Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][CH:20]([OH:30])[CH2:21][CH2:22]2)=[CH:17][C:16]3([CH3:32])O)[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH:17]=[C:16]3[CH3:32])[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CCC(O)CC1=CC3(C)O
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: CC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
A solution of 20-tert-butyldimethylsilyloxy-7-methyl-pregn-5-ene-3,7-diol (298 gm, 0.59 mol, product of Step 4) in toluene (3 L) and cyclohexanone (1.03 L) was azeotroped to remove 750 mL of solvent. A solution of aluminum isopropoxide (121 gm) in toluene (620 mL) was added and the solution azeotroped to remove another 650 mL of solvent. A reflux condenser was added and the solution refluxed overnight. The solution was cooled to 40° C. and Supercell™ (125 gm) and water (125 mL) were added. After stirring for 10 min, the mixture was filtered and the solids washed with toluene (550 mL). The solvent was removed by rotoevaporation to yield a orange liquid which was purified by column chromatography on silica gel eluted with hexane, followed by 5-10% ethyl acetate in hexanes. The title compound was isolated as a mixture of 20α- and 20β-isomers.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][CH2:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccccn4)cc3)oc2C)cc1
Yield: 79.8 %

Procedure:
Method E. Reaction of oxalyl chloride (75 λL, 0.9 mmol) and benzoic acid 4 (215 mg, 0 6 mmol) with subsequent coupling to 2-pyridinylmethylamine (68.2 λL, 0.6 mmol) gave benzamide 8 (221 mg, 83%) as a white powder: mp (EtOAc) 154-155° C.; 1H NMR δ 9.21 (t, J=6.0 Hz, 1 H, CONH), 8.52 (dd, J=4.8, 1.5 Hz, 1 H, H-6′), 8.04 (d, J=8.6 Hz, 2 H, H-2, H-6), 7.91 (d, J=8.6 Hz, 2 H, H-3, H-5), 7.77 (dt, J=7.8, 1.8 Hz, 1 H, H-4′), 7.67 (d, J =8.3Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 7.35 (d, J=7.8 Hz, 1 H, H-3′), 7.27 (dd, J=7.7, 4.8 Hz, 1 H, H-5′), 4.63 (s, 2 H, CH2SO2), 4.59 (d, J=6.0 Hz, 2 H, CH2N), 2.41 (s, 3 H, CH3), 2.14 (s, 3 H, CH3); 13C NMR δ 165.6, 158.6, 158.0, 149.9, 148.8, 144.5, 136.7, 135.6, 135.5, 129.6 (2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 122.1, 121.0, 53.0, 44.8, 21.0, 9.7; MS m/z 462.6 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.03; H, 5.00; N, 9.11%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])O.[Na+]>O1CCCC1.B.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a solution of 5-phenylisoxazol-3-carboxylic acid (551 mg) in tetrahydrofuran (15 ml), 3.7 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred at 80° C. for 10 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-50:50)) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5CS(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H). 164 b) 2-Methanesulfonylmethyl-phenylamine was prepared from 1-methanesulfonylmethyl-2-nitro-benzene (1.0 g, 4.6 mmol) in a manner analogous to Example 111a. Product isolated as an off-white solid (0.84 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86-6.76 (m, 2H), 4.30 (s, 2H), 4.28 (br s, 2H), 2.87 (s, 3H). MS=186 (MH)+. 164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+. 164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9](O)=[O:10])=[C:4]([F:27])[CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:41][O:42][NH2:43].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:23][CH2:24]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH:43][O:42][CH3:41])=[O:10])=[C:4]([F:27])[CH:3]=1
Reactant: CON
Reactant: O=C(O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CONC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 45 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.453 mmol) in dichloromethane (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.680 mmol) and 4-(dimethylamino)pyridine (2.266 mmol) at room temperature. This mixture was stirred for 10 min at which point O-methylhydroxylamine hydrochloride (0.906 mmol) was added. The reaction vessel was sealed and the mixture was stirred at room temperature for 18 h and at 45° C. for 24 h. The reaction was then cooled to room temperature and was treated with pyridine (0.5 mL). The reaction vessel was resealed and stirred overnight in an oil bath at 45° C. At this point the reaction was cooled to room temperature and treated with additional portions of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.680 mmol) and O-methylhydroxylamine hydrochloride (0.906 mmol). The reaction vessel was resealed and stirred in an oil bath at 45° C. for 2 h. The reaction mixture was then concentrated to dryness in vacuo. The resulting orange residue was dissolved in dichloromethane (10 mL) and was concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-40% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a clear oily solid (89 mg, 38% yield). MS(ES)+ m/e 470.1/472.1 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl>ClC1C=CC=CC=1Cl>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccccc1C1=CCCCCC1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: C1=C(c2ccccc2N2CCNCC2)CCCCC1
Temperature: 200 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a solution of 2-cyclohept-1-enylphenylamine (617 mg, 3.29 mmol) in 1,2-dichlorobenzene (8 mL) was added bis(2-chloroethyl)amine hydrochloride (705 mg, 3.95 mmol), and the mixture was stirred at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor to remove the hydrogen chloride gas in the reactor. This procedure was repeated several times. After 5 hours, the reaction mixture was air-cooled to room temperature, and then aqueous solution of potassium carbonate, ethyl acetate and methanol were added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate, and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 387 mg of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:26][CH2:27][S:28](=[O:30])(=[O:29])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccc(Cl)cn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 5-chloro-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}pyridin-2-amine (440 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 265 mg) and 2-chloroethanesulfonyl chloride (648 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (520 mg) as an off-white solid. The solid was crystallized from CH3CN—IPE to give a white solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>ClCCl>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([N:21]([OH:22])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 4-bromobenzaldehyde (185 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:30][O:31][CH2:32][C@H:33]([CH3:53])[O:34][C:35]1[CH:36]=[C:37]([OH:52])[CH:38]=[C:39]([C:41]2[NH:42][C:43]([C:46]3[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=3)=[CH:44][CH:45]=2)[CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:52][C:37]3[CH:38]=[C:39]([C:41]4[NH:42][C:43]([C:46]5[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=5)=[CH:44][CH:45]=4)[CH:40]=[C:35]([O:34][C@@H:33]([CH3:53])[CH2:32][O:31][CH3:30])[CH:36]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:14][CH:15]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
5-Chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (288 mg, 0.67 mmol) synthesized in Example (120b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (160 mg, yield 33%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CC(CCl)=NC=C1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of 5-benzyloxy-2-chloromethyl-4-pyridone (10.0 g) and triphenylphosphine (10.5 g) in N,N-dimethylformamide (50 ml) was stirred for 5 hours at 90°-100° C. The resulting mixture was poured into ethyl acetate (800 ml). The precipitate was collected by filtration, washed with ethyl acetate and dissolved in dichloromethane (500 ml). To the solution were added water (300 ml) and 38% aqueous formaldehyde (100 ml). The mixture was adjusted to pH 10-10.5 with potassium carbonate. After being stirred for 3 hours at 35°-40° C., the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The product was isolated by column chromatography on silica gel with ethyl acetate as an eluent to give 5-benzyloxy-2-vinyl-4-pyridone (6.02 g).
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.[C-]#N.[K+]>[C:21]([NH:29][NH:30][C:13]([CH:12]1[CH:10]([CH:9]([C:18]([OH:20])=[O:19])[NH2:8])[CH:11]1[C:15]([OH:17])=[O:16])=[O:14])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NNC(=O)c1ccccc1
Reaction time: 8 h
Yield: 104.6 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (88 mg, 0.25 mmol) in dry THF (2 mL) under argon was added benzoic hydrazide (209 mg, 1.54 mmol) and potassium cyanide (0.83 mg, 0.01 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 84 mg of the desired compound (72% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH3:18])=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:14]1[C:13]([CH3:18])=[C:12]2[C:16]([CH:17]=[C:9]([N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH3:19])[CH:10]=[CH:11]2)=[N:15]1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Cl)n3)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-1H-indazol-6-amine (2 g, 7.31 mmol) was dissolved in DMF (15 ml), and Cs2CO3 (2 g, 14.6 mmol) and 3-chlorobenzyl bromide (1.25 ml, 9.5 mmol) were added at room temperature. Mixture was stirred at rt for overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated. The aqueous layer was thoroughly extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to give 2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine as an off-white solid. 1H NMR (300 MHz, d6DMSO) δ 7.94 (d, J=6.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.36-7.38 (m, 2H), 7.32 (br s, 1H), 7.16 (m, 1H), 6.91 (m, 1H), 6.28 (d, J=6.1 Hz, 1H), 5.65 (s, 2H), 3.42 (s, 3H), 2.63 (s, 3H). MS (ES+, m/z) 398 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O/C=C/C(Cl)=O)C.OC1C=C[C:24]2[C:19](=[CH:20][CH:21]=CC=2)N=1.[Cl-].C(=O)/C=C/C>P(Cl)(Cl)(Cl)=O>[CH3:21][C:20]1[CH:19]=[CH:24][C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2ccccc2n1
Agent: C/C=C/C=O
Agent: CCO/C=C/C(=O)Cl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccccc2n1

Procedure:
Aniline 22 may be acylated with (E)-3-ethoxyacryloyl chloride and treatment of the resulting amide with sulfuric acid leads to hydroxyquinoline 29, which can be converted to the corresponding chloride 30 by heating in phosphorus oxychloride. Condensation of aniline 24 with crotonaldehyde in the presence of acid and an oxidant affords the 2-methylquinoline 31. The use of other aldehydes under similar conditions can lead to alternatively substituted quinolines. Oxidation of quinoline 31 with selenium dioxide can provide either aldehyde 32 or carboxylic acid 33, depending on the amount of oxidant used and the duration of the reaction. Reduction of aldehyde 32 with sodium borohydride provides the corresponding alcohol, and treatment of this with thionyl chloride may be used to give the chloride 34. Intermediates such as 30, 32, 33 and 34 may be converted to compounds of the present invention using a variety of known methodology. While the methodology shown in Scheme 6 is exemplified using aniline 22, it is understood that it may be applied to a variety of aniline substrates, such as those described herein, in order to provide various quinoline intermediates.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1=O)=O)C.C(OC(C1CC[N:28](CC2C=CC=CC=2)CC1=O)=O)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>[OH-].[OH-].[Pd+2].CCO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]2[CH:7]([NH:28][CH2:4]2)[CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reaction time: 24 h
Yield: 94.25 %

Procedure:
3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. A mixture of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (11.31 g, 38 mmol), di-t-butyl dicarbonate (8.78 g, 40.2 mmol), Et3N (5.4 mL, 38.7 mmol) and Pd(OH)2 on carbon (20% on dry basis-Pearlman's catalyst) (1.3 g) were taken into EtOH (110 mL). The mixture was hydrogenated at 60 psi for 24 h in a Parr bottle. The catalyst was removed by filtration and the filtrate was concentrated to dryness to tan solid. Crude residue was shaken well with hexane (100 mL) and filtered. The filtrate was concentrated to yield the title compound (9.70 g, 94.25%). MS (ESI) mass calcd. for C13H21NO5, 271.32; 1H NMR (400 MHz, CDCl3) 4.24 (q, J=7.1, 2H), 4.03 (s br, 2H), 3.49 (t, J=5.6, 2H), 2.32 (m, 3H), 1.47 (s, 9H), 1.31 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[NH2:28][OH:29]>CO>[NH2:25][C:24](=[N:28][OH:29])[C:22]1[CH:21]=[C:20]([Cl:26])[N:19]=[C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:17][CH2:16]2)[CH:23]=1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=NO)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
3,4-Dichloro-N-[1-(6-chloro-4-cyanopyridin-2-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 95; 150 mg, 0.362 mmol) was dissolved in MeOH (5 ml) and TEA (100 μl, 0.724 mmol) was added. Hydroxylamine hydrochloride (25.2 mg, 0.362 mmol) was added and the mixture was refluxed for 1 h. The solvent was removed in vacuo and the resulting precipitate was dissolved in DMSO and purified by semi preparative reverse phase HPLC eluting with CH3CN/H2O (0.1% TFA). (80 mg).