Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]1[C:25]([C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=2[O:33][CH2:34][C:35]([CH3:40])([N+:37]([O-])=O)[CH3:36])[NH2:29])=[CH:24][CH:23]=[N:22]1.CCN(C(C)C)C(C)C.C(Cl)(=O)C>ClCCl.CO.[Zn].CN(C=O)C>[NH2:37][C:35]([CH3:40])([CH3:36])[CH2:34][O:33][C:32]1[CH:31]=[CH:30][C:28]([NH:29][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=2)=[CH:27][C:26]=1[C:25]1[N:21]([CH3:20])[N:22]=[CH:23][CH:24]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Zn]
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.1 %

Procedure:
DMF (10 μL) was added to a mixture of 4-trifluoromethylbenzoic acid (61 mg, 0.32 mmol) and oxalyl chloride (27 μL, 0.32 mmol) in dichloromethane (0.5 mL) and the mixture was stirred for 45 min at room temperature. The solution of the crude acid chloride was added to a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (62 mg, 0.21 mmol) and DIEA (146 μL, 0.84 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 14 h, the mixture was diluted with dichloromethane, washed with 0.5M citric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was suspended in methanol (1 mL) and acetylchloride (164 μL, 2.3 mmol) was added slowly. A clear solution was obtained. Zinc dust (150 mg, 2.3 mmol) was added, and the mixture was stirred at 55° C. After 2 h, the mixture was allowed to cool to room temperature, and diluted with methanol. The precipitate was removed by filtration and washed with methanol. The combined washings were evaporated to dryness. The residue was suspended in 1M HCl, the mixture was cooled on an ice bath, and made alkaline with ammonium hydroxide. The solution was extracted with ethyl acetate, and the extract was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by RP-HPLC. The trifluoroacetate was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness to afford the free base (53 mg, 0.12 mmol, 57%). LCMS m/z (%)=433.3 (M+H 60.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (s, 6H), 3.67 (s, 2H), 3.68 (s, 3H), 6.28 (d, J=1.77 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.48 (d, J=1.77 Hz, 1H), 7.70 (d, J=2.53 Hz, 1H), 7.84 (dd, J=8.97, 2.65 Hz, 1H), 7.92 (d, J=8.34 Hz, 2H), 8.14 (d, J=8.08 Hz, 2H), 10.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)c(C(=O)O)c2n(c1=O)CCC2
Yield: 94.8 %

Procedure:
Compound 8c (225 mg, 0.88 mmol) was stirred in a solution of THF (4 mL), MeOH (2 mL), and 1N NaOH (2 mL) at r.t. for 20 h. The solution was made acidic with 1N HCl and extracted (3×) with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo to give 190 mg (95%) of compound 8d as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.16 (s, 1H), 4.01 (t, 2H, J=6.9 Hz), 3.26 (t, 2H, J=7.6 Hz), 1.96-2.17 (m, 5H). MS (ES) [m+H] calc'd for C10H10ClNO3, 228. found 228.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O)(=[S:3])[NH2:2].[ClH:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>C1COCC1>[ClH:22].[C:1]([O:4][CH2:5][CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:7])(=[S:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)NC(COC(N)=S)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=S)OCC(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
In a 100 mL flask equipped with magnetic stirrer, O-thiocarbamoyl-N-(t-butyloxycarbonyl)-(DL)-phenylalaninol obtained in Example 1 was dissloved in 40 mL of THF and was added with 20 mL of 6N aqueous hydrochloric acid solution. The reaction mixture was stirred at room temperature for 8 hours, followed by the neutralization with saturated aqueous potassium carbonate solution. Thereafter, the organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a yellowish liquid. This was dissolved in 30 mL of THF and added with anhydrous hydrochloric acid at 0° C., to obtained desirable white precipitates. To this was added 30 mL of anhydrous diethyl ether, with the aim of maximizing the precipitation. As a result, 1.32 g of the title compound was obtained: Yield 82%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.Cl>C1COCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([B:23]([OH:26])[OH:24])=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17]
Reactant: COB(OC)OC
Reactant: COc1cccc(-c2ccccc2F)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)ccc(-c2ccccc2F)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
In the atmosphere of argon, 19.7 g of 2′-fluoro-2,3-dimethoxybiphenyl and 500 mL of anhydrous THF were placed in a flask. 56 mL of a hexane solution of 1.6M n-butyllithium was added, and the reaction solution was stirred at room temperature for 4 hours. After cooling to −78° C., 30 mL of a THF solution of 27.8 g of trimethyl borate was added dropwise. While heating to room temperature, the reaction solution was stirred for 8 hours. 200 mL of 10% HCl was added to the reaction solution, and the resulting mixture was stirred for 2 hours. The reaction solution was extracted with ether. An aqueous phase was removed, and then an organic phase was washed with saturated saline. After drying the organic phase with magnesium sulfate, the organic phase was concentrated, and residues were washed with hexane, whereby 15.2 g (yield: 65%) of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cn2cnnn2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cnnn2)cc1C(=O)O
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate (0.45 g, 1.73 mmol) and methanol/tetrahydrofuran (1/1, 10 mL). Add a 1 M aqueous solution of lithium hydroxide (5.8 mL, 5.8 mmol). After 4 hours, partition the reaction mixture between water and ethyl acetate. Acidify the aqueous with a 10% aqueous citric acid solution, extract four times with ethyl acetate, combine the ethyl acetate layers, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid: Rf=0.60 (silica gel, 1/1 methanol/dichloromethane).
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>CC#N.CCOC(C)=O>[C:17]1([O:16][C:14](=[O:15])[NH:12][C:9]2[CH:10]=[N:11][C:6]([N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(-n2nccn2)nc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1ccc(-n2nccn2)nc1)Oc1ccccc1
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To a solution consisting of 6-[1,2,3]triazol-2-yl-pyridin-3-ylamine (1.00 g, 6.21 mmol) in CH3CN (10 mL) was added phenyl chloroformate (0.389 mL, 3.10 mmol) dropwise at rt. After 16 h, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated aq. NaCl. The organic layer was separated, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (0.808 g, 93%). MS (ESI+): calcd. for C14H11N5O2, 281.09. m/z found, 282.1 (M+H)+.
Reaction SMILES: Cl.Cl.NC1C=C(C2C(C3C=CC(O)=C(N)C=3)=NC3C(=CC=C(C(O)=O)C=3)N=2)C=CC=1O.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:36]([OH:38])=[O:37].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([C:53]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)=O)=O)=[CH:47][CH:46]=1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([C:53]2[C:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:50][CH:49]=3)=[N:32][C:33]3[C:41](=[CH:40][CH:39]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[N:42]=2)=[CH:60][CH:59]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: Nc1cc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(O)c(N)c2)ccc1O
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1

Procedure:
The AB2 monomer, 2,3-bis(3-amino-4-hydroxyphenyl)quinoxaline-6-carboxylic acid dihydrochloride, is synthesized by condensing 3,4-diaminobenzoic acid and 4,4′-dimethoxybenzil to afford 2,3-bis(4-methoxyphenyl)quinoxaline-6-carboxylic acid, followed by demethylation in hydrobromic acid in acetic acid to form 2,3-bis(4-hydroxyphenyl)quinoxaline-6-carboxylic acid. The latter is then nitrated using nitric acid (70% conc.) in acetic acid at room temperature, yielding 2,3-bis(3-nitro-4-hydroxyphenyl)quinoxaline-6-carboxylic acid. The desired monomer is prepared by catalytic reduction in the presence of palladium catalyst in 10% hydrochloric acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21](C=O)C.[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36](I)[CH:37]=2)[C:32]([OH:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[C:31]1=[O:49])[CH3:26].C1(C)C=CC=CC=1>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2]>[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36]([C:20]#[N:21])[CH:37]=2)[C:32]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])([OH:48])[C:31]1=[O:49])[CH3:26]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(I)cc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To Pd2(dba)3CHCl3 (5.69 mg, 5 mol %) and triphenyIphosphine (5.76 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The mixture was stirred at room temperature for 30 minutes to give orange/yellow mixture. To this was then added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-chloro-6-iodooxindole (57.0 mg, 1.1×10−4 mol) followed by Zn(CN)2 (17.2 mg, 0.8 eq., 60%). The resulting suspension was heated to 60° C. (bath temperature) and stirred at that temperature for 3 hours. The mixture was allowed to cool and diluted with EtOAc:toluene (10 mL, 1:1). The mixture was washed with H2O (2×10 mL) and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo to give the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([CH3:20])([CH3:19])[C:16](O)=[O:17])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si]([NH:41][OH:42])(C)C>C(Cl)Cl>[OH:42][NH:41][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH:14]([S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)NO
Reactant: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)NO)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
3-(3,4-Dimethoxyphenylsulfonyl)-2,2-dimethyl-7-phenylheptanoic acid (0.5 g, 1.2 mmol) is dissolved in CH2Cl2 (6 mL), cooled in ice and 2 M oxalyl chloride in CH2Cl2 (1.7 mL, 3.5 mmol) is added. The reaction is warmed to room temperature and after 4 hours the solvent is removed in vacuo and the residue azeotroped twice with chloroform. The residue is dissolved in CH2Cl2 (4 mL) and trimethylsilylhydroxylamine (0.42 mL, 3.6 mmol) is added. The reaction is stirred 15 minutes and then the solvent is removed in vacuo, CH2Cl2 (10 mL) added and the solution washed with 1 N HCl. The organic layer is dried over MgSO4 and the solvent removed in vacuo to yield 3-(3,4-dimethoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoic acid hydroxyamide (0.34 g, 83%): 1H NMR (300 MHz, CD3OD) δ 7.45 (dd, J=8.3, 2.0 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.21-7.05 (m, 4H), 6.98-6.95 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86-3.84 (m, 1H), 2.38-2.33 (m, 2H), 1.93-1.84 (m, 1H), 1.69-1.64 (m, 1H), 1.43 (s, 3H), 1.34-1.23 (m, 3H), 1.23 (s, 3H), 0.98-0.85 (m, 1H); MS (FAB) m/e 450 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([N:19]2[CH2:24][C:23]3[CH:25]=[N:26][C:27](Cl)=[CH:28][C:22]=3[N:21]([CH3:30])[C:20]2=[O:31])[CH:15]=[CH:16][C:17]=1[F:18]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:27]2[N:26]=[CH:25][C:23]3[CH2:24][N:19]([C:14]4[CH:15]=[CH:16][C:17]([F:18])=[C:12]([NH2:11])[CH:13]=4)[C:20](=[O:31])[N:21]([CH3:30])[C:22]=3[CH:28]=2)=[CH:5][CH:4]=1
Reactant: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cc3c(cn2)CN(c2ccc(F)c(N)c2)C(=O)N3C)cc1
Temperature: 180 °C

Procedure:
By analogy to Example A24, 6-chloro-4-(methylamino)nicotinaldehyde (from Example A24), 4-fluoro-3-nitroaniline and sodium triacetoxy borohydride are combined in glacial acetic acid to give crude 2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)-N-methylpyridin-4-amine, which is reacted with diphosgene by the procedure of Example A75 to give 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. Zn Dust is reacted with a suspension of 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one and NH4Cl in MeOH/THF (1:1) to provide 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. By analogy to Example A25, 4-methoxybenzylamine and 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one are combined and heated to 180° C. to provide 7-(4-methoxybenzylamino)-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, which is further reacted with trifluoroacetic acid to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.N/[C:10](=[CH:15]\[CH3:16])/[C:11](OC)=[O:12]>>[OH:8][C:7]1[C:2]2=[N:1][C:15]([CH3:16])=[CH:10][C:11](=[O:12])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: C/C=C(\N)C(=O)OC
Reactant: Nc1ncccc1O
Product: Cc1cc(=O)n2cccc(O)c2n1
Yield: 79.6 %

Procedure:
A mixture of 110.0 g of 2-amino-3-pyridinol and 130.0 g of methyl 2-aminocrotonate are heated at an internal temperature of 110°-115° for approximately 4 hours. The solid product is sublimed in vacuo to give about 140.0 g of product, m.p. 144°-145°.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[O:8][C:9]=2[CH2:15][CH2:16][CH3:17])=[O:14])=[CH:27][CH:28]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1oc(C2CCCCC2)nc1C(=O)O
Product: CCCc1oc(C2CCCCC2)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H32N4O3 (m/e) 400, obsd 401 (M+H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](F)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:18][NH2:19].CS(C)=O>O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]([NH:18][NH2:19])[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1cccc(F)c1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: NNc1cccc(S(=O)(=O)c2ccccc2)c1
Temperature: 118 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of 1-benzenesulfonyl-3-fluoro-benzene (1.34 g, 5.7 mmol), hydrazine hydrate (1.4 mL) and dimethyl sulfoxide (2 mL) was stirred at 118° C. for 18 h, then cooled and poured into water (100 mL). The resulting colourless crystals were collected by filtration to give the title compound (1.34 g, 95%). 1H NMR (DMSO-d6): 7.95-7.84 (2H, m), 7.73-7.56 (3H, m), 7.37-7.21 (3H, m), 7.06 (1H, d), 6.96 (1H, dd), 4.14 (2H, br m).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cnc(Br)cc2[nH]1
Solvent: CN(C)C=O
Product: Clc1ccc2cnc(Br)cc2n1
Temperature: 80 °C
Yield: 95 %

Procedure:
7-Bromo-1,6-naphthyridin-2(1H)-one (Preparation 67, 800 mg 3.55 mmole) was treated with phosphorus oxychloride (18 mL) and catalytic DMF (2 drops). The reaction was heated at 80° C. for 2.5 hours. The phosphorus oxychloride was evaporated and the residue was azeotroped with toluene (15 mL). The solid was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (30 mL) with ice (10 g). The aqueous layer was washed with EtOAc, the organic layers combined, washed with sodium bicarbonate solution, brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound (826 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[O:12][C:13]2[C:14](=[C:16]([C:20](O)=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.Cl.Cl.[NH2:25][C@H:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[C@H:26]([NH:25][C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:13]3[O:12][C:11]([C:4]4[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=4[O:2][CH3:1])=[N:15][C:14]=13)=[O:21])[CH2:27]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
A mixture of 2-(2,4-dimethoxyphenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.33 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (66 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg, 0.66 mmol) and 1-hydroxybenzotriazole (89 mg, 0.66 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min, then triethylamine (0.18 mL, 1.32 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dimethoxyphenyl)benzoxazole-4-carboxamide (61 mg, 46%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.68 (d, J=7.0 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 6.68-6.65 (m, 2H), 4.32-4.26 (m, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.50 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.86 (m, 4H), 2.83 (dd, J=14.5, 4.5 Hz, 1H), 2.22-2.17 (m, 1H), 2.10-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 408 (M+H); HPLC 96.1% (AUC), tR=12.82 min.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][OH:19])([CH:6]=[CH:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:3]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19])([CH:6]=[CH:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCC=CC(C=O)(CC)CSc1ccccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC=CC(C=O)(CC)CSc1ccccc1C=O
Reaction time: 18 h
Yield: 65.3 %

Procedure:
A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5]O.P(Br)(Br)[Br:17]>O1CCCC1.O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5][Br:17]
Reactant: COc1c(C)c(C)c(OC)c(CO)c1C
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CBr)c1C
Yield: 119.9 %

Procedure:
A solution of 16.5 g (78.5 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzylalcohol in 90 ml of tetrahydrofuran was cooled to 0° C., to which 14.2 g (52.5 mmol) of phosphorus tribromide was added with stirring. After stirring at the same temperature for 30 minutes, the reaction mixture was diluted with water and extracted with isopropyl ether. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried, from which the solvent was evaporated off. The residue was crystallized from methanol, to give 17.2 g (80.0%) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide. m.p. 71°-72° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]([OH:18])=[O:17]>C(Cl)(Cl)Cl>[C:1]([C:14]1[S:10][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc(C(=O)c2ccccc2)s1
Yield: 50 %

Procedure:
Using the procedure of Example 1, 8.45 gm of benzoyl chloride, 7.1 gm of thiophene-2-acetic acid [prepared by process of Cagniant, Bull. Soc. Chim., 1949, p.847] and 18 gm aluminum alumina chloride suspended in chloroform were reacted to obtain, after crystallization, a 50% yield of 5-benzoyl-thiophene-2-acetic acid melting at 144° C. The product occurred in the form of colorless crystals insoluble in water.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=NC=C([C:31]([F:34])([F:33])[F:32])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cncc(C(F)(F)F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-5-(trifluoromethyl)pyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=377.4 (M+H+).