Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][O:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:3])[CH3:2].[CH3:25][C:26]([CH3:28])=O>>[CH:1]([C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:26]([CH3:28])[CH3:25])[CH2:10][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)[C@H](COCC1CCNCC1)NC(=O)OCc1ccccc1
Product: CC(C)[C@H](COCC1CCN(C(C)C)CC1)NC(=O)OCc1ccccc1
Yield: 91.3 %

Procedure:
Using alkylation method A, benzyl N-[(R)-1-(isopropyl)-2-(piperidin-4-ylmethoxy)ethyl]carbamate (1.1 g, 3.2 mmol) and acetone (5 mL, 68 mmol) afforded 1.1 g (92%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:26](NCC)[CH3:27].C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:26]#[CH:27])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCNCC
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(Br)cc1-c1ccccc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
A mixture of (2-phenyl-4-bromobenzoyl)-methionine methyl ester (100 mmol), diethylamine (300 mmol), trimethylsilylacetylene (110 mmol), bis(triphenylphosphine) palladium diacetate (5 mmol) and copper(I) iodide (3 mmol) in toluene is heated at 60° C. until TLC analysis indicates the starting methyl ester has disappeared. The reaction mixture is concentrated in vacuo, redissolved in ether, filtered through silica gel, and concentrated. The residue is then dissolved in THF, and is treated with tetrabutylammonium fluoride (120 mmol). After TLC analysis indicates that no starting material is left, the reaction mixture is diluted with ether, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified with column chromatography on silica gel to give the title product.
Reaction SMILES: [CH2:1]([C@H:3]1[NH:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2].[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH2:1]([C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:4]1)[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CC[C@@H]1CNCCN1
Solvent: C1COCCO1
Product: CC[C@@H]1CN(S(N)(=O)=O)CCN1

Procedure:
To a solution of (3R)-3-ethylpiperazine (0.5 g) in dioxane (10 ml) was added sulfamide (0.373 g) and the reaction mixture was then heated at reflux in dioxane for 3 d. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield (3R)-3-ethylpiperazine-1-sulfonamide as a white solid. A mixture of (3R)-3-ethylpiperazine-1-sulfonamide (0.260 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.438 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.350 g) in dioxane (10 ml) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.705 g
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]2COS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:13]1[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:16][CH2:17][C:10]21[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11]2)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1COS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1N=[N+]=[N-]
Temperature: 60 °C

Procedure:
10 mmol of tert-butyl 2-benzyl-6-methanesulphonyloxymethyl-2,7-diazaspiro[4.5]decane-7-carboxylate are dissolved in 20 ml of N,N-dimethylformamide and the solution is admixed with 15 mmol of sodium azide. The reaction mixture is heated at 60° C. for 6 hours, then poured into water and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.Cl.[OH:34][CH:35]([C:37]1([OH:41])[CH2:40][NH:39][CH2:38]1)[CH3:36].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:39]2[CH2:40][C:37]([CH:35]([OH:34])[CH3:36])([OH:41])[CH2:38]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CC(O)C1(O)CNC1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (362 mg, 0.921 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (337 mg, 2.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (296 mg, 0.602 mmol, 65% yield): MS (EI) for C18H16F3IN2O3: 493 (MH+).
Reaction SMILES: [N:1]([C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)=[N+]=[N-].Cl.[OH-].[Na+]>CO.CCOC(C)=O>[N:9]1[C:10]2[CH:11]=[CH:12][N:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1nccc2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nccc2ncccc12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 69.2 %

Procedure:
To a suspension of 5-azido-1,6-naphthyridine (3.4 g, 19.9 mmol) in MeOH (40 mL) was added hydrochloric acid (30 mL). Stannous chloride dihydrate (22.5 g, 99.5 mmol) was added. The mixture was stirred at 75° C. for 3.5 h. A yellow precipitate was formed. The mixture was filtered to give a yellow solid. The solid was suspended in EtOAc (200 mL). NaOH (saturated aqueous solution) was added to adjust pH to 9. A white precipitate was formed. The mixture was filtered and the filtrate was extracted with EtOAc (200 mL×6). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 2.0 g of the crude product as a yellow solid. ESI MS: m/z 146 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.COC(C1C(Cl)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:62]1([CH:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)[CH2:66][CH2:65][CH2:64][CH2:63]1>>[Cl:1][C:2]1[C:3]([C:18]([N:70]2[CH2:71][CH2:72][CH:67]([N:62]3[CH2:66][CH2:65][CH2:64][CH2:63]3)[CH2:68][CH2:69]2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: O=C(O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1Cl
Reactant: C1CCN(C2CCNCC2)C1
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1Cl
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: O=C(c1ncc(-c2cccc(C(F)(F)F)c2)cc1Cl)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 7) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow oil. MS: 438.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C@:2]1([CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C@H:26]([CH2:29]OS(C)(=O)=O)[O:25][C:24]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C@H:26]([CH2:29][N:4]3[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH2:8][O:9][CH2:10][CH2:11][O:12][C@H:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH2:3]3)[O:25][C:24]=2[CH:35]=1
Reactant: CS(=O)(=O)OC[C@H]1COc2ccc(F)cc2O1
Reactant: C[C@]1(COCCOC2CCCCO2)CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COCCO[C@H]2CCCCO2)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Yield: 23.6 %

Procedure:
(S)-3-Methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine (100 mg, 0.39 mmol), methanesulfonic acid (R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester (102 mg, 0.39 mmol), K2CO3 (59 mg, 0.43 mmol) and KI (3 mg) were refluxed in dry DMF (3 ml) for 5 h. Water was added to the cooled mixture, followed by extraction with EtOAc (3×15 ml). The extracts were washed several times with water and finally with brine. After drying and filtering, the solvent was evaporated to give 143 mg of the crude product. This was chromatographed on silica (heptane/EtOAc, 70:30) to give 39 mg of the title compound as a colorless oil.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:19])=[C:10]2[CH:17]=[C:16]([CH3:18])[S:15][C:11]2=[C:12]([CH3:14])[N:13]=1)=[O:7])CCC.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C[O-].[Na+].CO.Cl>[OH:19][C:9]1[C:8]([C:6]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])=[N:13][C:12]([CH3:14])=[C:11]2[S:15][C:16]([CH3:18])=[CH:17][C:10]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C)c2sc(C)cc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C)c2s1

Procedure:
4-Hydroxy-2,7-dimethyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (30 mg, 0.11 mmol, example 5-b-A) and glycine (75 mg, 1.0 mmol) were suspended in 2.0 mL of 0.5 N NaOMe in methanol. The resultant mixture was heated to 120° C. for 10 min. using a CEM microwave reactor. The reaction mixture was cooled, and diluted with 0.25 N HCl until pH<3. The mixture was extracted two times with ethyl acetate, and the organic fractions were dried over anhydrous magnesium sulfate and concentrated to 27 mg of a pale yellow solid. MS: (−) m/z 279.01 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.[N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[NH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[O:12][CH2:11][CH2:10][C@H:9]2[NH:8][C:6]1[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=[C:2]([N:25]2[C:26]3[CH:27]=[N:28][CH:29]=[CH:30][C:31]=3[N:23]=[CH:24]2)[N:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: c1cc2nc[nH]c2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(-n2cnc3ccncc32)nc1N[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C

Procedure:
A solution of (R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine in acetonitrile was treated with 3H-imidazo[4,5-c]pyridine and potassium carbonate. The mixture was stirred at reflux for 6 hours, cooled to room temperature, diluted with 150 mL of EtOAc, and washed twice with 30 mL portions of water. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (1% MeOH/DCM) provided N—((R)-8-fluorochroman-4-yl)-2-(3H-imidazo[4,5-c]pyridin-3-yl)-5-nitropyrimidin-4-amine as the first eluting isomer: (1H-NMR (300 MHz, CDCl3) δ 9.8 (s, 1H), 9.4 (s, 1H), 9.2 (s, 1H), 8.9 (d, 1H), 8.6 (d, 1H), 7.8 (d, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 5.8 (q, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H).). N—((R)-8-Fluorochroman-4-yl)-2-(1H-imidazo[4,5-c]pyridin-1-yl)-5-nitropyrimidin-4-amine eluted second: (1H-NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 9.2 (s, 1H), 9.1 (s, 1H), 8.9 (d, 1H), 8.6 (d, 1H), 8.4 (d, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 5.7 (q, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H).).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=2)=[CH:5]1)([CH3:3])[CH3:2].[CH3:18][Mg]Br.C(OCC)C>C1COCC1>[OH:17][CH:16]([C:14]1[S:15][C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[CH:12][CH:13]=1)[CH3:18]
Reactant: C[Mg]Br
Reactant: CC(C)n1cc(-c2ccc(C=O)s2)ccc1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(=O)n(C(C)C)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-carbaldehyde (0.205 g, 0.829 mmol) in THF (10 mL) was cooled to 0° C. A solution of 1.5M methyl magnesium bromide in diethyl ether (1.65 mL, 2.48 mmol) was added slowly at 0° C. and the mixture was stirred for 2 h at rt. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), dried over Na2SO4 and concentrated under vacuum to obtain crude 5-(5-(1-hydroxyethyl)thiophen-2-yl)-1-isopropylpyridin-2(1H)-one as an off-white solid (0.150 g, 71% yield). LC-MS m/z calcd for [M+H]+ 264.1. found 264.1.
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.[CH3:12][C:13]1[C:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[CH3:40])=[C:16]2[NH:17][C:18]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:19][C:20](=O)[N:15]2[N:14]=1.P(Cl)(Cl)([Cl:43])=O>>[Cl:43][C:20]1[N:15]2[N:14]=[C:13]([CH3:12])[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=3[CH3:40])=[C:16]2[N:17]=[C:18]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn2c(=O)cc(C3CCOCC3)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CCN(CC)c1ccccc1
Product: Cc1nn2c(Cl)cc(C3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 0 °C

Procedure:
To a suspension of N,N-diethylaniline (0.83 g, 5.54 mmol) and 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.02 g, 2.52 mmol) stirred under nitrogen at 0° C. was added neat phosphoric trichloride (1.93 g, 12.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 80° C. for 2 hr. Reaction mixture was concentrated. The residue was dissolved with DCM (50 mL) and icy water (15 mL). The pH of aqueous layer was adjusted by 10 N NaOH solution to 5. Two layers were separated. Organic layer was washed with brine (15 mL) again. Organic layer was dried, concentrated to dryness. Product was purified on a silica gel column (ethyl acetate/hexane gradient solvents). The product was obtained and used in subsequent steps. (463 mg, 43%); LC/MS: MS (ES+) m/e 424 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=4[N:16]=3)=[N:9][N:8](CC3C=CC(OC)=CC=3)[C:5]2=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:15]=4[N:16]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(-c3nnc4c(n3)N(COCC[Si](C)(C)C)C(=O)C4(C)C)c3cc(F)cnc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2nc(-c3n[nH]c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.148 g (7.546 mmol) of the compound from Example 35A were taken up in acetonitrile (110 ml) and water (55 ml), 12.411 g (22.638 mmol) of ammonium cerium(IV) nitrate were added and the mixture was stirred at room temperature for 20 min. Plenty of water was then added, and a precipitate was filtered off. This solid was washed with water and then with a little diethyl ether. This gave, after drying under high vacuum, 1.53 g (47% of theory) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])[CH:29]=4)[CH:25]=3)[CH:16]=[CH:15][C:13]=2[N:14]=1>N1C=CC=CC=1>[C:37]([C:34]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[C:27]([NH:26][C:24]1[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:40])[O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:7])[S:11][C:12]=2[CH:18]=1)=[O:39])([CH3:36])[CH3:35])#[N:38]
Reactant: O=C(Cl)c1cocn1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
1,3-Oxazole-4-carbonyl chloride synthesized above was suspended in pyridine (4.0 mL) at 0° C., N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vi) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in methanol (4.0 mL). 1N Aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 1N hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (70 mg, 29%) as a colorless solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C=[CH:11][C:12](=[O:18])CCCC=C.C=CC=C>C(O)(=O)C>[C:12]([O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[CH:2]=[CH2:1])(=[O:18])[CH3:11]
Reactant: C=CCCCC(=O)C=C
Reactant: C=CCCCC(O)C=C
Agent: C=CC=C
Solvent: CC(=O)O
Product: C=CCCCC(C=C)OC(C)=O

Procedure:
1,7-Octadien-3-ol, Compound (III), which is the starting material for preparing 1,7-octadien-3-one of this invention can easily be synthesized by dimerizing butadiene using a palladium complex as a catalyst in the presence of acetic acid to obtain 3-acetoxy-1,7-octadiene, Compound (I), and then hydrolyzing the same. (See Tetrahedron Letters, No. 26, page 2451, 1967 incorporated herein by reference which teaches the synthesis of 4-acetoxy-2,7-octadiene and 1-acetoxy-2,7-octadiene by dimerizing butadiene in the presence of a bis(triphenyl phosphine) (maleic anhydride) palladium catalyst and acetic acid at 120° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CCC2)cc1
Temperature: 3 °C

Procedure:
1-(4-Chlorophenyl)cyclobutanecarboxylic acid (6.63 g, 31.492 mmol) and 2-(4-methoxyphenyl)ethanamine (5.00 g, 33.067 mmol) were treated with dichloromethane (470 mL). The suspension was cooled to 3° C. and N,N-dimethylpyridin-4-amine (4.04 g, 33.1 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.35 g, 33.1 mmol) were added. The reaction mixture was allowed to warm to room temperature and was stirred over night. The reaction mixture was washed successively with 2N hydrochloric acid (2×) and water (2×). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash-chromatography (silica, dichloromethane:methanol=9:1) to give a pale yellow solid. Yield: 10.58 g (30.8 mmol, 98%).
Reaction SMILES: [ClH:1].[N:2]1([C:7]2[CH:8]=[C:9]([N:13]3[CH2:18][CH2:17][N:16](CC4C=CC=CC=4)[CH:15]([CH2:26][NH:27][C:28](=[O:40])[C:29]4[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=4)[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][N:4]=[CH:3]1>[Pd]>[ClH:1].[N:2]1([C:7]2[CH:8]=[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:26][NH:27][C:28](=[O:40])[C:29]4[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=4)[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(c3cccc(-n4ccnc4)c3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(c3cccc(-n4ccnc4)c3)CCN2)cc1

Procedure:
In a manner similar to Example 1, react N-[[4-[3-(1H-imidazol-1-yl)phenyl-]-1-(phenylmethyl)piperazin-2-yl]methyl]-4-[(methylsulfonyl)amino]benzamide hydrochloride (2.5 g, 4.4 mmol) with H2 over Pd on carbon (1.2 g) to obtain the title compound.