Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH2:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.[C:22]1([C@H:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:1]([O:4][CH2:5][C@@H:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:11][CH:12]=1)[NH:20][C:29](=[O:30])[C@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:32])(=[O:3])[CH3:2]
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: CCCC(C)COc1ccc([C@@H](N)COC(C)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)COc1ccc([C@H](COC(C)=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of (2R)-2-amino-2-(4-(2-methylpentyloxy)phenyl)ethyl acetate.HCl (400 mg, 1.432 mmol) and (S)-2-phenylpropanoic acid (323 mg, 2.15 mmol) in tetrahydrofuran (8 mL) at 0° C. was added N,N-diisopropylethylamine (0.875 mL, 5.01 mmol) followed by HATU (817 mg, 2.15 mmol). The cooling bath was removed and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (25 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30%→45% ethyl acetate in hexanes; 40 g column) and dried under vacuum to afford (2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethyl acetate (430 mg, 73.0% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.22-7.37 (m, 5H), 6.95 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 5.87 (d, J=8.1 Hz, 1H), 5.16 (td, J=7.7, 4.5 Hz, 1H), 4.25 (dd, J=11.5, 7.4 Hz, 1H), 4.14 (dd, J=11.3, 4.5 Hz, 1H), 3.74 (dd, J=8.8, 5.8 Hz, 1H), 3.65 (dd, J=8.8, 6.8 Hz, 1H), 3.59 (q, J=7.1 Hz, 1H), 1.95 (s, 3H), 1.85-1.95 (m, 1H), 1.49 (d, J=7.3 Hz, 3H), 1.24-1.47 (m, 3H), 1.13-1.23 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 412.2 [(M+H)+, calcd for C25H34NO4 412.3].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH2:14][C:15](N1CCCC1)=[O:16].Cl.[O:23]1CCOCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[CH2:14][C:15]([OH:16])=[O:23]
Reactant: O=C(Cc1ccc(CN2CCCC2)cc1Cl)N1CCCC1
Reactant: C1COCCO1
Agent: Cl
Product: O=C(O)Cc1ccc(CN2CCCC2)cc1Cl
Yield: 25 %

Procedure:
A solution of 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine (crude, max. 44.70 mmol) in dioxane (100 ml) was stirred at r.t. A 6 M HCl solution was added. The mixture was stirred and refluxed for 3 days. The mixture was concentrated in vacuo. The residue was taken up in water and the mixture was brought to pH 10 with a 4 N NaOH solution. The solution was washed with diethyl ether (3×40 ml). The aqueous layer was acidified to pH 3 with a 6 N HCl solution. The mixture was concentrated in vacuo. The residue was purified by neutral high performance liquid chromatography (Column: Lana 300×50 mm, 10 μm; Mobile Phase: 0-20% CH3CN in water; Flow Rate: 80 ml/min; Finished Time: 25 min). The desired fraction was collected and evaporated in vacuo. Yield: 2.8 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (25% yield over last 3 steps).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([F:12])[CH:4]=1.CCN(C(C)C)C(C)C.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:12][C:5]1[CH:4]=[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:23]([CH3:22])[CH2:28]2)[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])c(F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
A solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (232 mg, 1 mmol) and Hunig's base (0.192 mL, 1.1 mmol) in DMF (3 mL) was treated with 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (200 mg, 1 mmol) in DMF (3 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated, re-dissolved in DCM and washed with water and brine, then dried and concentrated. The crude product was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as a colourless gum (327 mg). δH (CDCl3, 400 MHz) 8.03 (1H, m), 7.34 (1H, dd), 7.27 (1H, m), 4.22 (1H, br.s), 3.84 (1H, d), 3.58 (1H, d), 3.47 (1H, d), 3.13 (1H, td), 2.72 (1H, m), 2.54 (1H, m), 2.22 (1H, dd), 2.09 (1H, m), 1.46 (9H, s), 1.26 (3H, d) [δvalues corrected for incorrectly referenced TMS at 0.62 ppm on spectrum].
Reaction SMILES: [Cl:1]C1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[ClH:33].[CH:34]([N:37]([CH2:41][CH2:42]Cl)[CH:38](C)C)(C)C.O>CN(C=O)C>[ClH:1].[Cl:33][C:9]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]([CH2:42][CH2:41][N:37]([CH3:34])[CH3:38])[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.515 g) is dissolved in DMF (10 mL), and K2CO3 (0.778 g) and diisoproplyaminoethyl chloride-hydrochloride (0.56 g) are added. The reaction mixture is heated to 95° C. for 14 h, then allowed to stir at room temperature overnight. The mixture is then poured into H2O and an oil formed, which is isolated by decanting the liquid. The oil is dissolved in MeOH/CH2Cl2, and etheral HCl is added to adjust the pH to 2. The mixture is concentrated in vacuo to give the title compound as the hydrochloride salt.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C[O:10][C:11]([C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1)=O.CC#N>C1COCC1>[OH:17][CH2:16][C:13]1([C:11](=[O:10])[CH2:2][C:3]#[N:5])[CH2:15][CH2:14]1
Reactant: COC(=O)C1(CO)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCC(=O)C1(CO)CC1

Procedure:
To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL, ×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 4.03 (s, 1 H) 3.58 (br. s., 2 H) 1.15-1.16 (m, 2 H) 0.92-0.95 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[C:5]([N:13]2[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]2)=[C:4]([F:21])[C:3]=1[F:22].CN(C)CCN(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.C(OC(=O)C)C>[CH3:19][C@@H:17]1[CH2:18][N:13]([C:5]2[C:6]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:7][C:2]([CH:33]=[O:34])=[C:3]([F:22])[C:4]=2[F:21])[CH2:14][C@H:15]([CH3:20])[O:16]1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(c2c(C3OCCO3)cc(Br)c(F)c2F)C[C@H](C)O1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(C3OCCO3)cc(C=O)c(F)c2F)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,6S)-4-(4-bromo-6-(1,3-dioxolan-2-yl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (previously described in WO2004031195, page 81, 0.500 g, 1.32 mmol) and tetramethylethylene-diamine (0.12 mL, 2.12 mmol) in tetrahydrofuran (12 mL) at −78° C. is added t-buthyllithium (1.94 mL, 3.31 mmol). The reaction is stirred at −78° C. for 1.5 h and dimethylformamide is added. The reaction is stirred at −78° C. for an additional 30 min and warmed to rt. Mixture is diluted with ethylacetate (50 mL) and washed with saturated aqueous NH4Cl. (50 ml) and brine (30 mL). Dried over Na2SO4 and concentrated to give the title compound (433 mg): LCMS (M+H) 327.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH2:23][CH2:24][CH3:25])/[C:18]([O:20]CC)=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CCOC(C)=O>[Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH2:23][CH2:24][CH3:25])/[C:18]([OH:20])=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCC/C(=C\c1c(Cl)c(OC)c2ccccc2c1OC)C(=O)OCC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Product: CCC/C(=C\c1c(Cl)c(OC)c2ccccc2c1OC)C(=O)O

Procedure:
Compound 42b was prepared from 41b (0.028 g, 0.077 mmol) as described above for 29a to give 0.026 g (0.077 mmol, 100%) of the product as a red solid following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:18]([O:20]C)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 94.5 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 53 (4.0 g), 1 mol/L of an aqueous sodium hydroxide solution (21 mL), and methanol (200 mL), to give the captioned compound (3.6 g, 93%) as an amorphous solid product.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(C(=O)Nc2nc(-c3ccc(OC)cc3)c(Cc3ccccc3)s2)cc1
Yield: 58.7 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and p-methoxybenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 58.7%, mp: 58-59 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.73 (3H, s, OCH3), 3.85 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.89 (4H, t, J=8.44 Hz, ArH), 7.22˜7.35 (5H, m, ArH), 7.45 (2H, t, J=8.68 Hz, ArH), 7.82 (2H, t, J=8.68 Hz, ArH), 10.27 (1H, br, CONH); EI-MS m/e (%): 430.1 (M, 89), 135.0 (100); HREI-MS Calcd. for C25H22N2O3S: 430.1351. found: 430.1361.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][CH3:18])=[C:6]([NH:19][C:20](=O)[CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH2:17]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[CH:5][C:6]=2[N:19]=[C:20]1[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cccs1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCC1CCCCC1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 86.6 %

Procedure:
0.59 g 4-(2-Ethyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were reacted with 10 ml of 4M hydrochloric acid in dioxane at 130° C. in a microwave reactor for 20 min. 1 ml water was added and the mixture was heated to 130° C. for 30 min. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 0.47 g (88%) of 1-(2-Ethyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](CO)([OH:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C1COCC1.O>CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:28][C:29](=[O:31])[CH2:30]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: OCC1(O)CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-(hydroxymethyl)cyclobutanol (7.6 mmol) in a THF-water mixture (200 mL, 3:1) was added NaIO4 (1.95 g, 9.2 mmol) at 0° C. The reaction mixture was slowly warmed to rt and stirred for 4 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with brine (2×75 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Jones Flashmaster, 70 g/150 mL cartridge), eluting with 1:9 EtOAc/Hex→1:1 EtOAc/Hex to afford the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.70-3.62 (m, 2H), 3.94-3.85 (m, 3H), 7.56-7.45 (m, 4H), 7.64 (d, J=5.2, 1H), 7.94-7.89 (m, 3H), 8.20-8.18 (m, 2H), 8.28 (dd, J=0.4 Hz, 8.4 Hz, 1H), 8.52 (t, J=0.8 Hz, 1H). MS (ES+): m/z 425/427 (3/1) [MH+]. HPLC: tR=3.7 min (Mass Directed purification system polar 5 min method).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCOCC1.Cl.[CH3:29][N:30]([CH3:47])[C:31]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH2:35][CH:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O.C(O)C>[CH3:47][N:30]([CH3:29])[C:31]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([NH:20][CH2:19][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:39])[CH2:33][CH2:32]1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Reactant: NCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
1-Hydroxybenzotriazole (273 mg, 2.0 mmol), 3-phenylpropylamine (0.142 ml, 1.0 mmol) and N-methylmorpholine (0.222 ml, 2.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (298 mg, 1.0 mmol) in dry dimethylformamide under argon. Dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added to the clear solution at 0° C. The reaction mixture was stirred at RT for 3 d, the urea which had precipitated out was filtered off with suction and the filtrate was introduced into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). 5 M sodium hydroxide solution (12 ml, 60 mmol) was added to the aqueous phase and the mixture was diluted with water (300 ml) and stored at 5° C. for 3 d. The product was thereby produced as a colourless compound and was to be obtained in a yield of 58% (220 mg) by filtration, taking up of the residue in ethanol and concentration.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][CH2:21][C:22](O)=[S:23]>>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:22](=[S:23])[CH2:21][CH3:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CCC(O)=S
Product: CCC(=S)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and methylthioacetic acid. m.p.: 63-70° C. 1H-NMR (CDCl3) δ: 10.78 (1H, br s), 8.42 (1H, br s), 8.16 (1H, d, J=9.2 Hz), 7.86-7.79 (2H, m), 7.68-7.53 (3H, m), 7.31 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=9.2, 1.8 Hz), 3.39 (2H, s), 2.23 (3H, s)
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:13]=1[NH2:23]>>[Cl:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]2[C:13]=1[NH:23][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1N
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2[nH]c1=O
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 50.9 %

Procedure:
439.0 mg (3.0 mmol) of diethyl oxalate (from Sigma, used as received) was added to 210.6 mg (1.0 mmol) of 1,2-diamino-3-chloro-5-trifluoromethylbenzene (from PCR Inc., used as received), and the resulting yellow solution was heated at 180° C. (bath temperature) under Ar with stirring for 3.5 h, the solution became thick with formation of cream precipitate and hard to stir. The reaction mixture was allowed to cool to r.t., and triturated with hexane (10 mL). The precipitate was collected by vacuum filtration, washed with hexane (2×10 mL) (the combined hexane filtrate was saved), dried under 0.1 mmHg for 4 h affording 134.6 mg (58%) of the crude desired product as a yellow powder (95-98% pure by NMR), mp.330°-2° C. (dec.) (preheated block).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:29])[CH:9]([NH:21]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:21][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[OH:29]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To 1,1-dimethylethyl(1RS,2RS)-2-(6-chloro-2-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate (500 mg, 1.16 mmol) was added trifluoroacetic acid (8 ml) at 0° C., and the mixture was stirred for 10 min. The reaction solution was concentrated, diluted with water (20 ml) and extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS,2RS)-2-amino-1-(6-chloro-2-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (302 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH2:17][CH3:18])[C:14](O)=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][CH:13]([CH2:17][CH3:18])[C:14](=[O:15])[N:11]=1
Reactant: NC(=S)Nc1ccccc1Cl
Reactant: CCC(Br)C(=O)O
Product: CCC1SC(Nc2ccccc2Cl)=NC1=O

Procedure:
Synthesis was performed from N-(2-chlorophenyl)thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C=CC(=O)O
Product: O=C(O)CCn1cncn1

Procedure:
In a manner analogous to that described in Example (8a), 2.8 g of 1,2,4-triazole are reacted with 2.88 g of acrylic acid to form the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C([O-])(=O)C.[Na+]>C1C=CC=CC=1.O>[C:15]([O:13][CH2:12][C:10]1[O:11][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14])=[CH:8][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CN(C)CCCCc1ccc(CO)o1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)OCc1ccc(CCCCN(C)C)o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-[4-(dimethylamino)butyl]-2-furanmethanol (4.9 g), acetic anhydride (25 g) and fused and powdered sodium acetate (10 g) in benzene (25 ml) was stirred at room temperature for 24 hr. The reaction was diluted with water (100 ml) and extracted with ethyl acetate. The combined extracts were distilled to afford a clear colourless oil b.p. 100°, 0.5 mm Hg. Found: C, 65.62; H, 9.03; N, 5.95. Calc. for C13H21NO3 : C, 65.24; H, 8.85; N, 5.85%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([Li])CCC.Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[Cl-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(OCCCCBr)cc1
Reactant: Cc1cc(C)on1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCCOc2ccc(C#N)cc2)on1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 123.7 %

Procedure:
To a solution of 5.86 g of 3,5-dimethylisoxazole in 120 ml of dry tetrahydrofuran at -70° C. under nitrogen was added during 14 minutes 36 ml of n-butyllithium (1.7M in hexane). The mixture was stirred at -70° C. for 30 minutes, and then 15.2 g of 4-(4-bromobutyloxy)benzonitrile in 40 ml of tetrahydrofuran was added over a 15 minute period. The reaction mixture was stirred for 1.5 hours at -70° C. and then allowed to warm to room temperature and stirred for 2.5 hours longer. Evaporation of the solvent gave a residue which was treated with 300 ml of ethyl acetate, 150 ml of concentrated sodium chloride solution and 12 ml of hyrochloric acid. The material which was soluble in ethyl acetate was isolated, combined with material from another run of the same scale and subjected to high pressure liquid chromatography with ether-hexane (1:1) to give 20 g of 5-[5-(4-cyanophenoxy)pentyl]-3-methylisoxazole as a colorless solid, m.p. 57° C.