Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C(#N)C>[CH2:24]([N:12]1[CH2:13][CH2:14][CH:9]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)=[O:8])[CH2:10][CH2:11]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
(3 g, 12.3 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride was suspended in acetonitrile (60 mL) and triethylamine (4.29 mL, 3-1 mmol), benzylbromide (1.61 mL, 14 mmol) and sodium iodide (2.8 g, 18 mol) were added. The mixture was stirred at 80° C. overnight and after cooling the mixture was filtrated, water was added and the aqueous phase was extracted with 100 mL of dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrated concentrated and purified with column chromatography on silica using dichloromethane/Methanol (95/0.5) to yield 3.6 g, (12 mmol, 99% yield) of the title compound as a brown solid. MS (m/e): 298.4 (M+H+).
Reaction SMILES: C([OH:3])C.[CH2:4]([N:6]([CH2:9]C)CC)C.CS(Cl)(=O)=O.[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[NH:6]1[CH2:9][CH2:17][CH2:18][CH:19]([C:20]([OH:16])=[O:3])[CH2:4]1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Reactant: CCO
Agent: CS(=O)(=O)Cl
Product: O=C(O)C1CCCNC1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
Ethanol, 2-(5H-dibenzo[a,d]cyclohepten-5-yloxy)-, as prepared in Part B above (2 g) is dissolved in 40 ml of dry tetrahydrofuran to which triethylamine (1.7 g) is added at once. Methanesulfonyl chloride (0.014 g) is added dropwise and the mixture stirred for 20 min, after which it is filtered and evaporated. Then the methanesulfonate is dissolved in 80 ml of 2-butanone to which ethyl 3-piperidinecarboxylate (1.9 g) is added at once. 3.3 g of K2CO3 are added and the mixture refluxed overnight, then cooled, filtered and evaporated. The remaining oil is chromatographed on dry silica using 70% hexane: 30% ethyl acetate: 2% triethylamine as eluent. 3.4 g (75% yield) of 3-piperidinecarboxylic acid, 1-[2-[5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl]], ethyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[C:23]([O:24][CH3:25])[CH:22]=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[ClH:1].[CH3:17][N:18]([CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[C:23]([O:24][CH3:25])[CH:22]=1)[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: COc1ccc(CCN(C)c2nc(N)c3cc(OC)c(OC)cc3n2)cc1OC
Product: Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 5 g of 2-chloro-4-amino-6,7-dimethoxy quinazoline, 30 g of N-methyl-homoveratryl amine (Lloydia 33, 15-18) and 1 g of triethylbenzyl ammonium chloride was heated with stirring to 110° C. over a 3 hour period. Then the excess of N-methyl-homoveratryl amine was distilled off in vacuo. On standing in the cold, a precipitate was formed from the solution of the evaporation residue in acetone. After filtration with activated charcoal, the precipitate was recrystallized from methanol. The N-methyl-N-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-homoveratryl amine hydrochloride obtained melted at 265°-270° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].O>CS(C)=O>[C:11]1([S:17]([C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Br:1])[CH:9]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1ccc(F)cc1Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Temperature: 125 °C
Yield: 32.4 %

Procedure:
A mixture of 2-bromo-4-fluorobenzaldehyde (10.2 g, 50 mmol) and sodium benzenesulfinate (8.21 g, 50 mmol) in DMSO (100 mL) was heated at 125° C. overnight. Upon cooling the mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 4/1) to give 4-benzenesulfonyl-2-bromo-benzaldehyde (5.26 g, 32% yield) as white crystalline solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N:22](CC)CC)C.ClC(OCC)=O.[NH4+].[OH-]>O1CCCC1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:22])=[O:19])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(N)=O)cc1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid (2.13 g, 7.71 mmol) prepared in 3) was dissolved in tetrahydrofuran (32 ml) in nitrogen atmosphere, and triethylamine (1.16 ml, 8.41 mmol) and ethyl chloroformate (0.726 ml, 8.41 ml) were dropwise added under cooling with ice, followed by stirring for 30 minutes. Then, a 28% ammonia aqueous solution was dropwise added, followed by stirring for 5 minutes. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate twice. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.60 g, 76%) as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]#[N:13])=[CH:5][C:4]=2[N:3]1[CH2:14][CH:15]=O.[C:17]([O:21][C:22]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH3:3].[C:12]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2](=[O:1])[N:3]2[CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:30][CH2:29]2)=[N:8][CH:7]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(C#N)cc32)CC1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
A mixture of 6-oxo-5-(2-oxoethyl)-5,6-dihydro-1,5-naphthyridine-3-carbonitrile (0.50 g, 2.05 mmol), 4-t-butoxycarbonylaminopiperidine (0.80 g, 4.00 mmol) and 3A molecular sieves in DCM (4.5 ml) and MeOH (4.5 ml) was stirred at rt for 4 h. The mixture was then treated with NaBH(OAc)3 (0.94 g, 4.43 mmol), stirred at rt for 18 h, filtered through a thin pad of celite, evaporated, dissolved in 10% MeOH/DCM and washed with sat. aq NaHCO3. The aqueous phase was re-extracted twice with 10% MeOH/DCM, the combined organics dried, and the residue was subjected to column chromatography on silica gel using a DCM:MeOH:aq NH3 gradient to provide the desired compound (0.411 g, 50%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2]1.[Cl:12][C:13]1[CH:31]=[CH:30][C:16]2[O:17][C:18]3[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=3[CH2:20][N:21]([C:22]([NH:24][NH2:25])=[O:23])[C:15]=2[CH:14]=1>>[O:11]=[C:9]([NH:25][NH:24][C:22]([N:21]1[CH2:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17][C:16]2[CH:30]=[CH:31][C:13]([Cl:12])=[CH:14][C:15]1=2)=[O:23])/[CH:8]=[CH:7]/[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1.[O:10]=[C:9]([NH:25][NH:24][C:22]([N:21]1[CH2:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17][C:16]2[CH:30]=[CH:31][C:13]([Cl:12])=[CH:14][C:15]1=2)=[O:23])/[CH:8]=[CH:7]\[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=C(O)CC=Cc1ccsc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(/C=C/Cc1ccsc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(/C=C\Cc1ccsc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-4-(3-thienyl)-3E-butenyl]hydrazide (trans) (30) and 8-chlorodibenz[b,f][1,4 ]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-4-(3-thienyl)-3Z-butenyl]hydrazide (cis) (31) were prepared in the manner described in Example 7 on a 5.2 mmol scale from 4-(3-thienyl)-3-butenoic acid (29), prepared as described above in Example 29, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, to yield 33% trans and 14% cis products after separation by column chromatography.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:32]=[CH:31][C:30]4[C:21](=[C:22]([C:44]5[CH:53]=[CH:52][C:51]([OH:54])=[C:50]6[C:45]=5[CH:46]=[CH:47][CH:48]=[N:49]6)[C:23]5[C:28]([C:29]=4[C:33]4[CH:42]=[CH:41][C:40]([OH:43])=[C:39]6[C:34]=4[CH:35]=[CH:36][CH:37]=[N:38]6)=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:59])CCC>C(#N)C>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:19]3[CH:32]=[CH:31][C:30]4[C:21](=[C:22]([C:44]5[CH:53]=[CH:52][C:51]([O-:54])=[C:50]6[C:45]=5[CH:46]=[CH:47][CH:48]=[N:49]6)[C:23]5[C:28]([C:29]=4[C:33]4[CH:42]=[CH:41][C:40]([O-:43])=[C:39]6[C:34]=4[CH:35]=[CH:36][CH:37]=[N:38]6)=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=3)[N:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+:59].[Li+:59]
Reactant: [Li]CCCC
Reactant: Oc1ccc(-c2c3ccccc3c(-c3ccc(O)c4ncccc34)c3cc(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)ccc23)c2cccnc12
Solvent: CC#N
Product: [Li+]
Product: [O-]c1ccc(-c2c3ccccc3c(-c3ccc([O-])c4ncccc34)c3cc(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)ccc23)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,5′-[2-(4,6-Diphenyl-1,3,5-triazinyl)anthracene-9,10-diyl)bisquinolin-8-ol (6.95 g, 10 mmol) is dissolved in acetonitrile (300 ml), and 2.5 M n-butyl-lithium (9.9 ml, 25 mmol) is added. The solution is stirred at room temperature for 1 h. The yellow precipitate is filtered off, washed with acetonitrile and dried in vacuo (5.8 g, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:23])([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:23][C:11]1([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(F)cc1)C1(F)CCNCC1

Procedure:
4-Fluoro-4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.122 g, 0.375 mmol) was solved in dichloromethane (2 mL) and trifluoroacetic acid (0.258 mL, 3.37 mmol) was added at 0° C. Aqueous NaHCO3 was slowly added until pH 9 and the mixture extracted with 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield g (0. mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 226.1 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C=C(C)C=1)C(O)=O.CC1C=C(C(Cl)=O)C=C(C)C=1.[CH3:27][C:28]1[CH:29]=[C:30]([C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:31]=[C:32]([CH3:34])[CH:33]=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:30]2[CH:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[CH:31]=2)=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1cc(C)cc(C(=O)N=C=S)c1
Agent: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cc1cc(C)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)cc(C)c4)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3,5-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 3,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 3,5-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:37](OCC)(=O)C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:37])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(benzyloxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (830 mg) was added 4 M hydrogen chloride/ethyl acetate (20 mL), and the reaction mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF and methanol, and the solution was subjected to NH silica gel column chromatography (ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (660 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=CC=1.[H-].[Na+].I[CH2:13][CH3:14].[O:15]1CC[CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:15][CH2:16][CH3:17])=[CH:8][C:13]=1[CH3:14]
Reactant: C1CCOC1
Reactant: CCI
Reactant: OCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc(Cl)c(C)c1

Procedure:
To a solution of 1-chloro-4-hydroxymethylbenzene (14.2 g, 0.1 mol) in tetrahydrofuran (250 ml) was added sodium hydride as a 40% suspension in oil (4 g, 0.1 mol) portionwise under nitrogen. When effervescence ceased iodoethane (15.6 g, 0.1 mol) was added and the solution heated at reflux for 8 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with dilute aqueous sodium hydroxide and brine, then dried (MgSO4) and evaporated to dryness. The subtitle compound was obtained as a clear oil (17.3 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6]([O:14]CC)=[C:5]([C:17]([O:19]CC)=[O:18])[C:4]1=[O:22])[CH3:2].[OH-].[Na+].C(O)C.C(O)(=O)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6]([OH:14])=[C:5]([C:17]([OH:19])=[O:18])[C:4]1=[O:22])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)c2ccc(C)nc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCn1c(=O)c(C(=O)O)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 1 g. of 1-ethyl-1,2-dihydro-4-ethoxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 14) in 15 ml. of 20% aqueous sodium hydroxide containing 5 ml. of ethanol was heated under reflux for 4 hours. The mixture was cooled and was acidified with glacial acetic acid and was diluted with water. The precipitate which formed was collected, air dried and was recrystallized from ethanol to afford 0.3 g. of the title compound, m.p. 162°-5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:3][C:4]=1[C:12]1[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=1
Reactant: Cn1ccc(-c2sc(N)nc2-c2ccco2)cc1=O
Reactant: O=C(O)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(-c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)cc1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-Amino-4-(2-furyl)-5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)thiazole (222 mg, 0.812 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and isonicotinic acid (199 mg, 1.62 mmol), PyBOP (926 mg, 1.78 mmol) and triethylamine (0.497 mL, 3.56 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=17:3), followed by reslurrying with methanol to afford the entitled Compound 123 (158 mg, 52%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][CH:10]([C:16]([CH3:18])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[ClH:9].[NH2:8][C:4]1[N:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([CH3:18])[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1cccc(N)n1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2cccc(N)n12
Product: Cl
Yield: 57.1 %

Procedure:
To a suspension of 43.7 g (0.40 mol) of 2,6-diaminopyridine in 400 ml of ethanol was added 131.7 g (0.8 mol) of ethyl 2-chloroacetoacetate. The mixture was heated for 18 hours under reflux. After cooling, the resulting crystals was collected by filtration, washed with ethanol and ether successively to give 58.4 g of the desired compound (57.1%, pale yellow crystals).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[C:37]=[O:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:37]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(N=C=O)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: COc1ccc(NC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-methoxyphenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (55 mg, 0.18 mmol) and 1-isocyanato-4-methoxybenzene (27.5 mg, 0.18 mmol) according to General Procedure G to give 20 mg (24.2%) of a white solid. Anal. Calcd. for C26H33N5O2 m/z 447.3, found: 448.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.41 (d, J=9 Hz, 2H), 7.29 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 6.82 (d, J=3 Hz, 2H), 5.95 (d, J=7.6 Hz, 1H), 3.89 (d, m, 1H), 3.77 (m, 1H), 3.70 (s, 3H), 3.26 (m, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 1.89 (m, 3H), 1.68 (m, 1H), 1.60 (m, 2H), 1.45 (m, 1H), 1.23 (m, 6H), 1.10 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1)OCC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc(O[C@@H](C)C(=O)O)cc1)OCC
Yield: 97.7 %

Procedure:
A solution of (S,S)-3-[4-(1-tert-butoxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (1.10 g, 3.00 mmol) in CH2Cl2 (5.0 ml) and TFA (4.0 ml) and water (0.2 ml) was stirred for 12 hours. The mixture was concentrated to a residue and purified by silica gel chromatography with EtOAc/Hexanes (50%) to afford the acid product (0.91 g, 98%).
Reaction SMILES: [O:1]1CCN=C1C1C=CC(OCC2C=CSC=2)=CC=1O[CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+]>CO>[OH2:1].[CH3:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C1=NCCO1)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1CCCC(=O)O
Product: O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
A solution of ethyl (RS)-4-[2-(4,5-dihydrooxazol-2-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (500 mg) in methanol (50 mL) containing 10% w/v potassium carbonate (5 mL) is stirred at ambient temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and partitioned between water (100 mL) and ethyl acetate (100 mL) then acidified to pH 5 with 1 N HCl. The organic phase is washed three times with water (50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. Recrystallisation from cyclohexane/ethyl acetate gives (RS)-4-[2-(4,5-dihydrooxazol-2-yl))-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid hydrate as a white solid (160 mg), m.p. 107-109° C. [Elemental analysis:- C,65.9, H, 5.69, N, 2.94%. Calculated for C25H25NO5S.0.2H2O:- C,66.0, H, 5.59, N, 3.01%].
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27](C)[C:28]1C=CC(C#N)=CC=1.N[C@H](C(O)=O)CS>>[CH3:26][N:27]([CH3:28])[C:4]1[CH:5]=[CH:6][C:1]([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[N:11]=2)=[CH:2][CH:3]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: CN(C)c1ccc(C#N)cc1
Agent: N[C@@H](CS)C(=O)O
Product: COc1cc(C(=O)c2csc(-c3ccc(N(C)C)cc3)n2)cc(OC)c1OC

Procedure:
(2-(4-(Dimethylamino)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (2o) was prepared using the same method as used of compound 1h from 4-(dimethylamino)benzonitrile and cysteine. NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.88 (d, 2H), 7.80 (s, 2H), 6.73 (d, 2H), 3.96 (s, 3H), 3.95 (s, 6H), 3.05 (s, 6H); MS (ESI) m/z 421.1 (M+Na)+.