Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]1.CS(C)=O>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30]5)=[N:7][CH:6]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)cn1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)cn2)C1
Temperature: 95 °C

Procedure:
A solution containing 3-(6-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.070 g, 0.00019 mol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.224 g, 0.00112 mol) in Dimethyl sulfoxide (1.40 mL, 0.0197 mol) was heated at 95° C. for 18 h. The reaction was quenched with water then filtered and washed with water. The crude product was dried under high vacuum overnight to give tert-butyl (3R)-1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate which was dissolved in Methylene chloride (1.4 mL, 0.022 mol) and treated with trifluoroacetic Acid (0.72 mL, 0.0093 mol). The reaction was stirred at RT 18 h. The reaction was concentrated then submitted for rHPLC to give 191 (50.6 mg, 73% yield). ESI MS m/z=372.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.40 (d, J=1.7 Hz, 1H), 9.18 (s, 1H), 8.88 (d, J=2.3 Hz, 1H), 8.60-8.53 (m, 3H), 8.21 (dd, J=8.9, 2.4 Hz, 1H), 7.50 (dd, J=7.7, 5.1 Hz, 1H), 6.97 (d, J=9.0 Hz, 1H), 4.27 (dd, J=23.6, 12.1 Hz, 2H), 2.88 (dd, J=17.5, 7.2 Hz, 2H), 2.73-2.56 (m, 2H), 1.89 (d, J=12.0 Hz, 1H), 1.73 (d, J=13.5 Hz, 1H), 1.47 (dd, J=24.5, 12.1 Hz, 1H), 1.25 (ddd, J=16.2, 12.6, 4.0 Hz, 1H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[O:7][CH2:8][C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:39]([C@H:8]([O:7][C@H:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH3:28])[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCCC(OCC(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCC[C@H](O[C@@H](Cc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Temperature: 0 °C

Procedure:
Benzhydryl 4-(2-furyl)-3-oxaoctanoate (2.0 g, 5.28 mmol) was dissolved in 20 mL freshly distilled THF and cooled to -80°±5° C. under dry argon. Sodium bis(trimethylsilyl)-amide (1.0M in THF, 5.6 mL, 5.6 mmol) was slowly added keeping the temperature at -80°±5° C. After 15 m, freshly distilled and filtered (through basic alumina) benzyl bromide (0.7 mL, 5.81 mmol) in HMPA (4 mL) was added dropwise maintaining the reaction temperature at -75°±5° C. After 15 m, the reaction was allowed to warm to 0° C. for 1 h before quenching with water and extraction with ether. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, brine,dried over MgSO4, and purified by flash silica gel chromatography to give 771.3 mg (31%): [α]25D -65.5°; 1H NMR (300 MHz, CDCl3) δ0.81 (t, 3H, J=7 Hz), 1.22 (m, 4H), 1.80 (m, 2H), 2.91 (m, 2H), 4.12 (dd, 1H, J=9 Hz), 4.30 (t, 1H, J=7 Hz), 5.86 (m, 1H), 6.19 (m, 1H), 6.69 (s, 1H), 7.2 (m, 16H); mass spectrum (FAB): 486 (M+NH4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc(Cl)o2)n1
Product: Clc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)o1
Yield: 86 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(5-chloro-2-furyl)-4-chloromethyloxazole to give 2-(5-chloro-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 86%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 88-89° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:19])(=[O:30])=[O:29])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cc(F)cc(F)c32)c(C)c1

Procedure:
(5.7 mg, 33%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 2,4,6-trimethylphenylsulfonyl chloride (13.1 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[CH2:15][O:14][C:13]2[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:12]=2[Cl:11])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:41]([C:40]([F:39])([F:55])[F:54])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as an orange oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3,5-bis(trifluoromethyl)phenylboronic acid.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[S:35]>>[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=O)[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:23][NH2:24])=[O:20])[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)c1ccc2ccn(-c3ccc(SC)cc3)c2c1
Solvent: O
Solvent: CCO
Product: CSc1ccc(-n2ccc3ccc(C(=O)NN)cc32)cc1

Procedure:
A mixture of methyl 1-[4-(methylthio)phenyl]-1H-indole-6-carboxylate (2.50 g, 8.41 mmol), hydrazine monohydrate (4.08 mL, 84.1 mmol) and ethanol (40 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration and washed with ethanol to give crude 1-[4-(methylthio)phenyl]-1H-indole-6-carbohydrazide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](I)[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:28][CH3:29])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OCC)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Step 3 (0.500 g, 1.55 mmole) in anhydrous DMF (5.0 mL) under a dry N2 atmosphere was added KI (26 mg, 0.155 mmole), K2CO3 (0.643 g, 4.65 mmole) and ethyl iodide (272 uL, 4.65 mmole). After stirring overnight at room temperature, the mixture was poured into H2O (150 mL), saturated with solid NaCI and extracted with EtOAc (200 mL). The extract was then washed with brine (2×200 mL), dried over MgSO4, filtered and concentrated in vacuo to give a quantitative yield of the product as a tan solid: EIHRMS m/z 350.0564 (M+, C15H14ClF3O4, Calc'd 350.0533). 1H NMR (dmso-d6/300 MHz) 7.93 (s, 1H), 7.18 (d, 1H, J=3.0 Hz), 7.13 (d, 1H, J=2.8 Hz), 6.06 (q, 1H, J=7.3 Hz), 4.23-4.31 (m, 2H), 4.01 (q, 2H, 7.0 Hz), 1.29 (q, 6H, J=7.0 Hz).
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)C(=O)COc1ccc(Cl)cc1
Yield: 73.8 %

Procedure:
338 g (2.77 mols) of 1-bromo-3-methyl-butan-2-one were rapidly added dropwise to a mixture of 357 g (2.78 mols) of 4-chlorophenol and 483 g (3.5 mols) of potassium carbonate in 2.5 liters of methyl ethyl ketone. The mixture was heated under reflux for 16 hours and then filtered. The filtrate was concentrated by stripping off the solvent under reduced pressure, the residue was taken up in methylene chloride and the organic phase was washed twice with 2N aqueous sodium hydroxide solution, once with water and once with saturated aqueous sodium chloride solution. After drying, the organic phase was concentrated by stripping off the solvent. The residue which remained was distilled under a high vacuum. 435 g (74% of theory) of 1-(4-chlorophenoxy)-3-methyl-butan-2-one were obtained in this manner.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][SH:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:12][CH2:11][CH2:10][N:9]([CH3:13])[CH3:8])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CN(C)CCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 18.7 %

Procedure:
To sodium hydride (600 mg, 15 mmol 60% in mineral oil) were added DMF (10 ml), 2-dimethylaminoethanethiol (1.3 g, 9.2 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred at 100° C. for 10 hours. After addition of saturated brine the reaction mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (10% methanol/chloroform) to give the subject compound (24 mg, yield 21%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NS(C)(=O)=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a flask containing a solution of 29, Et3N (0.26 g, 2.55 mmol) and DMAP (0.032, 0.26 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (0.24 g, 2.13 mmol), dropwise at RT and the reaction allowed to stir overnight. After 18 h the reaction was diluted with CH2Cl2 (15 mL) and the reaction rinsed with 10% aqueous HCl (25 mL). The CH2Cl2 layer was dried (MgSO4) and concentrated to a dark amber oil. The crude product was purified by silica gel column chromatography to afford 170 mg (46%) of the title compound (269) as a colorless oil. An additional 90 mg of a mixture of 269 and N,N-bissulfonylated product was also isolated. 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 2.82 (s, 3H), 3.85 (s, 3H), 6.54 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.97 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 6.96 (d, J=6.6 Hz, 1H), 7.15-7.32 (m, 5H), 7.58 (d, J=9.1 Hz, 1H), 7.67 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].CO.[CH3:36][NH:37][CH3:38]>C1COCC1>[CH3:36][N:37]([CH3:38])[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8]
Reactant: CNC
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Step 4): A mixture of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (13.4 g, 30 mmol) and 2.0M MeOH solution of dimethylamine (45 ml, 90 mmol) in THF (100 ml) was refluxed for 22 hours. The resulting solution was evaporated to give 5-dimethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as yellow powders, 14.1 g (99.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH2:24](B(CC)CC)[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([CH2:24][CH3:25])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(CC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 95 °C
Yield: 64.3 %

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (251 mg, 0.76 mmol), triethylborane (4.6 mL of 1 M solution in hexane, 4.6 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and Na2CO3 (1.27 g, 6 mL of 2M solution in H2O) in toluene (20 mL) is heated for 48 hours at 95° C. After cooling to room temperature the mixture is diluted with water (10 mL) and extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), concentrated, and purified by flash chromatography (elution with hexane/EtOAc 10:1) to yield 159 mg 6-(2,6-diethyl-phenyl)-4-ethyl-2-methyl-nicotinic acid ethyl ester as a colorless oil: 1H NMR (CDCl3) 7.29 (dd, 1H), 7.13 (d, 2H), 7.00 (s, 1H), 4.47 (q, 2H), 2.68 (q, 2H), 2.59 (s, 3H), 2.36-2.27 (m, 4H), 1.45 (t, 3H), 1.24 (t, 3H), 1.05 (t, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)[CH3:7])[N:3]=[CH:2]1.[C:17]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][C:33](=[O:34])[CH:25]([NH:24][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:7])[N:3]=[CH:2]1
Reactant: Cc1c(CO)cccc1[C@H](C)c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: Cc1c(COC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cccc1[C@H](C)c1c[nH]cn1

Procedure:
The title compound was prepared from (S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0 mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCI (671 mg, 3.5 mmol) and DMAP (427 mg, 3.5 mmol) according to the procedure described in Example 3. Intermediate 12 was purified by a column chromatography using 35-100% ethyl acetate in hexane.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CC(C)=O>[C:13]([NH:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC(=O)Cl
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCC(=O)N[C@H](CCC(=O)O)C(=O)O
Temperature: 10 °C
Yield: 83 %

Procedure:
A solution of 75.0 g (510 mmol) of D-glutamic acid in one liter of aqueous acetone (50:50) was adjusted to pH 9.0 with 2N sodium hydroxide. The resulting solution was cooled to 10° C. and treated over 45 minutes with 114.2 g (770 mmol) of heptanoyl chloride, maintaining the pH at 9.0 with 2N sodium hydroxide. The reaction was allowed to warm to room temperature for three hours. The acetone was removed under vacuum, and the resulting aqueous solution was acidified with dilute hydrochloric acid and extracted three times with 700 ml portions of ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and concentrated. The resulting oil was triturated with hexane to give 109.8 g (83%) of desired product: mp 92°-96° C. IR (Nujol) 3300, 2700-3250, 1720, 1625 cm-1 ; NMR (D6 -DMSO) delta 4.20 (m, 1H), 2.28 (t, 2H), 2.20 (t, 2 H), 1.85-2.05 (m, 1H), 1.65-1.85 (m, 1H), 1.40-1.60 (m, 2H), 1.15-1.30 (m, 6H), 0.75 (t, 3H); [alpha]D =+9.6 (C=1.0, MeOH).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](NC(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[F:40][C@@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.BrC1SC=C(C(O)=O)N=1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@H:14]2[O:21][CH2:19][C@H:18]([F:40])[C@H:17]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:15]2)=[O:31])[N:6]=1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Agent: O=C(O)c1csc(Br)n1
Product: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 2-bromothiazole-4-carboxylic acid (commercial) gave tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].CCOP(O)N(C(C)C)C(C)C>O1CCOCC1>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][NH:14][C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1nc(Br)sc1NC
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCOP(O)N(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(NCCNC(=O)OC(C)(C)C)sc1NC
Temperature: 100 °C

Procedure:
Ethyl 2-bromo-5-methylamino-thiazole-4-carboxylate (546 mg, 2.059 mmol) and tert-butyl N-(2-aminoethyl)carbamate (1.3 g, 8.11 mmol) were combined in anhydrous 1,4-dioxane (15 ml). EDIPA (3 ml, 17.2 mmol) was added and the mixture was heated in a sealed tube for 23 hours at 100° C. The mixture was cooled to room temperature and partitioned between DCM and a saturated solution of sodium bicarbonate. Layers were separated, the aqueous phase was extracted twice with DCM and the combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica, gradient of 30 to 100% ethyl acetate in heptane) to yield 185 mg (0.537 mmol, 26%) MS(ESI) m/z=345.2 [M+1]+.