Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32]2)=[N:4][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](COCC[Si](C)(C)C)[N:9]=2)=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[CH3:1][C:2]1[C:3]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH2:36])[CH2:32]2)=[N:4][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)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1N1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To (R)-tert-butyl 1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate in MeOH (4 mL) was added 4.0 M of Hydrogen chloride in 1,4-Dioxane (6 mL). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 316 as an off-white solid (15.4 mg, 56.9%). 1H NMR (400 MHz, DMSO) δ 9.27 (d, J=1.7 Hz, 1H), 9.19 (s, 1H), 9.12 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 7.51-7.43 (m, 2H), 3.85 (dd, J=9.5, 5.6 Hz, 2H), 3.77 (dd, J=16.6, 7.1 Hz, 1H), 3.63-3.57 (m, 1H), 3.43 (dd, J=9.6, 5.6 Hz, 1H), 2.37 (s, 3H), 2.11 (td, J=12.2, 5.9 Hz, 1H), 1.74 (dq, J=13.8, 7.1 Hz, 1H); ESI MS m/z=372.2 (M+1)
Reaction SMILES: [N:1]([C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:5][OH:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1COCC1>[NH2:1][C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: [N-]=[N+]=N[C@H](CO)c1ccc(C(F)F)nc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H](CO)c1ccc(C(F)F)nc1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a stirred solution of (S)-2-azido-2-(6-(difluoromethyl)pyridin-3-yl)ethanol (1 g, 4.67 mmol) in 15 mL of THF was added PPh3 (2.45 g, 9.39 mmol). The resulting reaction mixture was stirred for 3 h, treated with 0.5 mL of water and stirred for 16 h. After completion of the reaction, the reaction mixture was treated with 2N HCl (15 mL) and extracted with EtOAc. The aqueous layer was treated with aq. NH3 and the volatiles were evaporated to afford a residue. Purification of the residue by column chromatography (small pad of neutral Al2O3, aq. NH3/MeOH/CH2Cl2, 1:14:85) afforded the title compound (0.74 g, 85% yield). MS: 189 [M+1]+; 1H-NMR (300 MHz, CD3OD): 8.72 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.75 (d, 1H, J=8.3 Hz), 6.73 (t, 1H, J=55.0 Hz), 4.39-4.43 (m 1H), 3.90 (dd, 1H, J=10.9, 4.7 Hz), 3.80 (dd, 1H, J=10.9, 6.2 Hz).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][C:5]=1[O:12][CH:13]([F:15])[F:14].B.[OH2:18].[OH-].[Na+]>C1COCC1>[F:14][CH:13]([F:15])[O:12][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][OH:18])[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:16])[F:1]
Reactant: C=Cc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 1,2-bis(difluoromethoxy)-4-vinylbenzene (10 g, 0.0431 mol; see step (iii) above) in 25 mL of THF was added, dropwise, borane-methyl sulfide complex (10 mmol; 10 mL of a 1 M solution in THF). The resulting mixture was stirred at 60° C. for 1 h, before being cooled to RT. Excess borane was decomposed by adding few drops of water and the resultant mixture refluxed for 1 h with 2 M NaOH (100 mL) 50% H2O2 (87 mL). The mixture was then extracted with dichloromethane, washed with water and then brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure gave the sub-title compound as a pale yellow liquid. Yield: 6 g.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:71][C:72]([CH3:76])([CH3:75])[CH2:73][OH:74]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:71][C:72]([CH3:76])([CH3:75])[CH2:73][OH:74])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NC(C)(C)CO)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.076 mmol) in DMF (3 ml) was added BOP (40 mg, 0.091 mmol) and DIPEA (20 mg, 0.10 mmol), followed by 2-amino-2-methylpropan-1-ol (15 mg, 0.15 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a yellow oil.
Reaction SMILES: [CH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]=1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][CH2:11][C:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:1]=1
Reactant: OCC1=CC2(CCCCC2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: BrCC1=CC2(CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of spiro[4.5]dec-1-en-2-yl-methanol (50 mg) obtained in Step 5 in chloroform (1 mL) were added triphenylphosphine (87 mg) and N-bromo-succinimide (87 mg) under ice-cooling, followed by stirring the reaction mixture at room temperature for 1 hour. Then, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (hexane) to give 2-bromomethyl-spiro[4.5]dec-1-ene (55 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[O:26][CH3:25])=[O:30]
Reactant: COc1ccccc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccccc1OC

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-methoxyphenyl)carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-methoxybenzoic acid using the general procedure described in example 3. HR MS: Obs. mass. 501.0984. Calcd. mass. 501.0984 (M+H).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[N:8][C:9]([O:23]C)=[C:10]([CH:22]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:12].CO>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][C:9]([OH:23])=[C:10]([CH:22]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)=[O:12]
Reactant: COc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.8 %

Procedure:
BBr3 (20 mL) was added dropwise to a mixture of compound 5-bromo-N-(4-fluorobenzyl)-2-methoxynicotinamide (2.0 g, 5.9 mmol) in DCM (10 mL) at −78° C. The mixture was stirred at RT for 10 h, and then MeOH (20 mL) was added to quench the reaction. The mixture was concentrated in vacuum to give the product of 5-bromo-N-(4-fluorobenzyl)-2-hydroxynicotinamide (1.8 g, yield: 95%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.9 (s, 1H), 10.0 (t, J=4.8 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H), 8.02 (s, 1H), 7.34 (dd, J=6.0, 8.8 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 4.50 (s, 2H). MS (M+H)+: 325/327
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C([O-])([O-])=[O:30].[Na+].[Na+].OO>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([NH2:15])=[O:30])[C:8]=2[N:7]=[C:6]1[C:16]1[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (1.10 g, 2.88 mmol) dissolved in ethanol (100 mL) and 3 M Na2CO3 (10 mL) was added 30% hydrogen peroxide (10 mL). After stirring overnight at room temperature, the reaction was concentrated. The residue was then redissolved in EtOAc, and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylic acid amide (0.83 g, 2.08 mmol, 72% yield). M.p. 260-261° C. 1H-NMR (200 MHz, CD2Cl2): δ8.10 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.71 (br d, J=8.1 Hz, 1H, H7), 7.59 (m, 1H, H4′), 7.43 (dd, J=7.7, 8.1 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.13 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.43 (s, 2H) CH2PhF2), 1.92 (s, 2H, NH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1)[C:19]#[CH:18]
Reactant: C#CCBr
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(C(CC)(OC)c2nccs2)c1
Yield: 94 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (31 g), 2-propynyl bromide (80% solution in toluene, 48.1 ml), potassium carbonate (48 g) and acetone (375 ml) was stirred and heated to reflux for 17 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between diethyl ether and water and the organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with hexane/ethyl acetate (1:1 v/v) to give 2-[1-(3-(2-propynyloxy)phenyl)-1-methoxypropyl]thiazole as an oil (34 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][N:25]5[CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](F)CN1
Product: CN1C[C@H](F)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 184) and formaldehyde following General Procedure R.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]=1[OH:28])[CH:23]=O>>[C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:23][C:22]1[CH:25]=[C:26]([O:29][CH2:30][CH3:31])[C:27]([OH:28])=[C:20]([Br:19])[CH:21]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Product: CCOc1cc(C=C2C(=O)Nc3ccc(C(=O)c4ccccc4)cc32)cc(Br)c1O

Procedure:
The title compound was synthesized in an identical manner to example 2 except 5-benzoyl oxindole was used in place of 5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride and 3-bromo-5-ethoxy4-hydroxy-benzaldehyde was used in place of 3,5-dibromo-4-hydroxy-benzaldehyde. 1H NMR (DMSO-d6) δ1.38 (t, J=7 Hz, 3H), 4.14 (q, J=7 Hz, 2H), 6.94 (d, J=8.2 Hz, 1H), 7.50-7.68 (m, 4H), 7.69-7.72 (m, 2H), 7.90 (s, 1H), 8.14 (s, 1H), 8.34 (d, J=1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H), 10.15 (s, 1H), 11.02 (s, 1H); APCI-MS: m/z 464 (m−H)−. Anal. Calcd for C24H18NO4Br: C, 62.08; H, 3.91; N, 3.02; Br, 17.21. Found: C, 61.98; H, 3.88; N, 3.08; Br, 17.28.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14](COCC[Si](C)(C)C)[C:15]([C:18]#[CH:19])=[CH:16][N:17]=1)=[O:7])(C)(C)C.Cl.[CH3:29][O:30][C:31]([NH:33][CH:34]([CH:38]([CH3:40])[CH3:39])C(O)=O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C.ClCCl.CN(C=O)C>[CH3:29][O:30][C:31](=[O:32])[NH:33][CH:34]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]#[CH:19])=[CH:16][N:17]=1)=[O:7])[CH:38]([CH3:40])[CH3:39]
Reactant: C#Cc1cnc(C2CCCN2C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.002 g, 2.56 mmol) was dissolved in dioxane (5 mL) and 4 M HCl in dioxane (5 mL) was added. The reaction mixture was stirred for 3 hours and concentrated. To the residue was added 2-Methoxycarbonylamino-3-methyl-butyric acid (561 mg, 3.20 mmol), HATU (1.22 g, 3.20 mmol) and DMF (15 mL). The stirred reaction mixture was cooled to 0° C. and DIPEA (2.23 mL, 12.8 mmol) was added). After stirring for 3 h, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (40% to 75% EtOAc/hexanes) to provide the coupled compound (741 mg, 65% over 2 steps). This material was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The stirred reaction mixture was heated to reflux for 4 h, then cooled to RT, and poured into a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (0% to 10% MeOH/DMC) to provide {1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (525 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:28][CH3:29])[N:17]=[C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=2)[N:14]([CH3:30])[CH:13]=1.C(N(C(C)C)CC)(C)C.[CH2:45]([S:47](Cl)(=[O:49])=[O:48])[CH3:46].[OH-].[Na+].[Cl-].[NH4+]>ClCCl>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:47]([CH2:45][CH3:46])(=[O:49])=[O:48])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:28][CH3:29])[N:17]=[C:18]([CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:19]=2)[N:14]([CH3:30])[CH:13]=1
Reactant: COc1nc(CN2CCOCC2)cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(CN4CCOCC4)cc23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.2 %

Procedure:
To a solution of Example 182D (54 mg, 0.112 mmol) in 5 mL dichloromethane was added diisopropylethylamine (58.9 μL, 0.337 mmol) and ethanesulfonyl chloride (26.6 μL, 0.281 mmol). The mixture was stirred at ambient temperature for 16 hours. Another 1.5 equivalents ethanesulfonyl chloride (16 μL) and 2.0 equivalents diisopropylethylamine (39 μL) were added. The mixture was continued to stir overnight. The mixture was concentrated. The residue was taken into dioxane (6 mL) and treated with sodium hydroxide (2810 μL, 2.81 mmol, 1N aqueous solution). The mixture was heated at 60° C. for 1 hour to hydrolyze the bis-sulfonamide to the manosulfonamide. To the reaction mixture, saturated ammonium chloride solution was added, extracted with ethyl acetate (3×), washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-8% methanol in dichloromethane to give the title compound (10 mg, 0.017 mmol, 16% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26](N(OC)C)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[Al].[Li].[Na]>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([CH:26]=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CON(C)C(=O)c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Al]
Agent: [Li]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C=O)s1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of the compound obtained in Step 1 (3.93 g) in THF (80 mL) was added lithium aluminium hydirde (499 mg) slowly (over 15 min) at 5–10° C. (under ice-cooling). The mixture was stirred at 5° C. for 1 h. 30 mL of aquaous solution of sodium pottasium tartrate (1M) was added slowly under ice-cooling, and then the mixture was stirred for another 0.5 h at r.t. The mixture was extracted with ethyl acetate, and the organic layer was dried over MgSO4, and concecntrated in vacuo to give pale yellow oil. This oil was triturated with IPE and EtOAc to give tert-butyl (4-{2-[2-(acetylamino)-5-formyl-1,3-thiazol-4-yl]ethyl}phenyl)carbamate as pale yellow powder (2.67 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][S:50](=[O:54])(=[O:53])[CH2:49][CH2:48]1>>[O:53]=[S:50]1(=[O:54])[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][NH:43][CH2:37][C@:21]23[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]2[C@@H:23]2[C@@:18]([CH3:39])([CH2:19][CH2:20]3)[C@@:17]3([CH3:40])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:41])([CH3:42])[C:12]([C:10]3[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24]2)[CH2:52][CH2:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCCN1CCS(=O)(=O)CC1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following steps 5 and 6 using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (50 mg, 55.0%). LCMS: m/e 737.5 (MH+), 2.53 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.85 (d, J=3.8 Hz, 1H), 7.01-7.14 (m, 1H), 6.98 (br. s., 1H), 5.37 (br. s., 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.56 (br. s., 4H), 3.43 (br. s., 4H), 3.21 (m, 3H), 3.12 (br. s., 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.16 (br. s., 4H), 1.75 (br. s., 10H), 1.53 (br. s., 8H), 1.31 (br. s., 3H), 1.19 (br. s., 5H), 1.10 (br. s., 3H), 1.05 (br. s., 3H), 0.99 (d, J=8.5 Hz, 6H). 19F NMR (376 MHz, MeOD) δ ppm −112.6 (s, 1 F).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9]C(O)=O)=[CH:6][CH:5]=1)#[N:2].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:9][CH2:8][C:7]1[CH:13]=[CH:14][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(CCC(=O)O)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1ccc(CCBr)cc1

Procedure:
A mixture of p-cyanomethylhydrocinnamic acid (18.9 g., 0.1 mole), red mercuric oxide (17.2 g., 0.08 mole), and carbon tetrachloride (180 ml.) is stirred at room temperature while bromine (16.0 g., 0.1 mole) is added dropwise during 40 minutes. The resulting mixture is heated at reflux for 1 hour. The mixture is then cooled, filtered, washed with dilute hydrochloric acid and water, and dried over magnesium sulfate. The solution is evaporated to leave the product as a yellow residual oil. It is purified by column chromatography on silica gel with benzene elution.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11](C(OC(C)(C)C)=O)[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32]C(C)(C)C)=[O:31])=[C:26]([F:37])[CH:25]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[OH:44][C:38]([C:40]([F:43])([F:42])[F:41])=[O:39].[OH:44][C:38]([C:40]([F:43])([F:42])[F:41])=[O:39].[NH2:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[C:26]([F:37])[CH:25]=2)=[CH:4][C:5]([C@H:8]2[CH2:9][C@@H:10]([C:20]([O:22][CH3:23])=[O:21])[NH:11][CH2:12]2)=[CH:6][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](c2cnc(N)c(-c3ccc(C(=O)OC(C)(C)C)c(F)c3)c2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)c2)CN1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (2S,4R)-1-tert-butyl 2-methyl 4-(6-amino-5-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyridin-3-yl)pyrrolidine-1,2-dicarboxylate (300 mg, 0.58 mmol) in DCM (6 mL) was treated with TFA (3 mL). After 1 h, the reaction was concentrated, then the residue was slurried in benzene, sonicated, then concentrated to provide 4-(2-amino-5-((3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl)pyridin-3-yl)-2-fluorobenzoic acid-2TFA (345 mg, 100% yield). LCMS (m/z): 360.2 (MH+), 0.34 min.