Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:27][C:28]([F:46])([F:45])[C:29]([C:32]1[CH:41]=[CH:40][C:39]2[CH2:38][C@@H:37]([C:42]([OH:44])=[O:43])[CH2:36][CH2:35][C:34]=2[N:33]=1)([CH3:31])[CH3:30].CI>C1COCC1>[CH3:2][C:37]1([C:42]([OH:44])=[O:43])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([C:29]([CH3:31])([CH3:30])[C:28]([F:27])([F:45])[F:46])[CH:41]=[CH:40][C:39]=2[CH2:38]1
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C(=O)O)CCc2nc(C(C)(C)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 34 %

Procedure:
A solution of LDA in THF (0.64 M, 4 mL, 2.56 mmol), prepared from N,N-diisopropylamine (358 μL, 2.56 mmol), 1.47 M of butyllithium in hexane (1.74 mL, 2.56 mmol) and THF (2 mL) was added dropwise to a 0° C. solution of (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (294 mg, 1.02 mmol) in dry THF (4 mL). After 2 min at 0° C., the dark red mixture was warmed to room temperature, and aged for 1 h, before recooling to 0° C. Neat methyl iodide (159 μL, 2.56 mmol) was added, and the mixture rapidly lightened to pale red. After 2 min at 0° C., the mixture was warmed to room temperature. After 1 h, the reaction was quenched by addition of water (5 mL), then partitioned between 1M KH2PO4 (30 mL) and DCM (40 mL). The aqueous layer was extracted with DCM (2×20 mL), the combined organic layers were dried (Na2SO4), filtered and concentrated to a yellow semi-solid, which was purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O). The combined purified fractions were concentrated to remove ACN, and the mixture buffered with 1M pH 6 phosphate buffer (30 mL), and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to afford the acid as a solid (104 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 10.76 (br s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 3.25 (d, J=16.6 Hz, 1H), 2.99 (br s with fine str, 2H), 2.66 (d, J=16.6 Hz, 1H), 2.27 (app dt, J=12.7, 5.9 Hz, 1H), 1.90 (app dt, J=13.8, 7.1 Hz, 1H), 1.58 (s, 6JH), 1.36 (s, 3H); m/z=302.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=1
Reactant: NCCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)NCCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a 0° C. solution of 5.24 g of 2-(2-aminoethyl)pyridine, 13.22 ml of pyridine and 50 ml of methylene chloride is added, dropwise, 15 g of product from Example 53 in 150 ml of methylene chloride. The reaction is stirred at 0° C. for 4 hours followed by 68 hours at room temperature. The reaction is diluted with chloroform, washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:75-100% ethyl acetate/hexane) to give 8.3 g of the desired product as colorless prisms.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1)(=[O:3])[CH3:2].[BrH:10].[Br:11]CC(C1C=C(C)C=CN=1)=O>>[BrH:11].[Br:10][CH2:2][C:1]([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1)=[O:3]
Reactant: CC(=O)c1nccn1C
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Product: Cn1ccnc1C(=O)CBr

Procedure:
* 2-bromoacetyl-1-methylimidazole hydrobromide was prepared from 2-acetyl-1-methylimidazole according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][CH:15](N)[CH2:16][OH:17]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:14][CH:15]1[CH2:16][O:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1
Reactant: CCCCCCCCCCCC#N
Reactant: CC(N)CO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCC1=NC(C)CO1
Yield: 91.9 %

Procedure:
10.9 g (60 mmoles) of undecyl cyanide was treated with 5 g (66.6 mmoles) of DL-2-amino-1-propanol in presence of 400 mg (1.5 mmoles) of cadmium acetate dihydrate in 1-butanol as outlined under Example 1. 13.2 g (92%) of product was obtained on distillation at 115°-117° C./1-1.5 mm Hg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:34][CH:35]1[CH2:39][CH2:38][CH2:37][NH:36]1>C(#N)C.C(OCC)(=O)C>[CH3:17][C:15]1[N:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:36]3[CH2:37][CH2:38][CH2:39][CH:35]3[CH3:34])=[CH:7][CH:8]=2)[S:13][C:14]=1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19]
Reactant: CC1CCCN1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1C(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(OCCCN3CCCC3C)cc2)sc1C(=O)N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 4-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}carbonyl)morpholine i107 (1.0 mmol, 1 eq, 0.38 g) in acetonitrile (10 ml), is added potassium carbonate (1.99 mmol, 2 eq, 0.27 g) and approximately 0.01 g of sodium iodide. The mixture is stirred at 80° C. for 30 minutes in a sealed tube before addition of 2-methylpyrrolidine (1.2 mmol, 1.2 eq, 0.12 ml). The mixture is then stirred at 80° C. overnight. The mixture is taken up in ethyl acetate and washed with a saturated solution of sodium bicarbonate, then dried over magnesium sulfate. The solvent is removed under reduced pressure and purified by chromatography over silica gel (eluent: dichloromethane/methanol/ammonia 96:3.6:0.4) to give 0.132 g of 4-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-thiazol-5-yl)carbonyl]morpholine 152 as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([CH:28]4[CH2:31][CH2:30][CH2:29]4)[N:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=34)[CH:13]=2)[CH:5]=1.[OH-].[Na+]>C1COCC1>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[N:19][C:18]=2[C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:32])=[O:2])[CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(C(=O)O)c4)c3)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 5 mL methanolic solution of 3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzoic acid methyl ester (600 mg, 1.40 mmol) with 5 mL THF was charged with 5 mL of 10 N NaOH and the reaction mixture was heated to 60° C. After 1 h, the reaction was allowed to cool to rt and the pH of the reaction mixture was lowered to 3-4. A white precipitate formed, which was filtered and washed with hexanes to afford the title compound as a white powder; 1H NMR (CDCl3, 400 MHz) δ 1.90-1.97 (m, 1H), 2.04-2.15 (m, 1H), 2.36-2.56 (m, 4H), 3.60-3.79 (m, 1H), 5.10 (s, 2H), 6.84 (d, J=5.2 Hz, 1H), 6.97-7.01 (m, 1H), 7.07 (d, J=5.6 Hz, 1H), 7.12-7.15 (m, 2H), 7.32-7.40 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 8.02 (s, 1H); MS (ES+): m/z 415.15 (100) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:11]=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:11]=[C:12]([CH3:19])[CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(Oc2ccc(Cl)cc2)c1
Yield: 105.6 %

Procedure:
A solution of 4-chlorophenol (1 g, 7.78 mmol), 3-fluoro-4-nitrotoluene (808 mg, 5.21 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in DMF (5 ml) was stirred at reflux for 6 h. The reaction mixture was allowed to cool and then re-dissolved in 2.5M NaOH (10 ml). This aqueous mixture was then extracted with ethyl acetate (3×15 ml) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. An ethyl acetate solution of the crude material was filtered through a pad of silica which upon evaporation in vacuo afforded 2-(4-chlorophenoxy)-4-methyl-1-nitrobenzene as a yellow oil (1.45 g). This oil was then dissolved in 10:1 EtOH:H2O (10 ml) and added to a refluxing solution of iron powder (1.20 g, 21.53 mmol) and ammonium chloride (147 mg, 2.74 mmol) in 10:1 EtOH:H2O (20 ml). Stirring at this temperature continued for a further 2 h, before the reaction mixture was allowed to cool. The mixture was then filtered through a pad of celite, which was further washed with ethyl acetate (250 ml). Concentration in vacuo followed by purification by flash chromatography (eluant: 8:2 to 1:1 hexane:ethyl acetate) afforded the title compound as a pale yellow solid (868.2 mg, 70%). 1H NMR (270 MHz, CDCl3): δ 2.20 (3H, s, CH3), 3.65 (2H, br s, NH2), 6.65-6.68 (1H, m, Ar—H), 6.72 (1H, d, J=10.9 Hz, Ar—H), 6.78-6.82 (1H, m, Ar—H), 6.85-6.91 (2H, m, Ar—H), 7.21-7.26 ppm (2H, m, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: Cc1nc(NC(=O)Nc2ccc(Cl)cc2)sc1C(=O)NCc1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use 4-chlorophenyl isocyanate in place of phenyl isocyanate to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 62% yield; m.p.>300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.14 (s 1H), 8.47 (t, J=6.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.35-7.17 (m, 8H), 4.35 (d, J=5.7 Hz, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.2, 140.1, 138.1, 129.2, 128.7, 127.7, 127.1, 126.8, 120.7, 43.0, 39.1; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.Cl>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)cc1

Procedure:
In a 500 mL three-necked flask were placed 14 g (51 mmol) of p-bromoiodobenzene, 5.2 g (52 mmol) of phenylacetylene, and 98 mg (0.50 mmol) of copper(I) iodide. After the atmosphere in the flask was placed with nitrogen, 200 mL of tetrahydrofuran (THF) and 9.0 mL of triethylamine (Et3N) were added to the flask, and the mixture was degassed by being stirred under reduced pressure. To this mixture was added 0.34 mg (0.50 mmol) of bis(triphenylphosphine)palladium(II) dichloride, and the mixture was stirred under nitrogen stream at room temperature for 20 hours. After a predetermined time, a 3% hydrochloric acid was added to the mixture, and an aqueous layer and an organic layer were separated in the mixture. Then, an organic substance was extracted with ethyl acetate from the aqueous layer. The obtained extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with hexane, so that, 7.41 g of target light-brown powder was obtained with a yield of 55%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.CN(C)CCCC(N=C=N)C.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:6]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-iodobenzoic acid (50 g, 153 mmol), 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (30.8 g, 153 mmol), 4-dimethylaminopyridine (18.6 g, 153 mmol) and t-butanol (69.4 g, 90 ml, 153 mmol) in dichloromethane (500 ml) was stirred at room temperature overnight. The reaction mixture was washed with 2MHCl and saturated NaHCO3. The organic phase was dried and evaporated to give the title compound as a light brown solid. (48 g; 85%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:3][C@H:4]([OH:33])[C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:31][O:30][C:29](=[O:32])[NH:28][C@@H:23]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:21](=[O:22])[NH:20][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:33])[CH2:3][C@H:2]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43](=[O:44])[O:42][CH3:41]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccc(C)cn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A solution containing the product from Example 89C (0.032 g, 0.059 mmol) in THF (0.5 mL) was treated with the product from Example 1F (0.014 g, 0.076 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, to give the title compound (0.028 g, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77 (s, 9H), 0.83(s, 9H), 1.58-1.39(m, 2H), 2.32(s, 3H), 2.77-2.69(m, 3H), 3.51(s, 3H), 3.54(s, 3H), 3.67-3.60(m, 1H), 3.81-3.78(d, J=9.93 Hz, 1H), 3.95-3.92(d, J=9.93 Hz, 1H), 4.17-4.01(m, 2H), 4.86-4.84(d, J=5.52 Hz, 1H), 6.63-6.60(d, J=9.56 Hz, 1H), 6.78-6.75(d, J=9.93 Hz, 1H), 7.14-7.06(m, 5H), 7.29-7.26(d, J=8.46 Hz, 2H), 7.61-7.58(d, J=9.19 Hz, 1H), 7.68-7.65(m, 1H), 7.80-7.73(m, 2H), 7.90-7.87(d, J=8.09 Hz, 2H), 8.47(s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH:18]=[C:17]([CH3:20])[C:16]=3[C:21]=2[CH:22]=[O:23])[N:4]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>CC(C)=O.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:21]([C:22]([OH:25])=[O:23])=[C:16]3[C:17]([CH3:20])=[CH:18][S:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C=O)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
0.6 g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4-formyl-3-methylbenzothiophene was dissolved in 80 ml of acetone. While stirring the solution at room temperature, 0.6 g of potassium permanganate dissolved in 10 ml of water was dropwise added thereto over a period of 15 minutes, and the mixture was further stirred at room temperature for 4 hours. It was then concentrated under reduced pressure to remove acetone, and then a saturated sodium bicarbonate aqueous solution was added thereto to make the mixture alkaline. The mixture was extracted with ethyl acetate, and then the aqueous layer was precipitated with 10% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain 0.47 g (yield: 76%) of the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:4].[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]cnc2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]cnc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-benzimidazol-5-yl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 185-189° C. (diethylether)
Reaction SMILES: [CH:1]1([N:4]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:1]1([NH:4][CH:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:14][CH:13]2[F:18])[CH2:2][CH2:3]1
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@H]1CCNC[C@H]1F
Product: CCc1cnc(N2CCC(NC3CC3)C(F)C2)nc1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described for Intermediate 87. LC (method 20): tR=1.80 min; Mass spectrum (APCI): m/z=265 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[C:13]3[C:12]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[C:20]1([S:19][C:17]2[CH:18]=[C:13]3[C:12]([C:26]4[CH:30]=[N:29][NH:28][CH:27]=4)=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(Sc3ccccc3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(Sc2cnc3[nH]cc(-c4cn[nH]c4)c3c2)cc1
Temperature: 90 °C
Yield: 59.3 %

Procedure:
A mixture of 7 (130 mg, 0.30 mmol) and 10% aq. sodium hydroxide (2.8 mL) in EtOH (5.8 mL) were heated at 90° C. for 1 h. The solution was cooled, partitioned between CH2Cl2/brine, the layers separated and the aqueous phase extracted with more CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give 8 as a white solid (52 mg, 59%); 1H NMR (400 MHz, CDCl3+6 drops CD3OD) δ 7.13 (m, 3H), 7.22 (m, 2H), 7.47 (s, 1H), 7.80 (s, 2H), 8.27 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].IC.[H-].[Na+].Cl.[C:31]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][C:18]1[C:17]([CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:10]3[C:6]([CH:5]([CH3:31])[C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:7][S:8][C:9]=3[CH:14]=2)=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)ccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1csc2cc(OCc3ccc(C)nc3C)ccc12
Reaction time: 8 h

Procedure:
To a mixture of ethyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (710 mg) and iodomethane (0.373 ml) and THF (10 mL) was added sodium hydride (60% in oil, 160 mg) at 0° C. The mixture was stirred 0° C. to room temperature under argon atmosphere overnight. To the mixture was added 1N HCl at room temperature, and the mixture was adjusted to pH 6-7 with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed successively with brine and water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (230 mg).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>CCCCC>[CH2:16]([NH:19][C:14]([NH:13][C:7]1([N:6]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:15])[CH2:17][NH:18][C:14]([NH:13][C:7]1([N:6]=[N:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:15]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: NCCN
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)NCCNC(=O)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 8.4 grams (0.0402 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 1.57 grams (0.0201 moles) of ethylenediamine. Solids formed and the reaction mixture was diluted with pentane and stirred for 3 hours at room temperature. The pentane was stripped from the reaction mixture leaving a semi-solid. The semi-solid was slurried in cold pentane and filtered. The white solid filter cake was air dried and weighed 10.0 grams (75% crude yield). The product melted at 165°-167° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1670 cm-1 and NH bands at 3300 and 3340 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[O:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CS(C)=O>[O:13]=[C:14]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:28]=1)[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19]
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)C(F)(F)F)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc(C(=O)CNC(=O)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
1.06 g of sodium carbonate or 3.26 g of cesium carbonate were added to a stirred solution of 2.47 g of 4-(1-oxo-2-trifluoroacetamidoethyl)-phenol (1e) in 5 ml of dimethyl sulfoxide at room temperature and, after 30 minutes, 1.83 g of ethyl bromoacetate were introduced. Precipitating crystalline solid gradually made the mixture more viscous. After about 2 hours, the mixture solidified to a thick, unstirrable crystal slurry.