Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31](OC(C)(C)C)=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)[O:3]1.Cl.[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])C(O)=O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.C(O)C>[CH3:54][CH:53]([CH3:55])[C@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[C:31](=[O:32])[N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24]1[NH:25][C:21]2[CH:20]=[CH:19][C:18]3[C:38](=[CH:39][CH:40]=[C:41]4[C:12]5[CH:11]=[CH:10][C:9]([B:4]6[O:3][C:2]([CH3:42])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]6)=[CH:14][C:13]=5[CH2:15][O:16][C:17]4=3)[C:22]=2[N:23]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CO4)[nH]1
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: CCO
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CO4)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (0.98 g, 1.7 mmol), concentrated HCl (2 mL) and ethanol (20 mL) was heated to 60° C. for 2 hours. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. The resulting crude material was dissolved in dimethylformamide (17 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (455 mg, 2.6 mmol), HATU (955 mg, 2.5 mmol) and diisopropylethylamine (3 mL, 17 mmol). The reaction was stirred at room temperature for one hour then diluted with ethyl acetate. The organics were washed with water (×2) and brine, dried with magnesium sulfate and concentrated. The resulting residue was purified by flash column chromatography to yield Intermediate methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate (780 mg, 72% yield over 2 steps).
Reaction SMILES: Br[C:2]1[C:20]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)=[O:22])=[CH:19][C:5]2[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.C[O-].[Na+].CN([CH:46]=[O:47])C>O>[CH:37]([N:23]([C:21]([C:20]1[C:2]([O:47][CH3:46])=[CH:3][C:4]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:5]=2[CH:19]=1)=[O:22])[C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)([CH3:39])[CH3:38]
Reactant: CN(C)C=O
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(Br)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(OC)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To tert-Butyl (3R)-3-[{[7-bromo-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (500 mg) were added CuBr (59 mg), NaOMe (1M methanol solution) (16.4 ml) and DMF (5.5 ml), and the mixture was stirred at 100° C. for 15 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (240 mg) as a colorless liquid.
Reaction SMILES: O=C1[C@H:10]2[C@H:5]([C@@H:6]3C[C@H:9]2[CH:8]=[CH:7]3)[C@@H:4]([NH:12][C@@H:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]([O:16]CC2C=CC=CC=2)=[O:15])O1.[ClH:28]>O>[ClH:28].[CH2:4]([NH:12][C@H:13]([C:14]([OH:16])=[O:15])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)C[C@H](NCc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 1 g of the product of Example 2, 8 ml of demineralized water and 0.8 ml of hydrochloric acid was stirred at 20° C. for one hour and was then heated at 60° C. for one hour and was cooled at 20° C. The mixture was diluted with 15 ml of water and was then extracted with methylene chloride. The organic phase was washed with aqueous N sodium hydroxide solution and with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of ether and a stream of hydrogen chloride was slowly bubbled therethrough. The mixture was vacuum filtered to obtain 350 mg of benzyl L-leucine hydrochloride melting at 135° C. and having a specific rotation of [α]D20 =-5.5°±1° (c=1% in 0.1 N hydrochloric acid). Circular Dichroism (dioxane): max. at 219 nm; Δε=+1.0.
Reaction SMILES: N1(C(C2CCCCC2C(O)=O)=O)CCOCC1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)=[N:25][C:21]=2[CH:20]=1.[CH3:35][O:36][C:37](=[O:50])[C@H:38]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:39][C:40](O)=[O:41]>>[CH3:35][O:36][C:37](=[O:50])[CH:38]([CH2:43][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)[CH2:39][C:40]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[NH:23][C:22]3[CH:33]=[CH:34][C:19]([Cl:18])=[CH:20][C:21]=3[N:25]=2)=[CH:31][CH:30]=1)=[O:41]
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Reactant: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Agent: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Product: COC(=O)C(CC(=O)Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1)CC1CCCCC1
Yield: 51 %

Procedure:
This compound was prepared by the procedure described in Example 1 part (a) from 4-(5-Chloro-1H-benzoimidazol-2-yl)-phenylamine and (R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester to give the crude product (2.0 g, 51%), which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15]([C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)=O>CO.CCOC(C)=O.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:19]1[N:18]=[C:17]([CH3:15])[NH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)Nc1c[nH]c(C)n1

Procedure:
N-(2-methylimidazolyl)-L-phenylalanine methyl ester was prepared from L-phenylalanine methyl ester hydrochloride (3.30 mmol) and 2-formyl-imidazole (3.63 mmol) utilizing the procedure of Example 9, first paragraph, to yield, after flash chromatography (3:50:50 v/v/v CH3OH/EtOAc/CH2Cl2 ; SiO2 gel), 0.55 g (65% yield) of pure product.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:40][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]3([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC1(O)CCCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of 1-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol (1.10 g, 2.99 mmol) in chloroform (15 mL) at rt was added m-CPBA (0.96 g, 3.89 mmol) in portions. The reaction was stirred for 1.5 h, then was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added followed by portionwise addition of p-toluenesulfonyl chloride (0.630 g, 3.29 mmol). The mixture was stirred at 0° C. for 1 h, then was filtered. The filtrate was diluted with dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to afford an orange solid, which was purified by HPFC (silica gel, eluted with 0-35% CMA/chloroform). The appropriate fractions were concentrated to afford a tan solid that was crystallized from chloroform/hexanes and dried at 75° C. under vacuum to afford 1-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol as white crystals (600 mg, 53%), mp 175-176° C. Anal. calcd for C22H30N4O2: C, 69.08; H, 7.91; N, 14.65. Found: C, 68.94; H, 8.21; N, 14.53.
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:16])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C@H:12](C)[CH:13]=O.N1C=CC=CC=1C1C=CC=CN=1.C1N2CCN(CC2)C1.[O:37]=O.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:16])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C:12](=[O:37])[CH3:13]
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Reactant: O=O
Agent: [Cu+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(=O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 80 °C
Yield: 58.8 %

Procedure:
(S)-2-{(E,3R,3aR,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}propanal (Compound 10: 43 mg, 0.151 mmol) synthesized according to the method described in Org. Lett. 2003, 5, 4859-4862 was dissolved in dimethylformamide (300 μl), and copper (II) acetate (3.1 mg, 0.0171 mmol), bipyridyl (2.8 mg, 0.0179 mmol) and triethylenediamine (17.4 mg, 0.155 mmol) were added thereto. The resulting mixture was heated to 80° C. and stirred for 4 hours with streaming oxygen. After cooling the mixture to room temperature, 2N hydrochloric acid was added thereto, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and evaporated. The obtained product was purified by flash column chromatography to obtain 1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanone (24.1 mg, 58.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:31]([NH2:33])=[O:32])=[N:9]2)=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[CH3:55][C:56]([OH:60])([CH:58]=[CH2:59])[CH3:57].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:14]2[CH2:13][CH2:12][C:11]3[C:10]([C:31]([NH2:33])=[O:32])=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2](/[CH:59]=[CH:58]/[C:56]([OH:60])([CH3:57])[CH3:55])=[CH:3][CH:4]=4)[C:16]=3[C:15]=2[CH:17]=1)=[O:30]
Reactant: NC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Reactant: C=CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)/C=C/c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 100 °C
Yield: 21.6 %

Procedure:
A 50 mL round bottomed flask with a magnetic stir bar was charged with 1-(4-bromophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (987 mg, 1.89 mmol), palladium (II) acetate (44 mg, 0.19 mmol), 1,1′-biphenyl-2-yl[di(tert-butyl)]phosphine (254 mg, 0.822 mmol), and dimethylformamide (20 mL). The resulting solution was sparged with argon for 10 minutes. To the solution was added 2-methyl-3-buten-2-ol (823 mg, 6.07 mmol) and triethylamine (614 mg, 6.07 mmol). The solution was sparged with argon for an additional 2 minutes. The flask was sealed with a rubber septum and heated to 100° C. in an oil bath for 90 minutes. The reaction was allowed to cool to room temperature and water was added. The resulting precipitate was collected and purified by silica gel chromatography (100% hexane to 100% ethyl acetate). The pure fractions were combined, concentrated to dryness, triturated with diethyl ether, and dried under vacuum to give 215 mg of 8-[(2-chlorobenzoyl)amino]-1-{4-[(1E)-3-hydroxy-3-methylbut-1-enyl]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (0.408 mmol, 21% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (s, 6H), 2.88–2.98 (m, 4H), 4.76 (s, 1H), 6.48 (d, 1H), 6.58 (d, 1H), 7.23 (d, 1H), 7.30–7.50 (m, 8H), 7.53–7.59 (m, 3H), 10.28 (s, 1H); MS (ESI+) for C30H27ClN4O3 m/z 527 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[N:6]=1.[Br:10]Br>Br>[BrH:10].[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7](=[O:9])[CH2:8][Br:10])[N:6]=1
Reactant: BrBr
Reactant: CC(=O)c1c[nH]c(C)n1
Agent: Br
Product: Cc1nc(C(=O)CBr)c[nH]1
Yield: 93.9 %

Procedure:
2.40 g (19.3 mmol) of 1-(2-methyl-4-imidazolyl) ethanone was dissolved in 30 ml of 48% hydrogen bromide. To the stirred solution at 25° was added over a 5 minute period 3.36 g (21 mmol) of bromine dissolved in 5 ml 48% hydrogen bromide. The reaction was heated to 70° for 2.5 hours and then concentrated in vacuo to a dark oil. A mixture of isopropyl alcohol/ether was added and trituration of the oil gave a solid. This was collected by filtration and washed with ether to give 2.8 g (51%) of 1-(2-methyl-4-imidazolyl)-2-bromoethanone hydrobromide, mp 181° (dec.); nmr (DMSO-d6) (δ): 8.71 (s, 1H); 4.77 (s, 2H); 2.63 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([C:31]#[N:32])=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:33]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.O.[Fe].CC(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][C:11](=[O:12])[NH:13][C:14]3[CH:19]=[C:18]([N:20]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:22]([C:31]#[N:32])=[CH:21]4)[CH:17]=[CH:16][C:15]=3[N:33]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(C2=Nc3ccc(-n4cc(C#N)c(-c5ccccc5)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-[5-(3-cyano-4-phenyl-pyrrol-1-yl)-2-nitro-phenyl]-3-oxo-propionamide (Example M7) by reductive cyclization with Fe/HOAc in THF/H2O at 80° C. according to the general procedure J (method d). Obtained as a brown solid (206 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4]([NH:6][CH2:7][CH:8]([NH:14][S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)(=[O:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].C(N(C(C)C)CC)(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][CH2:57][CH:58]([CH2:62][CH2:63][CH:64]2[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][CH2:65]2)[C:59](F)=[O:60])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].O>ClCCl>[C:73]([O:72][C:70]([N:67]1[CH2:68][CH2:69][CH:64]([CH2:63][CH2:62][CH:58]([C:59]([NH:2][CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4]([NH:6][CH2:7][CH:8]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])=[O:60])[CH2:57][CH2:56][CH:53]2[CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:51][CH2:52]2)[CH2:65][CH2:66]1)=[O:71])([CH3:76])([CH3:75])[CH3:74]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)F)CC1
Reactant: CCOC(=O)C(CNC(=O)C(N)c1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CNC(=O)C(NC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 3 h
Yield: 43.5 %

Procedure:
Ethyl 3-[(2-amino-2-phenylethanoyl)amino]-2-[(2-naphthylsulphonyl)amino]propanoate hydrochloride (1.7 g, 3 mmol) and diisopropylethylamine (0.8 g, 6.2 mmol) are added, at room temperature, to a solution of 4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl fluoride (ref. synthesis B-1) (1.55 g, 3 mmol) in 50 ml of dichloromethane. After stirring for 3 hours, water is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 1.2 g of a white solid.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:17]O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)C.ICI>CCOCC.C(OCC)(=O)C.Cl.CCOCC>[ClH:1].[C:2]1([C:8]2([CH2:14][O:15][C:16]3([C:19]4[CH:20]=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=4)[CH2:17][CH2:33]3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: CCOCC
Solvent: ICI
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(C(F)(F)F)cc(C2(OCC3(c4ccccc4)CCNCC3)CC2)c1
Temperature: 0 °C

Procedure:
The compound of Example 1 (c) (0.500 g, 0.922 mmol) was dissolved in anhydrous ether (10 ml) and diethylzinc (1.0M solution in hexanes, 1.84 ml, 1.84 mmol) was added. The solution was cooled to 0° C. and diiodomethane (0.15 ml 1.84 mmol) was added. The reaction was diluted with ethyl acetate (50 ml) and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 5% ethyl acetate/hexanes→10% ethyl acetate/hexanes. The product obtained was left standing in HCl/ether for 16 h. The solvent was removed in vacuo and the title compound suspended in ether and filtered. 1H NMR (DMSO-d6) δ 7.90 (1H, s), 7.50 (2H, s), 7.29-7.40 (5H, m), 3.36 (2H, s), 3.17 (2H, m), 2.74 (2H, m), 2.30 (2H, m), 2.01 (2H, m), 1.13 (4H, m). MS (Cl+) 444 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.[F-].[K+]>O1CCOCC1.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>[CH:23]1([C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=4)=[CH:3][CH:4]=3)[C:16]3[C:11]([CH:10]=2)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:25][CH2:24]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cccc(C(F)(F)F)c3)o2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) (0.05 g, 0.12 mmol) in dry dioxane (3 mL) were added [3-(trifluoromethyl)phenyl]boronic acid (0.046 g, 0.24 mmol), potassium fluoride (0.021 g, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol). The mixture was stirred at 100° C. in a sealed tube overnight. Solids were filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-40% EtOAc-hexanes gradient) and recrystallized by methanol to afford the title compound (0.0185 g, 32% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.69 (d, J=4.9 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 6.63 (d, J=3.4 Hz, 1H), 6.46 (s, 1H), 6.24 (d, J=3.4 Hz, 1H), 5.52 (s, 2H), 2.04 (m, 1H), 1.14 (m, 2H), 0.89 (m, 2H); MS (ES) m/z 475 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl:36][C:37]([F:47])([F:46])[O:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>CN1CCOCC1.CN(C=O)C.CCOC(C)=O>[Cl:36][C:37]([F:46])([F:47])[O:38][C:39]1[CH:40]=[CH:41][C:42]([NH:43][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:44][CH:45]=1
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Reaction time: 5 h

Procedure:
(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1, 57.3 mg, 0.2 mmol), HOBT (43.5, 0.284 mmol) and EDC (42.2 mg, 0.22 mmol) were dissolved in 0.3 M NMM in DMF (0.8 mL) at RT. 4-(Chlorodifluoromethoxy)aniline (36.8 mg, 0.19 mmol) was added and the RM was stirred for 5 h. The RM was then diluted with EtOAc and washed with 10% NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2 to 5% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound. HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH (50:50), 0.5 mL/min, UV 210 nm) tR=21.89 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=462.2/464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.33-3.44 (m, 1H) 4.12-4.24 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.77-7.89 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=O)[CH2:3][C:4]([O:6]CC)=[O:5].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1.CCOCC>[CH3:12][C:2]1([CH3:1])[CH:9]=[CH:10][O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(C)CC=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C=COC(=O)C1
Yield: 40.1 %

Procedure:
A solution of 11.16 g (0.065 mole) of ethyl 3,3-dimethyl-5-oxopentanoate and 11.2 g (0.073 mole) of phosphoryl chloride in 90 ml of toluene was heated under reflux for 14 hours. The mixture was diluted with ether, washed with an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to give, after distillation, 3.29 g (40% yield) of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one, bp 105°-110° C./2670 Pa (20 mm Hg).