Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:45]3[CH:46]=[CH:47][C:42]([N:39]4[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH2:38]4)=[N:43][CH:44]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1

Procedure:
Compound 15a (130 mg. 0.29 mmol) was subjected to Suzuki coupling conditions with 2-(4-BOC-piperazin-1-yl)pyridine-5-boronic acid pinacol ester using the methods described in Example 1, Step G to obtain compound 47a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C34H38N8O4: 623.2 (M+H). Found 623.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([O-:11])=[O:10])[C:6]([I:12])=[C:5]([O:13][CH3:14])[N:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([I:12])=[C:5]([O:13][CH3:14])[N:4]=1
Reactant: COc1nc(OC)c(I)c(C(=O)[O-])n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(OC)c(I)c(C(=O)O)n1
Reaction time: 8 h

Procedure:
18.0 g of methyl, 2,6-dimethoxy-5-iodopyrimidine-4-carboxylate are introduced in portions into a stirred solution of 2.4 g of sodium hydroxide in 70 ml of methanol and 4 ml of water. Stirring is allowed to continue overnight at room temperature, the methanol is distilled off and the residue is taken up in water. The aqueous phase is extracted using ethyl acetate, acidified to pH 2-3 using conc. hydrochloric acid and extracted using dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate and the solvent is distilled off in vacuo. 10.1 g of 2,6-dimethoxy-5-iodopyrimidine-4-carboxylic acid of melting point 125°-126° C. are obtained in this way.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[O:24][CH3:25])[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][O:29][CH2:30][CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[CH3:37].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:15]([NH:14][C:11]1[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]4[CH2:34][CH2:33][N:32]([CH3:37])[CH:31]([CH2:30][O:29][CH3:28])[CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=1)[CH2:16][CH2:17]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Reactant: COCC1CNCCN1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(NC2CCc4cccc(OC)c42)=N3)CCN1C
Yield: 33 %

Procedure:
Prepared from rac-2-chloro-N-[2-(7-methoxy-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 55, step A) (328 mg, 0.85 mmol), commercially available rac-2-methoxymethyl-1-methyl-piperazine (CAS no. 734507-92-7) (123 mg, 0.85 mmol) and diisopropylethyl amine (723 ul, 4.25 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (137 mg, 33%), MS (ISP) m/e=494.3 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:6]([C:7]#[C:8][Si](C)(C)C)[O:5][C:4](=[O:13])[NH:3]1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][C:2]1([CH3:14])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:13])[NH:3]1
Reactant: CC1(C)NC(=O)OC1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1OC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A mixture of 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (15.0 mmol) and K2CO3 (4.1 g, 30.0 mmol) in methanol (30.0 mL) was stirred at room temperature for 30 min. The solid was filtered off and washed with ether. The filtrate was concentrated, dissolved in ether (100 mL), washed with water (50 mL) and brine (50 mL), and dried over sodium sulfate. Solvent removal afforded 1.10 g (53%) of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone as a yellow oil: 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.39 (s, 3H), 2.68 (s, 1H), 4.82 (s, 1 H), 6.00 (br s, 1H).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32].[OH-].[Na+]>C1COCC1.CO>[NH2:33][C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:36]=[CH:35][CH:34]=1)=[O:32]
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Reactant: NC(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 9 from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-aminobenzoic acid amide in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:10])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.O.[SH-:12].[Na+]>>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[SH:12]
Reactant: [O-][n+]1cc(Cl)c(Cl)c(Cl)c1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: [O-][n+]1cc(Cl)c(S)c(Cl)c1

Procedure:
Prepared according to the procedure described for example 17 from 3,4,5-trichloro-1-oxido-pyridin-1-ium (0.75 g, 3.8 mmol) and sodium hydrosulfide hydrate (0.38 g, 4.57 mmol). The title compound was obtained as a brown solid (0.52 g, 70% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.89 (2H, s). MS m/z: 195.9 [M+H]+.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:26])[NH:23]2)=[CH:18][CH:17]=1>O1CCOCC1>[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22](=[O:26])[NH:23]2)=[CH:18][CH:17]=1
Reactant: O=C1CCc2ccc(F)cc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1ccc2ccc(F)cc2[nH]1
Yield: 18.9 %

Procedure:
DDQ (0.42 g, 1.9 mmol) was added to a solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (0.20 g 1.2 mmol) in dioxane (25 mL) and the resulting mixture was refluxed under an Argon atmosphere for 16 h. The mixture was concentrated under reduced pressure and sat aqueous Na2CO3 solution (25 mL) was added, and this was extracted with an organic mixture (MeOH/CH2Cl2 1:10, 3×50 mL). The combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by combi flash LC (SiO2; CH2Cl2/MeOH 10:1) to give the title compound (0.037 g, 18%). 1H NMR (DMSO-D6) δ 11.8 (s, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.74-7.65 (m, 1H), 7.05-6.95 (m, 2H), 6.43, (d, J=9.6 Hz); 13C NMR (CDMSO-D6) δ 163.0 (d, J=247 Hz), 161.9, 140.4 (d, J=13 Hz), 130.4 (d, J=11 Hz), 120.9, 116.1, 109.8 (d, J=23), 101.0 (d, J=25 Hz).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:52]1[CH2:56][CH2:55][C@H:54]([NH:57][C:58](=[O:60])[CH3:59])[CH2:53]1>CN(C)C=O.O>[C:58]([NH:57][C@H:54]1[CH2:55][CH2:56][N:52]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:53]1)(=[O:60])[CH3:59]
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), potassium carbonate (62 mg, 0.45 mmol, 2.92 equiv), potassium iodide (5 mg, 0.03 mmol, 0.20 equiv), and (S)—N-(pyrrolidin-3-yl)acetamide (38.5 mg, 0.30 mmol, 1.96 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 150 mL of water. The resulting solution was extracted with 4×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 38.7 mg (24%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.921-8.938 (d, J=5.1 Hz, 1H), 8.623-8.653 (d, J=9.0 Hz, 1H), 8.429 (s, 1H), 8.070-8.138 (m, 3H), 7.859-7.881 (m, 1H), 7.536-7.799 (m, 7H), 4.719 (s, 2H), 4.526-4.593 (m, 2H), 4.377-7.420 (m, 1H), 3.612-3.648 (t, J=5.4 Hz, 4H), 2.500 (m, 1H), 2.007-2.022 (m, 5H), 1.946 (s, 3H), 1.803-1.818 (m, 2H). MS (ES, m/z): 699 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[C@@H:59]2[CH2:60][CH2:61][CH2:62][CH2:63][C@H:58]2[N:57]=[C:56]1[C:64]1[CH:69]=[CH:68][C:67]([CH2:70][CH2:71][NH2:72])=[CH:66][CH:65]=1>CN(C=O)C>[NH:57]1[C@@H:58]2[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]2[N:55]=[C:56]1[C:64]1[CH:65]=[CH:66][C:67]([CH2:70][CH2:71][NH:72][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:23])=[CH:68][CH:69]=1
Reactant: NCCc1ccc(C2=N[C@@H]3CCCC[C@H]3N2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=N[C@@H]5CCCC[C@H]5N4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AG using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (56 mg, 0.16 mmol), EDCI (36 mg, 0.19 mmol), HOAt (26 mg, 0.19 mmol), DIPEA (0.084 mL, 0.48 mmol) and 2-{4-[(3aR,7aR)-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl]phenyl}ethanamine (82 mg, 0.14 mmol) in DMF (1 mL). The crude product was purified using Ambersep resin, then using prep method C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19]C(OC)=O)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[O-]CC.[Na+].CC(O)=O>CCO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC(=O)OC)cc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.35 g (4.1 mmol) of 2-(3-methoxycarbonyloxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester was dissolved in 30 ml of EtOH and cooled down to 5° C.; while stirring, 1.66 ml=1.45 g (4.5 mmol) of a solution of sodium ethoxide (21% in EtOH) was added and the reaction mixture then warmed up to ambient temperature. After 1 hour, it was poured into crashed ice/MeCl2, the pH was adjusted to 5-6 with AcOH (1N) and the reaction mixture was subsequently extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of MeCl2/MeOH) to finally give 0.95 g of the title compound as light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]\[C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1)([F:12])[F:11].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]([OH:23])[CH3:22])=[CH:15][CH:14]=1)([F:12])[F:11]
Reactant: CC(=O)/C=C\c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a stirred solution of (E)-4-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-en-2-one (7; 450 mg, 1.069 mmol) in CH3OH (20 mL) was added NaBH4 (216 mg, 3.20 mmol) at 0° C. under inert atmosphere. The reaction mixture was allowed to warm to RT and maintained for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with satd NH4Cl solution (5 mL) and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to afford 46 (230 mg, 0.54 mmol, 50%) as a viscous liquid. 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.50 (s, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.35-7.31 (m, 1H), 6.81-6.74 (m, 1H), 6.68-6.64 (m, 1H), 6.59 (d, J=16.5 Hz, 1H), 6.43 (dd, J=16.5, 5.5 Hz, 1H), 5.60 (d, J=14.5 Hz, 1H), 5.12 (d, J=14.5 Hz, 1H), 4.59-4.56 (m, 1H), 1.76 (br s, OH), 1.40 (d, J=7.0 Hz, 3H). MS (ESI): m/z 424 [M+H]+. HPLC: 98%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N+:15]([CH3:18])=[CH:16]Cl.[Cl-]>>[CH3:14][N:15]([CH3:18])[CH:16]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH:11]=[O:13]
Reactant: C[N+](C)=CCl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Product: CN(C)C=C(C=O)c1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrophenylacetic acid is treated with Vilsmeier reagent to give 3-(dimethylamino)-2-(4-nitrophenyl)-2-propenal. This product is treated with cyanoacetamide and sodium methoxide to give 1,2-dihydro-5-(4-nitrophenyl)-2-oxo-3-pyridinecarbonitrile. The preceding product is hydrolyzed with 1:1 concentrated hydrochloric acid-acetic acid to give 1,2-dihydro-5-(4-nitrophenyl)-2-oxo-3-pyridinecarboxylic acid. The above product is boiled with quinoline to give 5-(4-nitrophenyl)-2(1H)-pyridone. When the preceding product is treated with phosphorus oxychloride, 2-chloro-5-(4-nitrophenyl)pyridine is obtained. This product is treated with hydrazine to give 2-hydrazino-5-(4-nitrophenyl)pyridine. The above product is treated with ethyl orthoacetate to give the product of the Example.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[CH:9]1)(C)(C)C.[C:29]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:29][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:28])[CH:9]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(c2cn(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The intermediate from example 1, step d (33 mg, 0.08 mmol) was dissolved in DMF (1 mL) and treated with K2CO3 (28 mg, 0.2 mmol) followed by methyl iodide. The reaction was heated to 70°-80° C. for 1 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed several times with water then concentrated to dryness. The crude residue was then treated with TFA (2 mL) for 2 h. The reaction was concentrated and purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 8.22-8.20 (m, 1H), 7.88-7.85 (m, 2H), 7.81 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 5.94 (s, 1H), 4.80 (s, 2H), 2.88 (s, 3H); MS: ESI (negative): 355 (M−H).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:16])[CH:12](O)[CH:13]=[CH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11](=[O:16])[CH:12]=[CH:13][CH2:14][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: C=CC(O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=CCC1(C=O)CCCCC1
Temperature: 25 °C

Procedure:
To a solution of cyclohexanecarbaldehyde (6.3 mL) and 2-hydroxy-3-butenoic acid methyl ester (5 mL) in toluene (40 mL) was added para-toluenesulfonic acid monohydrate (20 mg), and the reaction mixture was heated under reflux by using a Dean-Stark apparatus for 16.5 hours. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=50:1 to 10:1) to give 4-(1-formyl-cyclohexyl)-but-2-enoic acid methyl ester (3.7 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C@H:10]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH3:11]>CCOCC>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C@H:10]([CH3:11])[CH2:9][OH:8]
Reactant: COC(=O)[C@@H](C)OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](CO)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-hydroxy-propionic acid methyl ester (10 g) and 3,4-dihydro-2H-pyran (15 mL) in DCM (400 mL) was added camphorsulfonic acid (50 mg) (exothermic reaction). The reaction mixture was stirred at ambient temperature for 2 hours, and washed with saturated bicarbonate solution (20 mL). The organic layer was dried, filtered and concentrated to obtain crude (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester, which was used as is in the next step. To a stirred suspension of LAH (4 g) in anhydrous ether (400 mL) at 0-5° C. was added (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester dropwise over 30 minute period. After completion of the addition, the cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was cooled to 0-5° C., and ethyl acetate was added dropwise to quench excess LAH, which was followed by the addition of saturated sodium sulfate solution and solid sodium sulfate. The resulting mixture was stirred at room temperature for 1 hour, the solid was filtered off, and the solid was washed with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography using a silica gel stationary phase (pre-treated with 0.1 triethylamine in hexanes) and hexanes in ethyl acetate to get (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol. 1H NMR (400 MHz, CDCl3): δ 4.51-4.75 (1H, m) 3.76-4.02 (2H, m) 3.42-3.62 (3H, m) 1.67-1.90 (2H, m) 1.46-1.63 (4 h, m) 1.10-1.24 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][C:13]#[N:14])=[N:9][C:8]=2[CH:15]=1)([O-])=O>[Pd].C1COCC1.C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][C:13]#[N:14])=[N:9][C:8]=2[CH:15]=1
Reactant: N#CCc1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCc1nc2cc(N)ccc2o1
Reaction time: 5 h
Yield: 29.6 %

Procedure:
The mixture of 5-nitro-2-benzoxazoleacetonitrile (8 g 39.4 mmole) and Palladium on carbon (1.2 g) in THF (100 ml) and acetic acid (2 ml) in a Parr bottle was hydrogenated at 50 psi for 5 h. It was filtered over a patch of celite (1.5 cm) covered with activated carbon (0.5 cm) and washed with isopropyl ether. The filtrate was evaporated and the residue was purified by flash chromatography and gave 5-amino-2-benzoxazoleacetonitrile (2.02 g, 30%).
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH2:13][CH3:14])=[CH:6][C:5]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[OH-:21].[K+].O>CO>[C:15]([C:5]1[CH:6]=[C:7]([CH2:13][CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCc1cc(C(C)(C)C)c(COC(=O)[O-])cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of (2-tert-butyl-4-ethyl-5-nitro-phenyl)methyl carbonate (3.9 g, 13.86 mmol) in methanol (100 mL) was added KOH (1.8 g, 32.08 mmol) at room temperature. The mixture was stirred overnight. Water was added and the reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-tert-butyl-4-ethyl-5-nitrophenol (2.8 g, 91%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.C(=O)([O-])[O-:11].[Li+:14].[Li+].C(=O)=O>O>[OH2:4].[C:5]([O-:11])(=[O:6])[C@@H:7]([C:2]([CH2:3][OH:4])([CH3:9])[CH3:1])[OH:8].[Li+:14]
Reactant: CC1(C)COC(=O)C1O
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Li+]
Solvent: O
Product: CC(C)(CO)[C@@H](O)C(=O)[O-]

Procedure:
A slurry of 1.00 kilogram of racemic DL-pantolactone and 300 grams of lithium carbonate in 1.5 liters of water was continuously stirred and heated at boiling temperature in a flask provided with a stirrer and reflux condenser for 1.5 hours. After all the evolved carbon dioxide had been expelled, the reaction mixture was filtered while hot and 25 grams of lithium carbonate was thus recovered therefrom. When the filtrate was cooled and stirred, 700 grams of crystals of racemic DL-lithium pantoate monohydrate having a melting point of 107°-110° C, amounting to 53.0% of the theoretical yield, separated and was collected. By evaporation of the mother liquor a further amount of DL-lithium pantoate, equivalent to 42% of the original DL-pantolactone, was recovered.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N:7]([CH3:18])[CH:6]=1)=[O:4].[OH-:21].[Na+].Cl>>[CH3:18][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:21])=[CH:6]1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cn1cc(C(=O)O)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 67 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1-methyl-6-(trifluoromethyl)-1H-indol-3-yl)ethanone (195 mg, 0.66 mmol) and 20% aqueous sodium hydroxide solution (5 mL) was refluxed with stirring for 10 hours. After cooling to room temperature, the mixture was poured into 1 M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual solid was washed with 2-propanol to give 107 mg (67% yield) of the title compound as a pale orange solid: