Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]O.C(N(C(C)C)CC)(C)C.[CH2:34]([C:38]1[N:39](C(OC(C)(C)C)=O)[CH:40]=[C:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]=1)[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:34]([C:38]1[N:42]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[C:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:40][N:39]=1)[CH2:35][CH2:36][CH3:37]
Reactant: OCc1ccccc1Cl
Reactant: CCCCc1nc(CCC(=O)OCC)cn1C(=O)OC(C)(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ncc(CCC(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of trifluoromethanesulfonic anhydride (163 μL, 0.966 mmol) in methylene chloride (1 mL) held at -75° C. under argon was added 2-chlorobenzyl alcohol (138 mg, 0.966 mmol) and diisopropylethylamine (168 μL, 0.966 mmol) in methylene chloride (2 mL) over one minute. After being stirred for 15 minutes, a solution of ethyl 3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate (285 mg, 0.878 mmol) in methylene chloride (2 mL) was added over a 3-minute interval at -75° C. The reaction mixture was then allowed to warm to room temperature and was stirred for 18 hours. The solvent was evaporated, and this crude product was flash chromatographed over silica gel with a gradient of ethyl acetate in hexane to give 179 mg (58%) of ethyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-propanoate as an oil. TLC on silica gel with 1:1 hexane/ethyl acetate showed a single product with an Rf of 0.41.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>ClCCCl.O.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([C:12]1[NH:11][C:15]([CH:4]=[O:5])=[CH:14][CH:13]=1)=[O:17])[CH3:20]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C=O)[nH]1
Temperature: -10 °C
Yield: 41.5 %

Procedure:
To DMF (1.3 mL, 17 mmol) cooled to 5-10° C. was added phosphorous oxychloride (1.5 mL) dropwise and the mixture was diluted with 1,2-dichloroethane (5 mL). The flask was then cooled to −10° C. and ethyl pyrrole-2-carboxylate (2.00 g, 14.4 mmol) in 1,2-dichloroethane (5 mL) was added dropwise over 5 min. The mixture was heated to reflux for 15 min, cooled to RT and ethyl acetate (15 mL), water (20 mL), and satd aq sodium bicarbonate (70 mL) were added. The layers were separated and the aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic layers were washed with saturated sodium carbonate (50 mL), dried (Na2SO4) and the solvents were removed in vacuo. The resulting solid was purified by column chromatography on silica gel (300 g), eluting with 30% ethyl acetate in hexane to yield 1.0 g (42%) of the title compound as a pale yellow crystalline solid. 1H-NMR (400 MHz, CDCl3): δ 9.89 (br s, 1H), 9.67 (s, 1H), 6.95 (d, 1H, J=4.1 Hz), 6.94 (d, 1H, J=4.1 Hz), 4.38 (q, 2H, J=7.1 Hz), 1.39 (t, 3H, J=7.1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH-:13])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:2]1
Reactant: [NH-]CCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To the solution of 3-(1H-indol-3-yl)propylamide (1.85 g, 9.83 mmol) in tetrahydrofuran (50 mL) is added lithium aluminum hydride (1.49 g, 39.31 mmol) at 0° C. The resulting mixture is warmed to room temperature and then refluxed for 2.5 hours. The mixture is then cooled to room temperature and quenched by slow addition of water (2 mL) followed by aqueous 15% sodium hydroxide (2 mL) and water (2 mL). The mixture is allowed to stir overnight and filtered through celite. The filtrate obtained is evaporated and the residue is subjected to flash column chromatography (50% dichloromethane: 40% methanol: 10% aqueous ammonia (40%)) to afford 3-(1H-Indol-3-yl)propylamine (1.61 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][C:31]1([CH3:38])[O:35][CH:34]([CH2:36]O)[CH2:33][O:32]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:36][CH:34]5[CH2:33][O:32][C:31]([CH3:38])([CH3:30])[O:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC1(C)OCC(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)O1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (2,2-dimethyl-[1,3]dioxolan-4-yl)methanol following General Procedure J.
Reaction SMILES: [CH2:1]([N:5]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]2)[N:7]([CH3:21])[C:6]1=[O:22])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:26])(=O)=O.II>C(O)(=O)C>[Cl:26][C:17]1[CH:16]=[C:15]2[C:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]3)[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:20]2=[CH:19][CH:18]=1
Reactant: CC(C)CN1C(=O)N(C)C2(NC(=O)NC2=O)c2ccccc21
Reactant: O=S(=O)(Cl)Cl
Agent: II
Solvent: CC(=O)O
Product: CC(C)CN1C(=O)N(C)C2(NC(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
1-Isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.76 g) as prepared in Example 37 is suspended in acetic acid (15 ml) and thereto are added sulfuryl chloride (0.3 ml) and a slight amount of iodine, and the mixture is stirred at room temperature for 19 hours. The reaction mixture is poured into ice-water, and the precipitates are taken by filtration and the crystals are dissolved in 10% aqueous sodium hydroxide. The undissolved materials are filtered off, and the filtrate is neutralized with 10% hydrochloric acid, and the precipitates are taken by filtration (this dissolution and precipitation procedure is repeated). The precipitates are taken by filteration and dried to give 6-chloro-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](Cl)=[O:28]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH:11][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Br:19])[CH:10]=1)=[O:4]
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)Cc2ccccc2Br)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (241 mg, 1.0 mmol), pyridine (0.5 mL), DMAP (10 mg) and 2-bromophenylacetyl chloride (253 mg, 1.1 equiv.) was stirred for one hour at room temperature. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was separated and concentrated under reduced pressure to give crude 5-[2-(2-bromo-phenyl)-acetylamino]-4′-methyl-biphenyl-3-carboxylic acid methyl ester, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:23])[C:5]2=1.Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:23][C:6]1[C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=3)[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:26]
Reactant: CCN(CC)CCCl
Reactant: Oc1cccc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Yield: 60.7 %

Procedure:
6-Fluoro-9-(4-fluorobenzyl)-9H-carbazol-4-ol (0.0584 g, 0.19 mmol), 2-diethylaminoethylchloride hydrochloride (0.0593 g, 0.35 mmol), potassium carbonate (0.0926 g, 0.63 mmol), sodium iodide (0.0061 g, 0.041 mmol) and DMF (2 mL) are heated at 85° C. for 3 h. After the mixture had cooled, it is partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (50 mL) using methanol/dichloromethane (1/99) to give 0.0471 g (61%) of the title compound; mp 75-76° C.; MS (ESI+) for C25H26F2N2O m/z 409.3 (M+H)+; IR (drift) 1585, 1507, 1481, 1461, 1343, 1269, 1221, 1159, 1145, 871, 820, 799, 776, 739, 712 cm−1; 1H NMR (CDCl3) δ1.14, 2.73, 3.10, 4.33, 5.44, 6.69, 6.93, 7.04-7.18, 7.36, 8.03. Anal. Calcd for C25H26F2N2O: C, 73.51; H, 6.41; N, 6.86. Found:C, 73.30; H, 6.59; N, 6.77.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C([O:43][C:44]([CH2:46][CH2:47][CH2:48][CH2:49]COS(C1C=CC(C)=CC=1)(=O)=O)=[O:45])C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:49][CH2:48][CH2:47][CH2:46][C:44]([OH:45])=[O:43])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC(=O)OCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@H]1OC(OCCCCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml of tetrahydrofuran is cooled to 0° C. At 0° C., 54.37 g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid benzyl ester, dissolved in 40 ml of tetrahydrofuran, is added in drops over 30 minutes while being stirred vigorously. It is stirred for three hours at 0° C. 300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little tetrahydrofuran and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[O:28]=[C:29]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.O>[NH2:27][C:4]1[N:3]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:29](=[O:28])[C:30]([O:32][CH3:33])=[O:31])=[CH:40][CH:39]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Reactant: COC(=O)C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1
Yield: 57.4 %

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (320 mg, 0.806 mmol), methyl 2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)acetate (320 mg, 0.95 mmol), dichlorobis(triphenylphosphine)palladium (79 mg, 0.11 mmol), and Na2CO3 (212 mg, 2.0 mmol) were added to a mixture of ethanol (10 mL) and water (10 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was dissolved in 10 mL of 0.5 M NaOH solution, filtered, and the filtration was extracted with EtOAc. The organic portion was dried and the solvent was removed to get 250 mg of the above-named compound. 1H NMR (300 MHz, CD3OD): δ δ 7.90 (m, 2H), 7.77 (s, 3H), 7.60 (m, 2H), 7.44 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H), 7.05 (s, 1H), 6.83 (m, 1H), 5.09 (m, 1H), 3.67 (s, 3H); M+1=541.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](Br)=[CH:7][C:5]=2[N:6]=1.CN(C)CCN(C)C.C([Li])(C)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCC>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([B:25]([OH:30])[OH:26])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Br)ccc2s1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Nc1nc2cc(B(O)O)ccc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 63 (459.1 mg) in anhydrous THF (30 ml) was added with N,N,N′,N′-tetramethylethylenediamine (1.51 ml, WAKO), cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of t-butyllithium in pentane (7.06 ml) and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (2.77 ml), stirred for 30 minutes, then warmed to room temperature and further stirred for 1.5 hours. The reaction mixture was added with 0.5 M aqueous sulfuric acid (7.5 mL) and extracted with diethyl ether (50 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 2-amino-5-benzothiazoleboronic acid. According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 12 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=2:1), the above compound was reacted with Intermediate 3 (344 mg), 2 M aqueous sodium carbonate (4.5 ml) and (Ph3P)4Pd (179 mg) and treated to obtain the title compound (Compound No. 284, 76 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[NH4+:15]>C(O)C>[NH2:15][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: [NH4+]
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1F

Procedure:
A mixture comprising 2,4-difluoro-5-nitrobenzonitrile (9.03 g, 0.049 mol) and ethanol (10-15 mL) was stirred at ambient temperature while concentrated ammonium hydroxide (40 mL) was slowly added to give a precipitate. The precipitate was isolated by filtration and lyophilized to give 4-amino-2-fluoro-5-nitrobenzonitrile (7.84 g, 0.043 mol) as an off-white solid; PB-CI/MS: 182=(MH+); 1H-NMR (300 Mhz, DMSO-d6): 6.856(d, 1H), 8.22(bs, 2H), 8.577(d, 1H). A mixture of 4-amino-2-fluoro-5-nitrobenzonitrile (3 g, 0.017 mol), PtO2 (≈300 mg) and methanol (20 mL)was hydrogenated (1 atm) for approximately 12 hours, filtered over celite and concentrated to dryness to provide 4,5-diamino-2-fluorobenzonitrile (2.5 g, 0.017 mol) as a brown solid PB-CI/MS: 152=(MH+); 1H-NMR (300 Mhz, DMSO-d6): 4.7(bs, 2H), 5.863(bs, 2H), 6.375(d, 1H), 6.56(d, 1H).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:15]1[CH:16]=[N:17][C:12]2[C:13]=1[NH:14][C:9]([CH:7]1[CH2:6][CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:4][CH:3]([CH3:2])[CH2:8]1)=[N:10][CH:11]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2cnc(C3CC(C)NC(c4ccccc4)C3)[nH]c1-2
Temperature: 110 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
A mixture of 2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyridine (Example 35) (50 mg, 0.17 mmol), acetic anhydride (Aldrich Chemical Company) (168 mg, 1.64 mmol, 9.7 eq), K2CO3 (227 mg, 1.64 mmol, 9.7 eq) and 4-N,N-dimethylaminopyridine (2.6 mg, 0.021 mmol, 0.12 eq) in anhydrous DMF (2.0 mL) was stirred under N2 at 110° C. overnight. After cooling to the room temperature, the reaction was quenched by the addition of saturated NaHCO, (5 mL) and extracted with CHCl3 (3×30 mL). The organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-25%):hexanes(100-75%) to afford 13 mg (22%) of the title compound as an off-white solid. Mp: 188-190° C. 1H NMR (CDCl3; 400 MHz): δ 11.43 (s, 1), 7.61 (d, 2, J=7.4), 7.43 (t, 2, J=7.4), 7.37 (t, 1, J=7.4), 4.88 (br s, 2), 4.06 (br s, 2), 2.58 (s, 3), 2.11 (s, 3), 1.73 (br s, 6). MS m/z: 335 (M+1), 333 (M−1). HRMS (NBA-NaI) m/z Calcd for M+H, C20H22N4O: 335.1888. Found: 335.1872.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].C1C=CC=CC=1.CCCCCC.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])=[O:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COc1ccc(C=O)c(C(=O)OC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C

Procedure:
4.87 g of 2-formyl-5-methoxybenzoic acid was dissolved in 30 ml of chloroform. With stirring at room temperature, a benzene/n-hexane (1:1) mixture solution of diphenyldiazomethane prepared in accordance with the procedure disclosed in Journal of the Chemical Society (Parkin I, pp. 2030-2033, 1975) was added to the above solution until the reaction solution showed a purplish red color. The resulting reaction solution was subjected to purification by silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant to obtain 8.2 g of diphenylmethyl 2-formyl-5-methoxybenzoate as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[O:20]C>Br.O>[OH2:15].[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[OH:20]
Reactant: COc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Agent: Br
Solvent: O
Product: CC1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A solution of 1.2 g of 6,7-dihydro-9-fluoro-8-methoxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 25 ml of 48% hydrobromic acid was heated at reflux for three hours, and was then cooled and diluted with about 100 ml of water. The product was separated by filtration and recrystallized from aqueous N,N-dimethylformamide to provide white solid 6,7-dihydro-9-fluoro-8-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. 293°-294° C. Analysis: Calculated for C14H12FNO4.0.25H2O=%C,59.7;%H,4.5;%N,5.0; Found: %C,59.5;%H,4.2;%N,5.0.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([C:20]4[N:31]=[N:32][NH:33][N:21]=4)[CH:18]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Nc3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 20.8 %

Procedure:
Using the general procedure for formation of tetrazole (Et3NHCl method) of Example 1 using 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrile (1.36 g, 3.39 mmol), sodium azide (662 mg, 10.2 mmol), and triethylamine hydrochloride (1.40 g, 10.2 mmol) to yield the title product as a yellow solid (313 mg, 21%): 1H NMR (DMSO-d6) δ 0.791 (t, 3H), 1.43 (sextuplet, 2H), 2.57 (m, 5H), 5.24 (s, 2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.08 (d, 1H), 7.24 (m, 2H), 7.32 (t, 1H), 7.44 (m, 2H), 7.79 (m, 2H), 8.55 (s, 1H), 12.84 (s, 1H); MS (esi negative) m/z (rel intensity) 442 (100).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:10][CH:9]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:8]2[CH2:7]1)(=[O:5])=[O:4])=[CH2:2]>Cl.CO>[CH:1]([S:3]([N:6]1[CH2:10][CH:9]2[CH:8]([CH2:13][NH:12][CH2:11]2)[CH2:7]1)(=[O:5])=[O:4])=[CH2:2]
Reactant: C=CS(=O)(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CO
Product: C=CS(=O)(=O)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
A mixture of tert-butyl 5-(vinylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (150 mg, 0.50 mmol) in HCl/MeOH (20 mL, 2.86 M) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to afford the crude product (110 mg) as a solid which was used directly in next step without further purification.