Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])([OH:8])[C:5]([OH:7])=[O:6].[O-][CH2:21]C.[Na+].[Na].CI>C(O)C.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])([OH:8])[C:5]([O:7][CH3:21])=[O:6]
Reactant: CC[O-]
Reactant: O=C(O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CI
Product: COC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl
Reaction time: 8 h

Procedure:
A solution of 10.0 g (0.034 mol) of 2,2′-dichlorobenzilic acid in 50 ml of ethanol was added dropwise to freshly prepared sodium ethoxide solution of 0.78 g (0.034 mol) of sodium and 100 ml of ethanol at 20° C. and stirred overnight. The solution was evaporated to dryness, the residue was dissolved in DMF and at 20° C. 9.57 g (0.0674 mol) of methyl iodide were added dropwise and the mixture was stirred for a further 72 hours. 300 ml of water were added dropwise to the resulting suspension while cooling with ice, it was extracted with diethyl ether, the organic phase was washed with water, dried over Na2SO4, and evaporated to dryness. Yield: 10.48 g (100% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]([CH3:16])[C:12](=[O:15])[CH2:13][N:14]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]([CH3:16])[C:12](=[O:15])[CH:13]([OH:30])[N:14]=1
Reactant: CCc1cc2c(s1)N(C)C(=O)CN=C2c1ccccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCc1cc2c(s1)N(C)C(=O)C(O)N=C2c1ccccc1Cl
Temperature: 25 °C
Yield: 41.3 %

Procedure:
5-(2-Chlorophenyl)-7-ethyl-1-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one (3 g) was dissolved in chloroform (60 ml) and m-chloroperbenzoic acid (4.3 g) was added thereto with stirring at room temperature. The mixture was further stirred for 8 hours. The reaction mixture was washed with 0.5N sodium hydroxide and water and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue obtained was dissolved in acetic anhydride (30 ml). The mixture was stirred while heating at 70° C. After cooling, the reaction mixture was poured into water and neutralized with sodium hydrogen-carbonate. After the mixture was extracted with ethyl acetate, the organic layer was washed with an aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (40 ml). A solution of sodium hydroxide (0.6 g) in water (10 ml) was added thereto at room temperature with stirring and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and water (50 ml) was added thereto. After the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 1.3 g of crude 5-(2-chlorophenyl)-7-ethyl-3-hydroxy-1-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one. This compound (0.7 g) was dissolved in toluene (20 ml) and 3-methylphenylisocyanate (0.31 g) was added thereto. The mixture was stirred for 2 days while heating at 90° C. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 0.25 g of (5-(2-chlorophenyl)-7-ethyl-1-methyl-oxo-1,3-dihydro-2H-thieno[2,3-e][1,4]-diazepin-3-yl)-N-(3-methylphenyl)carbamate having a melting point of 181°-182.5° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Cu][C:11]#[N:12].C(N)CN>CN1C(=O)CCC1>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[F:9]
Reactant: Nc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(F)c1

Procedure:
In NMP, compound [O], commercially available 4-bromo-2-fluoroaniline is cyanated with copper (I) cyanide and the resulting copper complex is decomposed with ethylene diamine (EDA) to yield compound [P], 4-amino-3-fluorobenzonitrile. Compound [P] is reacted with nitrosyl hydrogen sulfate (HSO4 --ONO2), prepared by mixing sodium nitrite and concentrated sulfuric acid in glacial acetic acid, and converted into the corresponding diazonium salt. The diazonium salt is brominated with copper (I) bromide in hydrobromic acid to yield compound [Q], 4-bromo-3-fluorobenzonitrile. Compound [Q] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [R], 4-bromo-3-fluorobenzimidate hydrogen chloride. In ethanol, compound [R] is reacted with gaseous ammonia to yield compound [S], 4-bromo-3-fluorobenzamidine hydrogen chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[F:19][C:20]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:23]([NH2:24])=[C:22]([O:30][CH3:31])[CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[F:19][C:20]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[C:5]([CH3:18])=[CH:4][N:3]=2)=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: Cc1cnc(Cl)nc1-c1cn(C)c2ccccc12
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 125 °C

Procedure:
A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)-1-methyl-1H-indole (Intermediate 80, 350 mg, 1.36 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 265 mg, 1.43 mmol) and p-toluenesulfonic acid (284 mg, 1.49 mmol) in 2-pentanol (25 mL) was heated at 125° C. for 24 h. The mixture was then cooled and concentrated in vacuo. The resulting gum was used without further purification; m/z: ES+ MH+ 240.13.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)[CH3:4].C(N(CC)C(C)C)(C)C.[N:23]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[C:24]=[O:25]>ClCCCl>[CH:26]1([NH:23][C:24](=[O:25])[NH:2][CH:3]([C:5]2[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=2)[CH3:4])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C=NC1CCCC1
Reactant: COC(=O)c1ccc(C(C)N)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(C)NC(=O)NC2CCCC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride (33.2 mg, 0.150 mmol) and N,N-diisopropylethylamine (104 μL, 0.60 mmol) dissolved in 1,2-dichloroethane (1 mL) was added isocyanatocyclopentane (24 mg, 0.22 mmol). The reaction solution was shaken at room temperature overnight. The solution was further diluted with DCE (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The layers were separated and the organic layer concentrated to afford methyl 5-(1-(3-cyclopentylureido)ethyl)thiophene-2-carboxylate as an oil residue. LC-MS: (FA) ES+ 297.
Reaction SMILES: CN(CCN(C)C)C.[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[C:25]12([P:35]([C:37]34[CH2:46][CH:41]5[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]5)[CH2:38]3)[CH2:44]4)Cl)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>CCCCCC.O>[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[C:16]2[P:35]([C:37]23[CH2:38][CH:39]4[CH2:40][CH:41]([CH2:42][CH:43]([CH2:45]4)[CH2:44]2)[CH2:46]3)[C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: c1ccc(-n2cccc2P(C23CC4CC(CC(C4)C2)C3)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.6 ml of TMEDA (15 mmol.) are added to a suspension of 1.43 g (10 mmol.) of N-phenylpyrrole in 30 ml of hexane. 6.25 ml of 1.6 molar n-butyllithium solution (10 mmol.) are added at room temperature. The mixture is then heated for 2.5 hours at reflux temperature (solution 1). In another flask, 3.36 g (10 mmol.) of di-1-adamantylchlorophosphane are mixed with 40 ml of hexane and heated to 76° C. (solution 2). The boiling solution 1 is then slowly transferred into solution 2, which is at 76° C., by means of a cannula. The mixture is then boiled for a further 2 hours at reflux, the solution is cooled, and 20 ml of water are added thereto. The organic phase is filtered off over magnesium sulfate. The solution is concentrated in vacuo; 15 ml of toluene are added thereto, and the mixture is heated to 60° C. and then cooled. After one day at room temperature, the product is filtered off. Yield: 3.3 g (75%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([F:20])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([F:20])=[C:18]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2F)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2F)OC1(C)C
Reaction time: 1 h

Procedure:
To a solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-fluoro-4-iodo-1H-pyrazole (80.0 mg, 0.188 mmol) in THF (2 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.58 mL, 0.75 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 mL, 0.94 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 2-7% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=425.28 (100) [MH+]. HPLC: tR=2.23 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.CCOCC>[C:15]([O:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=[CH:4][C:5](=[O:8])[CH:6]=[CH:7]1)(=[O:17])[CH3:16]
Reactant: O=C1C=CC(O)(c2ccccc2)C=C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1(c2ccccc2)C=CC(=O)C=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To 4-hydroxy-4-phenyl-2,5-cyclohexadienone (0.335 g, 1.8 mmol), acetic anhydride (0.276 g, 2.7 mmol, 1.5 equivalents) and triethylamine (0.273 g, 2.7 mmol, 1.5 equivalents) dissolved in dichloromethane (20 mL) was added 4-dimethylaminopyridine (DMAP) (0.044 g, 0.36 equivalents). The reaction mixture was stirred for 24 hours at room temperature, washed with 1 M HCl (20 mL) then saturated sodium hydrogen carbonate solution (2×20 mL) and the organic layer dried over magnesium sulphate. Removal of the solvent in vacuo gave an oil which was dissolved in ether, filtered and the solvent removed in vacuo to gave the title compound as a white solid. The yield was 62%; mp 100–101° C. (lit. 106–109° C.); 1H NMR (CDCl3) δ 7.48–7.36 (5H, m, ArH); 6.99 (2H, d, J 19.2 Hz, H-3, H-5); 6.36 (2H, d, J 10.2 Hz, H-2, H-6); 2.22 (3H, s, O2CCH3).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:30])C(=O)C1>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[C:21]=1[I:30])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(NC(=O)OCc1ccccc1)c1cn2ccncc2n1
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OCc1ccccc1)c1nc2cnccn2c1I
Reaction time: 8 h

Procedure:
To a solution of (1-imidazo[1,2-a]pyrazin-2-yl-ethyl)-carbamic acid benzyl ester (1.7 g, 5.74 mmol) in acetonitrile (10 mL) was added n-iodosuccinimide (1.3 g, 5.74 mmol) at rt and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide [1-(3-iodo-imidazo[1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 422.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22]([CH:24]1[CH:32]([NH2:33])[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25]1)[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:33][CH:32]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH2:25][CH:24]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC1Cc2cccnc2C1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2c3ncccc3CC2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.43, 7.68, 7.59, 7.16, 5.44, 5.19, 3.12-3.02, 2.82-2.63, 1.43-1.25, 0.88; HRMS (FAB) calcd for C18H24N4+H 297.2079, found 297.2080.
Reaction SMILES: C([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(C)C.C(O[C:15](=[O:17])[CH3:16])(=O)C.[C:18]1(C)[CH:23]=CC=C[CH:19]=1>>[CH:18]([CH2:16][C:15]([NH:6][C:5]1[CH:4]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:17])([CH3:23])[CH3:19]
Reactant: Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccccc1N
Product: CC(C)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture containing 300 ml of toluene and 31 ml of 2-isopropylaniline is cooled in ice, and 22 ml of acetic anhydride are added slowly. After 40 minutes with stirring at RT, the reaction medium is evaporated and the residue is then taken up with petroleum ether. The precipitate formed is drained. 35.9 g of the expected product are obtained after crystallization in petroleum ether, m.p.=81° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[NH2:13][C:14]1[CH:24]=[C:23]2[C:17]([C:18]([Cl:29])=[C:19]([O:25][CH2:26][CH2:27][Br:28])[O:20][C:21]2=[O:22])=[CH:16][CH:15]=1.NC(N)=S>>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:24]=[C:23]3[C:17]([C:18]([Cl:29])=[C:19]([O:25][CH2:26][CH2:27][Br:28])[O:20][C:21]3=[O:22])=[CH:16][CH:15]=2)=[S:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cccc(N=C=S)c1
Reactant: Nc1ccc2c(Cl)c(OCCBr)oc(=O)c2c1
Agent: NC(N)=S
Product: O=C(O)c1cccc(NC(=S)Nc2ccc3c(Cl)c(OCCBr)oc(=O)c3c2)c1
Yield: 64 %

Procedure:
7-(m-Carboxyphenylthiocarbamoylamino)-4-chloro-3-(2-bromoethoxy)isocoumarin was prepared from the reaction of m-carboxyphenyl isothiocyanate with 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarin, yield 64%, m.p. 157°-158° C.; mass spectrum m/e 361 (M+ -(COOH)PhNH+1). Anal. Calc.: C, 45.85; H, 2.84. Found: C, 45.73; H, 2.86. The bromoethoxy compound was then reacted with thiourea to give the product, yield 21%; mass spectrum (FAB+) m/e 493 (M+ -Br).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)C.[H-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](C2C=CC=CC=2)=O)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH3:28])=[CH:5][C:4]([OH:3])=[O:14])=[CH:25][CH:26]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(CC(=O)c2ccccc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=CC(=O)O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
The solution of ethyldiethylphosphonoacetate (1.2 eq, 0.25 g) in 4 ml of DMF was put into the flask and then cooled to 0° C. To the solution was added 60% sodium hydride (1.4 eq, 1.27 mmol, 51 mg) and then added 4-t-butylphenylacetophenone (0.16 g, 0.91 mmol) in 3 ml DMF slowly. The mixture solution was stirred for 4 hours. After conforming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, and washed with water. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was dissolved in MeOH/THF solution and added 1N NaOH solution, and then refluxed overnight. After conforming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, and acidified with 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained solid was purified with column chromatography to yield the title compound (134 mg, 68.1%)
Reaction SMILES: [O:1]=[C:2]1[CH:5]([N:6]2[C:10](=[O:11])[C:9]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]3[C:7]2=[O:16])[CH2:4][N:3]1[CH:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[S:19].N1C=CC=CC=1.S(Cl)(Cl)(=O)=O>ClCCl>[O:1]=[C:2]1[CH:5]([N:6]2[C:7](=[O:16])[C:8]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]3[C:10]2=[O:11])[CH2:4][N:3]1[C:17](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[S:19]
Reactant: COC(=S)C(Cc1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=S)C(=Cc1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)-3-phenylthiopropionate (5.1 g.) and pyridine (4.0 g.) were dissolved in dichloromethane (100 ml.), and to the solution, there was added dichloromethane (20 ml.) solution containing sulfuryl chloride (2.0 g.) at 35° to 40° C. in the source of 70 minutes with stirring. The stirring was continued at the same temperature for an hour. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure. Ethyl acetate (100 ml.) and water (50 ml.) were added to the residue obtained, and the resultant mixture was stirred for a while. The ethyl acetate layer was separated from the mixture and the remaining aqueous solution was extracted with ethyl acetate. This extract and the above ethyl acetate layer were combined, washed with three portions of diluted hydrochloric acid, three portions of saturated aqueous sodium bicarbonate, two portions of water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give an oily residue (4.95 g.), which was subjected to column chromatography on silica gel(30 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)-3-phenylthioacrylate (a mixture of trans and cis isomer) (4.23 g.).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[F:18].[N:20]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)=[C:21]=[S:22].C[OH:36].Cl>CN(C=O)C.O>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([N:20]2[C:16](=[O:36])[C:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:19])=[C:5]([F:18])[CH:6]=3)[C:21]2=[S:22])=[CH:24][C:25]=1[C:31]([F:32])([F:34])[F:33])#[N:28]
Reactant: CNC(=O)c1ccc(NC2(C#N)CCCC2)cc1F
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCC3)cc1F
Temperature: 130 °C

Procedure:
A mixture of N-Methyl 2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide (Formula 43) (57 mg, 0.22 mmol) and 4-isothiocyanato-2-trifluoromethyl benzonitrile (0.15 g, 0.65 mmol) in DMF (3 mL) was heated under microwave irradiation (open vessel) at 130° C. for 12 hours. To this mixture was added methanol (20 mL) and aq. 1 N HCl (5 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5) to give 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamide, NC55 (Formula 44) (8 mg, 7%) as a pale yellowish solid. 1H NMR δ 8.28 (dd, 1H, J=8.4, 8.4 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.96 (d, 1H, J=1.8 Hz), 7.84 (dd, 1H, J=8.3, 1.8 Hz), 7.27 (dd, 1H, J=8.4, 1.8 Hz), 7.17 (dd, 1H, J=11.7, 1.8 Hz), 6.67-6.77 (m, 1H), 3.07 (d, 3H, J=4.3 Hz), 2.32-2.41 (m, 2H), 2.13-2.21 (m, 2H), 1.85-1.96 (m, 2H), 1.49-1.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7](Cl)=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cscc1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1cscc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, a solution of 4-chlorothiophene-3-carboxylic chloride (13.5 g, 0.075 mol) in 30 ml of dioxane is dripped into a solution of aniline (7.7 g, 0.083 mol) in pyridine (160 ml). The mixture is stirred for 12 hours at room temperature and concentrated to dryness, and the residue is taken up in dichloromethane. The organic phase is extracted with aqueous citric acid solution, sodium bicarbonate solution and water, dried and concentrated to dryness. Yield: 16.7 g, 94%; m.p. 119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.Cl[C:25](OC1C=CC([N+]([O-])=O)=CC=1)=[O:26].[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][OH:46])[CH2:40][CH2:39]1>>[OH:46][CH2:45][CH2:44][N:41]1[CH2:42][CH2:43][CH:38]([NH:37][C:25]([NH:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([NH:12][CH:10]2[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]2)[CH:22]=[CH:21]3)=[O:26])[CH2:39][CH2:40]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCN(CCO)CC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(CCO)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) (200 mg, 0.655 mmol), 4-nitrophenyl chloroformate (132 mg, 0.655 mmol) and commercially available 4-amino-1-piperidine ethanol (94 mg, 0.655 mmol) in accordance with the general method 4 described in example 170 step C and was obtained as an off-white solid (160 mg, 26%); MS: m/e=476.2 (M+H+).