Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5][Cl:6].O.C(=O)(O)[O-].[Na+].[NH2:17][C:18]1[C:26]([CH:27]=[N:28][O:29][CH3:30])=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[Cl:31]>C(OCC)(=O)C.C(Cl)Cl>[NH2:17][C:18]1[C:26]([CH:27]=[N:28][O:29][CH3:30])=[CH:25][C:21]([C:22]([NH:2][C:3]([CH2:8][CH3:9])([CH3:10])[C:4](=[O:7])[CH2:5][Cl:6])=[O:23])=[CH:20][C:19]=1[Cl:31]
Reactant: CON=Cc1cc(C(=O)Cl)cc(Cl)c1N
Reactant: CCC(C)(N)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCC(C)(NC(=O)c1cc(Cl)c(N)c(C=NOC)c1)C(=O)CCl
Yield: 74 %

Procedure:
In a 5-liter three-necked round bottomed flask was placed 93 g of 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride and 885 mL of water. To the resulting solution were added 138.6 g of sodium bicarbonate followed by 500 mL of ethyl acetate. To the resulting well-stirred mixture was added 123.5 g of 4-amino-3-chloro-5-methoxyiminomethylbenzoyl chloride dissolved in 1000 mL of ethyl acetate at room temperature over a period of 50 minutes. After the addition was complete the reaction mixture was stirred at room temperature for 1 hour. The two phases were separated and the organic layer was washed with water (2×500 mL), brine (1×500 mL), dried over anhydrous magnesium sulfate and the solvent eliminated in a rotary evaporator yielding the crude product as a brown oil. This oil was passed through a short Silica Gel column using methylene chloride as elution solvent. Evaporation of the solvent yielded 133.3 g of the expected 4-amino-3-chloro-5-methoxyiminomethyl-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide as an off-white solid (mp 140-141° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: CNCCOC
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCCN(C)c1ncc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cn1
Temperature: 25 °C

Procedure:
28.2 mg (0.09 mmol) N-(1-(4-((2-chloropyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)-acetamide (I69.1) in 1.5 mL DMSO are added to 12.0 mg (0.14 mmol) N-(2-methoxyethyl)-methylamine followed by 21.8 μl (0.14 mmol) DIPEA. The reaction mixture is stirred at r.t. over night and is directly purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][NH2:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][NH:12][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])ccc1CNS(C)(=O)=O
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a stirred solution of (2-methyl-4-nitrophenyl)methanamine (178 mg, 1.071 mmol) in pyridine, cooled to 0° C., were added methane sulfonylchloride (0.16 mL, 2.0349 mmol). The resulting reaction mixture was stirred for 2 h. The mixture dissolved in dichloromethane and washed with 1N HCl. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain N-(2-methyl-4-nitrobenzyl)methanesulfonamide (100 mg, 38%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:4]O.C(N(CC)CC)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:4][C@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:2]([CH3:17])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CCl)Nc1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
(2R)-3-Methyl-2-{[4-(trifluoromethyl)phenyl]amino}butan-1-ol (1.67 g, 6.76 mmol) obtained in Step 1 was dissolved in methylene chloride (30 mL) and triethylamine (1.20 mL, 8.67 mmol), and methanesulfonyl chloride (0.63 mL, 8.14 mmol) was added dropwise under cooling. After stiring overnight, the mixture was worked-up according to a conventional method to give N-[(1R)-1-(chloromethyl)-2-methylpropyl]-4-(trifluoromethyl)aniline as a crude product. The obtained crude product was dissolved in dimethylformamide (20 mL), sodium azide (0.40 g, 6.15 mmol) was added, and the mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was worked-up according to a conventional method to give a crude product. The obtained crude product was dissolved in ethyl acetate (20 ml), 10% palladium/carbon (catalytic amount) was added, and the system was purged with hydrogen. The mixture was stirred overnight at room temperature, palladium/carbon was filtered off, and the solvent was evaporated to give the title compound (1.50 g, 6.09 mmol, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[C:4]([F:10])[CH:3]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-2,6-difluorophenol D1c (5.0 g, 24 mmol) is dissolved in dichloromethane (50 mL) and treated with imidazole (2.28 g, 33.5 mmol). The colorless solution is treated in portions, with stirring, with tert-butylchlorodimethylsilane (4 g, 26 mmol). The mixture is stirred at room temperature overnight. The mixture is diluted with water (150 mL) and extracted with dichloromethane. The organic phase is washed with sat. NH4Cl solution, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) affords (4-bromo-2,6-difluorophenoxy)(tert-butyl)dimethylsilane D1d as a clear oil. 1H-NMR (400 MHz, CDCl3) δ=7.05 (d, J=7.2 Hz, 2H), 1.00 (s, 9H), 0.19 (s, 6H); no MS spectrum could be obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[OH-].[K+].O>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 62.5 °C
Reaction time: 0.25 h

Procedure:
2-(1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in methanol (1000 ml) and N-methyl-4-piperidone (200 ml) was added thereto at 25° C. The reaction mass was stirred for 15 minutes and potassium hydroxide (300 g) was added at 25° C. The reaction mass was heated to 60-65° C. for 8 hours and cooled gradually to 25° C. Water (1500 ml) was added slowly and stirred the mixture till solid was obtained. The solid was filtered and dried at 50-55° C. under vacuum to obtain the title compound. (Yield: 80 g, HPLC Purity: 99%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:67])([F:66])[O:57][C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1.CN(C)C=O>>[NH2:65][C:60]1[CH:59]=[C:58]([O:57][C:56]([F:55])([F:66])[F:67])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:37]([CH3:39])[CH3:38])[CH2:31]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.14 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (1.3 g, 2.1 mmol) and N,N-Diisopropylethylamine (1.20 mL, 6.90 mmol) and 4-(trifluoromethoxy)benzene-1,2-diamine (0.482 g, 2.51 mmol) in N,N-Dimethylformamide (13.0 mL, 167 mmol). The reaction was stirred overnight at RT and was partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 filtered and concentrated. The residue was purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 95:5) to the desired amide (1.4 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH3:19]>C(O)(C)C>[NH2:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1N
Temperature: 110 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Example 1b, 796 mg, 3.0 mmol) and ammonia (25% aqueous solution, 10 mL) in isopropanol (40 mL) was stirred at 110° C. in a pressure reactor overnight. Most of the solvent was then removed under reduced pressure, and the reaction mixture was diluted with water. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as an off-white solid (680 mg, 92%). 1H NR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.0 Hz, 3H), 3.88 (s, 3H), 4.32 (q, J=7.0 Hz, 2H), 7.36 (dd, J=2.8, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 8.23 (bs, 2H), 8.77 (s, 1H). MS 247 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH3:15])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][P:16]([NH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH3:15])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:17])[CH3:20]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)/C(=N\OC)c1csc(N)n1
Solvent: c1ccncc1
Product: CCOC(=O)/C(=N\OC)c1csc(NP(=O)(OCC)OCC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of 4.6 g (0.02 mol) of ethyl 2-(aminothiazol-4-yl)-Z-2-methoxyiminoacetate in 40 ml pyridine at 10-20o was added 9.0 ml (0.6 mol) diethyl chlorophosphate. The solution was stirred at room temperature for 2 hours. Pyridine was evaporated and the residue was codistilled with benzene and partitioned between water and methylene chloride. The methylene chloride layer was washed with excess 10% aqueous HCl, water, aqueous bicarbonate, saturated sodium chloride, and dried over sodium sulfate. Upon evaporation, 5.5 g brown oil was obtained which was purified on Biosil A using hexane/ethyl acetate (1:4) to afford 2.8 g of yellow crystals, m.p. 96.5-98.0; NMR (300MH2, DCCl3) δ 1.35 (3t, 9, CH2CH3), 3.97 (S, 3, OCH3), 4.17 (q, 4, OCH2), 4.39 (q, 2, OCH2), 6.93 (s, 1, thiazole H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].O>CO.C1COCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(C)o4)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc3[nH]cc(-c4cccc(OC(C)C)n4)c3c2)o1
Temperature: 45 °C
Yield: 22.9 %

Procedure:
2-(3-(6-Isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-methyl-1,3,4-oxadiazole (214 mg, 0.438 mmol) in a round bottomed flask was dissolved in MeOH (1.500 mL) and THF (3.0 mL). Cesium carbonate (428 mg, 1.314 mmol) (Aldrich) was added, the flask was fitted with a reflux condenser and the contents of the flask were heated at 45° C. for 15 min. H2O (30 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried, filtered and concentrated. The residue was purified with RP-HPLC (10-90% MeCN in H2O with 0.01% TFA as additive) to give 2-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-5-methyl-1,3,4-oxadiazole (33.6 mg, 11.1%). MS (ESI, pos. ion) m/z 335.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.89 (br. s., 1H), 9.20-9.29 (m, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.82 (dd, J=8.5, 1.7 Hz, 1H), 7.57-7.72 (m, 2H), 7.46 (d, J=7.4 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 5.58 (dt, J=12.3, 6.2 Hz, 1H), 2.59 (s, 3H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.CN([P+](O[N:55]1[N:63]=[N:62][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[N:62]1([O:12][C:11](=[O:13])[C:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[N:55]=[N:63]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To a mixture of 47 (0.81 g, 1.7 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol) in dichloromethane (20 mL) was added BOP reagent (0.76 g, 1.7 mmol). After 45 min of stirring at room temperature, the mixture was diluted with ethyl acetate (150 mL) then washed with 1N HCl (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexanes:ethyl acetate (3:2). The solid obtained after concentration was further triturated with hexanes:ethyl acetate (4:1) to yield 0.75 g (76%) of 48.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[O:18]=[C:19]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]3[NH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][N:38]=3)[CH:32]=2)[O:27][C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([N:24]4[CH2:23][CH2:22][C:21]5([CH2:20][C:19](=[O:18])[C:33]6[C:28](=[CH:29][CH:30]=[C:31]([C:34]7[NH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][N:38]=7)[CH:32]=6)[O:27]5)[CH2:26][CH2:25]4)=[O:15])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)[nH]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnc(C(N)=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (54 mg) and 5-[4-oxo-spiro(chroman-2,4′-piperidin)-6-yl]-4H-1,2,4-triazole-3-carboxamide (102 mg) in DMF (4 mL) were added TEA (77 uL), HOBT (42 mg), and WSC (53 mg) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into H2O, extracted with CHCl3, dried over sodium sulfate, filtered, and concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of CHCl3/MeOH (1:0-10:1) as eluent to give the title compound as a colorless solid. 1H-NMR (400 MHz, CDCl3) δ: 8.78-8.60 (1H, m), 8.40-8.25 (1H, m), 7.29 (1H, s), 7.15 (1H, d, J=8.0 Hz), 7.09 (1H, d, J=4.0 Hz), 6.57 (1H, s), 6.52 (1H, d, J=4.0 Hz), 4.30-4.17 (1H, m), 3.95 (3H, s), 3.62-3.38 (3H, m), 3.38-3.32 (1H, m), 2.85 (2H, s), 2.28-1.70 (4H, m), 1.06-1.04 (2H, m), 1.00-0.97 (2H, m); MS [M+H]+=541.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C1C(=CC=CC=1)O.C1(C)C(C)=CC=CC=1.[OH-].[Ca+2:45].[OH-]>O.CO>[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Ca+2:45].[CH3:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCC(CCCCC)c1ccc(O)c(C(=O)O)c1
Agent: O=C(O)c1ccccc1O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCC(CCCCC)c1ccc(O)c(C(=O)[O-])c1

Procedure:
The title compound in 4 g of base oil XOMAPE 150 (13.2 g, Basicity Index 1.48) was prepared as outlined in Example 4 by employing 5-(pentadecy-6-yl)salicylic acid (Example 15, 3.3 g), a commercial lower alkyl (i.e. less than C20) salicylic acid (Infineum M7103, obtainable from Infineum UK Limited, 3.70 g), xylene (203 g), calcium hydroxide (4 g), and a promoter (methanol:water (97%:3%), 23.4 ml).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([NH2:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[S:4]1[CH:5]=[CH:6][C:2]([NH:15][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3]1
Reactant: NC(=O)c1ccccc1
Reactant: Brc1ccsc1
Product: O=C(Nc1ccsc1)c1ccccc1
Yield: 98 %

Procedure:
Using general procedure C, 3-bromothiophene was coupled with benzamide with the reaction time of 21 h. Chromatography gave 198.9 mg (98%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.34 (br s, 1H), 7.85 (dd, 2H, J=1.2, 8.1 Hz), 7.72 (dd, 1H, J=1.2, 3.0 Hz), 7.55-7.41 (m, 3H), 7.26 (dd, 1H, J=3.3, 4.8 Hz), 7.14 (dd, 1H, J=1.5, 5.4 Hz).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[C@@H:23]([NH2:27])([CH2:25][CH3:26])[CH3:24].C(O)=O.C(=O)(O)[O-]>CN(C=O)C>[C@@H:23]([NH:27][C:12]1[N:11]=[C:10]([NH:9][C@@H:4]2[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]2)[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1)([CH2:25][CH3:26])[CH3:24]
Reactant: CC[C@H](C)N
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C(N)=O)C[C@H]1O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC[C@H](C)Nc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a stirring suspension of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.2 g, 0.609 mmol) in DMF (3 mL) was added (S)-(+)-sec-butylamine (0.305 mL, 3.05 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was concentrated under reduced pressure and then purified using reverse-phased semi-preparative HPLC (5-75% methanol+0.1% formic acid in water+0.1% formic acid, over 26 min). Fractions containing product were concentrated under reduced pressure and the resulting residue was redissolved in methanol (5 mL), passed over a Varian StratoSpheres HCO3 resin SPE tube for formic acid removal (0.9 mmol bicarbonate equiv.), and then concentrated under reduced pressure to afford 2-((S)-sec-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide (0.129 g, 0.402 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-1.24 (m, 15H) 1.35-1.45 (m, 1H) 1.54 (br. s., 1H) 1.66 (d, J=12.89 Hz, 1H) 1.92 (br. s., 1H) 2.14 (br. s., 1H) 2.97 (br. s., 1H) 3.71-3.99 (m, 1H) 4.55 (d, J=5.86 Hz, 1H) 6.96 (br. s., 1H) 8.34 (s, 1H) 8.90 (br. s., 1H); MS (ESI) m/z 322.5 [M+1]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[S:21][C:20]([CH3:22])=[N:19][C:18]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:13][CH2:14]1)[O:11][CH2:10]2>N1C=CC=CC=1.CCOC(C)=O.[Zn]>[CH3:22][C:20]1[S:21][C:17]([C:12]23[CH2:13][CH2:14][C:9]([CH2:8][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH2:16][CH2:15]2)[CH2:10][O:11]3)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1
Reactant: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Reactant: C=CC(=O)OC
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCC12CCC(c3sc(C)nc3-c3ccccc3)(CC1)OC2
Temperature: 75 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of zinc powder (154 mg, 2.351 mmol), anhydrous pyridine (5 mL) and methyl acrylate (0.212 ml, 2.351 mmol) at 50° C. was added NiCl2.6H2O (56 mg, 0.235 mmol). The resulting mixture was warmed to 75° C. and stirred for 2 h until its green color turned to reddish brown. After cooling to 0° C., a solution of 5-(4-(iodomethyl)-2-oxabicyclo[2.2.2]octan-1-yl)-2-methyl-4-phenylthiazole (100 mg, 0.235 mmol) in anhydrous pyridine (3 mL) was added and the reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with EtOAc (10 mL) and the resulting precipitate was filtered off through a pad of CELITE®. The filtrate was washed with 1 N aqueous HCl and brine, dried (Na2SO4), and concentrated in vacuo to afford the title compound (77 mg, 85% yield) as a clear oil. LCMS, [M+H]+=386.0. 1H NMR (500 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.40-7.32 (m, 3H), 3.72 (s, 2H), 3.65 (s, 3H), 2.64 (s, 3H), 2.24 (t, J=7.4 Hz, 2H), 2.07-1.97 (m, 2H), 1.87-1.77 (m, 2H), 1.57-1.45 (m, 6H), 1.12-1.02 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1scc(-c2ccc(OC)cc2)c1-c1ccc(C#N)cc1C
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CCOC(=O)CCc1scc(-c2ccc(OC)cc2)c1-c1ccc(C#N)cc1C
Yield: 73.7 %

Procedure:
To a solution of (E)-ethyl 3-(3-(4-cyano-2-methylphenyl)-4-(4-methoxyphenyl)thiophen-2-yl)acrylate (Scheme I, 5A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.27 g, 0.669 mmol) in ethanol (40 mL) was added 10% Pd/C (0.25 g), and the reaction mixture was stirred at 20° C. under 20 Psi of hydrogen for 30 h. The reaction mixture was filtrated, and concentrated to give ethyl 3-(3-(4-cyano-2-methylphenyl)-4-(4-methoxyphenyl)thiophen-2-yl)propanoate (Scheme I, 6A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.2 g, yield 73.7%). 1H NMR (DMSO-d6 300 MHz): δ7.71 (m, 2H), 7.45-7.40 (m, 2H), 6.92 (m, 2H), 6.75 (m, 2H), 4.03-3.96 (m, 2H), 3.66 (s, 3H), 2.76-2.71 (m, 3H), 1.80 (s, 2H), 1.22 (s, 1H), 1.14-1.09 (m, 3H).