Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:7]4[C:2](=[O:1])[NH:3][CH:4]=[CH:5][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cccc2oc(-c3ccc[nH]c3=O)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A mixture of 2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxylic acid (102 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol), 1-hydroxybenzotriazole (108 mg, 0.80 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (99 mg, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.6 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and crystallizations from acetonitrile to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide (69 mg, 54%) as yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.80 (d, J=7.5 Hz, 1H), 8.49 (dd, J=7.3, 2.1 Hz, 1H), 8.18 (dd, J=7.8, 0.9 Hz, 1H), 7.80 (dd, J=6.3, 2.1 Hz, 1H), 7.72 (dd, J=8.2, 0.9 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 6.51 (dd, J=7.2, 4.0 Hz, 1H), 4.42-4.36 (m, 1H), 3.57-3.50 (m, 1H), 3.33-3.24 (m, 2H), 3.08-3.01 (m, 1H), 2.99-2.94 (m, 3H), 2.25-2.20 (m, 2H), 1.84-1.80 (m, 2H), 1.65-1.58 (m, 1H); MS (ESI+) m/z 365 (M+H); HPLC>99% (AUC), tR=11.31 min.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:30])[C@@H:5](/[CH:6]=[CH:7]\[C:8](=[O:10])[OH:9])[C@H:4]1[C:11]([O:13][CH:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12].C(O)(=O)C.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl>[CH3:2][C:3]1([CH3:30])[C@@H:5](/[CH:6]=[CH:7]\[C:8](=[O:9])[O:10][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[C@H:4]1[C:11]([O:13][CH:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]
Reactant: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A methanolic N hydrochloric acid solution was added dropwise at 15° C. with stirring to a mixture of 1.5 g of α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate solvated with one mole of acetic acid, 4.5 ml of dihydropyran and 10 ml of methylene chloride and the mixture was stirred at room temperature for 30 minutes. Calcium carbonate was added to the mixture which was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-ether mixture yielded 1.07 g of α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(tetrahydropyran-2-yloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47° (c=0.5% in benzene).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].IC.[C:26]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:26][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Reaction time: 16 h
Yield: 105 %

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and iodomethane (2.5 mL, 40.2 mmol) in DMF (25 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and stirred for 16 h. The reaction was quenched by addition of water and the solid was collected and dried to yield ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate as a yellowish solid (1.1 g, 100%): 1H NMR (DMSO-d6) δ 1.03 (t, J=7.0 Hz, 3H, 4.09 (s, 3H, 4.18 (q, J=7.0 Hz, 2H, 7.40-7.55 (m, 5H, 7.90 (d, J=9.2 Hz, 1H, 8.23 (dd, J=9.2, 2.3 Hz, 1H, 8.32 (d, J=2.3 Hz, 1H; MS (EI) m/z 325.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:18][S:19][C:20](SC)=[N:21][C:22]#[N:23]>C(O)C>[NH2:16][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:20](=[N:21][C:22]#[N:23])[S:19][CH3:18])[N:8]=2)[N:10]=1)[NH2:17]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)NCc1cccc(-c2csc(N=C(N)N)n2)n1

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.50 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N-CN] (0.29 g) in ethanol (10 ml) was refluxed for one hour to give 2-(diaminomethyleneamino)-4-[6-(3-cyano-2-methylisothioureido)methylpyridin-2-yl]thiazole of a crude product. After being concentrated to dry the above product, 40 weight % methanolic methylamine (1.6 ml) and N,N-dimethylformamide (10 ml) was added and the mixture was stirred at 60° C. for 5 hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and recrystallized from aqueous N,N-dimethylformamide to give 4-[6-(2-cyano-3-methylguanidino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (0.42 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCOC(C)=O.CCCCCC.CCOC(C)=O>O1CCOCC1>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: O=Cc1csc(Br)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1csc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a slurry of 2-bromothiazole-4-carbaldehyde (1.0 g, 5.21 mmol) in p-dioxane (5 mL) was added morpholine (1.36 g, 15.61 mmol) over 1 min. The mixture was heated to 100° C. for 1 h (monitored by TLC, EtOAc/hexane 1:1) and cooled to room temperature. EtOAc (20 mL) was added and the solid residue filtered off and washed with EtOAc (30 mL). The combined organic layer was washed with brine (30 mL) and concentrated. The residue was purified by silica gel flash column chromatography using 20 to 75% EtOAc in hexane to afford the title compound as a light tan solid (780 mg, 75%): 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.49 (s, 1H), 3.82 (t, 4H, J=4.8 Hz), 3.56 (t, 4H, J=4.8 Hz). MS (ES) m/z 199.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH3:3].CCCCCC.[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O.O>[CH3:12][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[NH:13][C:14](=[O:15])[N:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NOCc1ccccc1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCCN(OCc1ccccc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 60 °C
Yield: 63 %

Procedure:
A solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-(phenylmethoxy)-urea (1.62 g, 5 mmol) in 5 ml of dry dimethylformamide is added dropwise to a room temperature suspension of hexane washed sodium hydride (0.13 g, 5.5 mmol) in 3 ml of dry dimethylformamide with stirring. When gas evolution is complete, the suspension is warmed to 60° C. and 1-bromodecane (1 ml, 5 mmol) is added dropwise. The mixture is stirred for 30 minutes, cooled to room temperature, poured into water and extracted with diethyl ether. The diethyl ether extract is diluted with hexane and washed with water, dried, filtered, and evaporated to provide a colorless solid which is triturated with hexane to give 1.47 g of N'-[2,6-bis(1-methylethyl)phenyl]-N-decyl-N-(phenylmethoxy)-urea; mp 91°-93° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13](F)([F:15])[F:14])(=O)=O)=CC=1.[Li]CCCC.C(B([CH2:27][CH3:28])CC)C.Cl[C:30]([C:32]1[C:33]([CH3:43])=[CH:34][C:35]([CH3:42])=[C:36]([CH:41]=1)[C:37]([O:39][CH3:40])=[O:38])=[O:31].OP(O)(O)=O>C1COCC1.[Cu]I.CN(C)P(N(C)C)(N(C)C)=O>[F:14][C:13]([F:15])=[C:12]([CH2:27][CH3:28])[C:30]([C:32]1[C:33]([CH3:43])=[CH:34][C:35]([CH3:42])=[C:36]([CH:41]=1)[C:37]([O:39][CH3:40])=[O:38])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: COC(=O)c1cc(C(=O)Cl)c(C)cc1C
Reactant: CCB(CC)CC
Agent: [Cu]I
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C(=O)c1cc(C(=O)OC)c(C)cc1C)=C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of argon, was placed a solution of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.00 g, 3.93 mmol) in THF (30 mL). The solution was cooled to −78° C., then n-BuLi (5.0 mL, 1.6 M in hexane, 8.0 mmol) was added drop-wise and the mixture was stirred at −78° C. for 40 min Triethylborane (TEB) (5.0 mL, 1 M in THF, 5.0 mmol) was slowly added and the mixture was stirred at −78° C. for 1 h, then at room temperature for 3 h. The solution was cooled to 0° C., then hexamethylphosphoramide (HMPA) (6 mL) and CuI (1.5 g, 7.9 mmol) were added and the mixture was stirred at room temperature for 30 min. A solution of methyl 5-(chlorocarbonyl)-2,4-dimethylbenzoate (compound 255.2, 530 mg, 2.34 mmol) in THF (30 mL) was carefully added and stirred at room temperature for 30 min. The pH of the mixture was carefully adjusted to 7 with aqueous H3PO4 and the mixture was partitioned. The aqueous phase was extracted with ethyl acetate (3×20 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40) as eluent to obtain the title compound as a yellow oil (250 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:6]Cl.[C-:17]#[N:18].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:17]#[N:18])[CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1c(OC)cc(CCl)cc1SC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(CC#N)cc1SC
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To 16 g of 3-methoxy-5-methylthio-4-propoxybenzyl chloride in 100 ml of dry DMF was added 5 g (0.10 mole) sodium cyanide. The mixture was stirred for about 48 hours at room temperature under N2. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography to yield 14.5 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile as an oil. (95% yield).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1>[Pt].C(C(C)=O)C>[CH3:9][CH:1]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH:5]([CH2:6][CH3:7])[CH3:4])=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH2:2][CH3:3]
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: [Pt]
Solvent: CCC(C)=O
Product: CCC(C)Nc1ccc(Cc2ccc(NC(C)CC)cc2)cc1
Temperature: 121 °C
Yield: 95 %

Procedure:
4,4′-Methylenebis(benzeneamine) (MDA; 2.0 g), granular Pt(S)/C (1.0 g, Johnson Matthey), and methyl ethyl ketone (50.0 g) were charged to a 100 mL autoclave. The autoclave was degassed three times with H2 and then the mixture was heated at 121° C. for 2 hours under 85 psig (6.87×105 Pa) of H2. The reaction mixture was cooled to 22° C. and degassed. The granular Pt(S)/C catalyst settled to the bottom of reactor as soon as the agitation was stopped, making it easier to decant the product solution and recover the catalyst. GC analysis showed a 95% yield of N,N′-di(2-butyl)-4,4′-methylenebis(benzeneamine), and less than 0.4 area % of over-alkylated side-product.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[ClH:10].N([O-])=O.[Na+].O>O1CCOCC1.[Cu](Cl)Cl.C(OCC)(=O)C>[Cl:10][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1csc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 2.84 g (19.7 mmol) of 2-aminothiazole-4-carboxylic acid in 30 ml of 1,4-dioxane was added 50 ml of concentrated hydrochloric acid, followed by cooling to 0° C., and 10 ml of an aqueous solution of 2.04 g (29.6 mmol) of sodium nitrite was added charged dropwise thereto at 0° C. to 5° C. The reaction liquid was stirred at 0° C. for 2 hours, and then 2.93 g (29.6 mmol) of copper chloride was charged in separate portions thereto. The reaction liquid was returned to room temperature, followed by stirring for 8 hours. To the reaction liquid were added water and ethyl acetate, followed by extraction with ethyl acetate four times. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to prepare 1.77 g (yield 55%) of a target compound.
Reaction SMILES: FC1C2C(=O)C3C=CN=CC=3C(=O)C=2C(O)=CC=1.[Cl:19][C:20]1[C:25]2[C:26](=[O:35])[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[C:33](=[O:34])[C:24]=2[C:23]([OH:36])=[CH:22][CH:21]=1.FC1C2C(=O)C3C=CN=CC=3C(=O)C=2C([O:54][S:55]([C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)(=O)=[O:56])=CC=1>C(Cl)Cl>[Cl:19][C:20]1[C:25]2[C:26](=[O:35])[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[C:33](=[O:34])[C:24]=2[C:23]([O:36][S:55]([C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)(=[O:56])=[O:54])=[CH:22][CH:21]=1
Reactant: O=C1c2cnccc2C(=O)c2c(Cl)ccc(O)c21
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2cnccc2C3=O)cc1
Agent: O=C1c2cnccc2C(=O)c2c(F)ccc(O)c21
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2cnccc2C3=O)cc1

Procedure:
Following the procedure of Preparative Example 15 and using the mixture of 6-fluoro-9-hydroxybenzo[g]isoquinoline-5,10-dione and 6-chloro-9-hydroxybenzo [g]isoquinoline-5,10-dione obtained in Preparative Example 16 as starting material, an approximately 60/40 mixture of 6-fluoro-9-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione and 6-chloro-9-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione is obtained as a yellow powder, m.p. 193°-195° C. (from methylene chloride).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:24])[C:22]([Br:23])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:26])[C:22]([Br:23])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc3c(Br)c(O)cc(c23)C(=O)N1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Yield: 92.2 %

Procedure:
2-Benzyloxy-6-bromo-5-hydroxy-benzo[de]isoquinoline-1,3-dione (2.0 g, 5.0 mmol, from Example Y), potassium carbonate (2.75 g, 20.0 mmol), and dimethyl sulfate (2.7 g, 21.0 mmol) were reacted in acetone (300 mL) following the procedure as described in Example J to give 1.9 g of the title compound.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH3:6])=[O:4])=[O:2].[F:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>ClCCCl.CN(C)C1C=CN=CC=1>[C:1]([N:21]([CH2:20][CH2:19][O:18][C:17]1[CH:27]=[CH:28][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)[C:22](=[O:26])[O:23][CH2:24][CH3:25])([C:3]([O:5][CH3:6])=[O:4])=[O:2]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)NCCOc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)N(CCOc1ccc(Oc2ccc(F)cc2)cc1)C(=O)C(=O)OC
Temperature: 25 °C

Procedure:
With stirring and under nitrogen, a solution of methoxalyl chloride in 10 ml of 1,2-dichloroethane is added dropwise at +80° C. over 20 minutes to a solution of 10.0 g of ethyl 2-[4-(4-fluorophenoxy)phenoxy]ethylcarbamate and 0.3 g of 4-dimethylaminopyridine in 70 ml of 1,2-dichloroethane. The mixture is then stirred for 16 hours at +80° C. After cooling to room temperature, the reaction mixture is washed in succession with a cold 5% solution of sodium hydrogencarbonate, with 0.1N hydrochloric acid and, finally, with water, and dried over sodium sulfate. The 1,2-dichloroethane is completely removed by vacuum distillation. If desired, the crude ethyl N-methoxalyl-2-[4-(4-fluorophenoxy)phenoxy]ethylcarbamate can be purified by chromatography (eluant: 5:1 mixture of n-hexane/diethyl ether); nD20 : 1.5295.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:24][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCCCS
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O

Procedure:
25.1 g (100 mmols) of 3,5-dinitrophthalic acid N-methylimide, 19.8 g (220 mmols) of n-butylmercaptan, 41.5 g (300 mmols) of anhydrous potassium carbonate and 250 ml of absolute tetrahydrofuran are kept under reflux overnight. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up in methylene chloride/2N HCl. The extracts are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from cyclohexane, 11.96 g (41% of theory) of the title imide are obtained; melting point: 106°-108° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[C:12](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].Cl.[Cl:29][C:30]1[CH:37]=[C:36]([NH:38][NH2:39])[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>C(O)C>[F:26][C:2]([F:1])([F:27])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3=[N:39][N:38]([C:36]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:29])[CH:37]=4)[CH:17]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH:12]3[CH2:13][O:14][C:15]=2[CH:16]=1)(=[O:5])=[O:4]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: O=C1C(=Cc2ccc(F)cc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(N2N=C3c4ccc(OS(=O)(=O)C(F)(F)F)cc4OCC3C2c2ccc(F)cc2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A mixture of 3-(4-fluorobenzylidene)-4-oxochroman-7-yl trifluoromethanesulfonate; Preparation 35 (200 mg, 0.50 mmol), 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1) (152 mg, 0.75 mmol), and ethanol (5 mL) was stirred under argon at 80° C. for three hours. The mixture was cooled to room temperature and concentrated. Water was added, the residue extracted three times with methylene chloride, washed with brine, dried over magnesium sulfate, filtered and condensed. The crude product was purified by normal phase flash column chromatography on a 20 g silica gel column (100% methylene chloride). Pure fractions were pooled and condensed to give the title compound (yellow solid, 75 mg, 0.14 mmol, 28% yield). The title compound was largely present as (±)-(3SR,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazol-7-yl trifluoromethanesulfonate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (dd, J=12.89, 10.47 Hz, 1H), 4.22-4.35 (m, 1H), 4.42 (dd, J=10.34, 6.04 Hz, 1H), 6.00 (d, J=11.28 Hz, 1H), 6.77-7.51 (m, 8H), 7.68 (d, J=8.59 Hz, 1H), 8.10 (d, J=9.40 Hz, 1H). ES-MS m/z 553 (M+H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]#[C:13][NH2:14].N12CCCN=C1CCCCC2.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCCC1>[NH2:12][C:13]1[N:14]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:11][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: N#CN
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1sc(NC(=O)c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.9 %

Procedure:
To a solution of benzoyl isothiocyanate (4.00 mL, 29.70 mmol) and cyanamide (1.37 g, 32.50 mmol) in tetrahydrofuran (80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.90 mL, 32.80 mmol) at 0° C. The resulting reaction mixture was stirred at ambient temperature for 3 hours. Methyl bromoacetate (3.00 mL, 32.00 mmol) was added to the reaction mixture. The reaction mixture was kept stirring for 1 hour at ambient temperature. Another portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (4.90 mL, 32.80 mmol) was added. The reaction mixture was stirred at ambient temperature for another 16 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (200 mL), washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to give methyl 4-amino-2-benzamidothiazole-5-carboxylate (0.16 g, 2%); 1H NMR (CDCl3, 300 MHz) δ 7.60-7.41 (m, 5H), 5.43 (s, 2H), 3.95 (s, 3H); MS (ES+) m/z 277.3 (M+1).