Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O>O1CCOCC1.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:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C[C@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Yield: 41.4 %

Procedure:
To a solution of (S)-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (109 mg, 0.26 mmol), 2,4-difluorophenylboronic acid (49 mg, 0.31 mmol) and Pd(PPh3)4 (30 mg, 0.03 mmol) in dioxane (8 mL) was added a solution of CsCO3 (2 M, 1 mL) at 0□. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH2Cl2 twice. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((R)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (49 mg, 42%). LC-MS Method 3 tR=1.41, min, m/z=456; 1H NMR (CD3OD): 1.55 (m, 3H), 2.12 (m, 2H), 2.22-2.46 (m, 3H), 2.52 (m, 1H), 3.12 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 5.56 (m, 1H), 7.08 (m, 6H), 7.08 (m, 2H), 7.35 (m, 5H). 443-155-3.
Reaction SMILES: Cl.[OH:2][NH2:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:37]=[CH:36][C:16]([O:17][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)#[N:12]>CS(C)=O.C(OCC)(=O)C>[OH:2][NH:3][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:36][CH:37]=1)=[NH:12]
Reactant: NO
Reactant: CCOc1cc(C(Oc2ccc(C#N)cc2)C(=O)OC)ccc1OC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1cc(C(Oc2ccc(C(=N)NO)cc2)C(=O)OC)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To hydroxyamine HCl salt (363 mg, 5.2 mmol) in DMSO (5.0 mL) was added triethyl amine (0.725 mL, 5.2 mmol). After stirring at rt for 10 min, the cloudy solution was filtered directly into a round-bottom flask containing 9A (482 mg, 1.3 mmol). The mixture was stirred at 60° C. for 18 h before it was diluted with ethyl acetate and washed with 5% NaHCO3/brine. The organic extract was dried over Na2SO4 and concentrated to give 9B as a white solid. LC-MS 403 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].O>CN(C=O)C>[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=1)=[O:15]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(OC(=O)C(Cl)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
Sodium hydride (2 g) was added portionwise to a solution of 3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for 30 minutes and added dropwise at a temperature below 30° C. to a solution of 2-chloro-2-phenylacetylchloride (9.45 g) in DMF (50 ml). The mixture was stirred overnight, decomposed with water (5 ml) and the solvent was evaporated. Water was added and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: hexane/DIPE 100/0, 98/2 and 95/5). The pure fractions were collected and the solvent was evaporated [residue; yielding 10.82 g (79%)]. A small amount of the obtained residue was crystallized from DIPE, the precipitate was filtered off and the solvent was evaporated, yielding 1 g of (±)-3,5-dimethylphenyl α-chlorobenzeneacetate (intermediate 5; mp. 79.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[N:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CN(C=O)C.S(Cl)(Cl)=O.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[N:13][CH:12]=[C:11]([CH2:15][N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH3:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Reactant: Cc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nccn1Cc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
[6-(3-Chloro-4-fluoro-phenyl)-pyridazin-4-yl]-methanol (13 mg, 0.054 mmol) was dissolved in MeCl2 (1 ml) under argon and a drop of DMF was added. The mixture was cooled with an icebath, thionylchloride (0.02 ml, 0.27 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. After 30 minutes the reaction mixture was concentrated in vacuo. The residue was dissolved in ethanol and treated with 2-methyl-imidazole (22.3 mg, 0.27 mmol). The reaction mixture was refluxed for 12 hours then cooled to room temperature and concentrated. Ethyl acetate and a saturated NaHCO3 solution were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (CH2Cl2—MeOH 19:1) to provide 3-(3-chloro-4-fluoro-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridazine (4 mg, 24%) as a light brown oil, MS: m/e=303.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)CN(CCN1CCOCC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of [tert-butoxycarbonyl-(2-morpholin-4-yl-ethyl)amino]acetic acid methyl ester (0.79 g, 2.61 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 1 h, the solution was concentrated in vacuo. The oil was dissolved in CH2Cl2 (50 mL) and the resulting solution was washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (10×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (0.40 g, 76%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 3.69-3.74 (m, 7H), 3.45 (s, 2H), 2.69-2.73 (m, 2H), 2.45-2.52 (m, 6H), 1.84 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:25][C:24]3[C:23]([Cl:22])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1Cl
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Clc1cc(C2CN(Cc3ccccc3)CCO2)ccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 102.5 %

Procedure:
A mixture of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorobenzyl bromide (0.39 g; 1.64 mmol) and Cs2CO3 (2.55 g; 7.82 mmol) in CH3CN (20 mL) was heated under reflux overnight. After cooling to RT the resulting mixture was partitioned between EtOAc and water. The layers were separated and the organic layer, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2:MeOH 98:2) to afford 4-benzyl-2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.74 g)
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][N:3]([C:12](=[O:14])[CH3:13])[CH2:2]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:33][C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][N:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N1C=C(Br)c2ccccc2CC1

Procedure:
reaction of the 1-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone [J. Heterocycl. Chem. (1971), 8(5), 779-831] with dibenzoylperoxide and N-bromosuccinimide in carbon tetrachloride at reflux yielded the 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone; hydrogenation of the 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone with tritium using Pd/C in methanol in the presence of triethylamine yielded the 1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo [d]azepin-3-yl) -ethanone; treatment of the 1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone with conc. aq. hydrochloric acid in methanol gave the 1,1,2-tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][O:20][CH2:21][CH2:22]O.C(P(CCCC)CCCC)CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[OH:57])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1.O>[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][CH2:22][CH2:21][O:20][CH3:19])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
518 mg of 1,1′-(azodicarbonyl)dipiperidine (2.05 mmol), 156 mg of 2-methoxyethanol (2.05 mmol) and 0.42 ml of tributylphosphine (2.05 mmol) were added to a solution of 400 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.36 mmol) in toluene (14 ml), and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/2) to obtain 444 mg of 4-[2-(2-methoxyethoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester (yield: 86%).
Reaction SMILES: [S:1](=[O:11])(=[O:10])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:2].[C:12]([NH:15]C1C=CC(O)=CC=1)(=[O:14])[CH3:13].N1C=CC=CC=1>O1CCOCC1>[C:12]([NH:15][C:7]1[CH:8]=[CH:9][C:4]([O:3][S:1](=[O:10])(=[O:11])[NH2:2])=[CH:5][CH:6]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: NS(=O)(=O)Oc1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OS(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A reaction flask was charged with 43.8 g (0.252 mole) of sulfamic acid, phenyl ester; 12.6 g (0.084 mole) of 4-acetamidophenol, 9 ml of pyridine and 150 ml p-dioxane. The solution was heated at 75° C. for 18 hours. The solution was concentrated to a brown oil. The oil was portioned between 100 ml methylene chloride and 100 ml of 1.0N sodium bicarbonate. The mixture was refrigerated overnight then filtered to collect 15.8 g of white solid. 1H NMR spectrum indicated pure product but contaminated with sodium bicarbonate. The solid was added to 100 ml H2O and the mixture stirred for one hour. The solid was collected and dried to give 8.4 g of solid, mp 180°-181° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][P:21](=[O:29])([O:25][CH:26]([CH3:28])[CH3:27])[O:22][CH2:23][CH3:24])=[CH:16][C:15]=1[O:30][CH3:31].C(N(C(C)C)CC)(C)C>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][P:21](=[O:29])([O:25][CH:26]([CH3:28])[CH3:27])[O:22][CH2:23][CH3:24])=[CH:16][C:15]=2[O:30][CH3:31])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OC(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (7.5 g, 34.7 mmol) in dichloroethane and t-butanol (1:1, 10 mL) was treated with ZnCl2 (1M solution in ether, 35 mL) and stirred for half an hour at RT. The reaction mixture was cooled to 0° C. and a solution of ethyl propan-2-yl [(4-amino-3-methoxyphenyl) methyl]phosphonate (Compound 72E, 5 g, 16.28 mmol) in dichloroethane and t-butanol (1:1, 10 mL) followed by diisopropylethylamine (6 mL, 34.7 mmol) were added drop wise while stirring was continued for 24 hrs. The resulting white precipitate was filtered. The solid was dissolved in dichloromethane, washed with water (2×50 mL), dried over magnesium sulfate, filtered and evaporated to give 6.3 g of pure required isomer. 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.04 (s, 1H), 6.89 (d, J=8 Hz, 1H), 4.73-4.76 (m, 1H), 4.08-4.11 (m, 2H), 3.95 (s, 3H), 3.23 (d, J=21 Hz, 2H), 1.24-1.33 (9H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N1C=CN=C1)(N1[CH:30]=[CH:29]N=C1)=O.[C:36]([O-:39])([O-])=O.[Cs+].[Cs+].O>COCCOC>[CH2:29]([N:22]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([F:23])[CH:20]=2)[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:36]1=[O:39])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(F)cnc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]-5-fluoropyridine-2,3-diamine (0.85 g) and 1,1′-carbonylbis(1H-imidazole) (0.45 g) in DME (10 mL) was stirred at 100° C. for 4 h, and then Cs2CO3 (0.90 g) and 1,1′-carbonylbis(1H-imidazole) (0.892 g) were added successively. The mixture was stirred at 100° C. for 10 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (10 ml), and then Cs2CO3 (3.58 g) and iodoethane (1.29 g) were added successively. The mixture was stirred at 100° C. for 2 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOH (30 mL), and Pd/C (1.5 g) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 30 min, filtered and evaporated. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound (0.52 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].Cl.[C:19]([O:23][C:24](=[O:34])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30](=[O:33])[CH2:31][NH2:32])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:34])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30](=[O:33])[CH2:31][NH:32][S:13]([C:8]1[C:9]2[C:4](=[C:3]([N:2]([CH3:17])[CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:15])=[O:14])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)NCC(=O)N3CCC[C@H]3C(=O)OC(C)(C)C)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
5-Dimethylamino-l-naphthalenesulfonyl chloride (5.10 g, 18.9 mmol) was added in portions to a well-stirred solution of glycyl-L-proline tert-butyl ester hydrochloride (5.00 g, 18.9 mmol) and triethylamine (5.20 mL, 37.8 mmol) in dry tetrahydrofuran (175 mL). The mixture was stirred at room temperature for 4 hours before it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and brine. Following drying and solvent evaporation, the residue was chromatographed on silica gel (gradient elution with first 40% ethyl acetate in hexanes followed by 50% ethyl acetate in hexanes) and furnished 7.62 g (87%) of the title compound as a fluorescent green foam, m.p. 60°-67° C.; 1H NMR (CDCl3) δ 8.51 (dd, J=8.5, 3.3 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.21-8.16 (m, 1H), 7.58-7.43 (m, 2H), 7.15 (d, J=7.4 Hz, 1H), 5.85-5.79 (m, 1H), 4.27-4.23 (m, 1H), 3.76-3.62 (m, 2H), 3.48-3.21 (m, 2H), 2.84 (s, 6H), 2.10-1.75 (m, 4H), 1.33 and 1.32 (2s, 9H); 13C NMR (CDCl3) ppm 170.84, 170.45, 165.84, 165.46, 152.04, 134.31, 134.16, 130.79, 130.16, 130.12, 129.87, 129.52, 129.47, 128.77, 123.23, 123.17, 119.22, 119.13, 115.59, 83.00, 81.82, 59.99, 59.38, 46.97, 45.98, 45.64, 44.69, 44.58, 31.41, 29.13, 28.05, 27.96, 24.49, 23.80, 22.36; IR (KBr, cm-1) 3266, 2978, 2942, 2876, 2834, 1736, 1658, 1456, 1440, 1370, 1330, 1148, 792, 626, 574; MS m/z (MH+) calcd 461.1984, obsd 461.1982.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[B:22](OC)([O:25]C)[O:23]C>CCOCC>[S:9]1[C:10]2[C:2]([B:22]([OH:25])[OH:23])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=[CH:8]1
Reactant: Brc1cccc2ccsc12
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cccc2ccsc12
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
A solution of 7-bromo-1-benzothiophene (19.9 g, 0.094 mol) in absolute ether (200 ml) was treated with a 1.6 M solution of n-butyllithium in hexane (0.14 mol, 88 ml) at −78° C. The solution was stiffed at −78° C. for 10 minutes then treated with trimethyl borate (15 ml, 0.14 mol). The mixture was allowed to warm to −10° C. then quenched with an excess of dilute hydrochloric acid. The organic layer was separated, dried, evaporated, and the residue was recrystallised from aqueous ethanol to yield the title compound (10 g, 60%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:17][C:18]1[CH:19]=[C:20]([O:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1.Cl>C(OCC)(=O)C>[C:8]1([NH:14][C:15]([N:27]2[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[N:26]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(Oc2cccc(Cl)c2)n[nH]1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cccc(Cl)c2)nn1C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 86.4 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and phenyl isocyanate (0.15 g, 1.3 mmol) were added to a solution of 3-(3-chlorophenyloxy)-5-methylpyrazole (0.25 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, it was stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-phenyl-3-(3-chlorophenyloxy)-5-methylpyrazole-1-carboxamide (0.34 g, yield: 84.5%). 1H-NMR (CDCl3, TMS, ppm): δ 2.66 (d, J=0.8 Hz, 3H), 5.78 (q, J=0.8 Hz, 1H), 7.05-7.11 (m, 1H), 7.14-7.21 (m, 3H), 7.28-7.39 (m, 3H), 7.52-7.56 (m, 2H), 8.91 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6](C2C=C3C(=CC=2)NC(=NC#N)C23CCCCC2)=[CH:5]C=1)#N.[CH2:26]([OH:28])[CH3:27]>>[OH:28][CH2:26][CH2:27][N+:7]([CH3:8])([CH3:3])[CH3:6].[NH:7]([CH2:3][CH3:1])[CH2:6][CH3:5]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=NC#N)N2
Reactant: CCO
Product: CCNCC
Product: C[N+](C)(C)CCO

Procedure:
5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide (0.96 g) in ethanol (20 mL) was reacted with the bases set forth in Table 2 to form, upon cooling, filtering and drying, 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide salt as a solid. The 1H-NMR spectra (DMSO-d6) of the purified compound (X═H) and isolated salts (X═Na, K, choline, and Et2NH.H) were obtained and the data compiled in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:19])[C:14]([O:16]CC)=O)[CH:7]=[CH:6]2.[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH:20]([NH:23][C:14](=[O:16])[CH:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[OH:19])([CH3:22])[CH3:21]
Reactant: CC(C)N
Reactant: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1
Product: COc1ccc2cc(C(O)C(=O)NC(C)C)ccc2c1

Procedure:
Ethyl 6-methoxy-2-naphthylglycolate (0.1 mole) is stirred with 20 ml. of isopropylamine at about 35°C with stirring overnight and the temperature is then raised to reflux for 28 hours. The reaction mixture is evaporated in vacuo and the residue distilled to obtain N-isopropyl-6-methoxy-2-naphthylglycolamide.