Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](O)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:26])([CH3:25])[C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:28])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.5 mmol) and CDI (160 mg, 1 mmol) in DMF (2 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (285 mg, 3 mmol) and NaH (120 mg, 60%, 3 mmol) in DMF (5 mL), which had been stirred at room temperature for 3 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to “pH” 1-2 by addition of concentrated HCl. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (100 mg).
Reaction SMILES: [CH3:1]C1C=CC=C(C)C=1O.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21](=[O:22])[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:29])[NH:18]2)=[CH:13][CH:12]=1>>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21](=[O:22])[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:29])[NH:18]2)=[C:15]([CH3:1])[CH:16]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Product: Cc1cc(O)ccc1-n1[nH]c(=O)n(-c2ccccc2)c1=O

Procedure:
Compound 31 was prepared from 2,6-dimethylphenol in the same manner of compound 27, and was obtained as white solids (77%). 1H NMR (300 MHz, DMSO-d6): δ 11.22 (br s, 1H), 9.78 (s, 1H), 7.50-7.49 (m, 4H), 7.40 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.68 (dd, J=2.4, 8.7 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 158.65, 152.58, 138.57, 132.52, 129.57, 126.99, 126.51, 117.72, 114.19, 18.17. HRMS: calcd for C15H13N3O3 (MH+) 284.1030. found 284.1027.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)sc1ncc(CO)n12
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)sc1ncc(C=O)n12
Yield: 95.6 %

Procedure:
A solution of 7-Methoxy-imidazo[2,1-b]benzothiazole-3-methanol (Formula M-2) (4.0 g) in DMF (25 mL) was diluted with toluene (200 mL) and the warm solution was treated with MnO2 (8.84 g). The suspension was azeotropically distilled for 4 hours, cooled to 50°, and filtered. The combined filtrate and toluene washes were concentrated and the concentrate was diluted with water. Precipitated 7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3) (3.8 g) was filtered and recrystallized from acetonitrile to yield pure 7-Methoxy-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3) (3.79 g), m.p. 168-169°.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([SH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH2:10]([O:17][C:18](ON1C(=O)CCC1=O)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CO>[CH2:10]([O:17][C:18]([NH:1][C@@H:2]([C:6]([SH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(S)[C@H](N)C(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a round bottom flask was added (R)-2-amino-3-mercapto-3-methylbutanoic acid (5.06 g, 33.9 mmol), N-(benzyloxycarbonyloxy)succinimide (8.87 g, 35.6 mmol), MeOH (50 mL) followed by DIPEA (11.9 mL, 67.8 mmol). The reaction was stirred at rt for 1 hr. The reaction was concentrated and the residue was diluted with EtOAc (120 mL). The organics was washed with water (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (4.78 g, 16.9 mmol, 49.7% yield) as a clear oil. Anal. Calcd. for C13H17NO4S m/z 283.3. found: 282.3 (M−H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.45-7.30 (m, 5H), 6.09-5.84 (m, 1H), 5.20-5.01 (m, 2H), 4.37-4.18 (m, 1H), 1.53 (br. s., 3H), 1.39 (br. s., 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.43, 136.49, 128.44, 128.28, 128.02, 53.12, 41.51, 30.83, 29.72, 11.64.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:19])[NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:19])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(NC(=O)NCC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Yield: 94.1 %

Procedure:
Ethyl 4-(3-(cyclopropylmethyl)ureido)benzoate (55.3 mmol, 14.5 g) was suspended in ethanol (400 ml) and 4M sodium hydroxide (332 mmol, 83 mL) added. The reaction was then refluxed until complete saponification was achieved. The ethanol was removed by evaporation and the reaction neutralised with concentrated hydrochloric acid. The white precipitate was collected and washed with water. The material was dried under vacuum to give the title compound (12.19 g)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[S:31][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:29][N:28]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:35]1[CH2:34][CH2:33][N:32]([C:30]2[S:31][C:27]([C:26]([F:38])([F:25])[F:39])=[N:28][N:29]=2)[CH2:37][CH2:36]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate. The crude material was purified by chromatography (SiO2, dichloromethane/methanol 99:1) to yield the title compound as a colorless solid. MS (m/e): 479.2 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])[CH3:2].[CH3:27][S:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH:41]=O)=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:41][CH2:40][CH2:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc(CCCC=O)cc1
Reactant: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Product: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Yield: 29 %

Procedure:
The reductive amination reaction of [3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-acetic acid ethyl ester and 4-[4-(methanesulfonamido)phenyl]butyraldehyde was accomplished according to the procedure of Example 14.1, Step 14.1B to give the titled compound in 29% yield as a stiff foam; homogenous by TLC in 92.5:7.5 CH2Cl2 --MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=576 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CCO[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[C:19](=[CH:18][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)CN(C=C(C(=O)OCC)C(=O)OCC)Cc1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
N-benzylglycine ethyl ester (5.79 g, 30 mmol) was combined with diethyl ethoxymethylene malonate (6.48 g, 30 mmol) and stirred at 120° C. for 1 hr. The crude material was used directly for the next reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:28])[C:24]([Cl:27])=[C:25]([Cl:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl>C(O)(=O)C>[Cl:26][C:25]1[C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:22]=[C:23]([Cl:28])[C:24]=1[Cl:27]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 100 °C
Yield: 737.8 %

Procedure:
To a stirred solution of 1-[4,5,6-trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.166 g, 0.372 mmol) and acetic acid (6 mL) was added 6M aq. hydrochloric acid (6 mL). The reaction mixture was heated to 100° C. for 18 h and then cooled to 23° C. The precipitate was collected to yield the titled compound as the HCl salt (0.91 g, 74% yield). MS (ESI/CI): mass calcd. for C11H6Cl3N4O2, 330.0; m/z found, 331.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.92 (s, 1H), 8.34 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[NH2:33][N:34](C)[C:35](=O)OC(C)(C)C>C(O)C>[ClH:32].[F:27][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3([C:5]4[CH:4]=[N:33][N:34]([CH3:35])[C:6]=4[C:7]=2[CH:8]=1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: Cn1ncc2c1-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.6 g, 6.0 mmol) in ethanol (20 mL) was added hydrochloric acid (22.5 mL of 4 M, 89.8 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (21 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (1.1 mL, 7.2 mmol). The solution was allowed to stir overnight. To the thick beige-white slurry that formed was added hydrochloric acid (7.5 mL of 4 M, 29.9 mmol) (4 M in dioxane). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a white thick slurry developed. The slurry was allowed to slowly cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of ethanol in hexanes (2×). Residual solvents were further removed under reduced pressure providing 8-fluoro-1-methyl-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (1.9 g, 92%). 1H NMR (400 MHz, DMSO) δ 7.59 (dd, J=9.3, 2.8 Hz, 1H), 7.43 (s, 1H), 7.27-7.10 (m, 2H), 4.12 (s, 3H), 3.28-3.11 (m, 4H), 2.59 (s, 1H), 2.22-2.02 (m, 4H). ESI-MS m/z talc. 273.1, found 274.1 (M+1)+. Retention time 0.84 minutes (3 min run).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2)C=C.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>CCCCCC>[CH2:24]([C:6]1[C:5]([OH:4])=[CH:14][C:13]([CH3:15])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:16])[NH:11]2)[CH:19]=[CH2:20]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(C)c2[nH]c(=O)ccc2c1
Solvent: CCCCCC
Product: C=CCc1c(O)cc(C)c2[nH]c(=O)ccc12
Temperature: 200 °C
Reaction time: 11 h
Yield: 92.6 %

Procedure:
To 6-allyloxy-8-methylcarbostyril (10.11 (47.0 mmol)), N,N-dimethylaniline (25 ml) was added, and the mixture was stirred in a bath of 200° C. for 11 hours. Subsequently, the mixture was cooled. n-Hexane was added to the cooled mixture. The precipitated crystals were collected by filtration, and were washed with chloroform. The washed material was subjected to a recrystallizing procedure (chloroform--methanol--n-hexane) to obtain 9.36 g of 5-allyl-6-hydroxy-8-methylcarbostyril as colorless needles (92.6%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].I[CH3:19].[H-].[Na+].O>C1COCC1>[CH3:19][N:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1]
Reactant: CI
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
To ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3 g, 13 mmol) in THF (50 ml) was added iodomethane (4 ml, 65 mmol) and sodium hydride (630 mg, 60% in mineral oil, 15.6 mmol) at 0° C. After warming the reaction mixture to room temperature, it was stirred for 1 day. Water (20 ml) was added and extracted organic layer with diethyl ether. With normal-phase preparative LC, purification preceded to gave title compound (3 g, 94%) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:9]([N+:21]([O-])=O)[CH:8]=1.[Cl-].[NH4+]>O1CCCC1.O.C(O)C.[Fe]>[NH2:21][C:9]1[CH:8]=[C:7]([CH2:6][O:5][C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=2)[CH:12]=[CH:11][C:10]=1[S:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 4-[4-(3-Bromo-phenoxymethyl)-2-nitro-phenylsulfanyl]-phenol (325 mg, 0.752 mmol), iron dust (210 mg, 3.76 mmol) and ammonium chloride (60 mg, 1.13 mmol) in tetrahydrofuran (5 mL), water (1.5 mL) and ethanol (5 mL) was heated at reflux for 2.5 hours. After cooling to room temperature, the solution was filtered through a pad of celite, which was washed with methanol. The filtrate was then concentrated under vacuum, then dissolved in water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic extracts were dried and concentrated under vacuum to provide the title compound as a light yellow solid (240 mg, 79%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH2:29]1)=[O:27])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCOCCOC)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOCCOc1cccc2c1CN(C(=O)c1cc(C(C)C)c(O)cc1O)C2
Reaction time: 7 h
Yield: 16 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-{4-[2-(2-methoxy-ethoxy)-ethoxy]-1,3-dihydro-isoindol-2-yl}-methanone in methanol (5 mL) was hydrogenated at atmospheric pressure over 10% palladium on charcoal (12 mg) for 3 hours. A further portion of catalyst (12 mg) was added and hydrogenation continued for a further 7 hours. The mixture was filtered through Celite, eluting with methanol, then the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (basic method). This afforded the title compound as a white solid (17 mg, 16% over two steps). 1H NMR (methanol-d4) 7.25 (1H, t), 7.17 (1H, s), 6.95-6.82 (2H, m), 6.37 (1H, s), 4.89 (2H, br.s), 4.83 (overlaps with H2O, br.s), 4.16 (2H, br.s), 3.82 (2H, br.s), 3.66 (2H, br.s), 3.52 (2H, br.s), 3.39-3.28 (overlaps with MeOH, m), 3.20 (1H, sept), 1.21 (6H, d). MS: [M+H]+ 416.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6](/[CH:8]=[N:9]/[NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:9]=[CH:8]2
Reactant: Fc1ccc(N/N=C/c2cc(Br)ccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Temperature: 220 °C
Yield: 99.8 %

Procedure:
A 30 mL microwave vial was charged with 3.00 g (9.642 mmol) of N-[1-(5-bromo-2-fluorophenyl)meth-(E)-ylidene]-N′-(4-fluorophenyl)hydrazine and 3.14 g (9.64 mmol) of cesium carbonate and 10 mL of DMSO and sealed. The mixture was warmed at 220° C. in the microwave for 15 minutes cooled and opened at room temperature. The mixture was diluted with 10 mL of water and extracted with 20 mL of EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was absorbed onto silica gel and passed through a silica pad and eluted with 50% EtOAc-hexanes. The partially purified material from the pad was triturated with MeOH, collected by filtration, and dried to afford 2.8 g (99.7%) of 5-bromo-1-(4-fluorophenyl)-1H-indazole. MS m/z 279.11 (MH+).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1([CH3:18])[C:15]([CH3:17])([CH3:16])[O:14][BH:13][O:12]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[B:13]1[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:18])([CH3:10])[O:12]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cc(N)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 95 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To an oven-dried round bottom flask fitted with a stir bar was added 4-bromo-3-methylaniline (5.7 gm, 31 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.3 mL, 92 mmol, Aldrich Chemical Company), and PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, Mass.). The flask was sealed with a rubber septum, purged with Argon, and then charged with dry dioxane (100 mL) and triethylamine (26 mL). The reaction mixture was stirred vigorously at 95° C. for 16 h. After cooling to rt, the dioxane was removed in vacuo and the residue was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was washed with saturated NaHCO3 (2×75 mL), brine (50 mL), and was dried over MgSO4. Removal of the solvents in vacuo followed by flash chromatography of the residue yielded the product (3.3 gm, 46%) as a tan oil. 1H-NMR (CDCl3; 400 MHz): δ 7.61–7.64 (m, 1H), 6.48–6.58 (m, 2H), 3.60–3.90, (br s, 2H), 2.49 (s, 3H), 1.34 (s, 12H). ESI-MS (m/z): Calcd. for C13H20BNO2: 234.1 (M+H); found: 234.2
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:18]=[C:17]([NH2:27])[CH:16]=1>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:27][C:17]1[CH:16]=[C:15]([CH3:14])[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][N:18]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Cc1cc(N)ncc1-c1ccccc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)ncc1-c1ccccc1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzoyl isocyanate (1.4 grams) was reacted with 4-methyl-5-phenyl-2-pyridylamine (0.9 gram) in dichloromethane. There was an immediate exotherm and spontaneous reflux. The reaction mixture was then stirred at ambient temperature but no precipitate formed. After the mixture was stripped, the residue was recrystallized from ethanol yielding 1.0 gram of tan crystals, m.p. 210°-214° C. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[C:6](=[NH:12])[NH:5][C:4](=N)[C:3]1=2.Cl.[CH3:15][CH:16]1[CH2:21][N:20]([C:22]2[S:23][CH2:24][C:25](=[NH:27])[N:26]=2)[CH2:19][CH2:18][O:17]1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:12]=[C:6]1[C:7]2[CH2:8][CH:9]([CH3:11])[CH2:10][CH:2]([Br:1])[C:3]=2[C:4](=[C:24]2[S:23][C:22]([N:20]3[CH2:19][CH2:18][O:17][CH:16]([CH3:15])[CH2:21]3)=[N:26][C:25]2=[NH:27])[NH:5]1
Reactant: CC1CN(C2=NC(=N)CS2)CCO1
Reactant: CC1CC2=C(C(=N)NC2=N)C(Br)C1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: CC1CC2=C(C(=C3SC(N4CCOC(C)C4)=NC3=N)NC2=N)C(Br)C1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A, but substituting equivalent amounts of 4-bromo-6-methyl-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(2-methylmorpholino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, there is obtained as the product 1-imino-4-bromo-6-methyl-4,5,6,7-tetrahydro-3-[2-(2-methylmorpholino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[N:10]3[N:9]=2)=[CH:4][C:3]=1[N+:28]([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>CO.O>[NH2:28][C:3]1[CH:4]=[C:5]([C:8]2[S:12][C:11]3=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[N:10]3[N:9]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1cc(-c2nnc3sc(-c4ccc(C)c([N+](=O)[O-])c4)nn23)cc(OC)c1OC
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2nnc3sc(-c4ccc(C)c(N)c4)nn23)cc(OC)c1OC
Yield: 27.7 %

Procedure:
A mixture of 6-(4-methyl-3-nitrophenyl)-3-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (256 mg, 0.6 mmol) and tin(II) chloride (675 mg, 3 mmol) in methanol (25 mL) was refluxed under argon for 6 h. It was then diluted with water (30 mL) and neutralized with 2N aqueous sodium hydroxide to pH=12, and extracted with ethyl acetate (3×20 mL). The extracts were dried, concentrated and the residue was purified by column chromatography (EtOAc as eluent) to give 66 mg (28%) of the title compound as solid. 1H NMR (CDCl3): 7.71 (s, 2H), 7.23 (m, 2H), 7.17 (s, 1H), 4.00 (s, 6H), 3.94 (s, 3H), 2.26 (s, 3H).