Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:27][CH:26]=1)([CH3:33])[CH3:31]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87.0 mg, 0.214 mmol) and propan-2-amine (18.93 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (39.6 mg, 0.088 mmol, 41.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6H) 1.85-2.00 (m, 3H) 2.11-2.24 (m, 1H) 2.41-2.48 (m, 4H) 3.17-3.27 (m, 4H) 3.34-3.44 (m, 3H) 3.53-3.65 (m, 1H) 3.93-4.13 (m, 2H) 6.91 (d, J=9.09 Hz, 2H) 6.99 (d, J=2.02 Hz, 1H) 7.62 (d, J=2.02 Hz, 1H) 7.72 (d, J=9.09 Hz, 2H) 7.89 (d, J=7.83 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C25H32N6O2, 449. found, 449.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11]([NH:37][S:34]([C:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:35])=[O:36])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Reactant: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Reaction time: 20 h

Procedure:
4-Dimethylaminopyridine (151 mg) was added to a solution of 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl) acetic acid (the product of Example 68, 480 mg. 1.24 mmol) in anhydrous dichloromethane (10 ml) at ambient temperature. 2-Methoxy-4-methyl-1-benzenesulfonamide (from Preparation 11, 300 mg, 1.48 mmol) was added to the solution followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (355 mg, 1.85 mmol), and stirring was continued for 20 hours. The solution was washed twice with 2N hydrochloric acid, and dried (magnesium sulphate) and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and crystallised from dichloromethane and diethyl ether mixture to give the subtitle compound (535 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH3:10][CH:11]([OH:13])C.C(OC(=O)C)C>C(OC(=O)C)(=O)C>[C:11]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)(=[O:13])[CH3:10]
Reactant: CC(C)O
Reactant: O=C(O)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(C(=O)O)CC1

Procedure:
Piperidine-4-carboxylic acid (208 g, 1.63 moles) was dissolved in acetic anhydride and the resulting solution heated at reflux under a nitrogen atmosphere for 48 hours. The flask contents were allowed to cool then concentrated under reduced pressure to give a pale yellow oil which solidified on standing. Recrystallisation from propan-2-ol then afforded the title compound as an off white solid (160 g, 0.94 moles, 58%), mp 164-166° C. (IPA-ethylacetate), δH (300 MHz;CDCl3) 1.7 (2H, m), 2.0 (2H, m), 2.2 (3H, s), 2.6 (1H, m), 2.85 (1H, m), 3.2 (1H, m), 3.8 (1H, m), and 4.4 (1H, m).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:8][CH:9]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 30 mg, 0.75 mmol) in DMF (3 mL) was added 2-(4-Hydroxy-phenyl)-isoindole-1,3-dione (105 mg, 0.5 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (173 mg, 0.5 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 30 min and then was heated to 90° C. and stirred at 90° C. for 16 h. After cooled to it, the mixture was poured into 150 mL ice-water solution and then was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL), brine (30 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel to yield the title product, (120 mg, 55%)
Reaction SMILES: Cl[CH:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[NH2:15][C:13]1[S:14][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH:9]([CH3:11])[CH3:10])[N:12]=1
Reactant: CCOC(=O)C(Cl)CC(C)C
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(C)C
Yield: 39.7 %

Procedure:
Utilizing the procedure of Example 1, a mixture of 1.97 g (0.01 mol) of ethyl 2-chloro-4-methyl-pentanoate, 0.76 g (0.01 mol) of thiourea and 30 ml of ethanol was held at reflux for 18 hours. Ethanol was removed under reduced pressure. The residue was crystallized from hexane. The solid precipitates were dissolved in ether. The ether solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from benzene-ether to give 0.85 g (39.6%) of ethyl 2-amino-4-isopropyl-5-thiazolecarboxylate, m.p. 173°-176° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22]([CH3:28])[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl.O.C(O)=O.CC#N>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([N:22]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:28])=[N:20][N:21]=4)[CH:18]=3)[CH2:4][CH2:3]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CN(C)CCN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N(C)CCN(C)C)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 43b (140 mg, 0.36 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 218 mg, 0.54 mmol) and DIPEA (186 mg, 1.44 mmol) in DMF (6 mL) was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave a viscous yellow gum. HPLC (C6-Ph column, 10-40% MeCN in H2O, 0.1% HCO2H) gave the title compound as an off-white powder after freeze-drying (80 mg, 35%). LCMS (Method 5): Rt 3.67 min, m/z 636.3 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.30 (9H, s), 1.86-2.15 (3H, m), 2.19-2.30 (1H, m), 2.38 (3H, s), 2.57 (6H, s), 2.92 (3H, s), 3.00 (2H, t J 6.2), 3.46-3.60 (2H, m), 4.89 (1H, m), 5.42 (1H, t, J 3.9), 6.33 (1H, s), 7.16-7.36 (9H, m), 7.52 (1H, d, J 10.1), 7.90 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:22]([NH2:25])[C:23]#[CH:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:25][CH2:22][C:23]#[CH:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: C#CCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Prop-2-ynyl-amine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-prop-2-ynyl-amine as off-white semisolid, MS: 401 (MH+,1Br).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC.[F-].[Cs+].CN(C=O)C>[Cu]I.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.CC#N.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:24]2[N:25]=[CH:26][S:27][CH:28]=2)[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3cscn3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (189 mg, 0.668 mmol), 4-(tributylstannyl)thiazole (250 mg, 0.668 mmol), CuI (32 mg, 0.17 mmol), CsF (304 mg, 2.00 mmol), and Pd(PPh3)4 (39 mg, 0.033 mmol). The vial was capped and then placed under N2 atmosphere. To the vial was added DMF (4 mL). The vial was placed in a 80° C. heating block with stirring for 1 h. The mixture was allowed to cool to room temperature. To the reaction was added 4-(tributylstannyl)thiazole (250 mg, 0.668 mmol) and Pd(PPh3)4 (10 mg, 8.9 μmol). The vial was placed under N2 atmosphere and then returned to the 80° C. with stirring for 1 h. The mixture was cooled to room temperature and the mixture was then adsorbed onto diatomaceous earth (Celite®). The resulting powder was subjected to C18 chromatography (water:MeCN, 100:0 to 0:100) to afford 4-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)thiazole as a dark amber solid (58 mg, 26%). 1H-NMR (500 MHz, CDCl3) δ 8.90 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.06-8.02 (m, 2H), 7.63 (d, J=1.7 Hz, 1H), 7.03-6.98 (m, 2H), 4.66 (spt, J=6.1 Hz, 1H), 1.41-1.38 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4)CC3)nc2c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 92%). 1H NMR (300 MHz, CDCl3): δ 3.27 (s, 4H), 3.73-3.86 (m, 6H), 4.08-4.11 (m, 4H), 6.88-7.03 (m, 4H), 7.15 (s, 1H), 7.26-7.33 (m, 3H), 7.57-7.62 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=[O:26])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:29]COC(C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:29])[C:10](=[O:26])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: CCOC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of intermediate (21) (0.0132 mol), iodomethane (0.0264 mol) and benzyltriethylammonium chloride (0.00132 mol) in THF (50 ml) and sodium hydroxide 10N (50 ml) was stirred at room temperature overnight. EtOAc was added. The mixture was decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (2.9 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: toluene/2-propanol/NH4OH 70/29/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.45 g of 4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 167° C. (intermediate 22).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Oc3ccnc(C(=O)OC(C)(C)C)c3)cc2s1
Temperature: 75 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
To a solution of 2-(methylthio)benzo[d]thiazol-6-ol (5.0 g, 25.38 mmol, 1.0 eq) in 25 mL of N,N-dimethylformamide was added tert-butyl 4-chloropicolinate (8.13 g, 38.07 mmol, 1.5 eq) and cesium carbonate (20.67 g, 63.45 mmol, 2.5 eq). The reaction mixture was stirred at 75° C. for 6 hours. After the mixture was cooled to room temperature, the mixture was added 120 mL of water and aqueous phase extracted with ethyl acetate (3×150 mL), combined organic layers were dried over sodium sulfate. After filtration, the solid was purified by silica gel column eluted with ethyl acetate-hexane 0%-50% mixture to give 5.84 g of the titled compound as brown powder (62%). MH+=375.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=[C:18](SC)[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.ClC1C=CC=C(C(OO)=O)C=1.Cl.[CH3:48][NH:49][CH3:50].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=[C:18]([N:49]([CH3:50])[CH3:48])[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1cnc(SC)nc1O[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N(C)C)nc1O[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 50 mL of chloroform was dissolved 2.75 g of N-tert-butoxycarbonyl-trans-4-(5-ethoxycarbonyl-2-methylthiopyrimidin-4-yloxy)cyclohexylamine (a compound of Reference Example 9-49 prior to deprotection (hydrochloric acid-dioxane treatment)), 1.73 g of 75%-m-chloroperbenzoic acid was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Then, 1.14 g of dimethylamine hydrochloride and 2.79 mL of triethylamine were added thereto and the mixture was further stirred for 5 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was stirred. Then, the chloroform layer was collected by separation, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (solvent: hexane-chloroform (50:50 to 100:0)) to obtain 2.74 g of N-tert-butoxycarbonyl-trans-4-[5-ethoxycarbonyl-2-(dimethylamino)-pyrimidin- 4-yloxy]cyclohexylamine.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.Cl.[C:31]1([CH2:41][CH2:42][NH2:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH:32]=1>>[C:31]1([CH2:41][CH2:42][NH:43][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]2[CH2:9]4)[CH2:10]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH:32]=1
Reactant: NCCC1=CCCc2ccccc21
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: Cl
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCC1=CCCc2ccccc21

Procedure:
Following the procedure of Example 70, the title compound was prepared from 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.29 g (1.38 mmol) of 3,4-dihydro-1-naphthalene-ethanamine hydrochloride. The purified product after chromatography was obtained as a white foam, 0.41 g (59%); 1H NMR (CDCl3) δ1.48-1.99 (17H, m), 2.39-2.50 (2H, m), 2.67-2.82 (3H, m), 3.23-3.57 (3H, m), 3.99 (2H, t, J 5.0 Hz), 4.84 (1H, br s), 5.24 (1H, br s), 5.73 (1H, m), 6.16 (1H, m), 7.00-7.63 (9H, m), 8.12 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].C(N(CC)CC)C.Cl>C(Cl)Cl>[OH:12][CH2:11][CH2:13][NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise at 0° to a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml (about 0.02 mol) of triethylamine in 30 ml of methylene chloride. The mixture is then poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts are dried over magnesium sulfate and concentrated. After purification on silica gel using chloroform and chloroform/methanol 9:1) as the eluting agent, there are obtained 3.1 g of N-(2-hydroxyethyl)-4-chlorobenzamide.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][NH:9][CH3:10])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].O>C(#N)C>[C:2]([O:6][C:7](=[O:11])[CH2:8][N:9]([CH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=1)[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a stirred solution of sarcosine tert-butyl ester hydrochloride (8.1 g, 44.9 mmol) and triethylamine (17 mL, 122.4 mmol) in ACN (100 mL) was added 3-(bromomethyl)benzonitrile (8.0 g, 40.8 mmol) portionwise over a period of 10 minutes at 0° C. After being stirred at RT for 3 hours, the reaction mixture was poured into water and extracted with DCM. Then the organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a pale green liquid (9.0 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 7.72 (2H, m), 7.64 (1H, m), 7.54 (1H, m), 3.66 (2H, s), 3.18 (2H, s), 2.22 (3H, s), 1.41 (9H, s).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O>C1(C)C=CC=CC=1.O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:8]
Reactant: BrCc1ccccc1Br
Reactant: O=C1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: O=C1CCCCCC1Cc1ccccc1Br
Yield: 55 %

Procedure:
To a solution of cycloheptanone (56.1 g, 0.5 mol) in toluene (500 ml) was added morpholine (65.3 g, 0.75 mol) and tosic acid (100 mg). The reaction vessel was fitted with a Dean-Stark condenser and the reaction was refluxed for 24 hours. The toluene was removed in vacuo and the enamine was vacuum distilled. The enamine was collected as a pale yellow oil (46.5 g, 51%). To a solution of the enamine (10.0 g, 0.055 mol) in dioxane (50 ml) was added 2-bromobenzyl bromide and the reaction was refluxed overnight. Water (10 ml) was then added and the mixture was refluxed an additional 2 hours. The reaction was cooled and the solvent was removed in vacuo. The residue was partitioned between dichloromethane and 1N hydrochloric acid. The dichloromethane layer was washed with additional 1N hydrochloric acid (50 ml) and water (50 ml), dried (MgSO4), filtered, and reduced in volume to yield a crude orange oil (15.9 g). The mixture was vacuum distilled to yield the title compound as a clear oil (8.5 g, 55%) that was a semisolid at 23° C. ##STR91##