Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C.Cl>[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1Cc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cc2ccccc2)CCCC1=O
Reaction time: 0.05 h
Yield: 36.5 %

Procedure:
40% Methanolic Triton B (0.95 mL, 2.1 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (510 mg, 2.1 mM) in 30 mL of DMF at −10° C. After 3 minutes, 2-benzylbenzyl bromide (548 mg, 2.1 mM) was added and the resultant mixture stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate and 1 N HCl, washed twice with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The reside was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 324 mg (36%) of the 9-[(2-benzylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.45-7.0 (m, 10H), 6.9 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.2 (s, 2H), 4.15 (s, 2H), 4.05 (s, 3H), 2.5 (m, 4H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1466, 1443, 1411, 1283, 1200, 1119, and 749. MS (ES) m/e 422, 424.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1>C(O)C>[Cl:13][C:14]1[N:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:17]([C:21]([F:24])([F:22])[F:23])=[CH:18][N:19]=1.[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:19]=[C:18]([Cl:20])[C:17]([C:21]([F:23])([F:24])[F:22])=[CH:16][N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2nc(Cl)ncc2C(F)(F)F)cc1
Product: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Yet alternatively, 0.67 g 4-nitrophenol are dissolved in 5 mL ethanol. 4.6 mL of 1 M aqueous sodium hydroxide solution are added. The mixture is cooled to −15° C. A solution of 1.0 g 2,4-dichloro-5-trifluoromethylpyrimidine in 2 mL ethanol is added at −15° C. in portions. The suspension is stirred for 1.5 hours at −15° C. to −10° C. and then warmed up to 20° C. during 3 hours. The suspension is stirred 16 hours at 20° C. The precipitate is filtered and washed with a 1:1-mixture of methanol and purified water. The product is dried in a vacuum drying oven. 1.3 g (88% of theory) of title product is obtained with a regioisomeric purity of 88:12 (2-chloro-4-(4-nitrophenyloxy)-5-trifluoromethylpyrimidine:2-(4-nitrophenyloxy)-4-chloro-5-trifluoromethylpyrimidine).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)[CH2:4][CH2:3]1.[C:19](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.IC>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:19][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@H](O)CC2)cc1C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CI
Product: COC(=O)c1ccc([C@H]2CC[C@H](OC)CC2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Example 13 Step E (234 mg, 0.942 mmol) in DCM (4.7 mL) were added 2,6-di-tert-butylpyridine (0.318 mL, 1.41 mmol) and silver trifluoromethanesulfonate (266 mg, 1.04 mmol). The resulting solution was cooled to 0° C., and iodomethane (0.071 mL, 1.13 mmol) was added. After 30 min, the reaction mixture was allowed to warm to ambient temperature and was held at this temperature for 3 h, whereupon it was filtered through Celite, rinsing with DCM. The reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound. Analytical data for the major isomer (trans cyclohexyl): LCMS m/z 263.17 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=8.5 Hz, 1H), 7.08-7.06 (m, 2H), 3.86 (s, 3H), 3.38 (s, 3H), 3.24-3.17 (m, 1H), 2.58 (s, 3H), 2.49 (dt, J=12.0, 3.5 Hz, 1H), 2.21-2.18 (m, 2H), 1.94-1.92 (m, 2H), 1.54-1.46 (m, 2H), 1.39-1.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH2:3][C:4]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([CH2:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C1C=CN=CC=1.[FH:22].[Br:23]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:23][CH:11]1[CH2:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3][C:2]1([Cl:1])[F:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1=C(C(=O)OC)CC(Cl)=CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C(=O)OC)CC(F)(Cl)C(Br)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl 4-chloro-3,6-dihydrophthalate (0.19 g) and pyridinium poly(hydrogen fluoride) were mixed together at room temperature and N-bromosuccinimide was slowly added. The reaction mixture turned dark then light yellow. After stirring at room temperature for 3 hours, the reaction mixture was carefully poured into saturated sodium bicarbonate solution containing methylene chloride. The methylene chloride layer was dried with magnesium sulfate and the solvent removed under reduced pressure. NMR and GC-MS analysis of the reaction mixture revealed the major product to be the desired dimethyl 5-bromo-4-chloro-4-fluoro-3,4,5,6-tetrahydrophthalate along with some dimethyl 4-fluorophthalate.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:38])[CH2:21][NH:22]C(=O)[C@H](CC(C)C)NC(OC(C)(C)C)=O)=[O:15])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(COC(N(CC(NCCNC(=O)CNC(OC(C)(C)C)=O)=O)C)=O)C=CC=CC=1.[ClH:69].O>ClCCl>[ClH:69].[C:1]1([CH2:7][O:8][C:9]([N:11]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:38])[CH2:21][NH2:22])=[O:15])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCCNC(=O)CN(C)C(=O)OCc1ccccc1
Agent: CN(CC(=O)NCCNC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(CC(=O)NCCNC(=O)CN)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
N-(N-(1,1-Dimethylethoxycarbonyl)leucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide. N-(1,1-Dimethylethoxycarbonyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide (5.22 g, 8 mmol) was treated with excess hydrogen chloride in dichloromethane (50 mL) for 1 h. Water (50 mL) was added and the mixture was stirred vigorously for 15 min. The solvent and excess reagent were evaporated from the aqueous layer under reduced pressure to give crude glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide hydrochloride as a white solid. This material was stirred with N,N-diisopropylethylamine (3.231 g, 25 mmol) and N-(1,1-dimethylethoxycarbonyl)leucine 2,4,5-trichlorophenyl ester (3.19 g, 7.8 mmol) (Example II, Intermediate A) in dimethylformamide (30 mL) for 3 d. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and was washed with aqueous sodium hydroxide (5%), aqueous sulphuric acid (10%) and water and was dried with anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave N-(N-(1,1-dimethylethoxycarbonyl)leucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide (3.26 g, 78%).
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11](=[N:2][OH:3])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: NO
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(=NO)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of hydroxylamine hydrochloride (10.2 g, 147 mmol) was added to a suspension of 4,4'-dinitrobenzophenone (19 g, 70 mmol) in 100 ml of ethanol. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, and the solid collected by filtration. Recrystallization from ethanol provided the title compound (14.0 g, 70%) as pale yellow crystals. mp 194° C.; 1H NMR (D6 -DMSO) d 12.25 (s, 1H), 8.35 (d, 2H), 8.20 (d, 2H), 7.60 (d, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36]2.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>C(Cl)Cl>[CH2:45]([O:44][C:42]([C:37]1[NH:38][C:39]2[C:35]([CH:36]=1)=[CH:34][C:33]([NH:32][C:28]([C@H:9]1[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30])=[CH:41][CH:40]=2)=[O:43])[CH3:46]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.321 mmol), ethyl 5-amino-1H-indole-2-carboxylate (114 mg, 0.558 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 159 mg, 0.417 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by RP-HPLC chromatography (20-95% acetonitrile/water) to afford 5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carbonyl]-amino}-1H-indole-2-carboxylic acid ethyl ester (37 mg, 17.6%) as an off-white powder. LCMS (ES+) m/z Calcd for C34H32Cl2F2N4O3+H [(M+H)+]: 652.18. found: 6512.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][C:52]([C@@H:54]2[CH2:58][C@@H:57]([OH:59])[CH2:56][NH:55]2)=[O:53])[CH2:50][CH2:49]1>CN(C=O)C.C(Cl)Cl>[CH:48]1([NH:51][C:52]([C@@H:54]2[CH2:58][C@@H:57]([OH:59])[CH2:56][N:55]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])=[O:53])[CH2:50][CH2:49]1
Reactant: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (232 mg, 0.46 mmol), HOBt (68 mg, 0.51 mmol) and EDC (105 mg, 0.55 mmol) in DMF (8 mL) was added (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (excess) and TEA (0.95 mL, 0.6 mmol). The mixture was stirred at rt for 3 days. The reaction was diluted with DCM (200 mL), washed with NH4Cl, NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 92 mg of the titled compound. MS m/z 671 [M−1].
Reaction SMILES: C[C@@H](N)CC.BrC1C=C(C#N)C(N[C@H](C)CC)=CC=1C(OCC)=[O:10].[C:25]([C:27]1[C:37]([NH:38][C@H:39]([CH3:42])[CH2:40][CH3:41])=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([NH:43][CH2:44][CH3:45])[CH:28]=1)#[N:26]>>[NH2:26][C:25]([C:27]1[C:37]([NH:38][C@H:39]([CH3:42])[CH2:40][CH3:41])=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([NH:43][CH2:44][CH3:45])[CH:28]=1)=[O:10]
Reactant: CCNc1cc(C#N)c(N[C@H](C)CC)cc1C(=O)OCC
Reactant: CCOC(=O)c1cc(N[C@H](C)CC)c(C#N)cc1Br
Agent: CC[C@@H](C)N
Product: CCNc1cc(C(N)=O)c(N[C@H](C)CC)cc1C(=O)O

Procedure:
Synthesized according to the method of reagent preparation 50 by using (1R)-1-methylpropylamine in step 1 then following step 2 with the conversion of ethyl 2-bromo-4-cyano-5-{[(1R)-1-methylpropyl]amino}benzoate to ethyl 4-cyano-2-(ethylamino)-5-{[(1R)-1-methylpropyl]amino}benzoate according to the method described in step 1 then proceeding through steps 3 and 4. MS (EI) for C14H21N3O3: 280 (MH+).
Reaction SMILES: [CH2:1]([O:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([OH:30])=[C:23]([OH:31])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[CH2:1]([O:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([O:30][C:1](=[O:15])[CH3:2])=[C:23]([O:31][C:24](=[O:30])[CH3:23])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOC(=O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CCCCc1cc(OC(C)=O)c(OC(C)=O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.1 g of the product obtained in Example 29 in 2 ml of acetic anhydride was refluxed for 20 min. The solvent was evaporated invacuo and the residue crystallized from petroleum ether (b.p. 40° C.), m.p. 52°-54° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=C(NC)C=2.C(OC(=O)C)(=[O:23])C.[CH2:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C.O>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:31]([N:30]([CH3:28])[C:33](=[O:23])[CH3:34])[CH:32]=2
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CC
Reactant: CNc1ccc2cc(-c3c(I)ccnc3OC)[nH]c2c1
Solvent: O
Solvent: ClCCl
Product: COc1nccc(I)c1-c1cc2ccc(N(C)C(C)=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-amine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added acetic anhydride (8 mg, 0.08 mmol) and triethylamine (80 mg, 0.791 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-N-methyl-acetamide (18 mg, 53%) as a white solid. MH+ 422.0.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7](Br)[CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4].C([O-])(=O)C.[Na+]>C(O)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4]
Reactant: Cc1cc(Br)c(Cl)c(Cl)c1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(Cl)c1N
Yield: 89 %

Procedure:
A slurry of 6.50 g (25.5 mmol) of 2,3-dichloro-4-bromo-6-methylaniline and 8.37 g (102 mmol) of sodium acetate in 120 ml of acetic acid-ethanol (1:1, v/v) was treated with 0.65 g of 5% palladium on carbon. The mixture was hydrogenated in a Parr hydrogenation apparatus at an initial pressure of 50 psi for 10 minutes. The reaction mixture was filtered, and the filtrate was concentrated by evaporation at reduced pressure. The residue was partitioned between ether and water, and the organic layer was washed with 5% aqueous sodium hydroxide, dried and evaporated at reduced pressure. The residue was purified by Kugelrohr distillation to afford 4.00 g (89% of the desired product as a colorless oil, b.p. 60°-70° C. (0.15 mm). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1.[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]1=[O:39]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:27]2[CH:26]=[C:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:22])[CH:28]=2)=[N:3][C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:5][CH:6]=1
Reactant: CS(=O)(=O)Cc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Product: Cc1cc(-c2nc(CS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 146, step 2 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J=2.0 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.60-7.54 (m, 1H), 7.52-7.46 (m, 1H), 7.22-7.17 (m, 1H), 4.76 (s, 2H), 3.56 (s, 3H), 3.18 (s, 3H), 2.08 (s, 3H). LCMS: 422.1 (M+1)+
Reaction SMILES: [ClH:1].C[O:3][CH:4](OC)[C:5]1[NH:6][C:7]2[N:8]([CH:25]=[CH:26][N:27]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CC(C)=O>O>[ClH:1].[CH2:14]([O:13][C:11]([C:10]1[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[N:8]2[CH:25]=[CH:26][N:27]=[C:7]2[NH:6][C:5]=1[CH:4]=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)C1=C(C(OC)OC)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 ml of 6N hydrochloric acid is added to a solution of 4.4 g of 7-dimethoxymethyl-6-ethoxycarbonyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine in mixture of 10 ml of acetone and 10 ml of water and the mixture is stirred at room temperature for an hour, and then allowed to stand overnight. The solvent is distilled off under reduced pressure below 40° C. to give 4 g of 6-ethoxycarbonyl-7-formyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine hydrochloride, melting at 228° C. with decomposition.
Reaction SMILES: Cl.[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([NH2:19])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH3:61])[C:54]=3[F:62])=[CH:49][C:48]2=[O:63])CC(C)C)=N1>C(#N)C>[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([N:19]2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH3:61])[C:54]=3[F:62])=[CH:49][C:48]2=[O:63])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Reactant: CCO[C@@H](C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](C[C@H](C)OCC)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Yield: 50.1 %

Procedure:
A suspension of (2S,4S)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride salt (prepared as in Example 95, 124.5 mg, 0.335 mmol) in acetonitrile (7 mL) was treated with N,N-diisopropylethylamine (0.25 mL). At this time a solution of (E)-4-bromo-3-(3-ethoxy-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 114, 117 mg, 0.337 mmol) in acetonitrile (2 mL) was added and the resulting solution refluxed for 64 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (2 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 1.5 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 12 g, 10% to 70% (10% methanol/dichloromethane)/hexanes,) which afforded (2S,4S)-4-ethoxy-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (87 mg, 50%): HR-ES-MS (m/z) calculated for C26H35FN4O6 [M+H]+ 519.2614, observed 519.2615. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.19 (m, 12H), 1.36 (t, J=6.0 Hz, 3H), 1.75-2.02 (m, 2H), 3.15-3.30 (m, 1H), 3.33 (br. s., 1H), 3.40-3.55 (m, 1H), 3.89 (br. s., 2H), 4.06-4.21 (m, 2H), 4.29 (d, J=18.4 Hz, 1H), 4.49 (d, J=18.4 Hz, 1H), 4.67 (br. s., 1H), 4.85-4.99 (m, 2H), 6.44 (br. s., 1H), 6.91-7.06 (m, 1H), 7.05-7.29 (m, 2H), 7.53 (br. s., 1H), 10.69 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (101 mg, 0.199 mmol, 29.0% yield) as a solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([S:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[O:20][N:19]=1>>[CH3:30][S:29][C:24]1[C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: CSc1ncccc1-c1nc(CCl)no1
Product: CSc1ncccc1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2-(methylthio)pyridine: MS (ES) m/z 416 (M+1).