Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[N:23]=[N:24][N:25]([C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=3)[CH:26]=2)=[N:20][C:19]([N:34]2[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([N:25]2[CH:26]=[C:22]([C:21]3[C:16]([NH2:8])=[N:17][CH:18]=[C:19]([N:34]4[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]4)[N:20]=3)[N:23]=[N:24]2)=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cn(-c4ccc(N)cc4)nn3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cn(-c4ccc(N)cc4)nn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)-5-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-ylcarbamate (64 mg, 0.1016 mmol) was dissolved in DCM (5 mL) and treated with TFA (500 μL, 6.490 mmol). The reaction was allowed to stir at ambient temperature overnight and then the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (24.3 mg, 30% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (t, J=7.4 Hz, 3H), 3.11 (q, J=7.4 Hz, 2H), 3.30-3.33 (m, 4H), 3.50-3.52 (m, 4H), 6.77 (d, J=8.6 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.88 (s, 1H) and 9.09 (s, 1H) ppm; MS (ES+) 430.0
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
2-({1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (80 mg, 0.225 mmol) was dissolved in pyridine and propane-1-sulfonyl chloride (29 μl, 0.25 mmol) were added. The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. Toluene was added to the residue and the solvent was evaporated in vacuo (repeated twice). The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 36 mg (0.078 mmol, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:42]([C:31]3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=3)=[O:43])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Yield: 90 %

Procedure:
The title compound was prepared by the coupling procedure of Example 1, step (f) using 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 650 mg, 1.89 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 636 mg, 2.08 mmol). Silica gel chromatography (DCM) afforded the title compound (1.01 g, 90%) as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C32H44N4O5Si, 593.3 (M+H). found 593.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[CH:5]([NH2:25])[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1.CO.CCOCC.CCOC(C)=O>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[CH:5]([NH2:25])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(N)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(N)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
100 mg (0.29 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-aminonaphth-3 -yl)ethynyl]benzoate in a mixture of THF and methanol (Compound 56) was refluxed (2 hours) with 0.5 ml (0.5 mmol) of LiOH (1M aqueous solution). Thereafter the mixture was diluted with Et2O:EtOAc (1:1), and acidified with aqueous HCl to pH5. The organic phase was separated, washed (water and brine), dried (MgSO4) to yield the title compound.
Reaction SMILES: OC[C@@H](N)C(C)CC.COC(=O)[C@H]([C@H](CC)C)N.OCCN.[N+:23]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH2:36])=[CH:28][CH:27]=1)([O-:25])=[O:24].[N+](C1[C:49]2[C:44](=[CH:45]C=C[CH:48]=2)[C:43]([N:50]=[C:51]=[S:52])=[CH:42]C=1)([O-])=O>>[N+:23]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]=[C:51]2[NH:50][C@@H:43]([CH:44]([CH2:49][CH3:48])[CH3:45])[CH2:42][S:52]2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(N=C=S)c2ccccc12
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Agent: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-nitro-1-naphthylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1-naphthylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:7]2[C:8]([C:22]([O:24]C)=[O:23])=[CH:9][N:10]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[CH:14][CH:13]=3)[CH:11]=2)[CH2:6][CH2:5]1>O1CCCC1.O>[C:22]([C:8]1[C:7]([CH:4]2[CH2:6][CH2:5]2)=[CH:11][N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:9]=1)([OH:24])=[O:23]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Reaction time: 26 h

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate is added, at a temperature in the region of 20° C., to 1.3 g (4.4 mmol) of 4-cyclopropyl-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring for 26 hours at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 mL of water and then triturated with 15 mL of 1 N hydrochloric acid. After the solid residue has been filtered off and dried at a temperature in the region of 50° C. at atmospheric pressure, 1.05 g of 3-carboxy-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole are obtained in the form of a cream-colored solid melting at 195° C.
Reaction SMILES: [OH:1][CH:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:2](=[O:1])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: COC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)/C=C/c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
A solution of 10.7 g (43.4 mmol) of methyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate in 150 ml of methylene chloride was added dropwise at 0° to a suspension of 56.7 g (652 mmol) of manganese dioxide in 200 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours, filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether yielded methyl (E)-6-(4-methoxyphenyl)-4-oxo-5-hexen-2-ynoate of melting point 70°.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[CH2:19]([C:21]1[C:25]([CH2:26][CH3:27])=[C:24]([CH3:28])[NH:23][C:22]=1[C:29](O)=[O:30])[CH3:20]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:29]([C:22]3[NH:23][C:24]([CH3:28])=[C:25]([CH2:26][CH3:27])[C:21]=3[CH2:19][CH3:20])=[O:30])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: CCc1c(C)[nH]c(C(=O)O)c1CC
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: CCc1c(C)[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c1CC

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 3,4-diethyl-5-methyl-1H-pyrrole-2-carboxylic acid (commercially available).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH2:39])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C

Procedure:
To a solution of (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (48 mg) in N,N-dimethylformamide (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg) and 1-hydroxybenzotriazole ammonium salt (28 mg) at room temperature. The mixture was stirred at room temperature over night. The mixture was concentrated in vacuo. Ethyl acetate was added to the residue and the resultant was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give the title compound. The compound was triturated and washed with diethyl ether-ethyl acetate-hexane to give the title compound (11 mg, 23%) as a white powder. mp 107-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(OCCCC)(=O)C.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>CCCCCCC>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[O:28])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])#[N:13]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C1C=CC(=O)O1
Solvent: CCCCOC(C)=O
Solvent: CCCCCCC
Product: N#Cc1ccc(NC(=O)C=CC(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Yield: 100.2 %

Procedure:
5-amino-2-cyanobenzotrifluoride (210.6 mmoles; 40.00 g) and butyl acetate (80 mL) were added to a 250 mL round bottom flask, followed by the addition of maleic anhydride (231.9 mmoles, 23.20 g). The resulting suspension was heated to 60° C. for 3.5 h. The reaction mixture was cooled to 25° C. and then heptane (160 mL) was added dropwise over a period of 25 minutes. The resulting suspension was filtered and washed with a mixture of 4:1, hepatane:butyl acetate (30 mL) and heptane (45 mL). The cake was dried in vacuo to give 60 g (95% yield) of compound 516A.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:19])([CH3:23])[CH3:22]
Reactant: OC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 12.5 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and N,N-diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 10° C. under N2. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was added dropwise over 2 h, maintaining a temperature of 10-15° C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83%) as a pale, straw-colored oil. Exact Mass calculated for C9H17NO3: 187.1. Found: LCMS m/z=188.2 (M+H+), 210.3 (M+Na+); 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=6.3 Hz, 6H), 1.47 (m, 2H), 1.86 (m, 2H), 3.08 (m, 2H), 3.86 (m, 3H), 4.90 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][C:14]2[N:15]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[C:16]([C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)([CH3:21])[CH3:20])=[CH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:39]([OH:42])[C:40]#[CH:41].N1CCCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:29][C:24]1[CH:23]=[C:22]([C:19]([C:16]2[N:15]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[C:14]([S:13][CH2:12][C:9]3[CH:10]=[CH:11][C:2]([C:41]#[C:40][CH2:39][OH:42])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[N:18][CH:17]=2)([CH3:21])[CH3:20])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1Br
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1C#CCO
Temperature: 80 °C
Yield: 78 %

Procedure:
To a stirred solution of methyl 2-bromo-5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)benzoate (506 mg, 0.79 mmol, 1.0 eq), propargyl alcohol (0.07 mL, 1.2 mmol, 1.5 eq) and pyrrolidine (0.1 mL, 1.2 mmol, 1.5 eq) in dry, degassed DMF (4 mL) was added PdCl2(dppf)2 (30 mg, 0.04 mmol, 5 mol %) and CuI (15 mg, 0.08 mmol, 10 mol %). The reaction mixture was heated at 80° C. for 5 h at which time LCMS showed 85% conversion. The mixture was diluted with EtOAc, washed with brine, dried and concentrated. Purification by column chromatography (0 to 75% EtOAc/Hexanes) provided 378 mg (78% yield) of methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxyprop-1-ynyl)benzoate. MS (EI) m/z 615 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1)=[O:6])[CH3:3].[CH2:21]1COCC1.[OH-].[K+].CI>CN(C=O)C>[CH2:2]([O:4][C:5]([C:7]1([CH3:21])[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl-1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloride (150 g, 0.504 mol) was suspended in a solvent mixture of 750 ml THF and 750 ml DMF at room temperature. Addition of powdered KOH (56 g, 1.0 mol) was made in two equal lots keeping half an hour interval between two additions. To a clear reaction mixture methyl iodide (78 g, 0.55 mol) was added over period of 10 minutes and it was stirred for three hours at room temperature. The reaction was quenched by adding 4 ltr water followed by 1.5 ltr diethyl ether. Layers were separated. Organic layer was washed with water and dried over Na2SO4. Evaporation of organic solvent afforded a liquid, which was passed through a silica gel column to give 86 g (61%), titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[H-].[Na+].[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.Cl>C1COCC1.O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:32]45[CH2:41][CH:36]6[CH2:35][CH:34]([CH2:40][CH:38]([CH2:37]6)[CH2:39]4)[CH2:33]5)=[O:43])=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=3)(=[O:10])=[O:9])=[O:13])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 380A (101 mg, 0.25 mmol) in THF (3 mL) was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol), stirred for 30 minutes, treated with 1-adamantanecarbonyl chloride (60 mg, 0.30 mmol), stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 576 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ10.23 (s, 1H), 8.52 (d, 1H), 8.23 (dd, 1H), 8.19 (d, 1H), 7.95 (d, 2 H, 7.75 (m, 4H), 7.31 (tt, 2H), 2.05 (3s, 3H), 1.90 (m, 6H), 1.70 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:10].C(=O)([O-])[O-].[Na+].[Na+].[N:17]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[C:18]=[S:19]>C(O)C>[NH2:10][C:4]1[C:3]([NH:2][CH3:1])=[C:8]([NH:9][C:18]([NH:17][C:20]2[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[S:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Reactant: CNc1c(N)cccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1c(N)cccc1NC(=S)Nc1c(C)cc(C)cc1C
Yield: 59.4 %

Procedure:
To a mixture containing 0.25 g (1.82 mmol) of N2-methylbenzene-1,2,3-triamine and 0.40 g (3.7 mmol) of sodium carbonate in ethanol was added 0.32 g (1.86 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The reaction was heated at reflux and the solvent was removed under reduced pressure. Purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.34 g (60%) of product.
Reaction SMILES: C[Si](C)(C)[O:3][NH2:4].[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]>C(O)C>[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:25])[NH:4][OH:3])=[C:20]([F:26])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C#N)c(F)c2)C(=O)O1
Reactant: C[Si](C)(C)ON
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=N)NO)c(F)c2)C(=O)O1
Reaction time: 48 h

Procedure:
O-Trimethylsilylhydroxylamine (0.37 ml, 3.0 mmol) and 5-(S)-acetamidomethyl-3-[4′-cyano-3′-fluorophenyl]oxazolidine-2-one (0.277 g, 1.0 mmol) in ethanol (3.0 ml) were stirred at 80° C. in a sealed reaction vial for 2.5 h. The mixture was left at r.t. for 48 h, and the crystallized product filtered, rinsed with ethanol (ca. 0.75 ml), washed with ether, and dried under vacuum. Yellow crystals. Yield 0.260 g (84%). HPLC: Rt 2.6 min. MS (m/z): [M+H]+=311.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]([CH2:8][O:9]C(C)(C)C)[CH3:7].Cl>>[OH:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]([CH2:8][OH:9])[CH3:7]
Reactant: CC(COC(C)(C)C)OCCCO
Agent: Cl
Product: CC(CO)OCCCO
Yield: 91.3 %

Procedure:
HO(CH2)3OCH(CH3)CH2OC(CH3)3 (203.39 g) prepared in Example 2-2 was loaded into a round-bottomed flask and stirred with 5 N hydrochloric acid (1 L) at room temperature for 43 hours. The reaction solution was concentrated with an evaporator, and then, after addition of toluene, concentrated again with an evaporator to give the title compound (131 g). The NMR spectrum data of the product were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[CH2:5][C:6]1[N:10]([CH3:11])[C:9]([CH2:12]O)=[N:8][C:7]=1[CH:14]([CH3:16])[CH3:15].CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>S(Cl)(Cl)=O.O>[N:26]([CH2:12][C:9]1[N:10]([CH3:11])[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:19]=[C:18]([Cl:20])[CH:17]=2)=[C:7]([CH:14]([CH3:16])[CH3:15])[N:8]=1)=[N+:27]=[N-:28]
Reactant: CC(C)c1nc(CO)n(C)c1Cc1cc(Cl)cc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
In 5 ml of thionyl chloride was dissolved 160 mg (0.51 mmol)of [5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (59a), and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, and to the residue, 5 ml of dry dimethylformamide and 80 mg (1.23 mmol)of sodium azide were added. The mixture was stirred at room temperature for 3 hours, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 150 mg of 2-azidomethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (60)(yield 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CC(C)([O-])C.[K+].[N+:31]([CH3:34])([O-:33])=[O:32].FC1C=C(F)C=CC=1CC(N1C=CN=C1)=O.Cl>O.CS(C)=O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH2:34][N+:31]([O-:33])=[O:32])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(Cc1ccc(F)cc1F)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1F)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
To 120 ml of dichloromethane solution of (2,4-difluorophenyl)acetic acid (10 g, 58.1 mmol) at 0° C., 1,1′-carbonyldiimidazole (9.4 g, 58.1 mmol) was added slowly. The mixture was then stirred for 2.5 hours at room temperature. The solvent was removed. Then the solid residue was triturated with diethyl ether and dried. The white fluffy solid 1-[(2,4-difluorophenyl)acetyl]-1H-imidazole was used for the next step without further purification. In a separate flask, to the 100 ml of dimethyl sulfoxide solution of potassium tert-butoxide (7.2 g, 63.9 mmol) at 0° C., nitromethane (4.6 g, 75.5 mmol) was added. After stirring for 5 minutes, the 1-[(2,4-difluorophenyl)acetyl]-1H-imidazole made previously was added slowly. The mixture was left stirring overnight while the temperature was gradually warmed up to room temperature. The reaction mixture was poured into 250 ml water and then acidified with 2N HCl to pH=4. The aqueous was extracted with ethyl acetate. After washing with brine and drying with sodium sulfate, removal of the solvent afforded 9.4 g yellowish solid. 1H-NMR (400 MHz, CD3OD) δ 7.18 (m, 1H), 6.82 (m, 2H), 5.30 (s, 2H), 3.82 (s, 2H) ppm. ESI-MS m/z 214 (M−H)−.