Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O=[Pt]=O>[O:22]([C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21])[C:23]1[CH:24]=[CH:11][CH:12]=[CH:4][CH:5]=1
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Product: CN1CCC2(C)c3cc(NC(=O)Oc4ccccc4)ccc3N(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (2.2 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (220 mg) as a catalyst. The reduction was complete within 2 hours. The reduction mixture was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (0.100 g) and triethylamine (0.9 g) were added, the mixture was cooled to 0° C. and a solution of phenylchloroformate (1.4 g) in ethyl acetate (100 ml) was added over a period of 1.5 hours. The mixture was washed with water (2×100 ml), dried (Na2SO4), concentrated and purified by flash chromatography (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 1,2,3,3a,8,8a-hexahydro-5-(phenoxycarbonylamino)-1,3a,8-trimethylpyrrolo[2,3-b]-indole (0.66 g), which was transformed to the oxalate salt by dissolving in ether (200 ml) and methanol (20 ml) and adding a solution of oxalic acid (0.16 g) in ether.
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>CO>[OH:1][CH:2]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)[CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.5 g, 25.9 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (25.9 ml, 51.8 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (9.65 g, 90%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1)[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]3[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[CH:32][C:21]=3[N:20]=2)[CH2:14]1)=[O:12])=O)(C)(C)C>C(Cl)Cl>[NH2:8][C@H:9]([CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1)[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]3[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[CH:32][C:21]=3[N:20]=2)[CH2:14]1)=[O:12]
Reactant: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(C(=O)OC)cc21
Solvent: ClCCl
Product: COCCCn1c(C2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
Methyl 2-(1-((R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (43D) (0.22 mmol, 140 mg) in DCM (10 mL) was added TEA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (20-50% CH3CN in H2O) to afford methyl 2-(14(R)-3-amino-4-(naphthalen-2-yl)butanoyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (111) (0.05 mmol, 26 mg, yield: 22.7%). ESI-MS: m/z 543.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70-2.12 (m, 6H) 2.70 (d, J=6.51Hz, 3H) 2.87-3.06 (m, 2H) 3.06-3.19 (m, 4H) 3.19-3.25 (m, 2H) 3.30 (t, J=5.62 Hz, 1H) 3.27-3.32 (m, 1H) 3.74-3.85 (m, 2H) 3.89 (d, J=6.88 Hz, 3H) 3.96 (s, 1H) 4.18-4.60 (m, 3H) 7.44 (dd, J=9.03, 6.13 Hz, 1H) 7.48-7.56 (m, 2H) 7.63-7.72 (m, 1H) 7.80 (d, J=7.39 Hz, 1H) 7.84 (dd, J=8.91, 2.08 Hz, 2H) 7.87-7.95 (m, 3H).
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>C1COCC1.C(Cl)Cl>[C:1]([NH:20][CH:21]([CH2:22][OH:23])[CH2:24][O:25][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([C:29]2[O:28][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=2)=[CH:38][CH:39]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC(COCc1ccc(-c2nc3ccccc3o2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-trityl-1,3-dihydroxy-2-propanamine (3.7 g; 11 mmol) is dissolved in THF (22 ml) and cooled to 0° C. NaH (0.44 g; 11 mmol; 60% in oil) is added and the reaction is warmed to room temperature and allowed to stir for 2 hours. 4-(benzoxazol-2-yl)benzylbromide (1.6 g; 5.5 mmol) is added and the reaction allowed to stir for 15 hours. The reaction is diluted with CH2Cl2 and washed with H2O 2x, dried (Na2SO4), concentrated and purified by column chromatography with basic alumina and eluted with 2% MeOH/98% CH2Cl2 to obtain N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-hydroxy-2-propanamine as a white solid which is used directly in Step E.
Reaction SMILES: [NH2:1][OH:2].[F:3][CH2:4][CH:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1>C(O)C>[C:17]([O:16][C:15](=[O:21])[NH:14][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:1][OH:2])=[CH:8][CH:7]=1)[CH2:4][F:3])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(CF)c1ccc(C=O)cc1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CF)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.7 %

Procedure:
Hydroxylamine (459.6 μL of 50% w/v, 6.958 mmol) was added to a stirred solution of tert-butyl N-[2-fluoro-1-(4-formylphenyl)ethyl]carbamate (930 mg, 3.479 mmol) in ethanol (100 mL) and the reaction mixture stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water and extracted with ethyl acetate (×3). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl(2-fluoro-1-(4-((hydroxyimino)methyl)phenyl)ethyl)carbamate as an impure white solid (1058.2 mg, >100%). 1H NMR (400.0 MHz, DMSO-d6) 1.37 (s, 9H), 4.38-4.41 (m, 1H), 4.49-4.53 (m, 1H), 4.83-4.92 (m, 1H), 7.38 (d, 2H), 7.56 (d, 2H), 7.70 (d, 1H), 8.11 (d, 1H) and 11.24 (s, 1H) ppm; LC/MS m/z 227.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12].Br[CH2:14][C:15]1[C:16]([CH3:22])=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1.Cl>C1COCC1.O>[Cl:21][C:18]1[N:17]=[C:16]([CH3:22])[C:15]([CH2:14][O:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][C:7]2=[O:12])=[CH:20][CH:19]=1
Reactant: Cc1nc(Cl)ccc1CBr
Reactant: O=C1COCCN1CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)ccc1COCCN1CCOCC1=O
Temperature: 0 °C

Procedure:
Sodium hydride (190 mg of a 60%, 4.76 mmol) was suspended in THF (12.2 mL) and cooled to 0° C. 4-(2-Hydroxyethyl)morpholin-3-one (230 mg, 1.59 mmol) was added and the slurry was stirred for thirty minutes at 0° C. 3-(Bromomethyl)-6-chloro-2-methylpyridine (Example 421 Step 2) (350 mg, 1.59 mmol) was added and the solution was heated to 50° C. overnight. The reaction mixture was then cooled to ambient temperature, diluted with water, acidified using 1 N aqueous hydrochloric acid, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-2% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:12]2[CH2:13][C:8]3([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=[O:3].[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)=[CH:18][CH:17]=1>>[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][N:24]([C:2]([O:4][CH:5]3[CH:12]4[CH2:13][C:8]5([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]3[CH2:7]5)[CH2:11]4)=[O:3])[CH2:23]2)=[CH:18][CH:17]=1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Product: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CCC(c2ccncc2)C1

Procedure:
A procedure analogous to that described in Example 19 Step 1 was followed using 1-hydroxy-4-adamantyl chloroformate solution and 3-(4-pyridyl)pyrrolidine. The title compound was isolated as a mixture of isomers. LC-MS Method 1 tR=0.90 min, m/z=343, 1H NMR (CD3OD) [selected resonances] 4.69 (s, 0.5H), 4.78 (s, 0.5H), 8.03 (d, 2H), 8.78 (d, 2H)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]1)[CH2:7][CH2:6][CH2:5]2.I[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35]N(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:33]2>>[CH3:19][C:16]1([CH3:20])[O:15][CH2:14][C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:33]#[C:32][CH2:31][CH2:30][CH2:38][CH2:37][CH2:36][CH3:35])=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH2:18][O:17]1
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: CC(C)(C)OC(=O)NC1(CN2CCCc3cc(I)ccc32)COC(C)(C)OC1
Product: CCCCCCC#Cc1ccc2c(c1)CCCN2CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Yield: 35 %

Procedure:
When the product of Step B is substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the identical process afforded the title compound in 35% yield, as a brownish foam. 1H-NMR (CDCl3) 0.88 (m, 3H); 1.41 (m, 8H); 1.50 (m, 2H); 1.87 (m, 2H); 2.34 (tr, 2H, J=7.0 Hz); 2.72 (tr, 2H, J=6.3 Hz); 3.26-3.32 (m, 2H); 3.69 (5, 2H); 3.9 (s, 3H); 4.65 (s, 1H); 6.68 (d, 1H, J=8.7 Hz); 6.98 (s, 1H); 7.04 (d, 1H, J=8.7 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:14]1([CH:13]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9 g, 1.1 equiv.) in DCM (800 mL) was treated with TFA (15 mL, 2 equiv.). The resulting mixture was stirred at rt for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate. After filtration and concentration to dryness the residue was recrystallized from 2-propanol to give the title compound (11.0 g, 47%) as white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C1C=CC=CN=1)C>ClCCl>[C:36]([N:18]1[CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CCC2C(=O)OC(C)(C)C)cc1

Procedure:
tert-Butyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate (0.425 g, 0.96 mmol) in dichloromethane at 25° C. (10 mL) was treated with triethylamine (0.28 mL, 2.02 mmol) followed by benzoyl chloride (0.12 mL, 1.06 mmol) and dimethylaminopyridine (10 mg). After 18 hours aqueous workup gave tert-butyl 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylate. 1H NMR (dmso-d6, 300 MHz): 1.24 (s, 9H, t-bu), 1.82 (s, 3H, CH3), 2.0-4.0 (m, 8H, CH2), 4.65 (s, 1H, CH), 4.85 (s. 2H, CH2), 7.0-7.9 (m, 9H, ArH). Treatment with trifluoroacetic acid (4 mL) in dichloromethane (10 mL) for 6 hours gave, after concentration in vacuo followed by chromatography on silica gel eluting with dichloromethane/methanol, 1-benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic acid as a foam (0.328 g).
Reaction SMILES: Br[CH2:2][B-:3]([F:6])([F:5])[F:4].[K+:7].[CH3:8][C@@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][N:14]([CH2:2][B-:3]([F:6])([F:5])[F:4])[C@@H:9]([CH3:8])[CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20].[K+:7]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: F[B-](F)(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A mixture of potassium (bromomethyl)trifluoroborate (Aldrich, 1.20 g, 5.38 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Aldrich, 1.131 g, 5.65 mmol) in THF (7.00 mL) was heated at 80° C. under nitrogen for 24 h. The mixture was allowed to cool to ambient temperature and was then concentrated in vacuo. The residue was re-dissolved in acetone (125 mL) and treated with K2CO3 (1 eq). The suspension was stirred for 30 min and then filtered through a short plug of Celite® (diatomaceous earth). The filter cake was washed with additional acetone, and the combined organic filtrates were concentrated to give the crude product as a colorless foam (1.51 g, 88%). The pure material was obtained as a beige powder by adding acetone-ether (2:1) to the foam and then slowly adding hexanes while sonicating the mixture. 19F-NMR (377 MHz, d6-acetone) δ −141.28.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:17]2[C:16]([F:15])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2c(F)cccc2F)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2c(F)cccc2F)C1=O
Yield: 18.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.107 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.033 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH:1]12[S:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=O)[CH2:2]2.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:3]1[CH2:4][CH:5]2[S:8][CH:1]([CH2:7][CH2:6]2)[CH2:2]1
Reactant: O=C1CC2CCC(C1)S2
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CC4CCC(C3)S4)c[nH]c12
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 Å molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%).
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.CN(C)P(N(C)C)(N(C)C)=O.C([N-]C(C)C)(C)C.[Li+].Br[CH2:35][CH2:36][Cl:37]>C1COCC1>[Cl:37][CH2:36][CH2:35][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][CH:1]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: ClCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To the above described mixture of crude dimethyl cyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added the freshly prepared lithium diisopropylamide solution (preparation described above) over 30 min at −40° C. After stirring for 1 h at this temperature, 1-bromo-2-chloroethane (42 mL, 0.5 mol) was added over 1. The mixture was stirred for 3 h at −78° C. and then stirred overnight at room temperature. The reaction was quenched by the addition of aqueous hydrochloric acid solution (3 N, 420 mL). The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (200 mL×3). The combined extracts were washed with brine (2×300 mL) and dried over sodium sulfate. Concentration gave the title compound (116 g, yield 88%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (s, 3H), 3.65 (s. 3H), 3.46-3.42 (m, 2H), 2.33-2.21 (m, 3H), 2.05-1.85 (m, 4H), 1.58-1.42 (m, 2H), 1.25-1.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[O:18][C:14]=2[C:13]([O:24][CH3:25])=[CH:12][CH:11]=1.Cl>O1CCOCC1.CO.[OH-].[Na+]>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[O:18][C:14]=2[C:13]([O:24][CH3:25])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(CCc3c(Cl)cncc3Cl)ccc(OC)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CCc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Ethyl 4-[2-(3,5-dichloro-4-pyridyl)ethyl]-7-methoxybenzofuran-2-carboxylate (1.9 g) was dissolved in dioxane (20 ml)-methanol (5 ml), and 1 N aqueous NaOH (15 ml) as added thereto. The mixture was returned to room temperature and stirred for 30 minutes. After 1 N aqueous HCl was dropwise added thereto under cooling on ice, the precipitated crystals were collected by filtration and washed with water to give Compound N (1.72 g, 97%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([NH:25][CH3:26])=[O:24])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2nc(Cl)ncc2F)c1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (1 g, 5.98 mmol) in isopropanol (18 mL, 3 mL/mmol) was added DIPEA (1.6 mL, 8.9 mmol) and 3-amino-N-methylbenzamide (900 mg, 5.98 mmol) and the mixture was heated at 80° C. for 7 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL) and water (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography provided 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-N-methylbenzamide (800 mg, 50%) as a solid. Observed mass (M+1): 281.1
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1CC[CH2:16][CH2:15]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:16][CH2:15][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C1CCNC1
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Product: NC(=O)c1cc(N2CCCC2)ccc1N

Procedure:
According to the preparation of 25, pyrrolidine was used to afford 26 (0.7 g) as brown powder; MS m/z 205 (M+).
Reaction SMILES: [C:1]12([C:12]([O:14]C)=[O:13])[CH2:7][C:4]([C:8]([O:10]C)=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[K+].C(O)C.Cl>O>[C:1]12([C:12]([OH:14])=[O:13])[CH2:7][C:4]([C:8]([OH:10])=[O:9])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C12CCC(C(=O)O)(CC1)C2
Temperature: 60 °C

Procedure:
A mixture of Example 117A (3.18 g, 15.0 mmol), solid potassium hydroxide (8.4 g, 150 mmol), and a mixture of ethanol (75 mL) and water (15 mL) was heated at about 60° C. overnight. After cooling, the pH of the mixture was adjusted to about 1 by addition of 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporator to give a tan powder. The crude product was recrystallized from ethyl acetate/hexanes to give the title compound as a white solid that was used without further purification for the next step.