Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]([F:59])([F:58])[O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][NH:47][CH2:46][CH:45]([NH:49][C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:44]2)=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]([N:47]2[CH2:48][CH:43]([C:40]3[CH:41]=[CH:42][C:37]([O:36][C:35]([F:59])([F:34])[F:58])=[CH:38][CH:39]=3)[CH2:44][CH:45]([NH:49][C:50]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[O:57])[CH2:46]2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)c2ccncc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
51 mg (0.41 mmol) of pyridine-4-carboxylic acid together with 157 mg (0.41 mmol) of HATU and 67 mg (0.55 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 100 mg (0.27 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 112 mg (87% of theory)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:17]=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:20]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[2-(triphenylmethyl)(1,2,3,4-tetrazol-5-yl)]-1H-indazol-3-yl}phenylamine (0.246 g, 0.407 mmol) in tetrahydrofiran (4 mL) was added 2-methoxyacetyl chloride (0.056 mL, 0.61 mmol) and triethyl amine (0.284 mL, 2.035 mmol). The reaction mixture was stirred overnight at room temperature before being partitioned between ethyl acetate and water. The product was purified by column chromatography (40% ethyl acetate in hexanes) (0.104 g, 38% yield): ES-MS (m/z) M+ was not detected.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][Se:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[OH-].[K+].Cl(O)(=O)(=O)=O>C(O)COCCOCCO.O>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][Se:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2C[Se]CC1CN(Cc1ccccc1)C2
Agent: NN
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: OCCOCCOCCO
Product: c1ccc(CN2CC3C[Se]CC(C3)C2)cc1
Temperature: 140 °C
Yield: 101.8 %

Procedure:
A solution was made of 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (2.0 g, 6.8 mmol) and hydrazine (95%, 5.0 g, 148 mmol) in triethylene glycol (40 mL). Potassium hydroxide (85%, 10.0 g, 152 mmol) was added and the resulting mixture was heated to 140° C. in an oil bath under a nitrogen atmosphere for 12 hours. After cooling to room temperature, the solution was poured into water (200 mL) and the resulting suspension was extracted with ether (5×40 mL). The combined extracts were dried overnight (K2CO3) and cooled to 0° C. Perchloric acid (60%, 2.0 g, 11.9 mmol) was added dropwise. The yellow orange solid which formed was filtered and recrystallized (methanol) to give 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate (1.94 g, 75%) as white needles: mp 161.0°-162.0° C. (dec); IR (KBr) cm-1 3440, 1105; 1H NMR (DMSOd6) δ1.75 [d, 1 H, H(9), J=13.7 Hz], 1.88 [d, 1 H, H(9), J=13.6 Hz], 2.41 [br s, 2 H, H(1,5)], 2.64 [d, 2H, H(2,4)ax, J=12.21 Hz], 3.19 [d, 2 H, H(2,4)eq, J=12.10 Hz], 3.42 [m, 2 H, H(6,8)ax ], 3.61 [d, 2H, H(6,8)eq, J=11.83 Hz], 4.32 [d, 2 H, H(10-NCH2), J=5.75 Hz]; 13C NMR (DMSO-d6) ppm 22.0 [C(2,4)], 25.2 [C(1,5)], 28.5 [C(9)], 56.6 [C(6,8)], 60.5 [C(10 -N-CH2)], 128.9, 129.3, 129.8, 130.0 [ArC]; 15N NMR (DMSO-d6) ppm 51.56 [N(7)]; 77Se NMR (DMSO-d6) ppm 96.61 [Se(3)]. Analysis calculated for C14H20ClNO4Se: C, 44.14; H, 5.30; N, 3.68; Cl, 9.32; Se, 20.75. Found: C, 44.45; H, 5.38; N, 3.61; Cl, 9.52; Se, 20.67. ##STR24##
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].BrC1C=NN([CH:23]2CC[O:25][CH2:24]2)C=1>>[O:25]1[CH2:24][CH2:23][CH:1]([N:3]2[CH:7]=[C:6]([B:8]3[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]3)[CH:5]=[N:4]2)[CH2:2]1
Reactant: Brc1cnn(C2CCOC2)c1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole.
Reaction SMILES: [ClH:1].CC([CH:6]1[CH2:11][N:10](C([O-])=O)[CH2:9][CH2:8][N:7]1[C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])(C)C>C(O)(C)C.ClCCl>[ClH:1].[N:7]1([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:8][CH2:9][NH:10][CH2:11][CH2:6]1
Reactant: CNC(=O)COC(=O)N1CCN(C(=O)[O-])CC1C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(=O)COC(=O)N1CCNCC1
Reaction time: 1 h

Procedure:
25 ml of a 6N solution of hydrogen chloride in isopropanol are added to a solution of 2.68 g (8.9 mmol) of 2-(methylamino)-2-oxoethyl 1,1-dimethylethyl-1,4-piperazinedicarboxylate, obtained according to step 5.1., in 25 ml of dichloromethane. Stirring is continued at room temperature for 1 hour. The organic phase is removed by filtration through a hydrophobic cartridge and the acidic aqueous phase is concentrated under reduced pressure. After crystallization from isopropanol, 2.05 g of product are obtained in the form of a white solid, and are used without further purification in the following step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[N:10][CH:11]=1.C=O.[C:21]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:21])[CH:9]=[N:10][CH:11]=1
Reactant: COCCOc1cncc(OC[C@@H]2CCCN2)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: COCCOc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 50 °C
Yield: 85 %

Procedure:
To 5-methoxyethoxy-3-(2-(S)-pyrrolidinylmethoxy)pyridine from Example 197f (450 mg, 1.78 mmol) was added formaldehyde (37%, 8 mL) and formic acid (88%, 4 mL), and the mixture was heated at 50° C. for 4 h and then allowed cool to room temperature. The mixture was basified with saturated NaHCO3 and then extracted with Et2O. The organic layer was dried over Na2SO4 and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 2:1) to afford the title compound (402 mg, 85%): 1H NMR (CDCl3, 300 MHz) δ 2.00-2.08 (m, 4H), 2.45 (m, 1H), 3.05 (s, 3H), 3.45 (s, 3H), 3.65 (t, 2H, J=6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 4.15 (m, 1H), 4.30-4.35 (m, 2H), 4.52 (m, 1H), 7.25 (t, 1H, J=3.0 Hz), 8.02 (br, s, 2H); MS (CI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1.[NH4+].[Cl-]>CN(C=O)C>[CH:24]1([CH2:27][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])[CH:6]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (2 g, 6.5 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.171 g, 7.1 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropylmethyl bromide (0.967 g, 7.16 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.05 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC1C=C([N+]([O-])=O)C=CC=1OC1C2SC(C(NCCN3CCOCC3)=O)=CC=2N=CN=1.FC1C=C([N+]([O-])=O)C=CC=1O.[Cl:53][C:54]1[CH:55]=[C:56]([OH:63])[CH:57]=[CH:58][C:59]=1[N+:60]([O-:62])=[O:61]>>[Cl:53][C:54]1[CH:55]=[C:56]([CH:57]=[CH:58][C:59]=1[N+:60]([O-:62])=[O:61])[O:63][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: O=[N+]([O-])c1ccc(O)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 72 %

Procedure:
Starting from the chloride 20 (scheme 4) and following the procedure described above for the synthesis of compound 24 (scheme 4, example 22) remplacing 2-fluoro-4-nitrophenol with 3-chloro-4-nitrophenol, title compound 171 was obtained in 72% yield. LRMS (M+1) 307.7 (100%).
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C@@H:35]([O:43][CH3:44])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=2)[CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C@@H:35]([O:43][CH3:44])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=2)[CH:27]=1
Reactant: CO[C@@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to 8 mL of CH2Cl2. This mixture was added to 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[3-(2(S)-methoxy-3-phenylpropyl)phenyl]pyridine (290 mg, 0.59 mmol) at 0° C. under N2. The solution was stirred overnight at room temperature. After concentration in vacuo, the crude product (290 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm; UV detection, at 254 nm; mobile phase: A, water with 0.05% CF3COOH; B, CH3CN; 20-60% B in A in 8 min). The product-containing eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3CN. The pH of the residue was adjusted to 8.0 with saturated aqueous NaHCO3 solution, and the product was extracted into EtOAc (3×60 mL). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and concentration, the free amine (118 mg, 51%) was obtained as a yellow oil. LC-MS (ESI) m/z 389 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([O-:18])=O)[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[O:18])[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)c2cc(C(=O)[O-])cn2c2ccccc21
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cc(C(=O)Nc3nnn[nH]3)cn2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A mixture of 1.2 g (4.7 mmole) of 4,5-dihydro-5-ethyl-4-oxo-pyrrolo-[1,2-a]-quinoxaline-2-carboxylate acid (prepared by the process of French application No. 2,387,230), 0.81 g (5.0 mmole) of carbonyldiimidazole and 25 ml of anhydrous dimethylformamide was stirred until a clear solution was obtained and 0.425 g (5.0 mmole) of anhydrous 5-amino-tetrazole were added thereto. The mixture was stirred at room temperature for 30 minutes and was then filtered. The recovered product was washed with ethyl acetate and dried over P2O5 under vacuum to obtain 1.4 g of 4,5-dihydro-5-ethyl-4-oxo-N-(1H-tetrazol-5-yl)-pyrrolo-[1,2-a]-quinoxaline-2-carboxamide in the form of white crystals melting at 315°-318° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([CH3:16])=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.[BH4-].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OC(=O)[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)C.[OH-].[Na+]>O1CCCC1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:16])[N:13]([S:42]([C:39]4[CH:40]=[CH:41][C:36]([OH:35])=[CH:37][CH:38]=4)(=[O:44])=[O:43])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2cc(Cl)ccc2c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccc(Cl)cc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 3-chloro-6-methylphenanthridine (0.40 g, 1.76 mmol) in tetrahydrofuran (7 mL) was treated with freshly crushed sodium borohydride (0.33 g, 8.8 mmol). Trifluoroacetic acid (0.54 mL, 7.0 mmol) was added dropwise at a rate to keep the exothermic reaction and gas evolution under control. After the addition was complete, the heterogeneous reaction mixture was stirred until the temperature returned to 23° C. The mixture was then heated at reflux for 14 hours. The reaction was cooled to room temperature and neutralized with a saturated, aqueous sodium bicarbonate solution (150 mL). The mixture was filtered through a plug of glass wool into a separatory funnel and extracted with diethyl ether (4×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a light brown paste. The crude 3-chloro-6-methyl-5,6-dihydrophenanthridine was dissolved in pyridine (12 mL), treated with carbonic acid 4-chlorosulfonyl-phenyl ester ethyl ester (0.699 g, 2.64 mmol) and 4-(dimethylamino)pyridine (0.01 g, 0.08 mmol), and stirred at 80° C. for 14 hours. The reaction was cooled to room termperature, treated with a 0.1 N aqueous sodium hydroxide solution (100 mL, 10 mmol), and extracted with dichloromethane (6×50 mL). The combined organic phase was washed with a 2 N hydrochloric acid solution (2×40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous, brown oil. The viscous oil was purified by filtration through a plug of silica gel, eluting with a mixture of ethyl acetate-hexane (1:4). Concentration of the filtrate in vacuo, followed by trituration with ethyl acetate-hexane afforded the title compound as a homogeneous, white crystalline solid (0.25 g, 37%), m.p. 204° C.;
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn2c(=O)[nH]c3ccccc3n2c1=O

Procedure:
To a solution of 3 g of 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester of hot ethanol, there is added 10 ml of 10% aqueous sodium hydroxide and the mixture refluxed for 2 hours. The mixture is concentrated under reduced pressure and the residue dissolved in water. The solution is filtered and neutralized with dilute hydrochloric acid. The precipitated 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid is filtered and washed with a small amount of cold water. The product is crystallized from ethanol.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCCl>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (248 mg, 1.0 mmol) and 2,4-difluorobenzaldehyde (300 mg, 2.11 mmol) in 1,2-dichloroethane (10 mL) was added tetramethylammonium triacetoxyborohydride (0.6 g, 2.0 mmol). The mixture was stirred at 50° C. for 20 hours. The mixture was quenched by addition of saturated Rochelle's salt (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (5-40% EtOAc/Hexane) to give tert-butyl 1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (365 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=[C:12]([NH:21]CC3C=CC=CC=3)[C:11]=2[NH:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+]>O>[NH2:21][C:12]1[C:11]2[NH:10][C:9](=[O:29])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=1
Reactant: O=c1[nH]c2c(NCc3ccccc3)nc(C(F)(F)F)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1nc(C(F)(F)F)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 0 °C
Yield: 59 %

Procedure:
1-Benzyl-4-benzylamino-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-c]pyridine-2-one (2.63 g, 6.60 mmol) was dissolved in c.H2SO4 (50 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. and ice was added. K2CO3 (150 g) was dissolved in water (700 ml) and the reaction mixture was added dropwise. The aqueous was extracted with EtOAc (6×500 ml). The combined organics were washed with brine (200 ml), dried over MgSO4 and concentrated in vacuo to give the title compound (1.20 g) as a white solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C@@:8]1([OH:28])[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C:24](=[CH:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)#[CH:7]>O.C1COCC1.CO>[OH:28][C@:8]1([C@:9]2([CH3:10])[C@H:11]([C@H:14]3[C:24](=[CH:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:13]1)[C:6](=[O:2])[CH3:7]
Reactant: C#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 3 h

Procedure:
Mercuric oxide red (0.064 g) and concentrated sulfuric acid (0.086 ml) are stirred in water (1 ml) for 75 minutes at 67°. This mercuric oxide mixture is added to a mixture of 17β-ethynyl-17α-hydroxyandrosta-4,9(11)-dien-3-one (II A, Example 2, 0.84 g) in THF (5 ml) and methanol (24 ml) at 38°. This mixture is stirred for 3 hours and then cooled to 20°-25°. The mixture is quenched with phosphate buffer (pH=7, 10 ml) and then filtered to remove the insoluble mercury salts. The phases are separated and the aqueous layer is back-extracted with methylene chloride (3 times). The organic phases are combined and washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give the title compound. NMR (CDCl3) 0.70, 1.42, 2.33, 5.60 and 5.80δ.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([CH2:24][S:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)(=[O:23])=[O:22])=[CH:33][CH:32]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(CS(=O)(=O)c2ccccn2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CS(=O)(=O)c2ccccn2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with pyridine-2-thiol via Procedure Q. 260 mg of methyl 4-((pyridin-2-ylthio)methyl)benzoate was reacted via Procedure R to give methyl 4-((pyridin-2-ylsulfonyl)methyl)benzoate. 275 mg of methyl 4-((pyridin-2-ylsulfonyl)methyl)benzoate was hydrolyzed via Procedure M to give 4-((pyridin-2-ylsulfonyl)methyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((pyridin-2-ylsulfonyl)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyridin-2-ylsulfonyl)methyl)benzamide. MS (Q1) 464.1 (M)+.