Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC([O-])(C)C.[K+].[Br:36][C:37]1[CH:38]=[C:39]([C:50]2[CH:57]=[CH:56][C:53]([CH:54]=O)=[CH:52][CH:51]=2)[S:40][C:41]=1[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1.O>C1COCC1>[Br:36][C:37]1[CH:38]=[C:39]([C:50]2[CH:51]=[CH:52][C:53](/[CH:54]=[CH:2]/[CH:3]=[CH:4]/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:56][CH:57]=2)[S:40][C:41]=1[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1
Reactant: COc1ccc(-c2sc(-c3ccc(C=O)cc3)cc2Br)cc1
Reactant: C(=Cc1ccccc1)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2sc(-c3ccc(/C=C/C=C/c4ccccc4)cc3)cc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
10.83 g (23.6 mmol) of Cinnamyltriphenylphosphonium bromide was added to 2.70 g (24.10 mmol) of t-BuOK in 100 mL THF and the resulting solution was stirred at RT for 30 min. The reaction mixture was cooled to 0° C. and 8 g (21.4 mmol) of the aldehyde (62) was added in 35 mL THF. The solution was warmed to RT and stirred for 5 hrs. The solution was poured into 200 mL water. The precipitated product was separated by filtration to give 7.5 g (74% yield) of pure target molecule.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1.[C:31](Cl)(=[O:41])[C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:31](=[O:41])[C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CCO)CC2)ccc1OCc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(=O)N2CCN(CCOC(=O)c3ccc4c(c3)OCO4)CC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
1-[4-(4-fluorobenzyloxy)-3-isobutylbenzoyl]-4-(2-hydroxyethyl) piperazine (1.95 g) was dissolved in a mixture of dichloromethane (30 ml) and triethylamine (1.04 ml) and then, while being cooled with ice, piperonyloyl chloride (0.93 g) was added thereto dropwise. After being stirred for 12 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1), thereby yielding 1.92 g of the aimed compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34]C(N(C)C)N(C)C)(C)(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:30][OH:34])=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCNC(=O)Cc2ccc(Cl)cc2)ccc1OCc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 62.4 %

Procedure:
2.25 g (5.49 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)acetamide and 2.39 g (13.73 mmol) of t-butoxybis(dimethylamino) methane were mixed and stirred at 90° C. for 1.5 hours. The reaction mixture was cooled and tetrahydrofuran was added thereto. The reaction mixture was acidified with 5% hydrochloric acid and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water and 5% hydrochloric acid were added to the residue, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 1.50 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=1.C([O-])([O-])=O.[K+].[K+].Br[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=1.CN1C=CN=C1>[Cu]I.C1(C)C=CC=CC=1>[CH3:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([N:18]2[C:17]3[CH:16]=[C:15]([O:14][C:13]4[CH:28]=[CH:29][CH:30]=[C:11]([C:2]5[CH:3]=[CH:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=5)[CH:12]=4)[CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:43]=1
Reactant: c1cc(Oc2ccc3c(c2)[nH]c2ccccc23)cc(-c2ccc3ccccc3n2)c1
Reactant: Cc1ccnc(Br)c1
Agent: [Cu]I
Agent: Cn1ccnc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-n2c3ccccc3c3ccc(Oc4cccc(-c5ccc6ccccc6n5)c4)cc32)c1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To a dry pressure vessel equipped with a magnetic stir bar was added 2-(3-(quinolin-2-yl)phenoxy)-9H-carbazole (773 mg, 2.0 mmol, 1.0 eq), CuI (76 mg, 0.4 mmol, 0.2 eq), and K2CO3 (553 mg, 4.0 mmol, 2.0 eq). The vessel was evacuated and back-filled with nitrogen. The evacuation and back-fill procedure was repeated twice. Then 2-bromo-4-methylpyridine (1032 mg, 6.0 mmol, 3.0 eq), 1-methyl-1H-imidazole (158 uL, 2.0 mmol, 1.0 eq) and solvent toluene (32 mL) were added under nitrogen. After bubbling with nitrogen for 25 minutes, the mixture was stirred in an oil bath at a temperature of 120° C. for three days, and cooled to ambient temperature. The solid was filtered off and washed with ethyl acetate. The filtrate was concentrated and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1-3:1) as an eluent to afford the desired product Ligand ON11Me as a sticky liquid (955 mg) in 99%. 1H NMR (DMSO-d6, 400 MHz): δ 2.38 (s, 3H), 7.09 (dd, J=8.4, 2.4 Hz, 1H), 7.18 (dd, J=8.4, 2.4 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.54-7.60 (m, 3H), 7.72-7.77 (m, 2H), 7.97-8.04 (m, 4H), 8.13 (d, J=9.2 Hz, 1H), 8.21 (d, J=7.6 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.49 (d, J=4.8 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].[OH-].[Na+]>O1CCCC1.O>[CH2:29]([O:28][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH:25]([CH3:26])[CH3:27])=[O:23])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(C(=O)NC(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(C(=O)NC(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
2-Ethoxy-3-[4-(2-{4-(isopropylaminocarbonyl)phenyl}ethoxy)phenyl]propanoic acid ethyl ester (described in Example 106) (1 g; 2.34 mmole) was dissolved in tetrahydrofuran (10 ml). Lithium hydroxide (0.056 g; 2.34 mmole) dissolved in water (6 ml) was added slowly in portions during 20 minutes. The reaction mixture was stirred at room temperature for 3 hours and then diluted with water followed by careful evaporation of tetrahydrofuran. The residual water phase was extracted once with diethyl ether, then acidified and extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried with sodium sulfate and evaporated. The residue was dissolved in methanol (10 ml) and sodium hydroxide (0.109 g; 1.73 mmole) in water (3.5 ml) was added. The solution was evaporated and the residue redissolved in water. Freeze drying gave 0.643 g (65.2% yield) of 2-ethoxy-3-[4-(2-{4-(isopropylaminocarbonyl)phenyl}ethoxy)phenyl]propanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][CH:25]([CH3:27])[CH3:26])=[C:13]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][CH:25]([CH3:27])[CH3:26])=[C:13]([C:15]2[NH:23][C:18]3=[N+:19]([O-:36])[CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cccnc2[nH]1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc[n+]([O-])c2[nH]1

Procedure:
A solution (10 ml) of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine (0.2 g) and m-chloroperbenzoic acid (0.15 g) in chloroform was stirred at room temperature for 18 hr. The reaction mixture was washed with aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated to give the title compound as colorless crystals. purity 80%. M+H: 376.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:19][CH:18]3[CH:14]([CH2:15][N:16]([CH3:20])[CH2:17]3)[CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[OH-].[Li+].[CH2:23](OC(OCC)OCC)C>CO>[CH3:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[C:9]([N:12]3[CH2:13][CH:14]4[CH:18]([CH2:17][N:16]([CH3:20])[CH2:15]4)[CH2:19]3)[CH:8]=2)[N:1]=[CH:23]1
Reactant: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1N
Reactant: CCOC(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN1CC2CN(c3ccc4ncn(C)c(=O)c4c3)CC2C1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
2-Amino-N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)benzamide (Intermediate 8A) (100 mg, 0.36 mmol) was dissolved in triethoxymethane (1 mL) and sealed in a microwave vial. Heated at 160° C. for 10 minutes. Reaction allowed to cool to room temperature and lithium hydroxide solution added (0.5 mL, 1M in methanol) and reaction stirred overnight. Organic layer loaded onto a 1 g SCX cartridge. The crude material was purified by SCX, and the solvent removed under reduced pressure. The crude material was then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 3-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)quinazolin-4(3H)-one (56 mg, 0.2 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([I:9])=[CH:6][N:5]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Silver sulfate (7.1 g, 22.8 mmol) and 4-amino-2-chloropyridine (4.06 g, 31.6 mmol) were added to a solution of iodine (5.65 g, 22.3 mmol) in ethanol (100 mL) and the reaction mixture stirred at rt for 72 h. The bright yellow suspension was filtered, washed with methanol and the filtrate concentrated in vacuo. The residue was partitioned between saturated Na2CO3 solution (200 mL) and ethyl acetate (200 ml). After separation the organic layer was washed with Na2S2O3 solution (50 mL, 25%) and brine (50 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with iso-hexane/ethyl acetate (3:1 to 2.5:1) to give the title compound. δH (CDCl3): 4.81 (2H, br s), 6.63 (1H, s), 8.38 (1H, s); m/z (ES+)=254.86 [M+H]+; RT=2.5 min.
Reaction SMILES: [CH2:1]([S:8]([NH:11][CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]=2[O:16][CH:15]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:1]([S:8]([N:11]([CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]=2[O:16][CH:15]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)COc1cccc2c(CCNS(=O)(=O)Cc3ccccc3)coc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c(CCN(Cc3ccccc3)S(=O)(=O)Cc3ccccc3)coc12
Temperature: 25 °C
Reaction time: 27 h
Yield: 57 %

Procedure:
Methyl (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetate (143 mg) was dissolved in DMF (3 ml), and potassium carbonate (49 mg) and benzyl bromide (0.13 ml) were added to the obtained solution, followed by stirring the resulting mixture at room temperature for 27 hours and then at 50° C. for 14.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with 1N hydrochloric acid and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1-1/1) using silica gel to obtain the desired compound (100 mg, yield: 57%).
Reaction SMILES: C(OC(N1CCC([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[C:23]#[N:24])CC1)=O)(C)(C)C.[ClH:25].O1[CH2:31][CH2:30]OCC1>>[ClH:25].[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][N:24]2[CH2:31][CH2:30][CH2:16][CH2:17][CH2:23]2)[C:17]=1[C:23]#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(F)c2C#N)CC1
Reactant: C1COCCO1
Agent: Cl
Product: N#Cc1c(F)cccc1OCN1CCCCC1
Reaction time: 5 h
Yield: 66 %

Procedure:
4-(2-Cyano-3-fluorophenoxymethyl)piperidine-1-carboxylic acid tert-butyl ester (920 mg, 2.8 mmol) was dissolved in 5 mL of dioxane, and 3 mL of 4M HCl in dioxane was added over 1 minute at room temperature. Reaction stirred for 5 hrs and white precipitate was collected by filtration. Solids rinsed once with cold ether and dried to afford 2-fluoro-6-(piperidin-1-ylmethoxy)benzonitrile hydrochloride. (500 mg; 66% yield).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]Cl)[C:22]=1[CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO.C(OCC)(=O)C>[CH2:14]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:22]=1[CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 25.5 %

Procedure:
To a liquid prepared by dissolving with stirring 7.8 g (0.052 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 61.5 g (0.319 mol, 5.8 eq.) of a 28% sodium methoxide solution in 360 mL of methanol, a liquid prepared by dissolving the whole amount of 4-hexyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 30° C. Subsequently, the mixture was heated to reflux for 30 minutes and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 200 mL of ethyl acetate, and then the organic layer was washed with 80 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 15.2 g of an orange-colored oily matter. The product was recrystallized from ethyl acetate (5 vol.), to obtain 5.0 g of colorless crystals (HPLC: 99.1 Area %, yield 25.5%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH3:36])[C:11]([C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH2:24][N:25]4C(=O)C5C(=CC=CC=5)C4=O)[CH:18]=3)=[CH:12][CH:13]=2)[N:8]([CH:37]2[CH2:39][CH2:38]2)[CH:7]=1)=[O:5])C.[OH-].[Na+].[ClH:42]>CO>[ClH:42].[NH2:25][CH2:24][C:19]1[CH:18]=[C:17]([C:11]2[C:10]([CH3:36])=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH:37]3[CH2:38][CH2:39]3)=[CH:13][CH:12]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3cc(C)nc(CN4C(=O)c5ccccc5C4=O)c3)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2ccc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)cc(CN)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.31 g of 1-cyclopropyl-7-{2-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-6-methyl-4-pyridyl}-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester in 2 ml of methanol was added 1.78 ml of an aqueous 1 mol/l sodium hydroxide solution and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 5.3 with 1 mol/l hydrochloric acid and then precipitated crystals were filtered. The obtained crystals were dissolved in 6 mol/l hydrochloric acid and the solution was stirred with heating at 100° C. for 4 hours. After cooling the reaction mixture to room temperature, insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. Ethanol was added to the obtained residue and precipitates were filtered to obtain 0.15 g of 7-[2-(aminomethyl)-6-methyl-4-pyridyl]-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride. The obtained hydrochloride was dissolved in a mixed solvent consisting of 1.2 ml of ethanol and 1.2 ml of water. After adding 1.2 ml of an aqueous 1 mol/l sodium hydroxide solution to the resulting solution, carbon dioxide gas was blown therein. Filtration of the precipitates afforded 0.10 g of colorless crystals of 7-[2-(aminomethyl)-6-methyl-4-pyridyl]-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid.
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25](C(OC(C)(C)C)=O)[CH:26]=2)O1.C(#N)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH:11]([C:3]1[C:2]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)c1nn2ccccc2c1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To two 20 ml microwave reaction vials were each added 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine (486 mg, 1.69 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-pyrazolecarboxylate (500 mg, 1.69 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (139 mg, 0.17 mmol), acetonitrile (8 ml), and 1 M aqueous NaHCO3 solution (5 ml). The mixture was placed in a microwave reactor for 2 hours at 140° C. The reaction mixture from the two vials were combined and concentrated in vacuo, and the crude material was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 50% ethyl acetate in hexanes) to give the protected-analog. The protected analog was dissolved in 20% trifluoroacetic acid in dichloromethane (50 ml) and stirred at room temperature. The reaction was monitored by HPLC for completion (2 hours). The mixture was concentrated in vacuo, and the concentrated material was dissolved in 4N hydrochloric acid in dioxane. Ether was added to the acidic solution to precipitate out the desired material. The material was filtered and dried in vacuo under high vacuum to give 235 mg (31%) of 2-isopropyl-3-(1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine as the hydrochloric acid salt. 1H-NMR (250 MHz, DMSO-d6) δ 8.70 (broad s, 1H), 8.64 (d, J=7.0 Hz, 2H), 8.07 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.19 (dd, J=7.8, 6.8 Hz, 1H), 6.85 (t, J=6.8 Hz, 1H), 3.30 (sept, J=7.0 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H); LC/MS 227.1 m/z (M+H+). Compound 1104.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([O:17]C(C2C=CC(OC)=CC=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[OH:17][C@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2NC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Reaction time: 2.5 h
Yield: 107.8 %

Procedure:
A solution of (3R,4S)-tert-butyl 3-(benzyloxycarbonylamino)-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (2.18 g, 3.14 mmol) was stirred in a 10% TFA/dichloromethane solution (30 mL) for 30 minutes. The solution was concentrated under reduced pressure and the residue dissolved in ethyl acetate (15 mL) and treated with 2N HCl-diethyl ether (30 mL) for 1 hour. The resulting precipitate was collected by filtration and washed with ethyl acetate and dried to an off-white solid. The solid was dissolved in a 50% MeOH:dichloromethane solution (30 mL) and stirred with solid sodium carbonate (5 g) for 2.5 hours. The solids were collected by filtration and washed with 50% MeOH/dichloromethane solution and the filtrate concentrated under reduced pressure to give benzyl (3R,4S)-4-hydroxypyrrolidin-3-ylcarbamate (0.80 g, 99%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=C(C(O)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>ClCl>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=[C:1]([C:2]([Cl:4])=[O:3])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: ClCl
Product: O=C(Cl)c1cc(-c2ccco2)nc2ccccc12
Temperature: -10 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
5.2 ml (60.4 mmol) of oxalyl chloride were dissolved in 70 ml of CH2 Cl2. The solution was cooled at -10° C. and 8.5 g (35.5 mmol) of 2-(2-furyl)quinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 9.2 g of the title compound, used without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13].[NH4+].[OH-]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccnc2[nH]ccc12
Temperature: 125 °C

Procedure:
4-chloro-7-azaindole 24 was synthesized by reacting 1H-Pyrrolo[2,3-b]pyridine 7-oxide 23 with a chlorinating agent (e.g. POCl3) neat as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. The resulting solution after heating for 3-5 h at elevated temperatures (100-150° C.) was neutralized with a base (e.g. NH4OH) until a solid precipitated. The solid was isolated by filtration.