O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:15]
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC(C)C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 103.6 %

Procedure:
To a solution of methyl 3-hydroxy-5-[(1-methylethyl)oxy]benzoate (25 g) in DMF (250 mL) was added anhydrous potassium carbonate (297 mmol), and benzyl bromide (143 mmol). The mixture was stirred at 60° C. for 5 hours, then cooled to room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organics were combined and washed with further water, brine, dried (MgSO4) and concentrated in vacuo to give the desired compound (37 g) which was used without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:1][C@@H:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CC[C@@H](C)Oc1ccc(OCC(=O)OC)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC[C@@H](C)Oc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the above ester (2.50 g), methanol (20 ml) and 5 ml of 10% NaOH is stirred at RT for 24 hours. The reaction is then worked up by addition of water and 10% sulfuric acid to adjust the pH to 3 and extraction with ether. The combined organic layers are washed with water and with brine, dried, filtered and the filtrate stripped to give (R)-(-)-4-(1-methylpropoxy)phenoxyacetic acid, [α]D20 -21.369°.
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][CH:24]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:51][CH:50]=3)[C:25](=[O:47])[N:26]3[CH:35]([C:36]4[NH:37][CH:38]=[C:39]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:40]=4)[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)C3C(=CC=CC=3)C=2C=CC=1>CO>[NH2:23][CH:24]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:51][CH:50]=1)[C:25]([N:26]1[CH:35]([C:36]2[NH:37][CH:38]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:40]=2)[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:47]
Reactant: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2Cc3ccccc3CC2c2nc(-c3ccccc3)c[nH]2)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)Oc1ccc(CC(N)C(=O)N2Cc3ccccc3CC2c2nc(-c3ccccc3)c[nH]2)cc1

Procedure:
Piperidine in methanol (20%; 2 mL) was added to {1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (0.20 g, 0.28 mmol) at room temperature. After 30 minutes the reaction was concentrated under reduced pressure, and the residual 200 mg of desired product 2-amino-3-(4-tert-butoxy-phenyl)-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one was used as is without further purification (LC/MS; Measured MW (MH+): 495).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:10]([CH3:31])[C:11]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:12].[OH:32]O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:10]([CH3:31])[C:11]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:12])=[O:32]
Reactant: OO
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(C)Sc3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Solvent: CC(=O)O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(C)S(=O)c3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 250 mg of 5'-[2(RS)-(2,4-dichlorophenylthio)propionamido]-2',5'-dideoxy-5-ethyluridine in 10 ml of acetic acid was cooled to 0° C. and 60 ml of 30% hydrogen peroxide were added. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature overnight. An additional 60 mg of 30% hydrogen peroxide were added and the mixture was stirred for 24 hours. An additional 30 mg of 30% hydrogen peroxide were added and the mixture was stirred for an additional 4 hours and then evaporated to dryness. The residue was triturated with methanol and the resulting solid was removed by filtration and recrystallized from methanol to give 90 mg of 5'-[2(RS)-(2,4-dichlorophenylsulphinyl)propionamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 208°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[C:4]([F:11])[CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[C:4]([F:11])[CH:3]=1
Reactant: Fc1cc(Br)ccc1C1CO1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCNCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of (RS)-2-(4-bromo-2-fluorophenyl)oxirane (12.3 g) in THF (40 ml) was added 2-aminoethanol (33.9 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (3:1) and washed with saturated brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; gradient: 0% to 35% MeOH in dichloromethane containing a few drops of aq. NH3) to afford (RS)-1-(4-bromo-2-fluorophenyl)-2-(2-hydroxyethylamino)ethanol (12.0 g, 76%) as a brown oil. MS (ISP): 280.0 ([{81Br}M+H]−), 278.0 ([{79Br}M+H]+).
Reaction SMILES: P(=O)(O)(O)O.C(OC([NH:13][CH:14]1[CH2:17][N:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15]1)=O)(C)(C)C.O.[OH-].[Na+]>ClCCl>[NH2:13][CH:14]1[CH2:15][N:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17]1
Reactant: CCOC(=O)c1cccc(N2CC(NC(=O)OC(C)(C)C)C2)c1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc(N2CC(N)C2)c1
Reaction time: 27 h
Yield: 83.5 %

Procedure:
85% phosphoric acid (0.18 mL, 1.57 mmol) was added to a solution of ethyl 3-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}benzoate obtained in Example (223a) (200 mg, 0.62 mmol) in dichloromethane (0.8 mL) at room temperature, followed by stirring for 27 hours. Water and a 50% aqueous sodium hydroxide solution were added to the reaction solution, and then the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 114 mg of the title compound as a colorless oily substance (83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]>Br>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: Br
Product: CC(=O)c1ccc(O)c(Cl)c1N
Temperature: 110 °C
Yield: 23.3 %

Procedure:
1-(2-Amino-4-methoxy-3-chloro-phenyl)ethanone (71.55 g, 358 mmol) was dissolved in HBr (500 mL, 48% in H2O). The reaction was heated to 110° C. for 2 days. The reaction was cooled to rt then the solids were filtered. The solids were partitioned between EtOAc and ½ sat Na2CO3(aq). Organics were dried over Na2SO4, filtered and solvent removed under reduced pressure. 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone (15.5 g, 16%) was isolated by silica gel chromatography as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[O:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:9][CH2:10]1)[C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: COC(=O)CC1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1ccnc2ccc(OC)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccnc2ccc(OC)cc12)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 11.3 %

Procedure:
(4-Tert-Butoxycarbonylamino-cyclohexyl)-acetic acid methyl ester (1.00 g, 3.69 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. To the solution lithium hexamethyldisilazide in tetrahydrofuran (1M, 11.0 mL, 11.0 mmol) was added dropwise. The reaction mixture was stirred for 20 minutes at −78° C. and then 6-methoxy-quinoline-4-carboxylic acid methyl ester (1.60 g, 7.38 mmol) was added as a solution in tetrahydrofuran (10 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched by the addition of water (2 mL), the solvent removed in vacuo and the residue partitioned between ethyl acetate (2×100 mL) and water (20 mL). The pH of the aqueous phase was adjusted to 10 to obtain the maximum degree of extracted material into the organic phases. The organic phases were combined, dried over magnesium sulfate and the volatiles removed under suction. The resulting residue was purified by column chromatography on silica gel using an ethyl acetate and hexane solvent gradient to provide the desired compound as a colourless oil (190 mg, 12%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[F:26][C:27]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:4]1[N:3]=[C:2]([C:33]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: COc1ccc2[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)nc2c1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)nc2c1
Yield: 97.1 %

Procedure:
To a solution of 4-chloro-6-{2-[5-(methyloxy)-1H-benzimidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (150 mg, 0.416 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (134 mg, 0.540 mmol) and Na2CO3 (110 mg, 1.039 mmol) in 1,4-dioxane (1.8 mL) and water (0.6 mL) stirred under nitrogen at room temperature was added solid Pd(PPh3)4 (48.0 mg, 0.042 mmol) in one charge. The reaction vessel was sealed and heated in Biotage Initiator using initial high to 140° C. for 1 hour. The reaction mixture was partitioned between EtOAc/THF 25/25 mL and water 50 mL. The organic phase was washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was added to a silica gel column and was eluted with Hexanes/EtOAc to afford the title compound (180 mg). LC-MS (ES) m/z=446 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[NH2:10][C:11](N)=[O:12].Cl>O.C(O)(=O)C>[OH:8][C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][C:2]=1[NH:1][C:11]([NH2:10])=[O:12]
Reactant: NC(N)=O
Reactant: Cc1ccc(N)c(O)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(NC(N)=O)c(O)c1
Yield: 86 %

Procedure:
To 13 ml of water, there were added 5.00 g (40.7 mmol) of 6-amino-m-cresol, 9.76 g of (162.6 mmol) of urea, 4 ml of conc. hydrochloric acid and 0.8 ml of a mixture (1:1 (v:v)) of conc. hydrochloric acid and glacial acetic acid, followed by heating under reflux for 1.5 hours. After cooling, 20 ml of water was added. The crystals thus precipitated were filtered and dried to thereby give 5.81 g (35.0 mmol) of N-(2-hydroxy-4-methylphenyl)urea as dark brown crystals. The yield was 86%. After recrystallizing from acetonitrile, 2.00 g of N-(2-hydroxy-4-methylphenyl)urea was obtained as pale purple crystals. The recovering yield was 34%.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH:18](OCC)=O>C(OCC)C>[CH3:3][C@H:2]([NH:1][CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC=O
Reactant: CC(N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN[C@@H](C)Cc1ccccc1
Temperature: 100 °C

Procedure:
Amphetamine free base (100 mg, 0.71 mmol) was dissolved in ethyl formate (10 mL). The solution was heated under pressure in an ACE pressure reactor for 2 hours at 100° C. The reaction mixture was cooled down, and the solvent was evaporated under reduced pressure. The resulting carbamate derivative was dissolved in dried diethyl ether (5 mL). The solution was added dropwise to a suspension of lithium aluminium hydride (40.4 mg, 1.07 mmol) in diethyl ether (10 mL). The reaction mixture was refluxed for 5 hours. Thereafter, water was carefully added after the reaction mixture had been cooled down to 0° C. on an ice bath. The lithium salt was filtered over Celite™ diatomaceous earth in Buchner funnel. The granules obtained were washed thoroughly with excess diethyl ether. The combined ether phases were washed with 5% sodium hydroxide and brine before being dried with magnesium sulfate. The solvent was evaporated to yield 96 mg methamphetamine free base.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].CC(C)=[O:19]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:19][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)=O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1CO
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
(E)-Methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (15 g) was dissolved in acetone (200 ml) and the solution was cooled to 2° C. A solution of silver nitrate (22.35 g) in water (200 ml) at 4° C. was added to this. The temperature rose to 12° C. After stirring for 40 minutes the green/grey precipitate which had formed was filtered off and the filtrate partitioned between water and diethyl ether. The diethyl ether layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to give an oil which was purified by chromatography on silica gel, eluting with diethyl ether, to give (E)-methyl 2-[2-(hydroxymethyl)phenyl]-3-methoxypropenoate as a viscous oil (6.33 g, 54%). 1H NMR (CDCl3) 2.3(t,1H), 3.7(s,3H), 3.8(s,3H), 4.5(d,2H), 7.1(m,1H), 7.2-7.4(m,2H), 7.5(m,1H), 7.6(s,1H) ppm.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([Mg]Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH:14]([OH:15])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Br[Mg]CCc1ccccc1
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CCc1ccccc1
Yield: 79.9 %

Procedure:
To a rapidly stirred -78° C. solution of Boc-Leucinal (1.50 g, 6.97 mmol) in anhydrous ether (10 ml) was added a -78° C. solution of phenethyl magnesium bromide (7 mmol) in anhydrous ether (40 ml) dropwise over the course of 15 minutes, and 45 minutes later the mixture was acidified. The oragnic phase was separated, washed with brine (2×10 ml) and dried (Na2SO4). Filtration and evaporation provided an oil (1.79 g) which was chromatographed with 150 g of 40 m SiO2 (7/3, hexane/ether) to give the desired compound (0.17 g). Mass spectrum: M+ =321.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:32]=[C:33]([O:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:30][C:31]1[CH:32]=[C:33]([O:38][S:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:34]=[CH:35][C:36]=1[Cl:37])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CCc1ccsc1
Reactant: O=S(=O)(Oc1ccc(Cl)c(CBr)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3cc(OS(=O)(=O)c4ccccc4)ccc3Cl)ccc2n1CCc1ccsc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-1-[(2-thiophen-3-yl)ethyl]-1H-indole-2-carboxylic acid ethyl ester (0.42 g, 1.33 mmol) in dry DMF (10 mL) was added Cs2CO3 (0.65 g, 1.99 mmol). After stirring at 60° C. for 30 min, benzenesulfonic acid 3-bromomethyl-4-chlorophenyl ester (0.48 g, 1.33 mmol), from Example 1(b) above, was added. The reaction was kept stirring at 60° C. for 18 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacua. Purification by flash column chromatography (silica gel, EtOAc/hexanes) afforded the partially purified product which was used directly in the next step without further purification (see Examples 1(h) and 2(c)).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>ClCCl>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-ol (0.050 μg), N,N-dimethylformamide (2.0 mL), potassium carbonate (0.059 g) and bromoacetic acid methyl ester (0.031 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane and this solution was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as brown solid, 0.11 g.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]2)[CH:2]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Product: Cc1cccc(-n2nnc(C(=O)O)n2)c1

Procedure:
This intermediate was prepared from m-tolylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:7][CH:5]([O:4][C:2]([N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1)=[O:3])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.46 g, 1.1 mL, 10.2 mmol) was reacted with 1-Boc-piperazine (Alfa Aesar, 1.5756 g, 8.37 mmol) and pyridine (870 mg, 0.89 mL, 11.0 mmol) in methylene chloride (10 mL) from −78° C. for 1 h and then at room temperature overnight to give piperazine-1,4-dicarboxylic acid tert-butyl ester 1-chloro-ethyl ester. A portion of piperazine-1,4-dicarboxylic acid tert-butyl ester 1-chloro-ethyl ester (682 mg, 1.67 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (201.4 mg, 0.327 mmol) in the presence of cesium carbonate (743.4 mg, 2.28 mmol) in dimethylformamide (7 mL) overnight to give 1-tert-butyl 4-(1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl)piperazine-1,4-dicarboxylate as an off-white lyophilized solid (259.9 mg, 91% yield). MS (ES+) m/z calcd. for C34H36Cl2F2N4O4: [(M+H)+]: 872, found: 872
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:8])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: CCNCC
Reactant: O=C(O)c1ccc(Cl)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (18.1 g, 80 mmol) in 500 mL of methylene chloride was added oxalyl chloride (60 mL of a 2.0 M solution in methylene chloride, 120 mmol) followed by N,N-dimethylformamide (0.2 mL). The reaction was allowed to stir at ambient temperature for 18 h. The volatiles were removed in vacuo to afford the crude acid chloride intermediate. The residue was taken up in 500 mL of methylene chloride and then there was added diethylamine (16.5 mL, 160 mmol). The resulting solution was allowed to stir at ambient temperature for 2 h, and then the mixture was concentrated to an oil. The residue was purified (ISCO, 0-30% EtOAc/hexane, 45 min) to afford 11.4 g (51%) of the title compound as a pale yellow oil.