Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)[C:22]([C:37]#[N:38])=[C:21](SC2C=CC=CC=2)[N:20]=1.Cl>COCCOC.O>[NH2:18][C:19]1[N:20]=[C:21]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[C:22]([C:37]#[N:38])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:24]=1[C:25]#[N:26]
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: O=C(O)c1cccc(CO)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(N)nc(OCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.65 g (14.68 mmol) of potassium tert-butoxide were suspended in 15 ml of 1,2-dimethoxyethane. After addition of 0.97 g (5.87 mmol) of 3-(hydroxymethyl)benzenecarboxylic acid (Example 66A) and 1.14 g (2.94 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 35A), the mixture was stirred at 60° C. overnight. After cooling of the reaction mixture, 50 ml of water were added. With ice-cooling, the clear solution was acidified to pH 1 using conc. hydrochloric acid. The aqueous phase was decanted from the viscous precipitate formed. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). The aqueous phase was evaporated and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:43][CH:42]3[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH:37]2[CH2:43][CH:42]3[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
To a solution of pivalic acid 6-{2-{ethyl[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) in ethanol (1 ml) was added an aqueous solution of 1N sodium hydroxide (0.2 ml), and the solution was stirred for 1.5 hours at 60° C. The solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (12 mg).
Reaction SMILES: [CH2:1]([C@H:16]([NH2:20])[C:17]([OH:19])=[O:18])[CH2:2][C:3]([NH:5][C@H:6]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:7][SH:8])=[O:4].[N:21]([O-])=[O:22].[Na+].CC(C)=O>O.Cl>[N:21]([S:8][CH2:7][C@@H:6]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[NH:5][C:3](=[O:4])[CH2:2][CH2:1][C@@H:16]([C:17]([OH:19])=[O:18])[NH2:20])=[O:22]
Reactant: O=N[O-]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 76 %

Procedure:
1.53 g (5 mmol) L-glutathione (GSH) was dissolved in a mixture of 5.5 ml water and 2.5 ml (2 N) aqueous HCl solution cooled in ice bath, then 0.345 g (mmol) sodium nitrite was added. The mixture was stirred for 40 min at 5° C., then 10 ml acetone was added and the solution was stirred for further 10 min. The precipitated brown deposit was filtered and subsequently washed with ice-cold water (5×1 ml), acetone (3×10 ml) and ether (3×10 ml). Thus 1.29 g (3.8 mmol) of S-nitrosoglutathione was obtained (76% yield).
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:14][CH2:15][CH3:16])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1CCCC1.B.CO>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:14][CH2:15][CH3:16])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(CCC)c1cccc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCN1CC2C(C1)C2(CCC)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a stirred solution of 3-hexyl-6-(3-nitrophenyl)-6-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 64, 0.28 g, 0.78 mmol) in tetrahydrofuran (3 ml), under nitrogen, was added borane tetrahydrofuran complex (1M in tetrahydrofuran, 1.7 ml, 1.7 mmol) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature, methanol (1.5 ml) was added and then the reaction mixture was heated under reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (14 ml) and refluxed for 5 h. The reaction mixture was concentrated in vacuo, methanol (14 ml) was added and the reaction mixture was refluxed for a further 3 h before concentrating in vacuo. The crude residue was purified by chromatography on a Biotage Flash12™ cartridge packed with silica gel (8 g), eluting with hexane:ethyl acetate (4:1) to give the title compound as a yellow oil (0.2 g, 79%).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.C[NH:18]N>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH:5]=[N:18]1
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccccc2[N+](=O)[O-])cn1
Yield: 92.1 %

Procedure:
A solution of 60 g of 3-(dimethylamino)-2-(2-nitrophenyl)acrolein (see Example 10) and 16.1 g of methylhydrazine in 200 ml of toluene was refluxed for 10 hours, then concentrated to dryness in vacuo. The residue was recrystallized from 1-chlorobutane/hexane (about 1:1) to yield 51 g of the title compound; m.p. 41°-44° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:53]=[C:48]3[CH2:49][O:50][CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:53]=[C:48]3[CH2:49][O:50][CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCOC3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 61 %

Procedure:
Following the procedures as described in Example 113j, reaction of 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (200 mg, 0.52 mmol) and 129c (170 mg, 0.52 mmol) gave 129d as a yellow solid (185 mg, 61%). LCMS: [M+H]+ 584
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1nccnc1C1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nccnc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-fluoro-3-(piperidin-4-yl)pyrazine (0.311 g, 1.716 mmol) dissolved in DCM (5 mL) was added triethylamine (0.286 mL, 2.06 mmol), then acetyl chloride (0.134 mL, 1.89 mmol). The reaction mixture was stirred at RT for 1 h then partitioned between DCM and water. The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone as a yellow oil. MS (ESI, pos. ion) m/z: 224.0 (M−56).
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([F:31])[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[CH:18]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[C:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[CH:19][C:17]2[CH:18]=[C:13]([OH:12])[CH:14]=[C:15]([F:31])[CH:16]=2)=[CH:22][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Oc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3-fluoro-4′-acetoxystilbene (1.09 g, 3 mmol) in dry CH2Cl2 (120 mL) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water, dried over Na2SO4, filtered and evaporated. The 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 61%) was obtained as white solid. To a solution of the crude 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 1.8 mmol) in MeOH (7.5 ml) was added 3.7 ml 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3-fluoro-5,4′-dihydroxystilbene (0.33 g, 780%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.624 (s, 2H), 7.46 (m, 2H), 7.06 (q, 2H), 6.84 (m, 4H), 6.66 (dt, 1H); 13C NMR (Aceton-d6, 75 MHz) δ 164.90 (d), 159.96 (d), 158.57, 142.02 (d), 130.84, 129.63, 129.10, 125.55 (d), 116.53, 110.28 (d), 104.44 (d), 102.00 (d); 19F NMR (Aceton-d6, 282 MHz) δ-32429.72 (t); HRMS (EI+) found 230.0738, calcd 230.0743 for C14H, FO2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:35]C([O-])=O)(=O)[O:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:30][CH2:29][CH2:28][CH:27]([O:26][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:26][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])=[O:35])[C:10]2=[O:24])[C:14]1=[O:16])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC(CCC)OC(=O)OC(=O)[O-]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCC(CCC)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(CCC)CCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 49.2 %

Procedure:
2.14 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione (Pigment Red 254), 7.26 g of 4-heptyl pyrocarbonate from Example B1, 0.30 g of 4-dimethylaminopyridine and 150 ml of dry tetrahydrofuran are mixed and the mixture is stirred at room temperature for 165 minutes. The suspension is filtered through a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure and the residue is admixed with 50 ml of isopropanol. After 16 hours the precipitate is filtered off with suction and dried under reduced pressure to leave 1.90 g (49% of theory) of 2,5-di-4-heptyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as orange crystals. NMR (CDCl3) [ppm]: δ=7.67 (d,4H), 7.46 (d,4H), 4.98 (m,2H), 1.55 (m,8H), 1.30 (m,8H), 0.90 (t,6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10]([CH:12]=O)=O>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:7]=1)=[N:8][CH:10]=[CH:12][N:9]=2
Reactant: O=CC=O
Reactant: Cc1ccc(N)c(N)n1
Solvent: CO
Product: Cc1ccc2nccnc2n1
Reaction time: 18 h
Yield: 80 %

Procedure:
6-Methyl-pyridine-2,3-diamine (1.01 g, 8.2 mmol) was dissolved in MeOH (40 ml) and glyoxal (14 ml of a 40% aqueous glyoxal solution). Allowed to stir 18 h. The MeOH was removed, and the crude was taken up in ethyl acetate. It was washed three times with a 1 N HCl solution. The combined acid washings were washed twice with ethyl acetate. The acidic water was made basic with the addition of solid sodium carbonate, and it was extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried using MgSO4, and concentrated under vacuum to yield the title product (980 mg, 80%) as a brown solid. 1H NMR (DMSO-d6): δ=9.09 (d, 1H,J=1.8 Hz), 8.99 (d, 1H, J=1.8 Hz), 8.47 (d, 1H, J=8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 2.78 (s, 3H). Calculated mass=145, [M+H]+=146.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]2=[O:24])=[CH:17][CH:18]=1)#[N:23]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccc(C#N)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1ccc(Cn2c(=O)c(-c3ccccc3)cc3c(O)c(C(=O)NCCC(=O)O)ncc32)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A mixture of 1-(4-cyano-benzyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (694 mg, 7.9 mmol) and NaOMe solution (12 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 31 mg of the title compound as a brown solid. MS: (−) m/z 467.24 (M−1).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:10]([C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:12])[C@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Product: C[C@H]1CCCN(C(=O)c2ccccc2Oc2ccccc2)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 2-phenoxybenzoic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 470, [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][CH:17]([OH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:9][CH:8]=1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:24][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(NCC(O)c1ccccc1)c1ccc(NC(=O)c2ccccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ncc(-c3ccccc3)o2)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.1 %

Procedure:
under an N2 atmosphere, 2-chloro-N-(4-(((2-hydroxy-2-phenylethyl)amino)carbonyl)phenyl)benzamide (0.578 g, 1.46 mmol) was dissolved in DMF (7.00 ml). Dess-Martin periodinane (0.745 g, 1.76 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate and a saturated aqueous solution of sodium bisulfate. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and hexanes. The resulting solid was collected by filtration. The solid was suspended in pyridine (8.00 ml) and POCl3 (4.00 ml). The reaction was heated to 70° C. for 3 hours. The reaction was poured into a cooled 5% NaHCO3 solution and stirred vigorously for 15 minutes. The mixture was then extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 25% to 50% ethyl acetate in hexanes. The resulting solid was triturated with ethyl acetate/hexanes and collected by filtration to afford 2-chloro-N-(4-(5-phenyloxazol-2-yl)phenyl)benzamide (0.920 g, 16.8%). ESI m/z=375.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:34](O)[CH2:35][OH:36]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[O:36][CH2:35][CH2:34][O:19]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COc1cc(OC)cc(-c2cc(C=O)c([N+](=O)[O-])cc2F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2cc(C3OCCO3)c([N+](=O)[O-])cc2F)c1
Temperature: 130 °C
Yield: 89 %

Procedure:
A mixture of 6-fluoro-3′,5′-dimethoxy-4-nitrobiphenyl-3-carbaldehyde (1.7 g, 5.6 mmol) and 4-toluenesulfonic acid (95.8 mg, 0.6 mmol) in 1,2-ethanediol (4.3 mL) and toluene (60 mL) was heated at 130° C. for 3 hours. After that, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed by water (100 mL*3) and brine (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1 to 5/1) to afford the title compound (1.8 g, 89%) as a yellow solid. MS (ES+) C17H16FNO6 requires: 349, found: 350 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].O.[CH3:22][CH2:23]OCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[C:7]([CH:22]=[CH2:23])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: CCOCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (58 g) in dimethylformamide (350 ml) containing yinyltri-n-butyltin (116 ml) and tetrakis(triphenylphosphine)palladium(0) (3.5 g) was stirred at 75° C. for 3 hours. The reaction nixture was poured into water (600 ml) and ether (600 ml). The organic layer was washed with water (5 times), brine (700 ml) and dried over sodium sulphate. Removal of the solvent in vacuo was followed by recrystallisation of the residue from propan-2-ol, to give the title compound as a pale brown solid, m.p. 75-6° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (100 g) in chloroform (1 L) was added N-chlorosuccinimide (120 g) at ambient temperature and the mixture was stirred at 50° C. for 18 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude crystals was washed with diisopropyl ether and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3-chloro-4-hydroxybenzaldehyde (85.8 g) as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:13]([O:20][CH2:21][C:22]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][C:24]2([CH2:27][C:26](=O)[CH2:25]2)[CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:8][CH:26]1[CH2:27][C:24]2([CH2:29][C:22]([CH2:30][O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([CH2:21][O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23]2)[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(C1)CC(COCc1ccccc1)(COCc1ccccc1)C2
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CNC2CC3(C2)CC(COCc2ccccc2)(COCc2ccccc2)C3)cc1
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
Benzylamine (1.06 ml, 9.70 mmol) and acetic acid (0.56 ml, 9.70 mmol) were added to a dichloromethane (50 ml) solution of the compound (1.70 g, 4.85 mmol) obtained in Step 3 above, the resulting mixture was stirred for 10 minutes under ice cooling and then sodium cyanoborohydride (610 mg, 9.70 mmol) was added to the reaction mixture. After stirring at room temperature for 24 hours, saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=40:1 (v/v)] to give 1.27 g (60%) of the title compound as an oil.