Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:6]([OH:8])=O.Cl.Cl.[CH:23]([O:26][C:27](=[O:49])[CH:28]([OH:48])[C@@H:29]([NH:37][C:38](=[O:47])[C@H:39]([CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1)[NH2:40])[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:25])[CH3:24].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH:23]([O:26][C:27](=[O:49])[CH:28]([OH:48])[C@@H:29]([NH:37][C:38](=[O:47])[C@H:39]([CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1)[NH:40][C:6](=[O:8])[CH:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[F:1])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:25])[CH3:24]
Reactant: CC(C)OC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(Cc1ccccc1F)Cc1ccccc1F
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1F)Cc1ccccc1F

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 67 mg of bis(2-fluorobenzyl)acetic acid and 100 mg of (2RS, 3S)-3-[N-(L-histidyl)amino]-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester dihydrochloride, and to the solution were successively added 0.06 ml of diphenylphosphoryl azide and 0.1 ml of triethylamine with stirring under ice-cooling. The mixture was still stirred for 16 hours, and the reaction mixture was evaporated under reduced pressure. To the residue was added an aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=10/1) to 23 mg of (2RS, 3S)-3-{N-[bis(2-fluorobenzyl)acetyl]-L-histidyl}amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester having an Rf2 value of 0.59 as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCCC1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
16-Hydroxyhexadecanoic acid (5.43 g, 19.9 mmol) was dissolved in tetrahydrofuran (190 ml) and pyridine (2.36 g, 29.9 mmol) was added. Palmitoyl chloride (5.48 g, 19.9 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in chloroform, washed with water (3×50 ml), and the organc phase was dried (MgSO4). After evaporating under reduced pressure, the residue was purified on a silica column, eluted with chloroform with increasing methanol concentration (from 1% to 2% methanol in chloroform) to give 8.41 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, 3H, CH3), 1.20-1.35 (s, 46H, --CH2 --), 1.55-1.70 (m, 6H, --CH2 --), 2.25 (t, 2H, --CH2 --C(O)--O), 2.45 (t, 2H, --CH2 --COOH), 4.05 (t, 2H, --O--CH2). 13C NMR (75 MHz, CDCl3): δ 14.01, 22.57, 24.10, 24.91, 25.82, 28.53, 28.75, 28.94, 29.08, 29.15, 29.25, 29.36, 29.54, 31.81, 34.29, 35.16, 64.27, 76.48, 76.90, 77.10, 77.32, 169.50, 173.91.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][N:28]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COS(OC)(=O)=O>CC(C)=O>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:1])[CH2:31][CH2:30]2)=[N:27][N:28]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CN1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
K2CO3 (621 mg, 4.5 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (988 mg) in acetone (30 mL). Me2SO4 (105 μl, 1.6 mmol) was slowly added at 0° C. The mixture was stirred at rt for 6 h, then concentrated and purified by reverse phase column chromatography (gradient elution 0-80% of acetonitrile in water) to give (2S,5R)-6-(benzyloxy)-2-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (198 mg, 33% for two steps) as a yellow solid. ESI-MS (EI+, m/z): 398.3 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:51][CH2:50][CH2:49]1>>[O:21]=[S:17]1(=[O:22])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[N:32]=3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([C:9]([N:8]2[CH2:6][CH2:51][CH2:50][CH2:49]2)=[O:40])[CH:15]=1
Reactant: C1CCNC1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCCC3)CC2)nc1C

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 768 and pyrrolidine (30 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (127 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[NH2:24][OH:25]>CO.[OH-].[K+]>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=[N:24][OH:25])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CC(=NO)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine prepared according to DE 199 09 767 A1 is dissolved in methanol containing 10% by weight of KOH and stirred for 5 hours at room temperature. Methanol is evaporated, the residue is washed with water and dried in vacuo. A solution of 95.24 g (0.3 mol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine and 29.7 g (0.45 mol) 50% aqueous hydroxylamine solution in 150 ml of methanol is stirred under reflux during 5 h. The suspension is then cooled to −8° C. and filtered. The solid is washed with 100 ml of a cold (−20° C.) methanol and dried to afford 64 g (64.1%) of the title compound as a white, microcrystalline powder, mp 130-145 oC. C20H32N2O2 (332.49) calculated C 72.25%, H 9.70%, N 8.43%; found 72.19% C, 9.54% H, 8.43% N.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5(NS(C(C)(C)C)=O)CC[CH2:28]5)=NC=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44].BrC1C=C[C:51]([C:54](C)([CH3:57])[C:55]#[N:56])=CC=1>>[O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:28]=[CH:27][C:24]([C:54]([CH3:57])([CH3:51])[C:55]#[N:56])=[CH:23][CH:22]=4)=[C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cn2)CCC1
Product: CC(C)(C#N)c1ccc(-c2c(-c3ccccc3)oc3c(ccn4c(=O)n(COCC[Si](C)(C)C)nc34)c2=O)cc1
Yield: 99 %

Procedure:
Following the procedure used to prepare 2-methyl-propane-2-sulfinic acid (1-{5-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-pyridin-2-yl}-cyclobutyl)-amide, 2-(4-bromo-phenyl)-2-methyl-propionitrile was reacted to give the title compound (55 mg, 99%). LCMS (Method A): RT=4.83 min, [M+H]+=553.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOCCOc1ccc(C(=O)OC)cc1F
Yield: 89.1 %

Procedure:
Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) methyl 3-fluoro-4-hydroxybenzoate, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4% diethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 8.55 g of white crystals, 89%, m.p. 33-36.5° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses. ##STR22##
Reaction SMILES: [CH2:1](C(C)=O)[CH:2](C)C.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].C(Br)C>O>[CH2:18]([N:10]([CH2:8][CH3:9])[C:11]1[CH:12]=[C:13]([O:17][CH2:1][CH3:2])[CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: CC(=O)CC(C)C
Reactant: CCN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCBr
Solvent: O
Product: CCOc1cccc(N(CC)CC)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 liter reactor is charged with 150 ml of methyl isobutyl ketone, 73.1 g of 3-diethylaminophenol and 153.3 g of ground potassium carbonate. The mixture is stirred for 30 minutes, then 72.7 g of ethyl bromide are added and the autoclave is closed. The reaction mixture is heated first for 3 hours to 115°-129° C. and then for a further 5 hours at 140°-142° C. (pressure: 4 bar). After cooling to c. 25° C. and addition of water, the product is isolated with the organic phase, which is washed with water and concentrated by evaporation, to give 80.67 g (97.2% yield) of 3-diethylaminophenetol with a titre of 94.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li][C:12](C)(C)[CH3:13].C(I)C>C1COCC1>[CH2:12]([C:7]1[S:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:8]=1)[CH3:13]
Reactant: Cc1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2cc(C)ccc2s1

Procedure:
2-ethyl-5-methylbenzo[b]thiophene was prepared in the same manner as described in Example 40A. Reaction of 5-methylbenzo[b]thiophene (3.4 mmoles, 0.50 g), t-BuLi (1.7 m, 5.1 mmoles, 3.0 ml) and ethyl iodide (6.8 mmoles, 0.54 ml) in THF (10 ml) yielded 0.58 g (97%) of a light yellow liquid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[N:14]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)=[C:15]=[O:16]>ClCCCl>[CH3:5][C:2]1([CH3:6])[C:3](=[NH:4])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=2)[C:15](=[O:16])[NH:1]1
Reactant: CC(C)(N)C#N
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=N
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 47.3 %

Procedure:
To a solution of compound 9 (641 mg, 7.62 mmol) and triethylamine (168 mg, 1.66 mmol) in 1,2 dichloroethane (8.4 mL) at 0° C. under argon was dropwise added a solution of the isocyanate 8a (1.54 g, 7.28 mmol) in 1,2 dichloroethane (3.5 mL). The solution was stirred at 0° C. for 35 min and the ice bath was then removed and stirred at room temperature for an additional 30 min. The solution was then evaporated to dryness and purified by flash chromatography using EtOAc/Hexane (6:4) as an eluant to give pure compound 10a (1.02 g, 47%). 1H NMR (300 MHz, Acetone-d6) δ: 1.54 (m, 6H), 7.45 (broad s, 1H), 8.12 (d, 1H, J=8.46 Hz), 8.29 (dd, 1H, J1=6.90 Hz, J2=1.61 Hz), 8.46 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][CH2:8][C:7]2=[O:18])([O-:3])=[O:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][N:22]([CH:24]=[C:8]1[C:7](=[O:18])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9]1)[CH3:23]
Reactant: CCC(=O)N1CCC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(OC)N(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.976 g), N,N-dimethylformamide dimethyl acetal (8.568 g), and triethylamine (1.818 g) in benzene (24 ml) was refluxed with stirring for 2.5 hours and cooled to room temperature. The resulting precipitates were collected by filtration, washed with cold ethyl acetate, and dried to give 3-dimethylaminomethylene-6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (3.345 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[NH:7][C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9])=[O:5].C1(C)C(C)=CC=CC=1.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[N:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9])=[O:5]
Reactant: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: COCC(=O)N(c1c(C)cccc1C)N1CCOC1=O
Reaction time: 2 h

Procedure:
236.1 g (0.75 mol) 2-Chloroethyl 2-(methoxyacetyl)-2-(2,6-dimethylphenyl)-hydrazinecarboxylate, 375 ml xylene and 187 ml water are stirred with external cooling, while 82.5 ml (0.82 mol) of an aqueous solution of sodium hydroxide (containing ~0.4 g NaOH per ml) are added at a rate to maintain the internal temperature at approx. 20°. The mixture is stirred after completion of the addition for 1 hour at 20°, and for 2 hours at 0°. The solid is filtered off, washed with 150 ml water and dried to yield the title compound as a slightly coloured solid, m.p. 102°-103°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Reactant: ClCc1cscn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1cscn1
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of Example 79A (2.65 g, 9.4 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.247 g, 10.3 mmol). The reaction mixture was stirred for 30 min. and then treated with commercially available 4-(chloromethyl)thiazole (1.25 g, 9.4 mmol). The resulting mixture was stirred at room temperature for 18 hr, poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organics were washed with water, brine (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound (2.56 g, 72% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 3.77 (s, 3H), 5.50 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.38-7.52 (m, 2H), 7.63 (dd, J=14.5, 2.6 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H). MS (DCI) m/z 398 (M+H)+; MS (DCI) m/z 380 (M+H)+. Anal. Calculated for C16H14ClN3O2S2: C, 50.59; H, 3.71; N, 11.06. Found: C, 50.57; H, 3.02; N, 11.03.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([N:7]2[CH:6]([CH3:22])[C:5]3[C:9](=[CH:10][C:2]([C:32]4[CH:31]=[N:30][N:29]([CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28][O:23]5)[CH:33]=4)=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH3:13])=[CH:15][CH:16]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2C)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Combine 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (64 g, 177 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 g, 295 mmol), potassium carbonate (70 g, 506 mmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (9 g, 11 mmol), dioxane (800 mL), and water (212 mL) under nitrogen and heat to 70-75° C. for 16 hours. Add 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 g, 54 mmol) and heat to 80-85° C. for 2 hours. Concentrate under reduced pressure to 200 mL, add ethyl acetate (500 mL) and water (500 mL), stir for 30 minutes, and filter the solids. Combine the solids and the organic layer and evaporate under reduced pressure. Dissolve the residue in dichloromethane and filter through a pad of silica gel. Wash the silica gel pad with dichloromethane/ethyl acetate (1:0) and then (2:1) and evaporate to dryness under reduced pressure. Slurry the solid in a 2:1 mixture of petroleum ether/ethyl acetate (600 mL) for 30 minutes at 25-30° C. and filter to collect the solid to give the title compound as an off-white solid (68 g, 89%). ES/MS m/z: 432 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([OH:18])=O)[CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:26][CH2:25][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:18])[CH:8]=2)[CH:3]=1
Reactant: COC(=O)c1cc2cc(C(=O)O)ccc2cc1O
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCOC(=O)c1ccc2cc(O)c(C(=O)O)cc2c1
Temperature: 50 °C

Procedure:
In 10.0 g of tetrahyrofuran, 1.00 g of 2-hydroxy-6-hydroxycarbonyl-3-methoxycarbonylnaphthalene is suspended. To this, 0.94 g of thionyl chloride and a small amount of N,N-dimethylformamide are added, and heated to 50° C. After allowing to proceed the reaction for about 3 hours, the solvent and other volatile are evaporated. To the residue, a solution of 1.27 g of n-decanol dissolved in 10.0 g of tetrahydrofuran is added, and reacted for about 20 hours under reflux. After evaporating the solvent, 15.0 g of N,N-dimethylformamide, 15.0 g of methanol, and 180.0 g of 5% aqueous sodium hydrogencarbonate are added, and reacted for 20 hours at 60° C. After removing insoluble matter, the pH of the reaction mixture is adjusted to pH 2 at 50° C., and the precipitate is recovered by filtration. The product was washed with warm water and methanol, and dried to yield 1.33 g of 2-hydroxy-3-hydroxycarbonyl-6-decyloxycarbonylnaphthalene as a white-yellow powder (melting/decomposing point: 269.2° C. (dec.)).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([NH:49][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of of 2-bromo-4-methylthiazole-5-carboxylic acid (9.00 g, 40.0 mmol) in anhydrous tetrahydrofuran (140 mL) was added N,N-diisopropylethylamine (20.76 mL, 121.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.87 g, 56.0 mmol). The reaction mixture was stirred at ambient temperature for 0.5 hours and 1-hydroxybenzotriazole (7.60 g, 56.0 mmol) and benzyl amine (6.00 g, 56.0 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 hours, then concentrated to half volume in vacuo, diluted with dichloromethane (400 mL), and washed with water (400 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/1) to afford the title compound as a colorless solid in 70% yield (8.89 g): mp 92-94° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.41-7.23 (m, 5H), 5.94 (br s, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 311.0 (M+1), 313.1 (M+3).
Reaction SMILES: Br[C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]3[CH:15]=[N:16][NH:17][C:13]=3[CH:12]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:9]=2[N:10]=1)=[O:4].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:41])=[C:29]([CH:40]=1)[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31].O>C(O)CO>[Cl:41][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:2]([CH3:23])([C:3](=[O:4])[NH:5][C:6]2[S:7][C:8]3[C:14]4[CH:15]=[N:16][NH:17][C:13]=4[CH:12]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:9]=3[N:10]=2)[CH3:22])=[CH:40][C:29]=1[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31]
Reactant: CCOC(=O)CCNC(=O)c1cc(N)ccc1Cl
Reactant: CC(C)(Br)C(=O)Nc1nc2c(C(F)(F)F)cc3[nH]ncc3c2s1
Solvent: OCCO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1cc(NC(C)(C)C(=O)Nc2nc3c(C(F)(F)F)cc4[nH]ncc4c3s2)ccc1Cl
Temperature: 25 °C
Yield: 13.4 %

Procedure:
0.1 g (0.25 mmol) of 2-bromo-2-methyl-N-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl)-propionamide and 0.23 g (0.85 mmol) of ethyl 3-(5-amino-2-chlorobenzoylamino)-propionate were heated at 100° C. in 4 ml of ethylene glycol. After the completion of the reaction was confirmed by HPLC, the mixture was cooled to room temperature, and 4 ml of water was added to the mixture. The mixture was extracted with 4 ml of ethyl acetate twice, dried over 3 g of anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 20 mg of ethyl 3-{2-chloro-5-[1-methyl-1-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylcarbamoyl)-ethylamino]-benzoylamino}-propionate.