Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH2:12](O)[CH3:13].OS(O)(=O)=O>>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:13]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(OC)c1

Procedure:
3-Methoxy-benzoic acid ethyl ester is prepared from 3-methoxy-benzoic acid using a standard protocol with ethanol/H2SO4 according to L.-F. Tietze & T. Eicher, Reactions and Syntheses in the Organic Chemistry Laboratory; University Science Books, Mill Valley, Calif., 1989). Title compound: b.p. 151° C. (25 mm Hg); single peak at tR=6.51 min (System 1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:27]3[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C1CNCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCNC(=O)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol) and piperazin-2-one (30 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-45% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (17 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 3.43 (br. s., 2 H) 4.08 (t, J=5.18 Hz, 2 H) 4.27 (s, 2 H) 6.38 (d, J=2.27 Hz, 1 H) 7.41 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 8.00 (d, J=8.34 Hz, 2 H) 8.11 (d, J=2.27 Hz, 1 H) 8.23 (br. s., 1 H) 10.93 (s, 1 H). ESI-MS: m/z 395.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[NH:5][CH2:4][NH:3]1>[Co]=O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[N:5]=[CH:4][NH:3]1
Reactant: CC1CC(C)(C)NCN1
Agent: O=[Co]
Product: CC1CC(C)(C)NC=N1
Yield: 10 %

Procedure:
Heating a mixture of 12.6 g. of 4,4,6-trimethyl hexahydropyrimidine and 0.5 g. of cobalt oxide on kieselguhr for 9 hrs. at 185°-190° C. yielded 10% of 4,4,6-trimethyl-3,4,5,6,-tetrahydropyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17].O>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][C:16](=[O:18])[CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2chloro-3-aminopyridine (51.4 g, 400 mmol) in dichloromethane (800 mL) at 0° C. was added triethylamine (31.0 mL, 440 mmol) followed by acetyl chloride (62.0 mL, 440 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into water (800 mL) and the layers were separated. The organic layer was treated with Darco™-G-60 (activated charcoal), heated to reflux, filtered over Celite™ (diatomaceous earth manufactured by Celite Corp., Santa Barbara, Calif.) and concentrated to an oil. The oil was crystallized in diisopropyl ether and the solids were filtered to afford 42.4 g (62% yield) of N-(2-chloro-pyridin-3-yl)-acetamide. M. p.=81-83° C. 1 NMR (400 MHz, CDCl3) δ2.23 (s, 3), 7.21 (dd, 1, J=8.1, 4.7) 7.67 (bs, 1), 8.06 (dd, 1, J=4.7, 1.3), δ8.66 (d, 1, J=7.9). 13C NMR (100 MHz, CDCl3) δ24.93, 123.34, 129.06, 131.89, 143.81, 144.08, 168.79.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:12]Br.C([O-])(O)=O.[Na+].ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:12][C:6]1[C:7]2[S:11][N:10]=[CH:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: COc1cccc2sncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Br)c2sncc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of 4-methoxy-benzo[d]isothiazole (prepared as described above) (1.0 g, 6.05 mmol) in carbon tetrachloride (20 mL) at 0° C. was added bromine (310 μL, 6.05 mmol) in carbon tetrachloride (10 mL). The reaction was allowed to stir at 0° C. for 3 h and was then warmed to rt. Saturated aqueous NaHCO3 and dichloromethane were added and the organic phase was separated. The aqueous phase was extracted with 2×20 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:20] to yield the title compound (980 mg, 66%): δH (300 MHz, CDCl3): 9.09 (1H, s), 7.52 (1H, d, J=8.1 Hz), 6.67 (1H, d, J=8.4 Hz), 4.00 (3H, s).
Reaction SMILES: [CH2:1]([C:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH2:29]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(C=Cc1ccccc1)C(Cc1ccccc1)(Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)C(Cc1ccccc1)(Cc1ccccc1)C(=O)CCc1ccccc1
Yield: 65.1 %

Procedure:
4,4-Dibenzyl-1,7-diphenyl-1,6-heptadiene-3,5-dione (12b, 70 mg, 0.2 mmol) and palladium on activated carbon (0.10 g, 10%) were combined in ethyl acetate (25 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 5 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to give a solid. The solid was recrystallized from hexane to give 60 mg (86%) of a white solid: mp 101-102° C. [expected mp 100.5-101.5° C.]; 1H NMR: δ 2.56 (t, 4H, J=7.4 Hz), 2.74 (t, 4H, J=6.8 Hz), 3.29 (s, 4H), 7.04 (m, 20H); 13C NMR: δ 29.6, 37.3, 42.5, 71.1, 126.1, 126.8, 128.4, 129.6, 136.0, 140.6, 207.8; Anal. Calcd for C33H32O2: C, 86.05; H, 7.00. Found: C, 86.28; H, 7.11.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:40]2[CH:48]=[C:47]3[C:43]([C:44](C4C=CC=CC=4)=C(Br)C3=O)=[CH:42][CH:41]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:30])[C:2]=1[C:40]1[CH:48]=[CH:47][C:43]([CH3:44])=[CH:42][CH:41]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cc1
Yield: 70 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (70%).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2C(F)(F)F)C1
Yield: 84 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (200 mg, 84.0%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](Cl)([Cl:11])[C:9](=O)[CH2:8][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[NH:6]1)=[O:4].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[CH2:8][C:9](=[N:25][OH:26])[C:10]=1[Cl:11])=[O:4]
Reactant: NO
Reactant: COC(=O)C1NC(c2ccc(Cl)c(OC)c2F)CC(=O)C1(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)C1=C(Cl)C(=NO)CC(c2ccc(Cl)c(OC)c2F)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
3-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-chloro-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (33; 1.612 g, 4.63 mmol) was suspended in MeOH (20 mL). Hydroxylamine hydrochloride (966 mg, 13.9 mmol) was added followed by pyridine (3 mL). The reaction mixture was stirred for 18 h at room temperature and then for 4 h at 40° C. The solvent was removed by rotary evaporation. H2O (100 mL) was added, and the resulting solid was filtered, washed with H2O followed by MeOH to give 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (34; 1.353 g, 81%) as a white powder: mp 174-176° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H, NOH), 7.35 (dd, JF-H=1.5 Hz, JH-H=8.7 Hz, 1H, aromatic), 7.17 (dd, JF-H=JH-H=8.7 Hz, 1H, aromatic), 6.93 (br s, 1H, NH), 4.69 (m, 1H, H6), 3.88 (s, 3H), 3.79 (s, 3H), 3.03 (dd, J=4.5, 16 Hz, 1H, H5a), 2.74 (dd, J=9.0, 16 Hz, 1H, H5b); Anal. Calcd for C14H13Cl2FN2O4: C, 46.30; H, 3.61; N, 7.71. Found: C, 46.77; H, 3.64; N, 7.42.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(Cl)c1Cl
Yield: 74 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,3-dichlorobenzenesulfonyl chloride (13.5 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 74% yield (13.7 mg). MS (ESI+) calcd mass for C13H9Cl2N5O2S 368.985401, found 368.984901.
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:18])[CH:11]=1)([C:4]1[N:5]([CH3:9])[CH:6]=[N:7][CH:8]=1)[CH3:3].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)([C:4]2[N:5]([CH3:9])[CH:6]=[N:7][CH:8]=2)[CH3:3])=[CH:11][C:12]=1[F:18])#[N:15]
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cccc(CCC(=O)NC(C)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (0.074 g, 0.25 mmol), 3-(3-methoxyphenyl)propionic acid (0.054 g, 0.3 mmol) (K. J. Hwang et al., J. Org. Chem. (1992), 57[4]1262), EDC (0.275 g, 1.2 mmol), HOAT (0.055 g, 0.40 mmol), and triethylamine (0.167 mL, 1.2 mmol) were combined in DMF (3 mL) and stirred under Ar at ambient temperature for 20 hr. The reaction mixture was partitioned between EtOAc (120 mL) and H2O (100 mL), the organic layer separated, washed with dilute NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH2:16]([N:23]1[C:28]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=2[C:26](=O)[O:25]C1=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:28]2[C:27]([C:26]=1[OH:25])=[CH:32][C:31]([Cl:33])=[CH:30][CH:29]=2)=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccc(Cl)cc12
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 90 °C
Yield: 85 %

Procedure:
Neat diethyl malonate (19.07 mL, 125 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 5.52 g, 138 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min then cooled to room temperature. A solution of Compound 59 (39.88 g, 138 mmol) in dimethylacetamide was added slowly and the mixture heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered, washed several times by water, and dried at room temperature under vacuum to yield 38 g (86%) of white solids. 1H NMR (DMSO-d6): δ 1.31 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.45 (s, 2H), 7.17 (d, J=7.2 Hz, 2H), 7.2 (m, 2H), 7.31 (t, J=6.8 Hz, 1H), 7.37 (d, J=9.2 Hz, 1H), 7.65 (dd, J=2.8, 9.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 12.90 (b, 1H); EIMS: 358 (M+H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4]C.[C:7](=O)(OCCCCC)N.[C:16](=[O:24])([O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])N.C12CCCC1CCNN=2>C(O)CC(C)C>[C:16](=[O:24])([O:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:7])[O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CCCCCOC(N)=O
Reactant: CCCCCO
Reactant: CC(C)CCOC(N)=O
Agent: C1CC2=NNCCC2C1
Solvent: CC(C)CCO
Product: CC(C)CCOC(=O)OCCC(C)C
Yield: 89 %

Procedure:
The procedure described in Example 4 is followed, but the n-pentanol and n-pentyl carbamate are replaced respectively by isoamyl alcohol and isoamyl carbamate, and diazabicyclo-[4,3,0]-nonene is used as the catalyst. After completion of the reaction, analysis by gas chromatography shows that 66.9% of isoamyl carbamate have been converted and 120.3 parts of diisoamyl carbonate (89% of theory, based on converted isoamyl carbamate), of boiling point 106°-108° C./18 mbar, have been formed.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.C(N(CC)CC)C.[C:34]([Cl:42])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[ClH:42].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine Hydrochloride (0.224 g, 0.6 mmol) in dry THF (30 mL) was added triethylamine (0.167 mL, 1.20 mmol), followed by dropwise addition of benzoyl chloride (0.07 mL, 0.6 mmol). The reaction was stirred vigorously under N2 blanket at room temperature for 2 h. The reaction was quenched with H2O (25 mL) and diluted with ethylacetate (25 mL). The layers were separated and the organics washed with 1 N HCl (20 mL), sat. Na2CO3 (20 mL), brine (20 mL), dried (MgSO4), and concentrated to a residue. After chromatographic purification (5% MeOH/CH2Cl2), N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-benzamide was precipitated as its hydrochloride salt from dioxane/HCl(gas) treatment (0.162 g, 0.355 mmol). Yield=59%. 100% purity at 254 nM; LCMS (APCI): 457.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 10.81 (bs, 1H), 9.88 (s, 1H), 8.13 (d, J=8.36 Hz, 1H), 8.09 (d, J=8.36 Hz, 1H), 7.95 (d, J=8.36 Hz, 1H), 7.62–7.42 (m, 5H), 7.30 (d, J=8.02 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=8.02 Hz, 1H), 4.10 (bd, J=12.32 Hz, 2H), 3.68 (bd, J=12.32 Hz, 2H), 3.50–3.33 (m, 6H), 3.32 (s, H2O), 3.10–3.00 (m, 2H), 2.47 (DMSO), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:26](Cl)(=[O:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:26]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:24][CH:25]=1)(=[O:28])[CH3:27]
Reactant: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 79.2 %

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.6 g) was dissolved in tetrahydrofuran (9.0 ml). Under ice cooling, acetyl chloride (0.14 ml) was added dropwise thereinto and the resultant mixture was stirred for 2 hr. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.518 g) as a pale yellow oil (yield: 79.2%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of 4-trifluoromethyl-phenylamine (2.6 mL, 21 mmol) and 3-nitro-benzaldehyde (3.44 g, 23 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 3 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford (3-nitro-benzylidene)-(4-trifluoromethyl-phenyl)-amine (5.88 g, 95%) as a light yellow oil: LC/MS m/e calcd for C14H9F3N2O2 (M+H)+: 295.24, observed: 295.1.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27](=[O:29])[CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27](=[O:29])[CH3:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.78 g, 0.138 mol) in CH2Cl2 (50 mL) was added drop wise, over a 30 minutes period, to a stirred solution of (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (CAS RN: 55420-70-7) (19.80 g, 0.092 mol) and trifluoroacetic acid (1.05 mL, 0.009 mol) in CH2Cl2 (100 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:2) afforded the title compound (28.3 g, 88%) as a yellow oil. ES-MS m/e: 348.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]>N1C=CC=CC=1>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[S:6][C:5]([NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[N:4][C:3]=2[C:18]([NH2:20])=[O:19])=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a mixture of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.2 g, 0.70 mmol) in pyridine (5 mL) was added a solution of 4-methyl-3-nitrobenzoyl chloride in pyridine (3 mL) at 0° C. under nitrogen atmosphere. The mixture was allowed to warm up to rt, and stirred for 16 hrs at rt. The solvent was evaporated, and the crude residue was suspended into EtOAc (20 mL). The resulting solids were collected by filtration and washed with MeOH (2×5 mL) to give 0.21 g (66% yield) of the titled compound.