Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
To a solution of 5.82 g (30 mmol) of 2,4-dichloro-5-nitropyrimidine (N. Whittaker, J. Chem. Soc., 1951:1565–1570) in 100 mL THF at −78° C. is added dropwise over 5 minutes a solution of 5.11 g (60 mmol) of cyclopentylamine in 20 mL THF. After a further 10 minutes at −78° C., the mixture is allowed to warm to room temperature, and the solvent is removed under vacuum. The residue is then extracted into EtOAc, washed with water, and dried with Na2SO4. Removal of the solvent and chromatography on SiO2, eluting with hexane/EtOAc (95:5) gives 6.20 g (85%) of the title compound: mp (hexane) 80–81.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-:26][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0 M BH3 -THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3 M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1 H), 7.42 (t, J=7.8, 1 H), 7.31 (d, J=7.8, 1 H), 7.02 (t, J=7.8, 1 H), 2.73 (s, 2 H), 1.56 (s, 9 H), 1.49 (s, 6 H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([OH:10])=[O:9])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+]>O>[CH2:15]([O:14][C:12]([NH:4][CH:3]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[C:8]([OH:10])=[O:9])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C(=O)O)C(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)C(NC(=O)OCc1ccccc1)C(=O)O
Yield: 100.8 %

Procedure:
Using a similar method to above 3-methyl-D,L-aspartic acid (10.0 g, 67 mmol), benzyl chloroformate (12 ml, 100 mmol) in 50% NaOH (16.7 g, 208 mmol ) in water (125 ml ) yielded N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid 19.0 g as a low melting solid. 1H NMR (90 MHz, CDCl3 /d6DMSO): δ 1.1 (3,d), 2.9 (1,dt), 4.4 (1,m), 4.95 (2,s) 5.9 (1,bd) 7.2 (5,6) 7.9 (1,bs) .
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])=[C:23]([C:31](O)=[O:32])[N:22]=[N:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])=[C:23]([C:31]([NH:37][CH:34]2[CH2:36][CH2:35]2)=[O:32])[N:22]=[N:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCF)c(OCc2ccccc2)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCCCF)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-{2-(benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-(5-fluoropentyl)-1H-1,2,3-triazole-4-carboxylic acid (0.49 g) obtained in Example 137b) in acetonitrile (5 ml) were successively added cyclopropylamine (0.09 ml), triethylamine (0.18 ml), HOBt (0.20 g) and WSC (0.25 g), and the reaction mixture was stirred at room temperature for 3.5 hr, and then at 60° C. for 1 hr. After allowing the reaction mixture to cool, the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a colorless amorphous substance (0.31 g, 59%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[C:4]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:3]1=2.[C:17](O)(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:17]([O:1][CH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[C:4]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:3]1=2)(=[O:19])[CH3:18]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCC2O
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
5,6-Dihydro-4-hydroxy-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (2.00 g, 0.0071 m), glacial acetic acid (0.92 g, 0.015 m) and 4-dimethylaminopyridine (0.085 g, 0.0007 m) were dissolved in dry tetrahydrofuran (30 ml) and the solution was cooled to 0° C. under nitrogen and stirred while a solution of dicyclohexylcarbodiimide (1.61 g, 0.0078 m) in dry tetrahydrofuran (10 ml) was added over 10 minutes. After stirring at 0° C. for 1 hour and at ambient temperature for 2 hours, an additional 0.46 g (0.0077 m) of glacial acetic acid was added and stirring was continued at ambient temperature for one hour more. The mixture was filtered and the solid was washed with tetrahydrofuran. The combined filtrate and washings were evaporated in vacuo to give a quantitative yield (2.31 g) of crude product. This material was combined with 1.14 g of identical product from a previous run and chromatographed on silica gel, eluting with 10% methanol-chloroform, to yield 2.57 g (75%) of product. Recrystallization from nitromethane afforded an analytical sample melting at 187.5°-188.5° C.
Reaction SMILES: C([Li])CCC.[Br-].[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:42][C:43]([F:53])([F:52])[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O>CCCCCC.O1CCCC1>[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH:22]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43]([F:52])([F:42])[F:53])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2cccc(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(F)(F)C(=CCCc1cccc(Oc2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of butyllithium in n-hexane (8.5 ml of 1.6 molar) was added, dropwise, at room temperature and under a nitrogen atmosphere over 10 minutes to [3-(3-phenoxyphenyl)propyl]-triphenylphophonium bromide (7.67 g; 13.75 mmol) in absolute tetrahydrofuran (40 ml). After stirring for 2 hours, α,α,α-trifluoroacetophenone (2.18 g; 12.5 mmol) dissolved in absolute tetrahydrofuran (10 ml) was added dropwise. After stirring for 3 hours at room temperature, the mixture was added to ice-water, extracted with ether and the extract dried over sodium sulphate and evaporated. After chromotography on silica gel using hexane-toluene, there was obtained 4-(3-phenoxyphenyl)-1-phenyl-1-trifluoromethyl-1-butene (3.31 g=71.9% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5](=[NH:9])[O:6][CH2:7][CH3:8].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:9]=[C:5]([O:6][CH2:7][CH3:8])[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[C:3]=1[F:13])=[O:19]
Reactant: CCOC(=N)c1cccc(Cl)c1F
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1cccc(Cl)c1F

Procedure:
starting from ethyl 3-chloro-2-fluorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2-fluoro-3-chlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(3-chloro-2-fluorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 137°-140° C.;
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.0 g (6.7 mmol) of 4-formylbenzoic acid was dissolved in 20 ml of dichloromethane. 0.67 ml (8.0 mmol) of pyrrolidine, 1.35 g (8.0 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 2.8 ml (20.5 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 5 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[Na].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[N:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]1=[O:16]
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Reactant: CCOC(=O)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)OC(c2c(Cl)cccc2OC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Anhydrous sodium 5-(2-chloro-6-methoxyphenyl)oxazolidine-2,4-dione (542 mg., 2.06 moles) from Example 119 and ethyl chloroformate (291 mg., 2.68 mmoles) were combined with 20 ml. of toluene and the mixture refluxed for 3 hours, cooled to room temperature, stirred for a further 16 hours, and evaporated to solids (415 mg.). The solids were recrystallized from toluene to yield purified 5-(2-chloro-6-methoxyphenyl)-3-ethoxycarbonyloxazolidine-2,4-dione. (212 mg., m.p. 196°-200° C.).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2cscn2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cscn2)c1

Procedure:
3-Thiazol-4-yl-benzoic acid methyl ester (0.91 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-(3-thiazol-4-yl-phenyl)-propionic acid tert-butyl ester (1.54 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20])[C:29](=[O:30])[C:28]1[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=1
Reactant: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 176, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[N:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[N:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2nnccc2n1C
Reactant: ClI
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2nnccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a cooled (0° C.) solution 7-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid ethyl ester (242 mg, 0.626 mmol) in DCM (6 mL) was added iodine monochloride (1.25 mL 1M in DCM 17.0 mL) dropwise over 1 minute. The mixture was allowed to warm to ambient temperature, stirred for 1 hour, then partitioned between ethyl acetate and a saturated solution of sodium thiosulfate. The organic layer was separated, washed with water, dried (Na2SO4), filtered and evaporated to give a residue. The residue was subjected to flash chromatography (Si-PPC, 1:1 DCM:ethyl acetate eluent) to provide the title compound as an orange solid (242 g, 88%). LCMS (method B): RT=3.03 min, M+H+=441.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:16]=[C:15]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:31])([F:30])[O:29][C:25]=5[CH:24]=4)[CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:34])=[CH:5]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(N(CC)CC)C>CN(C)C=O>[F:30][C:28]1([F:31])[O:27][C:26]2[CH:32]=[CH:33][C:23]([C:20]3([C:18]([NH:17][C:15]4[N:16]=[C:11]([C:6]5[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH2:3][CH2:2][NH:1][C:36](=[O:37])[O:38][CH2:39][CH3:40])[CH:5]=5)[C:12]([CH3:34])=[CH:13][CH:14]=4)=[O:19])[CH2:22][CH2:21]3)=[CH:24][C:25]=2[O:29]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CCN)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)NCCn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a flask containing N-(6-(1-(2-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (36 mg, 0.08 mmol), ethyl chloroformate (10 mg, 0.09 mmol), and triethylamine (32 μL, 0.23 mmol) was added N,N-dimethyl formamide (1 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse-phase preparative liquid chromatography to give the product (11 mg, 25%). ESI-MS m/z calc. 540.18. found 541.7 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:21])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=3)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:21])[C:9]3[C:14]([S:15](=[O:18])(=[O:19])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=3)#[N:2]
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(C(N)=O)cc1S2(=O)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The amide (0.79 g) of Example 21 was added to a mixture of dimethyl formamide (100 ml) and thionyl chloride (2.0 ml) at -10° C., and stirred at -10° C. for 2 hrs. The mixture was poured on to ice-water and the precipitated product filtered off and washed with water, recrystallised from dimethylformamide, and dried at 155° C./15 mm. Hg, m.p. 290° C. (decomposes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:23][CH2:22][CH2:21]1>C(O)C>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]1[C:23]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:22]=2[CH2:21][CH2:20][CH2:25]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccccc1Cl
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2Cl)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (69 mg, 0.26 mmol) and of crude 6-bromo-2-(2-chloro-phenyl)-cyclohexanone (79 mg, 0.28 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (55 mg, 46%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.77 (s, 1H), 7.46 (s, 1H), 7.35 (m, 1H), 7.13 (m, 2H), 7.08 (d, 1H), 6.96 (m, 1H), 6.85 (s, 1H), 6.68 (d, 1H), 4.53 (m, 1H), 3.54 (s, 3H), 2.77 (m, 2H), 2.33 (s, 3H), 2.24 (m, 1H), 1.80-1.99 (m, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][CH3:50])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:42]2[CH:41]=[C:40]([F:39])[CH:45]=[CH:44][C:43]=2[O:49][CH3:50])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1nc(C(=O)Nc2cnn(C)c2N2CCC(CN)CC2)c(N)s1
Yield: 26 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-fluoro-2-methoxyphenyl boronic acid gave 390 as a pale brown solid (24 mg, 26% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.12 (s, 1H), 8.19 (d, J=10.0 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.28 (d, J=7.1 Hz, 1H), 7.26-7.22 (m, 2H), 3.99 (s, 3H), 3.67 (s, 3H), 3.16-3.00 (m, 4H), 2.47 (d, J=5.6 Hz, 2H), 1.78 (d, J=11.5 Hz, 2H), 1.30-1.17 (m, 3H). LCMS (ES+) m/z 460 (M+1)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].[CH3:11][CH2:12]O.OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:11]([O:8][C:7](=[O:9])[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:12]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccco1
Temperature: 63 °C
Yield: 93.9 %

Procedure:
Furan-2-yl-oxo-acetic acid (15 g, 107 mmol), dissolved in CHCl3 (420 ml), was treated with EtOH (9.6 ml, 165 mmol) and H2SO4 (1 ml) and heated to 63° C. for 12 hours. Next, the reaction mixture was transferred to a separatory funnel and washed with sat. NaHCO3 (100 ml). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated providing 16.9 g (66%) of the above subtitle compound, which was carried forward without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@:19]([O:49][Si](C)(C)C)([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:72][CH2:73][O:74][C:75]([CH3:77])=[O:76]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@@:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=4)[O:31][CH2:77][C:75]([O:74][CH2:73][CH3:72])=[O:76])([OH:49])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(C[C@]2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (10 g) in THF (50 ml) was added tetrabutylammonium fluoride (41 ml, 1M solution in THF) at room temperature. After being stirred for 4 hours, the mixture was diluted with EtOAc. The mixture was washed with 1N-HCl solution and brine and evaporated. The residue was dissolved in DMF (50 ml), followed by addition of K2CO3 (5 g) and ethyl bromoacetate (2.0 ml) at room temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between EtOAc and water. The organic layer was washed with water and brine and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}-acetate (5.3 g).
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27].O.NN>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26]([NH:7][NH2:8])=[O:27]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CC#N
Solvent: O
Product: NNC(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
HOBt (823 mg, 6.09 mmol), and EDCI (1.2 g, 6.09 mmol) were added to a suspension of 2-chloro-isonicotinic acid (800 mg, 5.08 mmol) in acetonitrile (10.3 ml) at room temperature. After two h a solution of hydrazine monohydrate (0.493 ml, 10.2 mmol) in acetonitrile (5.0 ml) was added drop-wise at 0° C. After 30 min, the solvent was removed using a roto-evaporator and the residue was diluted with ethyl acetate, quenched with water, dried over sodium sulfate, filtered and concentrated to afford 2-chloro-isonicotinic acid hydrazide (493 mg, 57%, yellow solid). 1H NMR (DMSO) d (ppm): 10.21 (bs, 1H), 8.55 (d, 1H), 7.82 (s, 1H), 7.75 (d, 1H), 4.69 (bs, 2H).