Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>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.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), Cul (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[C:16]=3[N:15]=[C:14]([NH2:26])[N:13]=2)(=O)=O)=CC=1.[ClH:27]>C(Cl)Cl.O1CCOCC1>[Cl:27][C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:16]=2[N:15]=[C:14]([NH2:26])[N:13]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reactant: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nc(Cl)c2c(n1)C1(CCCC1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 1D (300 mg, 0.803 mmol) in CH2Cl2 (10 mL) was added HCl in dioxane (0.6 mL, 4M), and the mixture stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel, eluting with 5-20% EtOAc/hexane, to provide the title product. 1H NMR (300 MHz, CDCl3) δ 4.79 (s, 2 H), 2.60 (t, J=6.35 Hz, 2 H), 2.02-2.13 (m, 2 H), 1.82-1.92 (m, 2 H), 1.63-1.79 (m, 6 H), 1.55-1.62 (m, 2 H). MS (DCI+) m/z 357 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C@@H:18]([NH2:20])[CH3:19])=[C:14]([CH:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[CH:13]=1.[CH3:29][C:30]1[N:31]=[CH:32][N:33]([C:35]2[C:44](=[O:45])[N:43]3[C:38]([C:39](=[O:46])[O:40][CH2:41][CH2:42]3)=[CH:37][CH:36]=2)[CH:34]=1>O1CCCC1>[F:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:39]([C:38]2[N:43]([CH2:42][CH2:41][OH:40])[C:44](=[O:45])[C:35]([N:33]3[CH:34]=[C:30]([CH3:29])[N:31]=[CH:32]3)=[CH:36][CH:37]=2)=[O:46])[CH3:19])=[C:14]([CH:23]([CH3:28])[C:24]([F:25])([F:26])[F:27])[CH:13]=1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Reactant: CC(c1cc(F)ccc1OC[C@H](C)N)C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc(C(=O)N[C@@H](C)COc3ccc(F)cc3C(C)C(F)(F)F)n(CCO)c2=O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminum hydride (1.5 M in toluene, 1.63 mL, 2.44 mmol) was added to a solution of (2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-amine (P13) (fractions that were enriched in the lower Rf diastereomer were used, see step 4 of Preparation 13; 324 mg, 1.22 mmol) in tetrahydrofuran (5 mL). After the vigorous bubbling subsided, the reaction mixture was stirred for 2 hours at room temperature. 7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (299.7 mg, 1.222 mmol) was added, and the reaction mixture was heated to 60° C. for 24 hours. It was then cooled to room temperature, carefully quenched with 1 M aqueous sodium hydroxide solution, and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a sticky orange-tan oil. This was used in the following step without additional purification. Yield: 430 mg, 0.84 mmol, 69%. LCMS m/z 511.3 (M+1). On large scale, use of diisobutylaluminum hydride was less successful; in this case, simply dissolving P13 and P14 in methanol, boiling the solution down to a thick homogeneous oil and heating at 110° C. provided superior results.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([I:10])[CH:3]=1.Br>C(O)(=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([I:10])[CH:3]=1
Reactant: COc1cc(Br)cc(I)c1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)O
Product: Oc1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 352.9 %

Procedure:
1-Bromo-3-iodo-5-methoxy-benzene (6.29 g, 20.1 mmol) was suspended in a solution of hydrogen bromide in acetic acid (33%, 150 mL). Tetrabutylammonium bromide (0.5 g, 1.55 mmol) was added and the mixture was heated to reflux under vigorous stirring for 2 d. After cooling to room temperature the mixture was extracted with methylene chloride (3×100 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (300 g, AcOEt/heptane 1:9). 3-Bromo-5-iodo-phenol (21.2 g, 96%) was obtained as pale brown solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:24][CH3:25])[C:7]([O:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=3)[CH2:35][CH2:34]2)[CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.C(OC(C)C)(C)C>O.CN1CCCC1=O>[C:1]([C:4]1[N:5]=[C:6]([CH2:24][CH3:25])[C:7]([O:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1[NH:43][C:42]1[CH:44]=[CH:45][C:39]([N:36]2[CH2:37][CH2:38][CH:33]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH2:34][CH2:35]2)=[CH:40][CH:41]=1)(=[O:3])[NH2:2]
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: CC(C)OC(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 68.4 %

Procedure:
A mixture of tert-butyl (3R)-3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (90 mg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (210 mg), diisopropylethylamine (140 μL), and N-methylpyrrolidone (500 μL) was reacted using a microwave reaction device at 150° C. for 2 hours. The reaction mixture was left to be cooled, and then water and diisopropyl ether were added thereto. The insoluble matter was collected by filtration to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-ethyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (101 mg) as a yellowish brown solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:13][CH:12]=2)=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)(O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)(C)O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzoic acid (0.09 g, 0.5 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=30:1) to give the pure product (0.11 g, 76%) as a white solid. LRMS (M+H+) m/z: calcd for 314.16. found 314. HPLC Purity (214 nm) 100%. 1H NMR (300 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.28-8.26 (m, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 5.86 (s, 1H), 5.08 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.17 (s, 3H), 2.11 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](Cl)=[O:25]>ClCCCl>[F:20][C:21]1[CH:22]=[C:23]([C:24]([N:8]2[CH2:9][CH2:10][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:18][C:19]=3[CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCCl
Product: O=C(c1ccc(F)c(F)c1)N1CCc2c([nH]c3ccccc23)C1c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
The title compound was prepared by the addition of 1-phenyl-2,3,4,9-tetrahydro-1H-beta-carboline (95 mg, 383 μmol), DCE (5 mL), 3,4-difluorobenzoyl chloride (88 mg, 498 μmol), and TEA (1.0 mL) to a 25 mL flask. The solution was allowed to stir at 55° C. for 16 hours. The reaction solution was concentrated, and the crude sample was chromatographed (SiO2, 100% hexane to 25% EtOAc) to yield 53 mg of title compound; 1H NMR (CDCl3) δ 8.02 (1H, br s), 7.53 (1H, d), 7.30-7.33 (6H, m), 7.15-7.23 (5H, m), 7.07 (1H, br s), 3.75 (1H, m), 3.41 (1H, m), 2.93 (1H, m), 2.84 (1H, dd); MS(ESI): 389(MH+).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:7]=1[CH2:17][CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]([CH:24]=[C:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:22][CH:21]=1)(=[O:4])=[O:3].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH:9]=[CH:8][C:7]=1[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:32][CH:33]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c(OS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)c(OS(C)(=O)=O)c1
Yield: 76.2 %

Procedure:
0.718 g (1.4 mmole) 5-(4-[2-(2,4-dimethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated over night in 100 ml ethyl acetate and 1 ml acetic acid with 1.4 g Pd/C (10%) as catalyst. The catalyst was filtered off and the filtrate was washed with water, dried with magnesium sulfate and evaporated in vacuo to give 0.55 g (yield 76%) of the desired product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: COc1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 85 mg (0.561 mmol) of 3-methoxybenzoic acid, 143 mg (0.561 retool) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.45, FD-MS: M+ =561.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl.BrC1C=CC2C3SC(C(OC)=O)=CC=3CCOC=2C=1>ClCCl.CN(C)C=O.ClCCCl>[O:1]1[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=2
Reactant: O=C(O)CCCOc1ccccc1
Agent: COC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenol (3.16 g, 33.6 mmol) in acetonitrile, was added ethyl 4-bromobutyrate (4.8 ml, 33.6 mmol), potassium carbonate (4.64 g, 33.6 mmol) and tetrabutylammonium iodide (370 mg, 1 mmol). The reaction mixture was stirred vigorously and heated to reflux for 2 days before being cooled, filtered, dried (MgSO4) and concentrated in-vacuo to yield 4-phenoxy-butyric acid ethyl ester. 4-Phenoxy-butyric acid ethyl ester was hydrolyzed to its corresponding carboxylic acid using sodium hydroxide mediated hydrolysis to yield 4-phenoxy-butyric acid. To a solution of 4-phenoxy-butyric acid (7.67 g, 29.6 mmol) in anhydrous dichloromethane was added oxalyl chloride (4.4 ml, 50.3 mmol) and one drop of dimethyl formamide and the reaction mixture stirred at room temperature for 30 minutes. Reaction mixture was concentrated in-vacuo and the residue dissolved in 1,2-dichloroethane (90 ml). This solution was added drop wise to a suspension of aluminum trichloride (4.73 g, 35. 5 mmol) in 1,2-dichloroethane (50 ml) at 0° C. Reaction mixture was left stirring in ice bath which rose to room temperature overnight. The reaction mixture was poured over conc. hydrochloric acid (30 ml) stirred into 10 0 g ice, and then stirred for a further 90 minutes until the ice fully melted. The aqueous phase was washed with dichloromethane 3 times, before the organics were combined, dried (Na2SO4) and concentrated in-vacuo. Purification by triturating with diethylether gave 3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[CH2:15][OH:16].[Br:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20](F)[CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:16][CH2:15][C:9]2[C:8]([F:7])=[CH:13][CH:12]=[CH:11][C:10]=2[F:14])[CH:19]=1
Reactant: Fc1cc(Br)ccn1
Reactant: OCc1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1COc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
15.5 ml (15.5 mmol) of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise at 0° C. to a solution of 1.72 ml (15.5 mmol) of (2,6-difluorophenyl)methanol and 1.6 ml (15.5 mmol) of 4-bromo-2-fluoropyridine in 50 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: cyclohexane/ethyl acetate, gradient 0% to 100%). This gave 4.12 g of the target compound (88% of theory).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[C:20]=3[F:28])=[N:15]2)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:27][C:21]1[C:20]([F:28])=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:6]3[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[O:8][N:7]=3)=[O:10])[CH3:29])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3F)n2)no1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3F)n2)no1
Yield: 57.3 %

Procedure:
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-2-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide (0.04 g, 0.096 mmol) of Example 233 was reacted with sodium borohydride (0.007 g, 0.192 mmol) using the method of Example 84. Yield of the title compound 0.023 g. 1H NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 1.51 (dd, 3H), 4.38 (m, 2H), 4.59 (m, 1H), 4.94 (m, 1H), 6.52 (m, 1H), 6.77 (dd, 1H), 7.63 (m, 1H), 7.74 (m, 1H), 8.12 (m, 1H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH2:20][NH:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])[CH2:15]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([C:4]([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][NH:24][C:22]([NH:21][CH2:20][C@@H:16]3[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:12]4[CH:32]=[CH:33][C:34]([Cl:35])=[C:10]([Cl:9])[CH:11]=4)[CH2:15]3)=[O:23])[CH2:27][CH2:28]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(NCC1CCNCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCN(C(=O)C2CC2)CC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Cyclopropanecarbonyl chloride (0.014 ml) was added to a solution of Intermediate 18 (0.54 g) and N,N-diisopropylethylamine (0.063 ml) in dichloromethane (2 ml). The solution was stirred for 3 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo and the residue was further purified using a silica gel solid phase extraction cartridge (1 g Varian Bond Elut) eluting with 0–1% methanol in ethyl acetate, to give the title compound as a clear gum (0.023 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: COCCN
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCNc1ccc([N+](=O)[O-])c(N)c1
Temperature: 135 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (21.6 g, 125 mmol), 2-Methoxy-ethylamine (28.1 g, 375 mmol) and anhydrous potassium carbonate (18.9 g, 137 mmol) in N,N-dimethylacetamide (40 ml) was stirred at 135° C. under nitrogen for 2 days. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 30 minutes The resulting precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford N1-(2-methoxy-ethyl)-4-nitro-benzene-1,3-diamine (16 g, 61%) as a yellow-orange powder, and used in the next step without further purification.
Reaction SMILES: [CH3:1]N(N=O)C(N[N+]([O-])=O)=N.C(OCC)C.[OH-].[Na+].[S:18]1[C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1>C1COCC1>[CH3:1][O:28][C:27]([C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][S:18][C:22]=2[CH:23]=1)=[O:29]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2ncsc2c1
Yield: 102 %

Procedure:
Add 1-methyl-3-nitro-1-nitrosoguanidine (5.0 g, 33.9 mmol) to a mixture of diethyl ether (20 mL) and 1N aqueous NaOH (20 mL) at ambient temperature. Separate the organic layer and add it slowly to a solution of benzothiazole-6-carboxylic acid (1.0 g, 5.58 mmol) in THF (50 mL) at 0° C. Evaporate the solvent to obtain the desired intermediate as a yellow solid (1.1 g, 100%). MS (ES+) m/z: 194 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:26]([S-:28])#[N:27].[K+].BrBr>C(O)(=O)C>[OH:11][CH2:10][CH:9]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH:8]([OH:25])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:26]([NH2:27])[S:28][C:3]=2[CH:4]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(C(O)C(CO)N2CCC(Cc3ccccc3)CC2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(O)C(CO)N3CCC(Cc4ccccc4)CC3)cc2s1

Procedure:
To a stirred solution of 5 g of (+) three 1-p-aminophenyl-2-(4-benzylpiperidin-1-yl)-1,3 propandiol and 5.7 g of KSCN in 30 ml of glacial acetic acid was added dropwise a solution of 2.36 g of Br2 in 25 ml of glacial acetic acid at room temperature.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:32][CH2:31][CH:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:30][CH2:29]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)cc1
Reactant: NCC1CCN(c2ccncc2)CC1
Solvent: CCO
Product: COc1ccc(NC(=O)c2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 23.8 %

Procedure:
A pressure tube (Aldrich) was charged with 2-chloro-N-(4-methoxyphenyl)pyridine-3-carboxamide (139 mg, 0.524 mmol), 1-(4-pyridyl)piperidine-4-methylamine (100 mg, 0.524 mmol), triethylanine (0.22 mL), and ethanol (3 mL). The mixture was placed in a 110° C. bath for 5 days. The mixture was concentrated and the residue purified by RPHPLC, yielding 52 mg (24%) of the title compound as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)C(F)(F)F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CI.C([O-])(O)=O.[Na+]>O.CO.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH3:12])[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1cc(Br)sc1C(=O)OC
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate(same as methyl 5-bromo-3-(2,2,2-trifluoroacetamido)thiophene-2-carboxylate described in Step 2 of Example 34) (996 mg, 3.00 mmol), potassium carbonate (829 mg, 6.00 mmol), DMF (6 mL) and methyl iodide (0.225 mL, 3.60 mmol) was stirred at 60° C. for 4 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL). Extraction with EtOAc (100 mL), washing with saturated aqueous NaHCO3 and brine, drying over MgSO4, filtration and concentration under reduced pressure gave brown oil. This residue was mixed with potassium carbonate (415 mg, 3.00 mmol), MeOH (20 mL) and water (10 mL). The mixture was stirred overnight at room temperature. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL). Extraction with EtOAc (100 mL), washing with brine, drying over MgSO4, filtration and concentration under reduced pressure gave brown oil. This residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to afford the title compound (674 mg, 90%) as a white solid: