Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrCCCCCCBr
Reactant: CSc1ccc(CCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(CCCOCCCCCCBr)cc1
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A mixture of 4-(methylthio)benzenepropanol (5.0 g), 1,6-dibromohexane (17.0 g), TAB (0.4 g) and aqueous sodium hydroxide (50% w/v, 20 ml) was stirred for 20 h, diluted with water (30 ml), and extracted with ether (2×100 ml). The dried extract was evaporated and the residue was purified by FCC eluting with cyclohexane followed by System A (19:1) to give the title compound as a colourless oil (7.0 g), T.l.c. (System A 9:1) Rf 0.5.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:24]2[CH2:23][CH2:22][N:21]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:20]([CH3:19])[CH2:25]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
89 mg (99%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 2-methyl-1-m-tolylpiperazine (36 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [C:1]1([S:7][CH2:8][N:9]=[C:10]=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:12].[K+:13]>CC(C)=O.C(O)(C)(C)C>[C:1]1([S:7][CH2:8][NH:9][C:10](=[S:12])[S-:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:13]
Reactant: S=C=NCSc1ccccc1
Reactant: [SH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: S=C([S-])NCSc1ccccc1

Procedure:
Potassium phenylthiomethyldithiocarbamate was prepared by the reaction of phenylthiomethyl isothiocyanate and potassium hydrosulfide in a t-butyl alcohol acetone mixture.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[I:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14](=[O:21])[C:13]2=[CH:22]OC>CN(C)C=O>[I:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14](=[O:21])[C:13]2=[CH:22][NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][C:6](=[O:8])[NH:7]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCC1CCC(=O)N1
Solvent: CN(C)C=O
Product: O=C1CCC(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)N1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
5-Aminomethyl-pyrrolidin-2-one (140 mg, ˜80-90% pure, 1.04 mmol) is stirred with 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (150 mg, 0.46 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The suspension become clear in 10 minutes and further stirring gave a pale yellow precipitate. The precipitate is filtered and washed with MeOH, Et2O and dried to provide the title compound (110 mg, 58%). MS (ESI): 411.8 (M+1)+1.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:31][CH3:32])[CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([N:31]([C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])[CH3:32])[CH:23]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CNc1cc(Cl)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(c1cc(Cl)ccc1C(=O)O)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 2 h
Yield: 58.4 %

Procedure:
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (800 mg, 2.16 mmol), 4-Chloro-2-methylamino-benzoic acid (400 mg, 2.16 mmol) and K2CO3 (298 mg, 2.16 mmol) were dissolved in about 8 ml DMSO. After stirred for about 2 h, the solution was poured into water to obtain the crude product. The crude product was purified by chromatography to obtain 600 mg solid rac-4-Chloro-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-benzoic acid
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:11].[SH:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:11]
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(C)ccc1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a DMF (1.5 ml) solution of this amide (131 mg, 0.35 mmol) and 2-mercaptobenzoxazole (58 mg, 0.385 mmol) were added 18-crown-6 (9 mg, 0.035 mmol) and potassium carbonate (58 mg, 0.42 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 30 g, eluent—hexane:ethyl acetate=4:1→3:1) to obtain 123 mg (yield 79%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[CH:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[N:5]2[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]2)=[O:23])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1cnn(-c2sccc2N)c1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cc(C)cn2)cc1

Procedure:
The title compound was prepared from 2-(4-methyl-1H-pyrazol-1-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B and purified by HPLC. Method [7] Retention time 6.16 min by HPLC (MH+ 328). 1H NMR (300 MHz, CDCl3) δ 9.93 (broad s, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 7.27 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.90 (d, J=6.0 Hz, 1H), 3.87 (s, 3H), 3.70 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [I:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[C:20]([O-])(O)=O.[Na+]>CO>[I:1][C:2]1[C:3]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc2ccccc2cc1I
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccccc2cc1I
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To 3-iodo-2-napthoic acid (Preparation 5) (6.50 g), were added MeOH (100 mL) and concentrated H2SO4 (2 mL), and the resultant heterogeneous mixture was refluxed for 13 hr. The reaction mixture was allowed to cool to RT, then neutralized with NaHCO3 (6.0 g), and the volatile component was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (300 mL). The organic layer was washed with Na2S2O3 solution (4.2 g+50 mL of water) and brine, dried (MgSO4), filtered and evaporated in vacuo. The resulting crude material was submitted to flash chromatography (sample was loaded as a silica gel mesh, 10% EtOAc/hexanes) to isolate the title compound as a light-yellow solid (5.50 g, 2 steps combined yield of 69%). 1H NMR (DMSO, δ=2.50): 8.66 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.0, 1H), 7.95 (d, J=8.0, 1H), 7.69-7.62 (m, 2H), 3.91 (s, 3H). (DCl) m/z (M+H)+=313.0. Anal. Calcd for C12H9IO2: C, 46.18; H, 2.91. Found: C, 46.28; H, 2.85.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17].[NH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC(O)C>[CH2:14]([C:13]1[N:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: NOCCCCNC(=O)OCc1ccccc1
Reactant: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCCc1nc2cnc3ccccc3c2n1OCCCCNC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 76.5 %

Procedure:
N-(4-chloroquinolin-3-yl)valeramide (1.97 g), benzyl (4-aminooxybutyl)carbamate (2.99 g), triethylamine (0.89 g) and 2-propanol (40.69 g) were combined and heated at 80° C. for 3.5 hours. The reaction was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. Dichloromethane (20 mL) was added to the resulting solid and the mixture was stirred for twenty minutes. Undissolved solid was removed by filtration and the filtrate was washed with two 10 mL portions of water that had been made slightly acidic by the addition of 20 drops of hydrochloric acid (1.2 M). The organic fraction was dried and concentrated under reduced pressure. The crude solid was recrystallized from tetrahydrofuran to provide 2.56 g of benzyl 4-{[2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butylcarbamate.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[C:19]([O:23][CH2:24][C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])([CH3:22])([CH3:21])[CH3:20]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:24][O:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)(C)OC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 26 %

Procedure:
Prepared according to the experimental procedure described in Preparation 61a from 1.07 g (3.39 mmol) of 1-amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide and 1.65 g (3.73 mmol) of (S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoic acid. After stirring the reaction mixture overnight, an excess of an additional 1.65 g (3.73 mmol) of the acid was added and the reaction stirred for yet 24 hours more. After precipitation and filtration of the product, two purification steps were needed. First by flash chromatography (70% to 100% DCM/hexanes) and a second purification by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%). 494 mg (26% yield) of the title compound were isolated as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:11])[CH:12]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(c1ccc(Cl)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Product: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 130 °C
Yield: 84.2 %

Procedure:
This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9 H), 2.40-2.80 (m, 4 H), 3.15-3.85 (m, 9 H), 4.26-4.30 (m, 1 H), 7.35 (d, 2 H), 7.38 (d, 2 H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:3](OCC)=[O:4].[BH4-].[Na+].[BH4-]>C(O)C>[NH2:1][C@H:2]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][OH:4]
Reactant: CCOC(=O)[C@H](N)CC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N[C@@H](CO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
The process is performed as in Example 1, starting with 6.2 g of ethyl (2R)-2-amino-3-cyclohexylpropionate and 1.93 g of sodium borohydride in 120 cm3 of absolute ethanol at about 5° C. for 10 minutes. The medium is warmed to room temperature and stirred for a further 3 h 30 minutes. After cooling again to about 5° C. and addition of a further 40.94 g of borohydride, followed by stirring at a temperature in the region of 20° C. for 65 hours, the reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. A solid is obtained, which is purified by chromatography under a pressure of argon (100 kPa) on a column of silica gel (particle size 40-63μ; 320 g), eluting with pure methanol. The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 5.16 g of (2R)-2-amino-3-cyclohexyl-1-propanol are obtained in the form of a sticky white solid. (Rf=0.25 in methanol on a Merck 60F254R silica plate).
Reaction SMILES: [Cr]([O-])(OC(C)(C)C)(=O)=[O:2].[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[CH:12]1[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:10][C:11]1[C:16](=[O:2])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:18])[C:12]=1[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)O[Cr](=O)(=O)[O-]
Reactant: CCCCC1C(C)CCCC1(C)C
Product: CCCCC1=C(C)C(=O)CCC1(C)C

Procedure:
18 g Of the mixture of alkenes obtained by dehydration of dihydro-β-ionol as described in example 1 was dissolved in 150 ml of methanol and hydrogenated at atmospheric pressure using 0.5 g of a catalyst consisting of 5% Palladium on charcoal. Hydrogenation was stopped when the uptake of hydrogen markedly slowed down. A 1:1 mixture of 1,3,3-trimethyl-2-(but-1-yl)-cyclohex-1-ene and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane was obtained. This mixture was oxidized with tert.butyl chromate as described in example 1, yielding a mixture of the title compound and 1,3,3-trimethyl-2-(but-1-yl)-cyclohexane. The mixture was fractionated yielding 6.75 g of the title compound boiling at 90°-92° C. (4 Torr).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[S:26][C:27]([F:34])([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[Br:1][C:25]1[N:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[C:22]([S:26][C:27]([F:34])([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][CH:24]=1
Reactant: CCOC(=O)C(F)(F)Sc1nccn1-c1ccc(C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)Sc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-bromosuccinimide (1 eq) was added in three portions to a solution of ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate (1 eq) in dichloromethane at 0° C. and then stirred at room temperature for 18 h. The mixture was washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate/hexanes) provided ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([O:26][C:27]([N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C:35]([OH:37])=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCOCC1>[CH2:19]([O:26][C:27]([N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C:35]([N:2]([CH3:1])[C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)=[O:37])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 15 h

Procedure:
Nα -Methyl-L-histidine (428 mg) and sodium carbonate (288 mg) was dissolved in water (5 ml) and the solution adjusted to pH 8.5. Benzyloxycarbonyl-L-pyroglutamic acid N-hydroxsuccinimido ester (933 mg) in dioxane (5 ml) was added and the solution stirred for 15 hrs at 22°. The solution was evaporated and the residue chromatographed on a silica gel column (15 × 330 mm) using isopropanol-ethyl acetate - acetic acid - water (3 : 1 : 1 : 1) as eluant to give, after evaporation of the appropriate fraction, the product (615 mg) as a white solid m.p. 192°-195° RF 3A 0.21 RF 3B 0.69 [α]D22 - 1.3° (c = 1, dimethylformamide)
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][C:9]1([F:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:24][NH2:25]>C(O)C>[F:15][C:9]1([CH2:8][C@H:7]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:6][NH:25][CH3:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1(F)CCCCC1
Reactant: CN
Solvent: CCO
Product: CNC[C@H](CC1(F)CCCCC1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
Crude (S)-2-(tert-butoxycarbonylamino)-3-(1-fluorocyclohexyl)propyl methanesulfonate and (n-Bu)4N+T (249 mg, 1.0 mmol) were dissolved in 33% methylamine in ethanol (50 mL). The mixture was heated to 50° C. for 17 h. The solution was cooled to rt and the volatile materials were removed in vacuo. The residue was dissolved in ether, washed with brine, dried over Na2SO4, filtered and evaporated. To afford crude (S)-tert-butyl 1-(1-fluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:26][C:27](=[O:29])[CH3:28])[CH:16]=[C:17]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1.[F-].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:26][C:27](=[O:29])[CH3:28])[CH:16]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:18]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(=O)Nc1cc(N)cc(-c2ncccc2F)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ncccc2F)c1
Yield: 50 %

Procedure:
Solution of 4-bromo-1-fluoro-2-nitrobenzene (3.0 g, 13.63 mmol), N-(3-amino-5-(3-fluoropyridin-2-yl)phenyl)acetamide (4.0 g, 16.36 mmol), and potassium fluoride (0.95 g, 16.36 mmol) in DMF was heated at 130° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to yield the title product in 50% yield (3.4 g). 1H NMR (300 MHz, DMSO-d6): δ 8.55 (brs, 1H), 8.23 (brs, 1H), 7.96 (m, 2H), 7.85 (m, 2H), 7.67 (d, 1H), 7.51 (m, 2H), 7.21 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](=[S:37])[NH2:36]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:37][C:35]([C:34]([CH3:39])([CH3:38])[CH3:33])=[N:36][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(N)=S
Reactant: C=CCOC(=O)Nc1cc(C(=O)Cc2ccnc(Cl)n2)ccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: O
Product: C=CCOC(=O)Nc1cc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 2-propen-1-yl {5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (35 g, 100.3 mmol in DMA, 500 mL), NBS (17.8 g, 100.3 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then 2,2-dimethylpropanethioamide (13 g, 111 mmol) was added at 0° C. The mixture was stirred at 80° C. for 2 h. The mixture was poured into water and extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound (36 g, 80.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.24-8.31 (m, 2H), 7.09-7.18 (m, 2H), 7.01 (d, J=5.5 Hz, 1H), 6.92-6.98 (br, 1H), 5.87-5.97 (m, 1H), 5.31-5.37 (m, 1H), 5.24-5.28 (m, 1H), 4.61-4.65 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([OH:8])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.C([Li])CCC.[CH2:37]1[O:42][C:40](=[O:41])[NH:39][C@@H:38]1[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([N:39]1[CH:38]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:37][O:42][C:40]1=[O:41])=[O:8]
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)O
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)CC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound of example 49 (2.51 g, 10.62 mmol) in anhydrous THF (60 mL) and containing triethyl amine (1.8 mL, 12.74 mmol) at −70° C. was added drop wise trimethylacetyl chloride. After 15 minutes, the reaction mixture was placed in an ice bath and stirred for 45 minutes after which time, the reaction mixture was cooled to −78° C. In a separate flask, n-butyl lithium (2.5 M in hexanes, 43 mL, 10.62 mmol) was added to a solution of R-4-benzyl-2-oxazolidinone in anhydrous THF at −78° C. After 15 minutes of stirring, this mixture was transferred by cannula to the former solution. The resultant mixture was stirred for 20 minutes at −78° C. followed by an additional 2 h in an ice bath. The reaction was quenched by the addition of a saturated solution of ammonium chloride. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted with brine, saturated sodium hydrogen carbonate, brine, and water, respectively. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude material was flashed using 30% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 300 MHz: 1.89(m, 1H); 2.05(m, 1H); 2.75(m, 3H); 3.00(m, 1H); 3.68(m, 3H); 3.75(s, 3H); 4.18(m, 2H); 4.65(m, 1H); 7.21(m, 5H), 7.33(m, 5H).