Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[F:24][C:25]([F:30])([F:29])[C@H:26]([NH2:28])[CH3:27]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:28][C@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: C[C@@H](N)C(F)(F)F
Product: C[C@@H](NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1)C(F)(F)F

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and (R)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. for C20H16F4N4O, 404.13; m/z found, 405.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=8.8, 1H) 8.34 (s, 1H), 8.01 (d, J=1.2, 1H), 7.90-7.80 (m, 1H), 7.58-7.40 (m, 4H), 7.29-7.18 (m, 2H), 6.69 (s, 2H), 4.68-4.56 (m, 1H), 1.16 (d, J=7.0, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:14]([O:16][C:17](=[O:36])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:21]([OH:34])=[C:20]([Br:35])[CH:19]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:36])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:21]([OH:34])=[C:20]([Br:35])[CH:19]=1)[CH3:15].[CH2:14]([O:16][C:17](=[O:36])[C:18]1[CH:19]=[C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)[C:21]([OH:34])=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)[CH:23]=1)[CH3:15]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: CCOC(=O)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
3-Bromo-4-hydroxy-5(m-trifluoromethylphenyl)-benzoic acid ethyl ester and 3,5-bis-(m-trifluoromethylphenyl)-4-hydroxy-benzoic acid ethyl ester were prepared as white solids (2.445 g, 34% and 2.811 g, 33%, respectively) from 3-bromo-4-hydroxy-5-iodobenzoic and 3-trifluoromethyl-phenyl boronic acid using a procedure similar to step 1 of Example 175. 3-Bromo-4-hydroxy-5(m-trifluoromethylphenyl)-benzoic acid ethyl ester 1H NMR (CDCl3) δ 8.22 (d, 1H); 7.98 (d, 1H); 7.74 (s, 1H); 7.70 (d, 1H); 7.68–7.53 (m, 2H); 6.10 (s, 1H); 4.38 (q, 2H); 1.40 (t, 3H); 3,5-bis-(m-trifluoromethylphenyl)-4-hydroxy-benzoic acid ethyl ester ester 1H NMR (CDCl3) δ 8.02 (s, 2H); 7.84 (bs, 2H); 7.77–7.60 (m, 6H); 5.67 (s, 1H); 4.38 (q, 2H); 1.40 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 69.4 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (44 mg, 0.17 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL microwave vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (85 mg, 0.118 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.32 (d, J=6.96 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=5.31 Hz, 1H), 8.11 (s, 1H), 7.76 (d, J=8.42 Hz, 1H), 7.68 (dd, J=11.81, 8.52 Hz, 2H), 7.33-7.45 (m, 2H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=7.97 Hz, 2H), 6.88-6.99 (m, 2H), 6.74 (d, J=8.06 Hz, 1H), 6.61 (d, J=5.13 Hz, 1H), 4.06 (q, J=6.96 Hz, 2H), 3.97 (s, 3H), 2.62-2.72 (m, 2H), 2.19-2.57 (m, 10H), 2.11 (s, 3H), 1.27 (t, J=7.05 Hz, 3H). MS (ESI): 719 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)[O:31][C:32]=2[CH3:33])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccco2)nc1COc1cc(CCl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccco4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (457 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (643 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])#[N:22].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:21]([CH:23]([C:35]1[CH:36]=[CH:37][C:38]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:39][CH:40]=1)[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])#[N:22]
Reactant: N#CC(CC(=O)OCc1ccccc1)c1ccc(O)cc1
Reactant: CON=C(COc1ccc(CO)cc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)OCc3ccccc3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged Toluene (20 mL). To the stirred solvent was added 2-(4-Hydroxymethyl-phenoxy)-1-phenyl-ethanone O-methyl-oxime (0.039 g, 0.14 mmol) and benzyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.04 g, 0.14 mmol) at 0° C. for 5 min. Then added tributylphosphine (0.043 g, 0.2 mmol) stirred at 0° C. for 15 min, was added 1,1′aza(dicarbonyl)dipiperidine (0.054 g, 0.2 mmol), this resulting mass stirred at RT for 16 h. The solvent removed, the residue was extracted with ethyl acetate. The organic layer washed with water and brine solution and dried by anhydrous sodium sulphate to and evaporated, purified by 100-200 silica column using pet-ether and ethylacetate. The product obtained as a colourless oily liquid (0.06 g, 79.00%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C>[C:1]([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]([OH:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Reaction time: 0.5 h

Procedure:
2-[(4-{[(4′-Fluorobiphenyl-4-yl)oxy]acetyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester 967 mg obtained in Example 2-1 was dissolved in ethanol (10 mL) and, under ice-cooling, sodium borohydride (75 mg) was added and the mixture was stirred for 2 hr 30 min. Water (10 mL) was added, pH was adjusted to about 3 with aqueous hydrochloric acid (1 mol/L), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue purified by column chromatography (Moritex Corporation Purif Pack SI 60 μm size 200 was used. elution solvent: hexane/ethyl acetate=9/1→6/4) to give the title compound as a pale-yellow oily substance (907 mg).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]1([CH3:46])[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1OBO>COCCOC.O.CCO>[C:37]1([CH3:46])[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccccc1OBO
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 28.9 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(PPh3)Cl2 (˜1 mol %), and Cs2CO3 (17.8 mg, 0.0547 mmol) in DME/H2O/EtOH (7/3/2, 0.5 mL). O-tolyl boronic acid (6.3 mg, 0.046 mmol) was added and the solution was heated in the microwave for 5 minutes at 160° C., filtered, and was purified by Prep HPLC to give 6 mg (23%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 451 (M−H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.78-1.86 (m, 2H), 2.19 (br d, 2H), 2.22 (s, 3H), 3.13-3.19 (m, 2H), 3.58 (br d, 2H), 3.81-3.92 (m, 3H), 5.43 (s, 1H), 6.34-6.40 (m, 1H), 6.88 (d, 1H), 7.23-7.43 (m. 10H), 7.54 (m, 2H), 8.14 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[O:15]=[C:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.O>O1CCCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OCc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2CO)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a solution of (2-bromophenyl)methanol (4.4 g) in dry tetrahydrofuran (90 mL) was added n-butyllithium (1.6 M hexane solution, 31 mL) at −78° C., and the mixture was warmed to room temperature over 2 hr. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (4.0 g) in dry tetrahydrofuran (30 mL) was added at −78° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane to 60% ethyl acetate/hexane) to give the object product (4.0 g, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:20]=1[CH3:30])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:30])[C:21]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(C)c1CCC(=O)O

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (43 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>CC(O)=O>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:20][C:2]1[CH2:3][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:6][C:7]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccc(Br)cc23)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 0.05 mol of N-(3-oxocyclohexyl)acetamide in 100 ml of glacial HOAc was stirred and heated at 80° C. while adding during 15-30 minutes a warm solution of 0.05 mol of 4-bromophenylhydrazine hydrochloride in 300 ml of glacial HOAc. After an additional 3 hr at 85°, most of the HOAc was evaporated. The residue was triturated with H2O, until solid, the resulting solid was filtered, and recrystallized from ethanol to give the title compound, mp 210°-211°.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[C:22]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:21]=2[C:20]([F:34])=[C:19](Cl)[N:18]=1.CC(O)C.CCN(C(C)C)C(C)C>CS(C)=O>[C:11]([O:10][C:9]([NH:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:19]1[N:18]=[C:17]([Cl:16])[C:22]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:25][C:21]=2[C:20]=1[F:34])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(Cl)nc(Cl)c2C1=O
Solvent: CS(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 78 °C
Reaction time: 34 h
Yield: 72.38 %

Procedure:
To the 5-L RBF containing tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (STEP A) was added tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (400.0 g, 1.246 mol, 1 eq). To this mixture was added IPA (400 mL), DMSO (400 mL) and DIPEA (282 mL, 1.3 eq). The resulting pink slurry was heated up to 78° C. and was stirred for 34 hours. The mixture was then cooled to room temperature and was stirred over the weekend. HPLC analysis indicated the presence of 1.6% of the starting material, 4.63% of the des-Boc side product, 72.38% of the desired product, and 11.23% of an isomer. 1H NMR analysis indicated a ratio of 5.49 of the IPA/DMSO. Isopropanol (200 mL) was added to the mixture to adjust the ratio to 6. The slurry was heated up to 78° C. Water (1.6 L) was added over a period of 1 hour at a rate which kept the temperature of the mixture above 64° C. The mixture was then cooled to room temperature and was stirred overnight. The slurry was filtered the next morning through a fritted glass funnel. The filter cake was washed with IPA/water/DMSO (800 mL, 6:4:1) and IPA/water (2×800 mL, 3:2) to give the title compound, which was dried under high vacuum at 40-45° C. until a constant weight was obtained (299.27 g, 48% yield with a 96.6% purity). 1H NMR (300 MHz, CDCl3) δ ppm 1.80-1.30 (m, 26H), 4.04 (m, 1H), 4.21 (m, 1H), 4.64 (d, J=0.9 Hz, 1H), 4.85 (br, 1H), 6.08 (br, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:34]([CH3:36])[CH3:35])[CH2:11][C@H:12]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:13]([OH:25])[CH2:14][NH:15][C:16](=[O:24])[C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:39](OC)([CH3:41])[CH3:40]>CC(C)=O>[CH2:1]([O:8][CH2:9][C@H:10]([CH:34]([CH3:35])[CH3:36])[CH2:11][C@H:12]1[C@@H:13]([CH2:14][NH:15][C:16](=[O:24])[C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[O:25][C:39]([CH3:41])([CH3:40])[N:26]1[C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCCCC(C)(C)C(=O)NC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](COCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of tert-butyl (2S,3S,5S)-5-(benzyloxymethyl)-1-(2,2-dimethylhexanamido)-2-hydroxy-6-methylheptan-3-ylcarbamate (3.8 g, 7.5 mmol) in acetone (50 mL) was added 2,2-dimethoxy-propane (6.0 g, 57.7 mmol). The resulting mixture was cooled to 0° C., BF3Et2O (100 mg, 0.7 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 2 h. TLC showed the starting material had been consumed. The reaction mixture was quenched with Et3N. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layers were washed with H2O and brine, dried over Na2SO4, and evaporated to produce (4S,5R)-tert-butyl 4-((S)-2-(benzyloxymethyl)-3-methylbutyl)-5-((2,2-dimethylhexanamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3.0 g, 73%); MS: 547 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:10]1[CH2:11][CH2:12][CH2:13][C:8]([CH2:15][C:16]#[N:17])([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:14]
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: N#CCC1(c2ccc(Cl)cc2)CCCC(Br)C1=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
1-(4-Chloro-phenyl)-2-oxo-cyclohexyl-acetonitrile (100 mg, 0.40 mmol) was dissolved in chloroform (1 mL). To this solution bromine (67.7 mg, 0.42 mmol) in chloroform (0.5 mL) was added drop wise at −11° C. The reaction was stirred for 1½ hours at 5° C., then for 1 hours t room temperature and finally for 1 hour at 50° C. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane as eluent to yield the title compound (104 mg, 79%) as colourless oil. NMR (CDCl3, 300 MHz): δ (ppm)=7.44 (d, 2H), 7.13 (d, 2H), 4.62 (dd, 1H), 2.99 (m, 2.80 (s, 2H), 2.58 (m, 1H), 2.14 (m, 1H), 1.92 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:15]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)[N:5]=2)=[O:17])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: COc1cccc(-n2nc(C(=O)O)cc2O)c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(OC)c3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 150 mg of 5-Hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid and 220 mg of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 98 mg of HOBT and 122 mg of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[CH2:14][C:15](Cl)=[O:16].[Cl-].[Cl-].[Cl-].[Al+3].[CH2:22]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C.ClCCl.C(=S)=S>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:15](=[O:16])[CH2:14][N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC#N
Solvent: S=C=S
Product: CC(=O)N1CCc2cc(C(=O)CN(Cc3ccccc3)Cc3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
1-Acetylindoline (16.1 g, 0.1 mol) and chloroacetylchloride (14.0 g, 9.6 mL, 0.12 mol) were added to carbon disulfide (200 mL) and heated to 40° C. Aluminium trichloride (42 g, 0.315 mol) was added portionwise to the mechanically stirred solution. After the addition was complete, the mixture was refluxed for 2 hours. The carbon disulfide was decanted and the remaining traces of carbon disulfide were evaporated using a stream of nitrogen while stirring the mixture (1 hour). Ice was added (exothermic!) to the dark green slurry with stirring under nitrogen. The ice mixture was stirred until a white homogenous mixture was obtained. The solid (32 g) was collected, washed with water, dried in air and reacted as such with dibenzylamine (60 g, 0.31 mol) at reflux temperature in dry acetonitrile (650 mL) overnight. The resulting mixture was cooled (10° C.) and dichloromethane (650 mL) was added. The precipitate was filtered, and the filtrate was concentrated to dryness. The residue was triturated with diethyl ether to afford a yellow solid (34.24 g) of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-[bis(phenylmethyl)amino]-ethanone: mp 130° C. (crystallized from ethyl acetate) and NMR (CDCl3) δ 2.2(s, 3H), 3.1(t, 2H), 3.7(s, 6H), 4.05 (t, 2H), 7.4 (m, 13H).