Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][C:21](Cl)=[O:22]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][C:21]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)=[O:22]
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=C(Cl)Cc1cc(F)ccc1F
Product: O=C(Cc1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Yield: 14 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with 2,5-difluorophenyl acetyl chloride as in General Procedure 2 to give the title compound as an off-white solid (14% yield). M.p. 152-153° C., LCMS: m/z=415.90 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.47-3.54 (m, 2H), 3.80-3.87 (m, 4H), 5.44 (bs, 1H), 6.90-7.04 (m, 3H), 8.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1.[NH2:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48])[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:34][C:35]([F:36])([F:37])[F:38])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)CC(F)(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)OCC)CC(F)(F)F)cc1OC
Yield: 45.4 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (61 mg) and (S)-3-aminohexan-1-ol (34 mg). The sub-title compound (24 mg) was obtained as a pale yellow gum; 1H NMR (CDCl3); 6.93 (1H, s), 6.89 (1H, d), 6.76 (1H, d), 4.62-4.59 (3H, m), 4.15 (2H, q), 4.10-4.04 (1H, m), 3.91 (2H, s), 3.87 (3H, s), 3.66 (2H, s), 3.44 (2H, s), 3.37-3.20 (4H, m), 2.33 (3H, s), 1.82-1.69 (1H, m), 1.42-1.32 (3H, m), 1.24 (3H, t), 1.09-0.98 (2H, m), 0.73 (3H, t).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Ni]
Product: CC(C)(C)c1c[nH]c2cc(N)ccc12
Reaction time: 3 h
Yield: 75.9 %

Procedure:
A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and Raney Nickel (0.5 g) was hydrogenated under H2 (1 atm) at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel (petroleum ether/ethyl acetate=4:1) to give 3-tert-butyl-1H-indol-6-amine (2.0 g, 77%) as a gray solid. 1HNMR (CDCl3) δ 7.58 (m, 2H), 6.73 (d, J=1.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J=0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]([CH3:19])[CH2:7]2)[N:5]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:4](=[O:37])[N:3]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41]N>CCOC(C)=O>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([N:5]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[C:4](=[O:37])[N:3]=[C:2]2[NH:1][CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])[CH2:7][CH:8]1[CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(CN)OC
Reactant: CC1CC2(CCN1Cc1ccccc1)C(N)=NC(=O)N2c1cc(F)ccc1-c1ccc(S(C)(=O)=O)cc1
Solvent: CCOC(C)=O
Product: COC(CNC1=NC(=O)N(c2cc(F)ccc2-c2ccc(S(C)(=O)=O)cc2)C12CCN(Cc1ccccc1)C(C)C2)OC
Temperature: 85 °C
Reaction time: 18 h

Procedure:
A solution of 4-amino-8-benzyl-1-[4-fluoro-4′-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (50 mg, 0.10 mmol) in 2,2-dimethoxyethylamine (2.0 ml) was sealed and allowed to stir at 85° C. for 18 h. The temperature was increased to 110° C., and the reaction was allowed to stir for an additional 16 h. The reaction was diluted with EtOAc and washed with brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 8-benzyl-4-[(2,2-dimethoxyethyl)amino]-1-[4-fluoro-4′-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one. LCMS (M+H) 609.0.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[OH-].[Na+].CO>C(OCC)(=O)C.Cl>[OH:14][C:7]1[CH:6]=[C:5]([C:15]([F:16])([F:17])[F:18])[N:4]=[C:3]([C:2]([F:20])([F:1])[F:19])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 95.5 %

Procedure:
A solution of ethyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate (product of Example 3, 15 g, 0.0495 mol) in 5% aqueous sodium hydroxide (60 ml, 0.148 mol) was refluxed for 3 hours. The reaction was complete as judged by TLC (10% methanol in ethyl acetate). The mixture was then poured into a mixture of ice in concentrated aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, and concentrated to give a light brown solid (13 g). It was treated with petroleum ether to give 11.9 g of a white solid (83%); mp 168°-172° C.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:27]=[C:26]([CH2:28][NH2:29])[O:25][N:24]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:29][CH2:28][C:26]2[O:25][N:24]=[C:23]([O:22][CH3:21])[CH:27]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(C3CCCC3)c2)on1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (135 mg, 0.47 mmol) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) (60.16 mg, 0.47 mmol) as starting materials; off white solid (59 mg, 37.8%). MS (ESI): 400 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[OH:7][C:8]1[CH:40]=[CH:39][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:38])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[O:6]=[C:3]([CH2:4][CH3:5])[CH2:2][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:38])=[CH:39][CH:40]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7.37 ml of 1-bromo-2-butanone, 20.0 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 21.18 g of cesium carbonate and 200 ml of anhydrous acetone was stirred at room temperature for 3 hours. At the end of this time, the acetone was removed by evaporation under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The ethyl acetate was removed by evaporation under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate, diethyl ether and diisopropyl ether, to give 19.36 g of the title compound, melting at 155.2° to 156.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[OH:24].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C@@H:12]2[O:24][C@H:11]2[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(C=Cc2ccc(OC)c(OC)c2)cc1OC
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OC)c2)cc1OC

Procedure:
Mixture: 50.0 g 166 mmol) of 3,3',4,4'-tetramethoxystilbene, 1000 ml of dichloromethane, 1000 ml of sodium hydrogen carbonate solution, 64.0 g (185 mmol) of m-chloroperoxybenzoic acid (about 50% strength).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[OH:17])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:28]>C(OCC)(=O)C>[NH2:28]/[C:6](/[C:5]1[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=1[N+:1]([O-:3])=[O:2])=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1
Reactant: O=C(c1ccccc1[N+](=O)[O-])c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Yield: 21 %

Procedure:
Prepared as in Example 1 from 2-(2-nitrobenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 21% of theory. M.p. 185°-186° C. (ethyl acetate).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH:8]=[O:9])[CH3:7])C.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:4]([CH2:5][N:6]([CH3:7])[CH:8]=[O:9])=[O:3])[NH2:13]
Reactant: CCOC(=O)CN(C)C=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C=O)CC(=O)NN
Yield: 84 %

Procedure:
As described for example 112a, (formyl-methyl-amino)-acetic acid ethyl ester (Hay, Michael P.; Wilson, William R.; Denny, William A. Tetrahedron (2000), 56(4), 645-657) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 96 h. The mixture was concentrated and chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 50:10:1) to afford the title compound as a colorless oil (yield: 84%). MS: m/e=100.1 [M+H−N2H4]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:29])[CH:3]=1.[Na+].[CH3:31][S:32]([O-:34])=[O:33].[OH-].[Na+]>CS(C)=O.O>[F:29][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Reactant: CS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 110 °C
Yield: 64.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.781 g, 1.68 mmol), methanesulphinic acid sodium salt (0.86 g, 80%, 6.71 mmol), Cul (1.28 g, 6.71 mmol) and NaOH (81 mg, 2.02 mmol) in DMSO (20 mL) and water (0.5 mL) was degassed, purged with N2 and heated at 110° C. for 48 h. After cooled to ambient temperature, the mixture was poured into water (75 mL) and EtOAc (75 mL), and filtered through Celite®. The solid on Celite® was further washed with EtOAc. The filtrate and washing were combined and transferred to a separatory funnel. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 followed by trituration with hot hexanes containing 1% of MeOH to give 0.5 g (64%) of 1,1-dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=3.0 Hz), 8.15-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.20-4.10 (m, 2H), 4.00 (d, 2H, J=6.3 Hz), 3.18 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.[Li]C(CC)C.CN([CH:30]=[O:31])C>CCOCC>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:30]=[O:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1C=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A solution of N-Boc-Piperidine (6.0 g, 32.4 mmol) in ether (65 mL) was cooled to −60° C. and treated with TMEDA (4.9 mL, 32.4 mmol) followed by sec-BuLi (54.8 mL, 71.2 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 10 min and then cooled to −78° C. The mixture was treated with a solution of DMF (3.8 mL, 48.6 mmol) in 6 mL of ether via syringe, stirred for 10 min, and then quenched with 60 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted three times with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an orange oil. Purification by column chomatography on silica gel with hexanes:EtOAc (4: 1) afforded 4.2 g (67%) of the product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ9.58 (s, 1 H), 4.69-4.51 (br. m, 1 H), 4.12-3.85 (br. m, 1 H), 2.85 (br. s, 1 H), 2.19-2.13 (d, 1 H), 1.72-1.23 (m, 15 H); 13C NMR (75 MHz) 201.4 (s), 80.4 (s), 43.0 (br. s), 28.3 (s), 24.7 (s), 23.6 (s), 20.9 (s) ppm.
Reaction SMILES: [OH-].[Na+].C([O:11][CH2:12][CH:13]([CH2:32][CH:33]([O:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:34])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=O)C1C=CC=CC=1>CO.O1CCCC1>[C:36]([O:35][CH:33]([CH3:34])[CH2:32][CH:13]([CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][OH:11])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCSCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CO)CC(C)OC(=O)c1ccccc1
Yield: 62.8 %

Procedure:
Using 6.89 ml (13.78 mM) of 2N aqueous sodium hydroxide, 4.017 g (6.89 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hexadecylthio-propyl benzoate m11 in 38 ml of methanol and 43 ml of tetrahydrofuran is converted to 2.071 g (62.8% yield) of the titled compound m12 by the same procedure as described in (125).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC([O-])(C)C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=1>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 4-amino-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added t-BuOK (257 mg, 2.29 mmol). The reaction was stirred at rt for 30 minutes, then 4-chloropicolinamide (249 mg, 1.59 mmol) was added. The mixture was microwaved at 120° C. for 3 hours, then cooled to rt and diluted with 25 mL of water. The resulted mixture was extracted with EtOAc (30 mL×3), and the combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as an orange solid (110 mg, 41.5%).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1ccc(Cl)nn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Cl)nn1
Yield: 81.8 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (342 mg, 1.7 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), in anhydrous toluene (8.5 mL) was treated with 3,6-dichloropyridazine (256 mg, 1.7 mmol, Aldrich Chemical Company) and triethylamine (0.24 mL, 170 mg, 1.7 mmol). The reaction mixture was heated to reflux for 16 hours, concentrated under reduced pressure, and the residue purified on SiO2 (5%MeOH/CH2Cl2/1%NH4OH) to provide the title compound (432 mg, 81% yield) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.42(s, 4.5H), 1.46(s, 4.5H), 1.91-2.05(m, 2H), 3.36-3.46 (m, 3H), 3.54-3.60 (m, 1H), 4.57(s, 0.5H), 4.70(s, 0.5H), 4.92(s, 0.5H), 5.07(s, 0.5H), 6.59(d, J=9.20 Hz, 1H), 7.34(d, J=9.56 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+, 328(M+NH4)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:7]=1)(=O)C.[OH-].[Na+].O>O1CCCC1>[C:13]([NH:12][C:8]1[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][N:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(COC(C)=O)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(CO)ccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
4-Acetoxymethyl-2-acetylaminopyridine (Reference compound No. 11-1, 6.6 g, 32 mmol) was dissolved in tetrahydrofuran (20 mL), and 2N aqueous sodium hydroxide solution (19 mL, 38 mmol) was added dropwise thereto under ice-cooling. The mixture was stirred for 40 minutes at room temperature, and water (100 mL) was added thereto. The whole was extracted with ethyl acetate (80 mL) six times, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with the mixed solvent of ethyl acetate and hexane, and then the solid was dried under reduced pressure at 40° C. to give 4.5 g of the title reference compound as a colorless solid. (Yield 86%)
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2
Temperature: 80 °C

Procedure:
A mixture containing [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (Example 20, Step D) (1.07 g, 0.003 mole), potassium carbonate (0.41 g, 0.003 mole) and benzyl bromoacetate (0.69 g, 0.003 mole) in dimethylformamide (35 ml) is heated at 80° C. for two hours. Then this mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride, washed with aqueous sodium bicarbonate and then water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a viscous oil which is triturated with ether to give 1.06 g. of product.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Product: CCNC(=O)c1ccc(N2CCNCC2)cc1
Yield: 77 %

Procedure:
Using N-ethyl-4-fluorobenzamide in the general procedure for nucleophilic aromatic substitution reactions with piperazine, the title compound was obtained (77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.07 Hz, 3H) 2.25 (br. s., 1H) 2.76-2.86 (m, 4H) 3.09-3.18 (m, 4H) 3.21-3.28 (m, 2H) 6.90 (m, J=8.84 Hz, 2H) 7.67-7.75 (m, 2H) 8.11 (t, J=5.31 Hz, 1H). ESI-MS: m/z 234.2 (M+H)+. mp=131.3-134.4° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3cccc(F)c3)nc2c1
Yield: 58.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (90 mg, 0.30 mmol, 1.00 equiv) and 3-fluorophenylboronic acid (63.4 mg, 0.45 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 60 mg (55%) of 3-(3-fluorophenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.