Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[CH2:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]1[C:16]2[CH:15]=[C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)[CH:22]=[CH:21][C:17]=2[CH2:18][CH2:19]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)ccc2C)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
A mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide (50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.26 mg, 0.15 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0076 mmol) in 1,2-dimethoxyethane (1.5 mL) and 2 M Na2CO3 (0.3 mL) was stirred at 80° C. for 16 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 30 mg (49%) of 1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.2. found 402.0 (M+1)+. Retention time 1.83 minutes.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][C:25](C4C=CC=CC=4)=[N:26]3)=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](O)(=O)[CH3:36].[OH-].[Na+]>CCO>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([C:36]4[CH:35]=[CH:3][CH:2]=[CH:1][CH:6]=4)[CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3ccc(-c4ccccc4)nc3c1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3cc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 17 %

Procedure:
Following the same reaction procedure and workup as for Compound 405, 450 mg (0.9 mmol) of the product from the previous step was cyclized with 40 mL acetic acid and saponified with 35 mL EtOH and 7 mL 1M NaOH to produce 70 mg (17% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH2:1])[CH:3]=2)[CH:8]=1)=[O:14])[CH3:20]
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc2cc(N)ccc2c1

Procedure:
To a solution of 6-amino-2-naphthoic acid (1 g, 5.34 mmol) in ethanol (20 mL), is added dropwise thionyl chloride (0.622 mL, 10.7 mmol). The resulting reaction solution is heated to reflux temperature under a N2 atmosphere for 3 hours. Concentration and trituration with methanol gives 6-amino-2-naphthoic acid ethyl ester as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=3[Cl:29])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Cl)cc(OC)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(Cl)cc(OC)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A mixture of methyl 4-chloro-3-{[(2,6-dichloro-4-methoxyphenyl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate (255 mg, 0.517 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.569 mmol) and triethylamine (0.0793 mL, 0.569 mmol) in tetrahydrofuran (5 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (215 mg, 0.469 mmol, 91%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.[NH2:13][C:14]([NH2:16])=[O:15]>>[NH:13]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:10])[NH:16][C:14]1=[O:15]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCCCC1=O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2

Procedure:
The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formula I, II or III can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of cyclohexanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclohexanecarboxy late. Reaction of ethyl 2-oxocyclohexanecarboxylate with urea at 175-185° C. produced 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione. Reaction of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazol. Reaction of 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazoline with methyl 3-(bromomethyl)benzoate in DMF , followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H )-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.O.CCOCC.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:16]#[N:17])[C:7]=1[F:8]
Reactant: CN(C)C=O
Reactant: Fc1c(Cl)ccnc1Br
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: N#Cc1nccc(Cl)c1F
Temperature: 100 °C

Procedure:
To a degassed solution of 2-bromo-4-chloro-3-fluoropyridine (7.3 g, 34.7 mmol) in DMF (50 mL) was added palladium tetrakistriphenylphosphine (4.01 g, 3.47 mmol) and zinc cyanide (4.07 g, 34.7 mmol) and heated to 100° C. for 20 minutes. After this time, more palladium tetrakis triphenylphosphine (4.01 g, 3.47 mmol) was added and heated to 100° C. for 90 minutes. The mixture was allowed to cool to room temperature and treated with water (200 mL) and ether (400 mL). The resulting mixture was filtered to remove insoluble solids, the filtrate was partitioned, and the aqueous layer was extracted with ether (400 mL). The combined ether extracts were washed with water (200 mL), dried (MgSO4), filtered, and the solvent removed in vacuo. This residue was purified by chromatography using silica gel column (330 g) eluting with a gradient of 10-100% CH2Cl2 in hexanes to provide the title compound. 1H NMR (CDCl3) δ=8.45 (d, 1H, J=5 Hz) and 7.65 (dd, 1H, J=5 Hz) ppm.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1>ClCCl>[Cl:4][CH:10]([C:9]([CH:6]1[CH2:8][CH2:7]1)=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.1 ml of sulphuryl chloride (38.2 mmol, 1.05 equivalents) were initially charged in 21 ml of dichloromethane, and 5.68 g of ethyl 3-cyclopropyl-3-oxopropanoate (36.4 mmol) were added dropwise on a water bath. The reaction mixture was stirred at RT for 2 h and then washed with water, 5% strength aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The crude product (6.8 g) was used without further purification for the next reaction.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCc1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 1.25 h
Yield: 87.3 %

Procedure:
To concentrate sulfuric acid (8 mL) was added portionwise N-(4-ethyl-phenyl)-acetamide (2.0 g, 12.27 mmol) and the mixture was cooled to −15° C., fuming nitric acid (0.505 mL, 12.27 mmol) was then added dropwise. The reaction mixture was stirred at a temperature ranging between −20 and −10° C. for 75 minutes. The reaction mixture was then poured into ice, neutralized by addition of sodium carbonate and extracted twice with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 100/0 to 70/30) to give 2.231 g (88% yield) of N-(4-ethyl-3-nitro-phenyl)-acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.[CH2:24]=O.C[O-].[Na+].[BH4-].[Na+]>CO.O>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:11])([F:12])[F:13]
Reactant: C=O
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.6 %

Procedure:
A solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 50 mg) in MeOH (14 ml) and paraformaldehyde (21 mg) was added to a suspension of NaOMe (44 mg) in MeOH (1 ml). The mixture was heated for 2 h under reflux and then cooled to 0° C. NaBH4 (29 mg) was added and the mixture was stirred for 1.5 h at room temperature. Additional NaBH4 (78 mg) was added and the mixture heated 30 min under reflux. Water (30 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (19 mg) as a light yellow foam. MS (m/e)=379.1 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A solution of 5-benzyl-3-methyl-6-propyl-5H-isoxazolo[5,4-d]pyrimidin-4-one (method 18) (3.167 g, 11.2 mmol) and sodium acetate (4.59 g, 56 mmol, 5 eq) in glacial acetic acid (26 ml) was treated with a preformed bromine solution (0.7 ml bromine in 10 ml of glacial acetic acid) (8.64 ml, 22.4 mmol, 2 eq). The mixture was stirred at 100° C. for 24 hrs. Excess bromine (8.64 ml, 22.4 mmol, 2 eq) was added to the mixture. The mixture was then stirred at 100° C. for another 24 hrs. Water was added to the reaction mixture, followed by aq. potassium carbonate. The mixture was extracted with DCM (50 ml×3), the combined organic phases were washed with water and dried, then concentrated to give the crude product which was purified by flash chromatography (elute: hexane-EtOAc). 2.5 g product was furnished as a white solid. 1H NMR (DMSO-d6): 0.79 (t, 3H), 2.18 (m, 1H), 2.35 (m, 1H), 2.58 (s, 3H), 5.12 (t, 1H), 5.25 (d, 1H), 5.80 (d, 1H), 7.27-7.42 (m, 5H).
Reaction SMILES: C([O:8][C:9](=[O:23])[CH2:10][N:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:12])C1C=CC=CC=1>CO.[C].[Pd]>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][N:11]([CH2:10][C:9]([OH:23])=[O:8])[CH3:12])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(CCNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(CCNC(=O)OC(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
162 mg (0.5 mmol) of {[2-(tert-butoxycarbonylamino)-ethyl]-methyl-amino}-acetic acid benzyl ester prepared in Process 3-A was dissolved in methanol (5 mL), and then 5% palladium-carbon was added to it, and this was stirred under a hydrogen atmosphere at room temperature for one hour. After filtering off the insoluble material, the filtrate was concentrated to yield 116 mg (100%) of {[2-(tert-butoxycarbonylamino)-ethyl]-methyl-amino}-acetic acid as a colorless viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][NH:31][C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:16]=2)=[O:19])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Product: CCc1cc(-c2cc(C(=O)NCCc3ccc([N+](=O)[O-])cc3)ccn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and 2-(4-nitro-phenyl)-ethyl-amine to afford the title compound. MS: m/e=407 (M+H).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([C:10]([O-:12])=O)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Li+].C(C1N=C(C([Cl:24])=O)SC=1)(C)C>>[CH:1]1([C:5]2[N:6]=[C:7]([C:10]([Cl:24])=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])c1nc(C2CCC2)cs1
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: [Li+]
Product: O=C(Cl)c1nc(C2CCC2)cs1

Procedure:
4-Cyclobutylthiazole-2-carbonyl chloride 267b was synthesized from compound 266b (5 g, 1 eq.), following the procedure as described for compound 214. MS (ESI, EI+): m/z=198 (MH+).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH3:21])([CH2:19]O)[CH2:17][OH:18].O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[OH:18][CH2:17][C:16]1([CH3:21])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(N)(CO)CO
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCC1=NC(C)(CO)CO1
Yield: 84.6 %

Procedure:
A mixture of 20.03 g (100 mmoles) of dodecanoic acid and 11.57 g (110) mmoles) of 2-amino-2-methyl-1,3propanediol in 10 ml of xylene was heated for 30 hours at 185°-190°C. with azeotropic removal of water. The reaction mixture was taken up in ethyl acetate and was washed with water to remove excess amino alcohol. The organic layer was dried, concentrated and the residue was distilled at 152°-155° C./ 1 mmHg to give 22.8 g (84.6%) of 4-hydroxymethyl-4-methyl-2-undecyl-2oxazoline.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1cc(F)ccc1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(F)ccc1Cl
Yield: 83.9 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (3.5 g, 16.9 mmol) and 2-chloro-5-fluoroaniline (2.21 g, 15.2 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (4.27 g, 75%) was obtained.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH3:8].[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:26])[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccccc1[C@@H](C)OC(=O)Nc1c(C)noc1-c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-o-tolyl-ethyl ester, 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester, and tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27].N12CCCN=C1CCCCC2>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([O:12][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: Cc1ccc2sc(C(=O)O)cc2c1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2sc(C(=O)OC(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-methyl-1-benzothiophene-2-carboxylic acid (1.50 g) in N,N-dimethylformamide (10.5 mL) was added 1,1′-carbonyldiimidazole (1.27 g), followed by stirring at room temperature for 2.5 hours. Subsequently, tert-butyl alcohol (1.44 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.17 mL) were added thereto, followed by heating at 50° C. for 24 hours. To the reaction mixture was added ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution in this order, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 5-methyl-1-benzothiophene-2-carboxylate (1.78 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:23]=[O:24].Cl>O1CCCC1.CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH:23]=[O:24])=[C:6]([F:8])[CH:5]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 3,5-difluoro-1-chlorobenzene (5.0 g, 34 mmol) in tetrahydrofuran (70 mL) at −78° C. was added a solution of n-butyllithium in hexane (12.1 mL, 2.5 M, 30 mmol). After stirring for 1 hour, dimethylformamide (5.2 mL, 67 mmol) was added, and the mixture was stirred for 1.5 hours. The mixture was warmed to ambient temperature, diluted with ether and poured into 150 mL of 0.5 M aqueous HCl. The aqueous phase was extracted 3× into ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, affording 5.72 g (96%) of 4-chloro-2,6-difluoro-benzaldehyde as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.04 (d, 2H, J=7.9 Hz) ppm.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: COc1cccc(CN)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccncc3)[nH]2)c1
Yield: 31.2 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.2 g) and 3-methoxybenzylamine (2.1 g) were dissolved in toluene (120 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(3-methoxyphenyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.4 g), melting point 197-199° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Fc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(F)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 35.5 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 206 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 71 mg of the target compound.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]([C:12](=[O:20])[CH:13]([CH3:19])[CH2:14][S:15][C:16](=[O:18])[CH3:17])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([CH3:19])[C:12]([N:8]([CH:9]1[CH2:10][CH2:11]1)[CH2:7][C:6]([OH:21])=[O:5])=[O:20])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CC1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-(cyclopropyl)glycine t-butyl ester (19.5 g, 0.0619 mol) was dissolved in a mixture of anisole (50 ml) and trifluoroacetic acid (250 ml). The resulting red solution was stirred for one and a half hours at room temperature. The solvent was evaporated and the residue was distributed between ethyl acetate and saturated sodium bicarbonate. The aqueous sodium bicarbonate layer was acidified cautiously with concentrated hydrochloric acid to pH 4-5. The precipitated product was extracted into chloroform and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give initially a colorless oil which was crystallized from diethyl ether to afford colorless crystals (9.7 g, 61%), m.p. 86°-88°. The dicyclohexylamine (DCHA) salt was prepared in ether to afford colorless crystals, m.p. 68°-70°.