Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1>[C:31]([C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:30]=1)#[N:32]
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: N#Cc1ccnc(Cl)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1

Procedure:
50 mg (0.15 mmol) 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 21 mg (0.11 mmol) 2-Chloro-4-cyanopyridine were dissolved in 200 μl NMP and irradiated in the microwave at 200° C. for 3 h. The reaction mixture was directly purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:10][C:3]1[C:2]([O:1][CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)cccc1C#N
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C#N)c1C

Procedure:
A mixture of 3-hydroxy-2-methylbenzonitrile [23.38 g described by S. Gabriel and A. Thieme, Ber., 52, 1079 (1919)] anhydrous potassium carbonate (26.7 g) and methyl iodide (16.43 ml) in acetone (255 ml) is refluxed for 4 hr, cooled and filtered. The filtrate is evaporated and dissolved in dichloromethane. The solution is washed with water, dried and evaporated. The residue is chromatographed on silica gel using dichloromethane-hexane(1:1) and the eluates are evaporated and crystallized from hexane to obtain 2-methyl-3-methoxybenzonitrile: (II: R1 =2-Me and Y=CN): mp 47°-48° C.; ir 2,220, 1,265 and 1,100 cm-1 ; and nmr (CDCl3) δ2.42 (s, 3H), 3.85 (s, 3H) and 7.15 (m, 3H).
Reaction SMILES: [Cl:1][C:2](Cl)([P:9]([O:17][CH:18]([CH3:20])[CH3:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].C([Li])CCC.Cl>CCOCC.CCCCCC>[Cl:1][CH:2]([P:9]([O:17][CH:18]([CH3:20])[CH3:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)OC(=O)C(Cl)(Cl)P(=O)(OC(C)C)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)OC(=O)C(Cl)P(=O)(OC(C)C)c1ccccc1
Yield: 78 %

Procedure:
To a solution of 7.1 g of 1-methylethyl 2.2-dichloro-2[(1-methylethoxy)phenylphosphinyl]acetate in 150 ml of ether was added 14 ml of a solution of 1.6 M n-butyl lithium in hexane at -70° over 15 minutes. The solution was then allowed to warm to -10° before adding 60 ml of 0.5 M aqueous HCl solution at -10° to 0°. The phases were separated and the organic phase washed with water then 5% NaHCO3 solution. The solution was then dried and stripped to give 5.0 g of 1-methylethyl 2-chloro-2[(1-methylethoxy)phenylphosphinyl]acetate as a light yellow oil ND25 1.5057.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CS(O[CH2:21][CH2:22][CH2:23][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])(=O)=O>CC#N>[C:32]([O:31][C:29]([N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CC(C)CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: CC#N
Product: COC(=O)c1cc(OCCCN(CC(C)C)C(=O)OC(C)(C)C)cc(C(=O)OC)c1
Reaction time: 16 h

Procedure:
Dimethyl 5-hydroxyisophthalate (0.30 g, 1.44 mmol) cesium carbonate (0.95 g, 2.88 mmol) and CH3CN (25 mL) were stirred for 30 min. 3-((tert-Butoxycarbonyl)(isobutyl)amino)-propyl methanesulfonate (0.63 g, 2.02 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]([CH3:33])[CH:22]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)[CH3:10])[C:5]([C:34]#[N:35])=[C:4]([CH3:36])[N:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>ClCCl>[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38].[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]([CH:22]2[CH2:23][NH:24][CH2:25]2)[CH3:33])[CH3:10])[C:5]([C:34]#[N:35])=[C:4]([CH3:36])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N(C)C2CN(C(=O)OC(C)(C)C)C2)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N(C)C2CNC2)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Crude tert-butyl (S)-3-((5-(1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)(methyl)amino)azetidine-1-carboxylate was dissolved in dichloromethane (1 mL). To this solution was added TFA (0.462 mL, 6.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. The solvent was removed with a stream of nitrogen and the crude product was purified by preparative HPLC (acid mode, 1-25% ACN/water gradient) to give a TFA salt of the title compound as a clear film (5.9 mg, 19% over two steps). 1H NMR (400 MHz, CD3OD) δ ppm 1.73-1.82 (m, 3H), 2.49-2.56 (m, 3H), 2.82-2.89 (m, 3H), 3.94-4.08 (m, 4H), 4.19-4.33 (m, 3H), 4.46-4.57 (m, 1H), 5.97-6.09 (m, 1H), 6.70-6.77 (m, 1H), 7.85-7.94 (m, 1H), 8.32-8.47 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C20H25N9, 392. found 392.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:20]([OH:24])(=[O:23])[CH:21]=O>O1CCOCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[CH:21][C:20]([OH:24])=[O:23])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C(O)C=C1CCc2ccc([N+](=O)[O-])cc2C1=O
Temperature: 90 °C

Procedure:
A mixture of 7-nitro-l-tetralone (30 g) (manufactured by Lancaster Co.), 80% sulfuric acid (10 ml) and dioxane (60 ml) was heated to 90° C. and a 40% glyoxylic acid aqueous solution (30 ml) was added by three portions of 10 ml each at an interval of 1 hour and heated and refluxed for 3 hours. After allowing to cool the reaction mixture, the precipitated solid was filtered, washed with cold water and dried under reduced pressure to obtain 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid (33.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[C:15]([CH2:14][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=3)[CH:7]=[O:8])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: COc1ccc(O)cc1C=O
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccnc2-c2ccnn2C(C)C)cc1C=O
Temperature: 70 °C
Yield: 65.1 %

Procedure:
A mixture of 5-hydroxy-2-methoxybenzaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K2CO3 (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehyde (590 mg, 65%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CC(CNC(=O)c1cccc(Cl)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=432.1, tR (minutes, Method G)=2.58
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([SH:13])[N:8]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].IC>CC(C)=O>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1ncnc(-c2ccccn2)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1ncnc(-c2ccccn2)n1
Reaction time: 8 h

Procedure:
To a stirred suspension of the product of step 1 (0.707 g, 3.72 mmol) in acetone (36 mL) was added sodium carbonate (0.79 g, 7.5 mmol) followed by iodomethane (0.35 mL, 5.6 mmol). After overnight stirring, the reaction was filtered free of undissolved solid and concentrated to afford product as light brown solid: 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.84-8.76 (m, 1H), 8.55-8.43 (m, 1H), 8.11-8.00 (m, 1H, 7.69-7.60 (m, 1H), 2.63 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C@H:14]([C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.BrC1C=C(C(N[C@H:38]([C:43]([NH:45][CH2:46][C:47]#N)=O)[CH2:39]C(C)C)C(F)(F)F)C=CC=1>>[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:13][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([C:39]2[CH:38]=[CH:43][N:45]=[CH:46][CH:47]=2)[CH:4]=1)[C:9]([F:12])([F:11])[F:10])#[N:24]
Reactant: CC(C)C[C@H](NC(c1cccc(Br)c1)C(F)(F)F)C(=O)NCC#N
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Product: CC(C)C[C@H](NC(c1cccc(-c2ccncc2)c1)C(F)(F)F)C(=O)NCC#N

Procedure:
Using the procedure described for example 8, where N2-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-trifluoroethyl]-N-(cyanomethyl)-L-leucinamide, the title compound was obtained as a colorless gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:23]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:23]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCCCCc1ccc2c(n1)NCCCC2)c1cnc(C)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H](CCCCCCc1ccc2c(n1)NCCCC2)c1cnc(C)nc1

Procedure:
A mixture of 8-13 (0.48 g, 1.36 mmol), 10% Pd/C (10 mL), and ethanol (10 mL) was stirred under a balloon of hydrogen for 4 hours. Filtration and concentration gave 8-14 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([C:17]=2[CH3:18])[C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=1.[CH2:20](O)[CH3:21].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([C:17]=2[CH3:18])[C:14]([O:16][CH2:20][CH3:21])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1ccnc(Cl)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc(C)c(Oc2ccnc(Cl)c2)c1C
Yield: 67 %

Procedure:
A three necked round bottom flask containing 5-(2-chloropyridin-4-yloxy)-4,6-dimethylnicotinic acid (11.7 g, 42.0 mmol) was charged with ethanol (250 mL), benzene (300 mL) and sulphuric acid (10 mL). The flask was fitted with Dean Stark apparatus and the reaction stirred at reflux overnight. The solution was cooled and carefully neutralized with saturated NaHCO3 solution. The material was extracted with EtOAc, dried, and concentrated to afford the title compound (8.6 g, 67%) as an oil which solidified to a white solid upon standing in a refrigerator (4° C.) overnight.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH:19]=2)=[O:13])=[N:8][C:7]=1[CH3:26])=[O:5])C.[OH-].[Na+]>C1COCC1>[CH3:26][C:7]1[N:8]=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH:19]=2)=[O:13])[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(NC(=O)c2cnc(-c3ccccc3)nc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)c2cnc(-c3ccccc3)nc2)sc1C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 4-methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid ethyl ester (0.15 mmol) and 10% aqueous NaOH solution (4 mL) in THF (10 mL) is stirred at 60° C. for 18 hours. THF is evaporated and the residue is acidified with 5% hydrochloric acid to pH ˜2.0-2.5. The precipitate is filtered and dried to afford 4-methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid as a solid. MS: 341 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCC(=O)Cl
Product: CCC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone oxime and propionyl chloride were treated in the same way as in Example 3 to obtain 3,5-di-t-butyl-4-hydroxybenzophenone O-propionyloxime.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH3:34][O:33][C:31]([C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:6][N:7]=1)[CH:23]=[CH:24]2)=[O:32]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: COC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and methyl 1H-indole-5-carboxylate (0.615 g, 21%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[C:17]([OH:19])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCOCCO
Agent: [H-]
Agent: [Na+]
Product: CCOCCOCCCCCCCC(=O)O

Procedure:
Illustratively, 2-butoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 6-bromohexanoic acid to give 7,10-dioxatetradecanoic acid. So also, 2-ethoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 8-bromooctanoic acid to provide 9,12-dioxatetradecanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCBr)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
Aniline 1 (12.69 g, 0.052 mol) was stirred in dichloromethane at 0° C. and 5-bromovaleryl chloride (8.9 mL, 0.052 mol) added followed by diisopropylethylamine (9 mL, 0.052 mol). The resulting white suspension was allowed to warm to room temperature and stirred for 3 h. The white solid was collected by filtration and recrystallised from ethyl acetate to give 2 as a white fluffy powder (10.22 g, 50%).
Reaction SMILES: I(O)(=O)(=O)=[O:2].C(OC([N:13]1[C@@H:17]([CH2:18][OH:19])[CH2:16][C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[C:14]1=[O:34])=O)(C)(C)C>C(#N)C.C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6].I(O)(=O)(=O)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C@H:15]2[C:14](=[O:34])[NH:13][C@@H:17]([C:18]([OH:2])=[O:19])[CH2:16]2)=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1N[C@@H](C(=O)O)C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing 6.0 g of periodic acid and chromium trioxide (13 mg) in wet acetonitrile (60 mL; 0.75 volume % water) was prepared. A portion of this solution (15 mL) was added dropwise to a solution of (3S,5R)-3-(4-benzyloxyphenyl)-5-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.02 g, 2.57 mmol) in wet acetonitrile (15 mL; 0.75 volume % water) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. At this time, more of the periodic acid/chromium trioxide solution (5 mL) was added. Stirring at 0° C. was continued for an additional 1 hour. After quenching with a solution of dibasic sodium phosphate (720 mg) in water (12 mL), the mixture was extracted twice with diethyl ether. The combined organic extracts were washed with aqueous sodium bisulfite solution (440 mg in 10 mL water) and brine. After drying over MgSO4, the solvent was evaporated to provide a yellow solid that was taken up in methylene chloride (100 mL) and cooled in an ice bath. Hydrogen chloride gas was bubbled through the cold solution for 2 minutes and the resulting mixture was stirred at 0° C. for 1 hour. The solvent and HCl were evaporated to afford a solid from which the title compound, 226 mg (28%) was isolated by trituration with a mixture of methylene chloride, diethyl ether and ethyl acetate. The trituration filtrate was dissolved in aqueous saturated NaHCO3 solution and washed twice with diethyl ether. After careful acidification with aqueous 6M HCl solution, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to provide more of the title compound, 123 mg (15%).
Reaction SMILES: [CH3:1][Ge:2]([CH3:16])([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:14])OCC[O:10]2)=[CH:5][CH:4]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O>[CH3:15][Ge:2]([CH3:1])([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:10])[CH3:14])=[CH:5][CH:4]=1
Reactant: CC1(c2ccc([Ge](C)(C)C)cc2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc([Ge](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 420 mg (1.5 mmol) of 2-(4-trimethylgermylphenyl)-2-methyl-1,3-dioxolane and 56 mg (0.19 mmol) of pyridinium p-toluenesulfonate (PPTS) in 1.35 g (62.5 mmol) of water and 10 ml of acetone was refluxed for 2 hours and stirred at room temperature for 1.5 days. The reaction mixture was extracted with petroleum ether. The extract was washed successively with 2N hydrochloric acid, water and sat.aq.NaHCO3, dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:25]([O:14][C:12]1[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.47 mmol) from Step D in DMF (6 mL) was added benzyl bromide (0.22 mL, 1.91 mmol) and then cesium carbonate (622 mg, 1.91 mmol). The reaction was stirred at 55° C. for 4 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a 4:1 mixture of the crude products. The products were separated by flash column chromatography on silica gel eluted with a gradient of 5 to 10% ethyl acetate in hexanes to first yield the desired higher Rf O-alkylation title product. HPLC/MS: 430 (M+1); Rt=4.9 min;
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH2:11][C@H:10]([OH:17])[CH2:9][OH:8]
Reactant: [H][H]
Reactant: O[C@H](COCc1ccccc1)Cc1ncc[nH]1
Agent: [Pd]
Solvent: CCO
Product: OC[C@@H](O)Cc1ncc[nH]1
Reaction time: 24 h
Yield: 89.5 %

Procedure:
(2S)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol (1.725 g) was dissolved in ethanol (30 ml); 10% palladium carbon (1.04 g) was added, followed by vigorous stirring in a hydrogen atmosphere at 60° C. and 5 atm for 24 hours. The catalyst was filtered off and the solvent was distilled off; the residue was purified by silica gel flush column chromatography to yield the titled compound (0.945 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1/[CH:8]=[N:19]/[NH:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1cnccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(N/N=C/c2cnccc2Br)cc1
Temperature: 50 °C

Procedure:
To a solution of 4-bromopyridine-3-carbaldehyde (2.50 g, 13.4 mmol) in ethanol (25 mL) and water (5 mL) was added 4-fluorophenyhydrazine hydrochloride (2.38 g, 14.6 mmol) (mixture turned a deep red) followed by sodium acetate (3.7 g, 27 mmol) in 5 mL of water (mixture turned a bright yellow). The mixture was warmed at 50° C. for 30 minutes to afford an orange precipitate. The mixture was cooled and diluted with water (50 mL) and the solid was collected by filtration. The filter cake was washed with water and dried to afford N-[1-(4-bromopyridin-3-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine.