Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[H-].[Na+].[CH3:26]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN1C(=O)COc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1ccc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=406.1 [M−H+].
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH3:27].C(Br)(Br)(Br)Br.[CH2:33]([O:40][P:41]([O-:50])[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[P:41]([O:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[C:7]([C:12](=[O:13])[C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH3:27])([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:50]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: COc1cc(C(=O)c2c(C)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Agent: BrC(Br)(Br)Br
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2c(C)oc3c(OP(=O)(OCc4ccccc4)OCc4ccccc4)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a mixture of 0.081 g (0.22 mmol) of (7-hydroxy-6-methoxy-2-methylbenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone, 0.086 g (0.261 mmol) of carbon tetrabromide and 0.063 ml (0.283 mmol) of dibenzylphosphite in 2.5 ml of anhydrous acetonitrile 0.046 ml of anhydrous triethylamine was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature, then diluted to 20 ml with ethyl acetate, washed with water brine, dried over anhydrous magnesium sulfate, filtered off and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/ethyl acetate, 9:1) to give the title compound as a colorless foam (0.13 g, 94%); 1H NMR (CDCl3) δ 2.42 (s, 3H, Me-2); 3.83 (s, 1H, OMe); 3.93 (s, 3H, OMe); 5.33 (m, 4H, CH2Ph); 6.89 (d, CH aromatic, J=8.7 Hz); 7.21 (dd, 1H, CH aromatic, J=8.72 Hz; J=1.2 Hz); 7.08 (s, 2H, CH aromatic); 7.29-7.43 (m, 10H, CH aromatic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6].CI.[C:23](=O)([O-])O.[Na+].CN(C)P(=O)(N(C)C)N(C)C>O>[CH3:23][NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6]
Reactant: Nc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Solvent: O
Product: CNc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulfamylbenzyl alcohol (8.8 g; prepared as described in Example 2), methyl iodide (2.1 ml), sodium hydrogen carbonate (5.0 g) and hexamethylphosphoric triamide (45 ml) is stirred at 22°-25° C. for 18 hours. The mixture is then diluted with water (about 500 ml) to precipitate crude 3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol. After recrystallization from aqueous ethanol it is obtained with a melting point of 167°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N+:6]([O-:18])[CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
5-Bromo-pyridin-2-yl-methanol (6.0 g, 31.9 mmol) was dissolved in dichloromethane (80 ml) and cooled to 0° C. A solution of 3-chloroperbenzoic acid (8.26 g, 47.9 mmol) in dichloromethane (20 ml) was slowly added, the ice bath was removed after completion of the addition, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed and the crude product was purified by silica gel chromatography using ethyl acetate to yield 3.68 g (56%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)[C:11](=[O:25])[N:10]([CH2:26][C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)[CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:11](=[O:25])[N:10]([CH2:26][C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CN2CC(c3ccc(F)cc3)C3(CCCN(C(=O)OC(C)(C)C)C3)C2=O)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CN2CC(c3ccc(F)cc3)C3(CCCNC3)C2=O)no1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 4-(4-fluorophenyl)-2-((5-methylisoxazol-3-yl)methyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (243.6 mg; 0.549 mmol) was solubilised in DCM (1 ml). Trifluoroacetic acid (0.86 ml; 11.14 mmol) was added and the mixture stirred at RT for 20 minutes before being concentrated in vacuo. The oil was dissolved with methanol (5 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (50 ml) and concentrated in vacuo to yield the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.CO.C1COCC1.CO.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([N+:50]([O-])=O)[NH:48][CH:49]=2)[CH2:40][CH2:39]1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([NH:50][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[F:27])=[CH:14][CH:15]=3)=[O:3])[NH:48][CH:49]=2)[CH2:40][CH2:39]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCN(C)CC4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 524.1 [M+H]+; tR=3.03 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.I[CH2:26][CH:27]([CH3:29])[CH3:28].[CH2:30]([O:37][C:38](=[O:70])[NH:39][C:40]1[N:69]=[C:43]2[N:44]([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=3)[C:45]([CH3:58])=[C:46]([C:56]#[N:57])[C@@H:47]([C:48]3[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=3)[N:42]2[N:41]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C>CN(C=O)C>[CH2:30]([O:37][C:38](=[O:70])[N:39]([C:40]1[N:69]=[C:43]2[N:44]([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=3)[C:45]([CH3:58])=[C:46]([C:56]#[N:57])[C@@H:47]([C:48]3[CH:49]=[CH:50][C:51]([C:54]#[N:55])=[CH:52][CH:53]=3)[N:42]2[N:41]=1)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)CI
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 μmol, 2.1 eq.), 18-crown-6 (30 mg, 113 μmol, 2.1 eq.) and 1-iodo-2-methylpropane (21 mg, 113 μmol, 2.1 eq.) were added to a solution of benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid (3 eq.) and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 76% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCCC1CC(c2ccc(F)cc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCCC2CC(c3ccc(F)cc3)=NO2)CC1
Yield: 63.7 %

Procedure:
4-[3-(4-Fluorophenyl)-4,5-dihydroisoxazol-5-yl]butanal (22.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 μL, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.8 mg (70.4%) of the target compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:36]([CH3:35])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N(C)c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and N-methylaniline.
Reaction SMILES: [CH2:1](O)C.C[O-].[Na+].[N:7]1[CH:8]=[CH:9][N:10]2[C:16]=1[CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[NH:12][C:11]2=[S:21].CI>O>[CH3:1][S:21][C:11]1[N:10]2[CH:9]=[CH:8][N:7]=[C:16]2[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1
Reactant: S=C1Nc2ccccc2Cc2nccn21
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSC1=Nc2ccccc2Cc2nccn21

Procedure:
Absolute ethanol (20,000 ml) was charged into a 20 gallon flask and stirred under nitrogen atmosphere; 517.62 g (9.58 moles) of sodium methoxide were added. After stirring for 30 minutes there was complete solution and 2,063 g (9.58 moles) of 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione were added. There was complete solution after stirring at room temperature for 1 hours. The solution was then cooled to 1°, and 1,360 g (9.58 moles) of methyl iodide were added over 30 minutes. The reaction mixture was stirred at 5° for 4 hours and at ambient temperature overnight. The turbid solution was then cooled to 5° and diluted with 50,000 ml of water. The resulting suspension was stirred for 4 hours at 5°. The solid was collected, and dried (5 mm Hg/60°) to give 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine, m.p. 87°-8°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[N:3]1.C(N=C=NC(C)C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CN(C1C=CC=CN=1)C.[NH:44]1[CH2:47][CH2:46][C@H:45]1[C:48]([O:50][CH3:51])=[O:49]>ClCCl>[CH3:51][O:50][C:48]([C@@H:45]1[CH2:46][CH2:47][N:44]1[C:8]([C:4]1[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=1)=[O:10])=[O:49]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: Cc1cc(C(=O)O)nn1C
Agent: CC(C)N=C=NC(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1C(=O)c1cc(C)n(C)n1
Reaction time: 24 h
Yield: 58.6 %

Procedure:
To a mixture of the 1,5-dimethylpyrazole-3-carboxylic acid (433.1 mg, 3.09 mmol, 1.0 eq), diisopropylcarbodiimide (0.74 mL, 4.73 mmol, 1.5 eq), camphorsulfonic acid (300.6 mg, 1.29 mmol, 0.4 eq) and dimethylaminopyridine (129.7 mg, 1.06 mmol, 0.3 eq) in dry dichloromethane (30 mL) was added (2S)-methyl azetidine-2-carboxylate (474.4 mg, 3.13 mmol, 1.0 eq) in dry dichloromethane (12 mL) at about room temperature. The mixture was stirred at about room temperature for about 24 hours under argon. The solid was filtered off and washed with ether. The organic filtrate was concentrated and the residue subjected to flash chromatography (1-10% methanol in dichloromethane) to give 429.9 mg (58% yield) of the product. 1H NMR (CDCl3) δ 2.22-2.77 (series of s and m, 5H); 3.64-3.84 (series of s, 6H); 4.08-4.73 (series of m, 2H); 4.89 and 5.29 (dd, 1H, J=9.4, 6.0); 6.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[N:11]([CH3:12])[C:10](=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][N:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CN1C(=O)CCC1Cc1ccc(N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC1Cc1ccc(N)cc1
Temperature: 0 °C

Procedure:
Boil 2.04 g of 5-(4-aminobenzyl)-1-methylpyrrolidin-2-one and 0.7 g of lithium aluminum hydride under reflux for 20 hours in 20 ml of tetrahydrofuran. Decompose the resulting reaction product by admixing it with ice water. After adding 10 ml of 6 N sodium hydroxide solution to the decomposed product, extract it with diethyl ether. Dry the ether extract over sodium sulfate and concentrate it to obtain the title compound in free-base form. Convert the thus-obtained base into the dihydrochloride [m.p. (from methanol/ether)>242° (decomp.)] with methanol/ethereal hydrochloric acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:39])[N:15]([C:25]2[CH:29]=[C:28]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])[S:27][C:26]=2[C:36]([OH:38])=[O:37])[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:33][C:32]([CH3:34])([CH3:35])[C:31]#[C:30][C:28]1[S:27][C:26]([C:36]([OH:38])=[O:37])=[C:25]([N:15]([C:16]([CH:18]2[CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH2:23]2)=[O:17])[N:14]([CH3:39])[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:29]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)N(C)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)N(C)C2CCNCC2)CC1
Yield: 0 %

Procedure:
Crude 4-[N′-[2-carboxy-5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-N-methyl-N′-(4-methyl-cyclohexanecarbonyl)-hydrazino]-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 500 mmol) (Example 127) was treated with TFA (3 mL, 4.6 mmol) at 60° C. for 10 min. After cooling, toluene (2-3 mL) was added and the mixture was concentrated, this was repeated several times, and a portion of this crude material was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-95% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 20 mg of the title compound as a white powder (bis-TFA salt): MS (m/z): 460.2 [M−H]+; HPLC retention time: 3.15 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:15]C(OCC1C=CC=CC=1)=O)[CH2:5][O:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8].N>CO.[Pd]>[NH2:15][C@@H:4]([CH2:5][O:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:2]
Reactant: COC(=O)[C@H](COC(C)c1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(OC[C@H](N)CO)c1ccccc1
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a solution of (S)-2-benzyloxycarbonylamino-3-(1-phenyl-ethoxy)-propionic acid methyl ester (1.1 g) in methanol (5 ml) were added ammonia in methanol (7 N solution, 0.22 ml) and palladium on charcoal (5%, 110 mg). The mixture was stirred vigorously under an atmosphere of hydrogen for 30 min. The catalyst was filtered off and the filtrate was evaporated. The crude product was purified by column chromatography (SiO2; dichloromethane/MeOH=98:2) to give (R)-2-amino-3-(1-phenyl-ethoxy)-propan-1-ol (280 mg, 86%) as a light yellow liquid. MS (ISP): 224.2 ([M+H]+)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH:10][C:11]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:12]=2[C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.Cl[CH2:23][C:24](=[O:26])[CH3:25]>CN(C=O)C>[O:26]=[C:24]([CH3:25])[CH2:23][O:14][C:13](=[O:15])[C:12]1[C:16]([F:21])=[CH:17][C:18]([F:20])=[CH:19][C:11]=1[NH:10][CH:7]1[CH2:8][CH2:9]1
Reactant: CC(=O)CCl
Reactant: O=C(O)c1c(F)cc(F)cc1NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COC(=O)c1c(F)cc(F)cc1NC1CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (2.3 g, 16.7 mmol) was added to a solution of example 6a (5.1 g, 23.8 mmol) in DMF (20 mL). The reaction mixture was stirred at 90° C. for 1 h. Chloroacetone (2.21 g, 23.8 mmol) was then added dropwise at room temperature and the reaction mixture was heated at 55° C. for 1.5 h. The reaction mixture was poured into ice. The precipitate was collected by filtration to give 6.53 g (quantitative) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.66 (s, 1H), 6.69 (dd, 1H, J=12.0, 1.2 Hz), 6.49 (dt, 1H, J=12.0, 1.2 Hz), 5.02 (s, 2H), 3.34-3.40 (m, 1H), 2.15 (s, 3H), 0.81-0.85 (m, 2H), 0.48-0.52 (m, 2H). MS (ES) [m+H] calc'd for C13H13F2NO3, 269; found 269.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21](=[O:23])[CH3:22])[O:11][N:10]=1)C>Cl>[C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:24])=[O:3])[CH:13]=1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2NC(C)=O)on1
Agent: Cl
Product: CC(=O)Nc1ccccc1-c1cc(CCCCC(=O)O)no1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Add 2N HCl solution (100 mL, in water) to 5-[5-(2-acetylamino-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (4.02 g, 12.2 mmol) and heat to reflux under N2 overnight Cool to room temperature and concentrate to afford the title compound (3.46 g, 96% yield). MS (IS) 259 (M−1)−.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:28]([S:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O)([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+]>CCOCC>[CH:28]([S:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=[CH2:2])([CH3:30])[CH3:29]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Sc1ccccc1C=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1ccccc1SC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 mL ether in a 50 mL round-bottomed flask at 0° C. under dry nitrogen. To the mixture was added in one portion potassium tert-butoxide (0.47 g, 4.16 mmol) and it was stirred for 10 min at room temperature. 2-(isopropylsulfanyl)benzenecarbaldehyde (0.50 g, 2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred for additional 24 h at room temperature. The mixture was added to 50 mL of saturated sodium bicarbonate solution, and then was extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The light yellow oil of the crude product was further purified by chromatography on silica gel using 95:5 petroleum ether 60-80 and ether as eluent to give a colorless oil (0.40 g, 81%).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C.[CH2:33]([C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].NC1C=CC=CC=1>C(#N)C>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[CH2:33]([C:43]1[CH:44]=[CH:45][C:46]([N+:47]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:48][CH:49]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCc1ccc(N)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: O=S(=O)([O-])O
Solvent: CCO
Solvent: CC#N
Solvent: Nc1ccccc1
Product: CCCCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
In a 500-ml round-bottom flask is placed 2.03 g (0.005 mole) of 2,4,6-triphenylpyrylium bisulfate. To this is added 150 ml of ethanol followed by 2.34 g (0.01 mole) of p-decylaniline. This mixture is refluxed for about 8 hours and allowed to cool. A quantity of the starting aniline precipitates and is removed by filtration. The ethanol is then removed to give a yellow waxy material which is washed with ether to give a white powder. This material is then dissolved in acetonitrile to cause the remaining aniline to precipitate. The acetonitrile is removed to give the desired product which is then rinsed with ether to remove any residual acetonitrile. The yield is 1.77 g (0.0028 mole) of 2,4,6-triphenylpyridinium bisulfate as confirmed by nuclear magnetic resonance (1H) and elemental analysis.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([N:21]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.N1C=CC=CC=1.N1(C2C=CN=CC=2)CCCC1.[C:44](Cl)(=[O:47])[O:45][CH3:46]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([C:15]2[C:16]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:44](=[O:47])[O:45][CH3:46])[CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:14]1
Reactant: NC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reactant: COC(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (0.0974 g, 0.281 mmol), pyridine (commercially available through Aldrich, 0.045 ml, 0.562 mmol), and 4-(pyrrolidin-1-yl)pyridine (PPY) (commercially available through Alfa Aesar, 0.042 g, 0.281 mmol) to stir at RT in DCM (0.937 ml). Methyl carbonochloridate (commercially available through Aldrich, 0.027 ml, 0.422 mmol) was added and allowed to stir overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage 50 g SNAP HP-silica column, eluting with a gradient of 1% to 6% MeOH in CH2Cl2, to provide methyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate.