Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][C:26]1[C:31](=[O:32])[C:30]([CH3:33])=[C:29]([CH3:34])[C:28](=[O:35])[C:27]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=1)[C:42](O)=[O:43]>C(Cl)Cl>[Cl:8][C:3]1[C:2]([NH:1][C:42](=[O:43])[C:41]2[CH:45]=[C:37]([CH2:36][C:27]3[C:28](=[O:35])[C:29]([CH3:34])=[C:30]([CH3:33])[C:31](=[O:32])[C:26]=3[CH3:25])[CH:38]=[CH:39][C:40]=2[O:46][C:47](=[O:49])[CH3:48])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)Nc1cccnc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
3-Amino-2-chloropyridine (0.141 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (2:1) to obtain the titled compound (0.149 g, 0.329 mmol, 45%).
Reaction SMILES: CC(C)([O-])C.[C:6]([OH:9])(=[S:8])[CH3:7].[CH2:10]([O:13][C:14]([N:16]1[CH2:20][C@H:19](OS(C)(=O)=O)[CH2:18][C@H:17]1[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][C:28]1=[O:34])=[O:15])[CH:11]=[CH2:12].O>CN(C)C=O>[C:6]([S:8][C@@H:19]1[CH2:20][N:16]([C:14]([O:13][CH2:10][CH:11]=[CH2:12])=[O:15])[C@H:17]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][C:28]2=[O:34])[CH2:18]1)(=[O:9])[CH3:7]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN1CCN(C)CC1=O

Procedure:
To a solution of pottasium t-butoxide (1.24 g) in N,N-dimethylformamide (15 ml) was dropwise added thioacetic acid (0.85 ml) under ice cooling with stirring. The mixture was stirred at the same temperature for 30 minutes. To the solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g) in N,N-dimethylformamide (15 ml) was added the mixture obtained above at ambient temperature with stirring. The mixture was stirred at 80°-90° C. for 1.5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1 v/v) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methylpyrrolidine (3.24 g).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[N:17]=[CH:18][N:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][N:22]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=[N:12]2)=[CH:7][CH:6]=1>O.C1COCC1.CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[N:17]=[CH:18][N:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A solution of lithium hydroxide monohydrate (62 mg, 1.46 mmol) in water (2.8 mL) was added dropwise to a suspension of methyl 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinate (277 mg, 0.732 mmol) in THF (4.8 mL) and methanol (1 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (245 mg, 92%) as a light brown solid. MS: m/e=363.2 [M−H]−.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[C:5]1\[C:6](=[O:14])[NH:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:3].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)/[C:5](=[CH:4]/[N:2]([CH3:1])[CH3:3])/[C:6]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C1\C(=O)Nc2ccccc21
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)/C=C1\C(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one (iii-a, 626 mg, 3.33 mmol) in DMF (10 mL) was added Nail (151 mg, 6.29 mmol) and the reaction was stirred at RT. After 10 min, benzyl bromide (500 μL, 4.20 mmol) was added and the mixture was stirred under an atmosphere of Ar for 22 h. The reaction was quenched with a few drops of water and poured into a separatory funnel containing EtOAc (150 mL) and was washed with water (2×100 mL), followed by brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hexane) to yield (3Z)-1-benzyl-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iv-a, 660 mg, 71%). N′H4OAc QC conditions. DAD Retention Time=1.71 min. M+H=279.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][C@H:13]1[CH2:14][CH2:15][C@@H:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18]1
Reactant: Cc1nc(O[C@H]2CC[C@@H](C(C)C)CC2)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nc(O[C@H]2CC[C@@H](C(C)C)CC2)c(Br)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
To a stirred solution of 3-bromo-2-(cis-4-isopropylcyclohexoxy)-6-methyl-5-nitro-pyridine (22.59 g, 63.24 mmol) in EtOH/H2O (600 mL/150 mL, 4/1 v/v), ammonium chloride (3.45 g, 63.24 mmol, 1.0 eq) and iron powder (14.27 g, 253.0 mmol, 4 eq) were added at room temperature under inert atmosphere (Ar). The reaction mixture was stirred for 3 h under heating to reflux. As TLC indicated that the starting material was consumed at this point in time, the reaction mixture was cooled to room temperature and filtered through a pad of celite. The resulting filtrate was concentrated in vacuo and the residue partitioned between a 2 molar aqueous NaOH solution (100 mL) and ethyl acetate (150 mL). After phase separation, the aqueous phase was extracted once more with ethyl acetate (2×100 mL). The organic layer was washed with brine (400 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to afford the title compound (21.01 g, 101%) in the form of an oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]([O:34][CH3:35])=[O:33])[C:18]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:35][O:34][C:32]([C:28]1[S:29][CH:30]=[CH:31][C:27]=1[N:17]([C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:33]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1

Procedure:
Hydrogenation of 4-[(2-methoxycarbonyl-thiophen-3-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid benzyl ester (3.0 g, 6.02 mmol)with Pd/black in EtOAc was carried out for 36 h at 40 psi was carried out as described for example 19, step III gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (1.0 g, 45.6%). NMR 1H (CDCl3, 400 MHz): 7.525 (d, J=5.3, 1H), 6.84 (d, J=5.3, 1H), 4.674 (tt, 1H), 3.81 (s, 3H), 3.1-2.94 (m, 2H), 2.74-2.6 (m, 2H), 2.26-2.2 (m, 1H), 1.9-1.0 (m, 11H), 0.75 (d, J=6.6, 3H), 0.7-0.5 (m, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=3)[CH:23]=2)[C:18]([O-])=O)=[CH:11][CH:10]=1)=[CH2:8].[OH-].[Na+].C(C1C=CC(COC2C=C(C=C(OCC3C=CC(C=C)=CC=3)C=2)CO)=CC=1)=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:86]>C1COCC1.CCCCCC.CC(C)=O.C(OCC)C.O.CCCCCC>[CH:7]([C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=3)[CH:23]=2)[CH2:18][Br:86])=[CH:11][CH:10]=1)=[CH2:8]
Reactant: C=Cc1ccc(COc2cc(OCc3ccc(C=C)cc3)cc(C(=O)[O-])c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: C=Cc1ccc(COc2cc(CO)cc(OCc3ccc(C=C)cc3)c2)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(COc2cc(CBr)cc(OCc3ccc(C=C)cc3)c2)cc1

Procedure:
A 1 L flask is charged with 10.0 g (268.6 mmol, 2.3 eq) of LiAlH4 in THF (250 ml) under an argon atmosphere. The resultant solution is cooled with an ice bath and 46.9 g (116.9 mmol) of ester (2A) in THF (250 ml) is added dropwise with stirring and the mixture, stirred over a 2 hour period. Thereafter water (10 ml) and 15% NaOH (10 ml) and finally water (24 ml) is added to the mixture. The grey precipitate is filtered and the filtrate is washed with diethylether. Thereafter water (500 ml) is added and the organic phase is collected. The remaining aqueous phase is further extracted with diethylether (3×500 ml) and the organic phases are collected and combined, dried over MgSO4 and evaporated to dryness. A colourless oil is obtained (38.7 g, 88.5%). Addition of a little hexane effects precipitation of white crystals of 3,5-di(4-vinylbenzyloxy)benzylalcohol (2B). A 1 L flask is charged with 64.5 g (173 mmol) of (2B) in THF (250 ml) under an argon atmosphere. Thereafter, 68.1 g (260 mmol, 1.5 eq) of PPh3 and then 86.2 g (260 mmol, 1.5 eq) of CBr4 are added and the resultant mixture stirred gently for 1 hour in an ice bath whereupon a milky suspension is obtained. To this suspension is added water (600 ml) and diethylether (400 ml). The organic phase is collected and the aqueous phase is further extracted with diethylether (2×500 ml). The organic phases are collected and combined, dried over MgS04 and evaporated to dryness. A yellow oil is obtained which is dissolved in hexane/acetone 9:1 and filtered over Kieselgel. The resultant solution is left to recrystallise to yield fine white crystals of 3,5-di(4-vinylbenzyloxy)benzylbromide (2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-chloro-1-(1-methylethyl)-1H-indazole-4-carboxylate (0.22 g, 0.871 mmol) was dissolved in methanol (6 mL) and THF (1 mL), followed by addition of NaOH (1.451 mL, 4.35 mmol) via syringe. The contents were stirred at RT for 3 h. The volatiles were removed in vacuo, the contents diluted with water, and then slowly acidified to pH 4-5 by addition of 1M HCl (solid precipitation occurred). The contents were then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The collected solid was dried under hi-vac for 2 h, and collected as 0.19 g (90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (d, J=6.57 Hz, 6H) 5.09 (quin, J=6.57 Hz, 1H) 7.70 (d, J=1.52 Hz, 1H) 8.25 (s, 1H) 8.40 (s, 1H), 13.54 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH:39]2[CH2:44][CH2:43][CH:42]([C:45]3[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]4[C:46]=3[CH2:47][N:48]([CH3:56])[C:49]4=[O:55])[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:54][C:51]3[CH:52]=[CH:53][C:45]([C@H:42]4[CH2:43][CH2:44][C@H:39]([N:36]5[CH2:35][CH2:34][N:33]([C:30](=[O:32])[CH3:31])[CH2:38][CH2:37]5)[CH2:40][CH2:41]4)=[C:46]4[C:50]=3[C:49](=[O:55])[N:48]([CH3:56])[CH2:47]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CC(=O)N1CCN(C2CCC(c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](N5CCN(C(C)=O)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compounds were prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 4-[4-(4-acetyl piperazin-1-yl)cyclohexyl]-7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 237A). The reaction mixture was purified by MDP. Example 237 was first peak to elute. 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=6.95 Hz, 6H), 1.50-1.73 (m, 7H), 2.02 (s, 2H), 2.12 (s, 3H), 2.50 (br. s., 2H), 2.62 (br. s., 3H), 3.13-3.21 (m, 2H), 3.22 (s, 3H), 3.42-3.75 (m, 4H), 3.93 (s, 3H), 3.99-4.10 (m, 4H), 4.38 (s, 2H), 6.90 (dt, J=8.08, 2.15 Hz, 1H), 6.94 (t, J=2.02 Hz, 1H), 7.34 (d, J=8.84 Hz, 1H), 7.63 (s, 1H), 8.28 (d, J=7.58 Hz, 1H), 8.40 (s, 1H), 8.64 (d, J=8.59 Hz, 1H), 10.51 (s, 1H). MS (ES+): m/z 788.31 [MH+] (TOF, polar). Example 238 eluted afterwards: 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=7.07 Hz, 6H), 1.87 (d, J=4.04 Hz, 2H), 1.91-2.03 (m, 2H), 2.12-2.25 (m, 7H), 2.84 (br. s., 2H), 3.21 (s, 3H), 3.23-3.33 (m, 4H), 3.86 (s, 3H), 3.93 (br. s., 2H), 4.04 (qdd, J=7.31, 7.31, 7.31, 7.14, 1.77 Hz, 4H), 4.38 (s, 2H), 6.94-7.00 (m, 2H), 7.36 (d, J=7.83 Hz, 1H), 7.71 (br. s., 1H), 8.23 (br. s., 2H), 11.20 (br. s., 1H). MS (ES+): m/z 788.31 [MH+] (TOF, polar).
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].F[C:20]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=1[C:22]#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:20]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=2[C:22]#[N:23])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C#N)c(C)c1Cl
Yield: 58.7 %

Procedure:
A mixture of 4-chloro-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (1.5 g, 5.5 mmol), 2-fluoro-5-methoxybenzonitrile (1.1 g, 7.2 mmol), and cesium carbonate (1.8 g, 5.5 mmol) in dimethylformamide (5 mL) was microwaved at 130° C. for 30 minutes. The solvent was removed in vacuo. The crude material was eluted through a silica gel column with a 0 to 70% ethyl acetate/heptane gradient to afford the title compound (1.3 g, 59% yield) as a white solid. MS (ESI) [m/e, (M+H)+]=403.5. 1H NMR (400 MHz, chloroform-d) δ ppm 7.32 (d, J=8.5 Hz, 1H), 7.18-7.22 (m, 1H), 7.12-7.18 (m, 1H), 3.84 (s, 3H), 3.41-3.51 (m, 2H), 3.32-3.41 (m, 2H), 2.15 (s, 3H), 1.54-1.66 (m, 2H), 1.48 (qd, J=7.7, 7.5 Hz, 2H), 1.26-1.40 (m, 2H), 1.17 (ddd, J=14.9, 7.4, 7.3 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H), 0.77 (t, J=7.3 Hz, 3H).
Reaction SMILES: NC1C=CC(C(F)(F)F)=CC=1N[C:13]([C:15]1[N:16]=[C:17]([NH:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[S:18][CH:19]=1)=[O:14].NC1C=C(C(F)(F)F)C=CC=1NC(C1N=C(NC2C(Cl)=CC=CC=2Cl)SC=1)=[O:42]>>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:17]1[S:18][CH:19]=[C:15]([C:13]([OH:14])=[O:42])[N:16]=1
Reactant: Nc1cc(C(F)(F)F)ccc1NC(=O)c1csc(Nc2c(Cl)cccc2Cl)n1
Reactant: Nc1ccc(C(F)(F)F)cc1NC(=O)c1csc(Nc2c(Cl)cccc2Cl)n1
Product: O=C(O)c1csc(Nc2c(Cl)cccc2Cl)n1

Procedure:
N-[2-Amino-5-(trifluoromethyl)phenyl]{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}carboxamide and N-[2-amino-4-(trifluoromethyl)phenyl]{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}carboxamide. According to the procedure described in step (f) of Example 11, the title compounds were obtained from 2-[(2,6-dichlorophenyl)amino]-1,3-thiazole-4-carboxylic acid (339 mg, 1.18 mmol, prepared analogously to the procedures described in Example 3) and 4-(trifluoromethyl)-1,2-phenylenediamine (207 mg, 1.18 mmol, Lancaster) as a light brown solid. MS (ESI, pos. ion) m/z: 447 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2].[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:37]4[S:36][CH:40]=[CH:39][N:38]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2]
Reactant: Nc1nccs1
Reactant: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (67.07 mg, 0.132 mmol), thiazol-2-amine (13.26 mg, 0.132 mmol), and THF (662 μl) to give a clear, colorless solution. The vial was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (265 μl, 0.265 mmol) was added drop wise. After 20 min, the mixture was loaded onto a 5-g silica gel loading column with DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 12-g column with 0 to 10% MeOH/DCM to give 1-(4-cyano-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (56.25 mg, 0.133 mmol, 101% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.70 (d, J=5.7 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.87 (dd, J=1.9, 8.8 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.56-7.52 (m, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.88 (d, J=4.6 Hz, 1H), 3.72 (s, 3H); m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH3:13][NH:14][CH3:15]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:14]([CH3:15])[CH3:13]
Reactant: CNC
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Product: CN(C)CC(=O)c1ccc(Cl)cc1Cl

Procedure:
In a manner similar to Preparation 40 react 2-bromo-1-(2,4-dichlorophenyl)ethanone with dimethylamine to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH:23][C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:23]([CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)[C@@H:24]([CH3:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1ccc(CCN[C@@H](C)Cc2ccccc2)cc1OC
Product: COc1ccc(CCN(C(=O)c2cccc(Br)c2)[C@@H](C)Cc2ccccc2)cc1OC

Procedure:
The title compound was prepared from 3-bromobenzoyl chloride and (S)-[2-(3,4 dimethoxyphenyl)ethyl]-(1-methyl-2-phenylethyl)amine D8 according to a procedure similar to that for Example 76.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][OH:51])[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][OH:51])[CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
A mixture of Intermediate 81d (319 mg, 0.85 mmol), Intermediate 29c (335 mg, 0.85 mmol) and DIPEA (294 μL, 1.69 mmol) in dioxane (10 mL) was stirred at 80° C. for 18 hours. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (362 mg, 66%). LCMS (Method 4): Rt 3.29 min, m/z 649 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Br:16]Br.O>ClCCCl>[Br:16][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:2]([CH3:1])[CH:7]=1
Reactant: BrBr
Reactant: CCCCCCOc1cc(C)ccc1C
Solvent: O
Solvent: ClCCCl
Product: CCCCCCOc1cc(C)c(Br)cc1C
Yield: 97.6 %

Procedure:
In 250 g of ethanol were dissolved 250 g (2.05 mol) of 2,5-dimethylphenol (or p-xylenol), 90 g (2.25 mol) of sodium hydroxide and 371 g (2.25 mol) of n-hexyl bromide. The solution was heated for 2 hours in an oil bath at 80° C. Water, 500 g, was added to the reaction mixture, from which an oily matter was separated. Vacuum distillation of the oily matter yielded 384 g of 2,5-dimethyl-1-n-hexyloxy-benzene. Next, 129 g (0.625 mol) of 2,5-dimethyl-1-n-hexyloxybenzene was dissolved in 625 g of 1,2-dichloroethane. To the solution kept in an ice bath, 100 g (0.625 mol) of bromine was added dropwise at a temperature below 5C. At the end of dropwise addition, 500 g of water was added. The organic layer was separated therefrom and washed with 300 g of an aqueous solution of 5 wt % sodium hydrogen carbonate. The organic layer was concentrated to remove the solvent, leaving an oily matter. Vacuum distillation (boiling point 114-124° C./0.5 Torr) of the oily matter yielded 174 g of 4-bromo-2,5-dimethyl-n-hexyloxybenzene.