Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:27][CH:26]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(Cl)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(Cl)cc3)(CC1)CC2
Yield: 38.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-chloroaniline (43.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-chlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (25.6 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]1[C:27]([C:28]([OH:30])=O)=[CH:26][N:25]=[CH:24]1.FC(F)(F)C(O)=O.[CH3:38][O:39][C:40]1[CH:60]=[CH:59][C:43]([O:44][C:45]2[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]([C:53]3([NH2:56])[CH2:55][CH2:54]3)=[O:52])=[CH:47][CH:46]=2)=[C:42]([C:61]([F:64])([F:63])[F:62])[CH:41]=1>CN(C=O)C>[CH3:38][O:39][C:40]1[CH:60]=[CH:59][C:43]([O:44][C:45]2[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]([C:53]3([NH:56][C:28]([C:27]4[O:23][CH:24]=[N:25][CH:26]=4)=[O:30])[CH2:54][CH2:55]3)=[O:52])=[CH:47][CH:46]=2)=[C:42]([C:61]([F:62])([F:63])[F:64])[CH:41]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: O=C(O)c1cnco1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnco4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
57.5 μL (0.41 mmol) of TEA and 48 mg (0.15 mmol) of TBTU were added to a solution of 15.4 mg (0.14 mmol) of oxazole-5-carboxylic acid in 1.5 mL DMF and the mixture was stirred for 5 min at RT. Then 67.5 mg (0.14 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) were added and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26].O>C(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]1=[O:26]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2F)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A solution of 32.9 mL (0.033 mole) of boron tribromide (1M in methylene chloride) in 50 mL of methylene chloride was stirred, and a solution of 3.5 grams (0.011 mole) of 3-(2-fluoro-4-methoxyphenyl)-1-methyl-6-trifluoromethyluracil in 50 mL of methylene chloride was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into water. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The methylene chloride extract and the organic layer were combined and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was conc-entrated under reduced pressure, yielding about 2.9 grams of 3-(2-fluoro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil, mp 185°-190° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]1=[O:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH:15](=[N:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CN1CCC[C@H](N)C1=O
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)CN1CCC[C@H](N=Cc2ccccc2)C1=O
Reaction time: 21 h
Yield: 89 %

Procedure:
To a solution of 22 (4.7586 g, 0.0200 mol) and benzaldehyde (2.1224 g, 0.0200 mol, 2.03 mL) in 50 mL CH2Cl2 at 0° under N2 was added anhydrous MgSO4 (5.0 g) and Et33N (4.05 g, 0.040 mol, 5.58 mL). The mixture was stirred from 0° to ambient temperature over 21 hrs, filtered under N2, and the solvent was evaporated. The residue was dissolved in 300 mL of diethyl ether, extracted with 50 mL portions of water (3×), brine, dried over MgSO4, filtered under N2 and evaporated to afford 5.13 g (89% yield) of product 23 as a light yellow viscous oil. The material was hydrolytically labile and was stored at 0° under a N2 atmosphere.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:13](C=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(N)=O)c(Br)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of 2-bromo-4-methylbenzoic acid (15.0 g, 69.8 mmol) in toluene (60 mL), thionyl chloride (10.3 mL) and DMF (0.10 mL) were added and stirred at 50° C. for 3 h. After cooling to room temperature, the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL), and the mixture was added to the solution of ammonia (25%, 60 mL). The white precipitate was filtered over Celite and dried in vacuo to afford 2-bromo-4-methylbenzamide (14.8 g, 99%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:18])([CH3:13])[CH3:12].[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([CH3:45])[N:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=1)[C:23]([NH:39][C:40]1[CH:44]=[CH:43][N:42]([CH3:45])[N:41]=1)=[O:25])[CH3:18])([CH3:12])[CH3:13]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
DIPEA (4.06 g, 23.4 mmol) was added to a suspension of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (2.43 g, 5.84 mmol), 3-amino-1-methylpyrazole (0.85 g, 8.76 mmol) and HATU (4.66 g, 12.3 mmol) in DMF (50 mL) and stirred at ambient temperature for 16 hours. The resultant mixture was partially reduced in vacuo, poured onto water (100 mL) and extracted with diethyl ether (2×50 mL). The extracts were washed with water and brine then dried (MgSO4), filtered and reduced to an opaque gum which partially crystallized. The crude product was purified by column chromatography, eluting with 0-100% ethyl acetate in isohexane, to give the title compound as a colourless oil (1.87 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[NH2:1][C:2]1[C:3]([NH2:9])=[CH:4][CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])[N:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2ccccc2F)nc1N
Temperature: 105 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 6-amino-2-bromo-5-nitropyridine (2.0 g, 9.2 mmol) and 2-fluorophenylboronic acid (2.57 g, 18 mmol) in dimethoxyethane (60 mL) were added 2M aqueous sodium carbonate solution (18 mL) and tetrakistriphenylphosphine palladium(0) (106 mg, 0.092 mmol). The mixture was stirred at 105° C. for 16 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (30 mL) and methanol (30 mL). To the solution was added 10% palladium carbon (200 mg), and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. After removal of the palladium catalyst by filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (1.87 g, 100%) as a reddish brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (2 g, 9.4 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (2.3 g, 7.5 mmol) prepared in Example 2 in dichloromethane (30 mL) were added triethyl amine (2.8 mL, 20 mmol) and AgF (1.1 g, 8.7 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2) to give as rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white foam (1.9 g, 49%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccncc1

Procedure:
The 4-(2-hydroxyethyl)pyridine (Lancaster, 0.153 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[S:25](Cl)(=[O:27])=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[S:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:27])=[O:26])=[CH:21][CH:22]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(-c2ccco2)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
2-Aminobenzenesulfonamide (61 mg, 0.35 mmol) was dissolved in pyridine (2.5 mL) and (E)-2-[4-(2-furyl)phenyl]ethenesulfonyl chloride) (see General procedure for synthesis of styrenyl sulfonyl chlorides) (95 mg, 0.35 mmol) was added. The reaction was stirred at RT overnight. The solvent was removed, the residue was partitioned between water and ethyl acetate, made acidic (HCl) and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water, treated with brine, dried (MgSO4), and evaporated to give the title compound (140 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2sc(C(=O)Nc3ccc(C(=O)O)cc3)c(OC(C)C)c2c1
Yield: 64.8 %

Procedure:
A mixture of 4.0 g of methyl 4-[[[5-methoxy-3-(1-methylethoxy)-benzo[b]thien-2-yl]carbonyl]amino]benzoate and 2 g of 50% NaOH in 100 mL of 10% aqueous methanol is heated on a steam bath for 15 minutes, then poured onto ice and acidified with 10% HCl. The resulting gum is extracted into 500 mL of diethyl ether. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude solid is triturated with t-butyl methyl ether to provide 2.5 g of product; mp 236°-239° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][C:12]=2[N:13]=1>C1COCC1.O=[Mn]=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(CO)cc2[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1nc2ccc(C=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-methanol (750 mg) and MnO2 (5 g) in THF (10 mL) was stirred at ambient temperature for 4 h. The mixture was filtered through Celite and the filtrate evaporated to give 2-(2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carbaldehyde as an oil. MS (ESI)m/z 251 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][SH:6].CC([O-])(C)C.[K+].Cl[C:15]1[C:24]([C:25]([NH:27][CH2:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.CCCCCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][S:6][C:15]1[C:24]([C:25](=[O:26])[NH:27][CH2:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Reactant: COC(=O)CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)CCSc1nc2ccccc2cc1C(=O)NCc1cccs1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
A solution of 361 mg (3.0 mmol) 3-mercaptopropionic acid methyl ester in DMF (18 ml) was cooled to 0° C. and mixed with 336.6 mg (3.0 mmol) potassium tert-butylate and stirred for 10 min. Then 908 mg (3.0 mmol) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV01) were added and the reaction solution was then heated slowly to 50° C. and stirred for 16 h at this temperature. It was then diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 614 mg (1.6 mmol, 53%) 3-[[3-[oxo-(2-thienylmethylamino)methyl]-2-quinolyl]thio]propanoic acid methyl ester. MS: m/z 387.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8]>>[C:3]([CH2:4][CH2:5][NH:11][CH2:10][CH:9]([CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH3:15])([O:2][CH3:1])=[O:6]
Reactant: CCCCC(CC)CN
Reactant: C=CC(=O)OC
Product: CCCCC(CC)CNCCC(=O)OC
Temperature: 35 °C
Reaction time: 2 h

Procedure:
While stirring at a temperature of 20° C., 90.3 grams (1.05 mole) of methylacrylate were dripped into 129 grams (1 mole) of 2-ethylhexylamine within a period of 30 minutes. The temperature was increased to 35° C. The mixture was stirred at 100° C. for 2 hours and was subsequently degassed at 50° C. under a high vacuum for 1 hour. The remaining residue was 210 grams (98 percent of theory) liquid N-(2'-carbomethoxy-ethyl)-2-ethylhexylamine. The 60 MHz-Nuclear Magnetic Resonance Spectrum s 3.7 ppm COOCH3 ; m 2.9 ppm; m 2.5 ppm; 0.7 to 1.5 ppm confirms the structure.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])([CH3:6])[CH3:5].CS(C)=O.[CH2:20](Br)[CH:21]=[CH2:22]>O>[OH:3][C:4]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH:21]=[CH2:20])=[CH:13][CH:14]=1)=[O:8])([CH3:5])[CH3:6]
Reactant: CC(C)(O)C(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1ccc(C(=O)C(C)(C)O)cc1
Reaction time: 0.25 h

Procedure:
6.6 g. (0.22 mol) of sodium hydride (80% strength in paraffin oil) are added in portions to 36.0 g (0.2 mol) of 4-hydroxyphenyl 2-hydroxy-2-propyl ketone in 450 ml. of dimethyl sulfoxide under an inert gas and the mixture is stirred for 15 minutes at room temperature. 26.8 g. (0.22mol) of allyl bromide in 40 ml. of dimethyl sulfoxide are then added dropwise at 30°-40° C., and the mixture is stirred for 15 minutes. The reaction mixture is poured into 2 l of water and then extracted with methyl t-butyl ether. By removing the solvent, 41.5 g. of compound IIh are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(CC)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC(Br)C(=O)OCC
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCC(Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)OCC

Procedure:
A solution of 6 g of 3-(4-chloropheyl)-6-hydroxy-1,2-benzisoxazole, 10.2 g of potassium carbonate, 5.12 g of ethyl 2-bromovalerate and 100 ml of methylethyl ketone is stirred under reflux for 3 hr. The reaction mixture is poured into 1 liter of ice/dil hydrochloric acid and the precipitate is collected and dried. Recrystallization from ether gives ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoate, mp 88° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-hydroxypropyl)carbamate XXVI (1.83 g, 6.3 mmol) in DCM was added TEA (1.38 mL, 10 mmol) was added. The mixture was cooled to 10° C. before adding mesyl chloride (0.77 mL, 10 mmol) dropwise. The reaction mixture was stirred for 30 min and then the solvent was removed under reduced pressure. The residue was dissolved in DCM, washed 1 M HCl (3×), 5% aq. NaHCO3 and dried over MgSO4. The solvent was again removed under vacuum to give tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-(methanesulfonyloxy)propyl)carbamate XXVII (2.31 g, 6.3 mmol, 99% yield). ESIMS found for C14H28N2O7S m/z 369 (M+H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)=O.[BH4-].[Na+]>CO>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[CH3:16])[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(c1cccc([N+](=O)[O-])c1)N1CCC(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.6 %

Procedure:
Piperidine-4-carboxylic acid cyclohexylamide (1.5 g 7.132 mmol) and 3-nitroacetophenone (1.77 g, 10.7 mmol) are dissolved in MeOH (40 mL). Tetraisopropyl-orthotitanate (3.167 mL, 10.7 mmol) is added and the mixture is stirred at RT for 18 h. NaBH4 (539.6 mg, 14.3 mmol) is added carefully. The mixture is evaporated under reduced pressure. DCM (25 mL) and water (25 mL) are added, following by 1 M NaOH solution (50 mL). The organic phase is separated and the aqueous phase is extracted with DCM (25 mL). The combined organic phases are dried over MgSO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel using a gradient of heptane/EtOAc 4:1 to EtOAc 100%. After concentration of the product-containing fractions, the title compound (0.375 g, 15%) is obtained as a colorless solid LC-MS A: tR=0.64 min; [M+H]+=360.26.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:25])[C:10]([C@@H:12]1[CH2:16][C@@H:15]([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:17][C@H:15]1[CH2:14][NH:13][C@H:12]([C:10]([N:9]([CH3:25])[CH3:8])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.5 mL of trifluoroacetic acid was added under ice cooling to a 25 mL chloroform solution of 3.50 g of the compound obtained in step 1-2b, after which the reaction mixture was stirred for 3 hours at room temperature. The solvent was then distilled off under reduced pressure, which gave 7.27 g of residue (yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)=Cc1ccc(O)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of the alkene (515) (0.481 g, 2.0 mmol) in ethyl acetate (20 mL) was added Pd/C (48 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight under a hydrogen balloon at room temperature, then filtered through a pad of celite and concentrated in vacuo to provide the intermediate ethyl 3-(3-chloro-4-hydroxyphenyl)-2-methylpropanoate (516A) (0.470 g, 96.9%) as a white solid. LC-MS ESI m/z: found 243.2 [M+H]+.