Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:18])[CH2:2][CH3:3].C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([O:30][C:31](=O)C)(=[O:29])[CH3:28]>O1CCCC1.N1C=CC=CC=1>[C:27]([O:30][CH2:31][N:6]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:18])(=[O:29])[CH3:28]
Reactant: CCCC1C(=O)NC1Sc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCC1C(=O)N(COC(C)=O)C1Sc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 273 mg (0.94 mmole) azetidinone from Step A, 26.3 mg paraformaldehyde and 178 mg (0.56 mmole) cesium carbonate was stirred in 20 ml dry tetrahydrofuran at ambient temperature 16.5 hours under nitrogen. A mixture of 430 μl pyridine and 2.56 ml acetic anhydride was added to the reaction mixture and the stirring continued 5 more hours. The solvents were removed in vacuo to give 604 mg crude product which was chromatographed on a silica gel flash column in hexane-ethyl acetate 3/1. This gave 102 mg (30%) of 1-acetoxymethyl-4-p-nitrophenylthio-3-n-propylazetidin-2-one.
Reaction SMILES: C(N(CC)CC)C.O.[NH:9]1[CH2:17][CH2:16][CH:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1.[C:18](=O)([O:24]C(C)(C)C)[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:19][C:18]([N:9]1[CH2:17][CH2:16][CH:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
8.6 g of triethylamine and 20 ml of water are added to a solution of 10 g of isonipecotic acid in 100 ml of dioxane and the mixture is heated to 60° C. 20.25 g of di-tert-butyl carbonate are then added dropwise and the mixture is stirred for 1 hour at 60° C. and refluxed for 30 minutes. It is concentrated under vacuum, the residue is taken up with water and acidified to pH 3 by the addition of 2 N HCl solution and the precipitate formed is filtered off to give 17 g of the expected product.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[NH2-].[Na+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:2]1([CH:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1ccccn1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1
Yield: 41 %

Procedure:
To a solution of benzyl cyanide (5.00 g, 42.7 mmol) and 2-chloropyridine (4.85 g, 42.7 mmol) in 15 ml of toluene was added finely powdered sodium amide (3.33 g, 85.4 mmol) in portions keeping the temperature between 20-30° C. The suspension was refluxed for 6 h. After cooling, 100 ml water is added and the product is worked up with ethyl acetate/water. After drying (MgSO4) and concentration, the crude material is purified by flash chromatography on silicagel using a 1:4 mixture of ethyl acetate and hexane as eluant to yield 3.40 g (17.5 mmol, 41%) of (RS)-phenyl-pyridin-2-yl-acetonitrile as a white solid, m.p. 89° C. and MS: m/e=194 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24]Br>CN(C)C=O>[Br:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCBr)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of step (i) (5 g) and potassium carbonate (13.14 g) in dimethylformamide (100 ml) was treated with 1,2-dibromoethane (8.2 ml) and stirred overnight at room temperature. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 4.6 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>>[OH:26][CH2:25][C:22]1([NH:21][C:18]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:11]([N:12]3[CH2:13][C:14]([F:16])([F:17])[CH2:15]3)=[CH:10][N:9]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Reactant: NC1(CO)CC1
Product: O=C(NC1(CO)CC1)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 53e) and (1-aminocyclopropyl)methanol (CAN 107017-72-1) as starting materials and isolated (85 mg, 51%) as a waxy solid; MS (ESI, m/z): 354.3 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(N)=[O:23].O>O1CCOCC1>[OH:23][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: NC=O
Reactant: O=C(CCl)c1c[nH]c2ccc(OCc3ccccc3)cc12
Solvent: C1COCCO1
Solvent: O
Product: O=C(CO)c1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 55 %

Procedure:
A solution of 19 in dioxane was added to formamide-water (10:1) and the mixture was stirred at 110° C. for 6.5 hrs., then was worked up as for 12 above. Purification by column chromatography gave 20 (55%) whose structure was established by spectral data. Calcd for C17H15NO3 : 281.1052 Found: 281.1052 (HREIMS).
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH3:13])=[N:10][C:9]([OH:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>C(OCC)(=O)C.C(O)(=O)C>[C:1]1([N:7]2[C:11]([S:12]([CH3:13])=[O:17])=[N:10][C:9]([OH:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OO
Reactant: CSc1nc(O)nn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(O)nn1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
An amount of 41.4 g of 1-phenyl-5-methylmercapto-3-hydroxy-1,2,4-triazole is suspended at 50°C in 400 ml of ethyl acetate. An addition is then made dropwise, within 15 minutes, of 60 ml of a 60% solution of peroxyacetic acid in glacial acetic acid at 45°-50°C. After completion of the addition, the solution is stirred for 2 hours at 50°C, and the cooled to 20°C. The precipitated product is filtered off, washed with water, and dried in vacuo. The resulting product is 1-phenyl-5-methylsulphinyl-3-hydroxy-1,2,4-triazole in the form of white crystals, M.P. 180°-182°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:12]=[C:10]1[NH:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:4]2([CH2:3][CH2:2][N:1]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:6][CH2:5]2)[O:11]1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (410 mg, 1.88 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) and treated with tert-butyl 4-oxopiperidine-1-carboxylate (via) (562 mg, 2.82 mmol), glacial acetic acid (226 mg, 3.76 mmol) and sodium triacetoxyborohydride (797 mg, 3.76 mmol). The reaction was stirred under nitrogen at room temperature for 72 hours. The reaction was concentrated under reduced pressure and the residue partitioned between 1.0 N HCl (50 mL) and diethyl ether (25 mL). The aqueous layer was separated and washed with diethyl ether (2×25 mL), basified with 1.0 N NaOH (aq) and extracted with dichloromethane (3×50 mL). The pooled extracts were washed with saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford tert-butyl 4-(2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-yl)piperidine-1-carboxylate (vib) as a crystalline white solid. LC/MS m/z 402.2 [M+H]+, retention time 1.84 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:20]([CH3:21])=[CH:19][C:17]([NH2:18])=[C:16]([F:22])[CH:15]=1.CCN(C(C)C)C(C)C.[CH:32]1([C:35]([N:37]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43]([NH:45][NH2:46])=[O:44])[CH2:38]2)=[O:36])[CH2:34][CH2:33]1>ClCCl>[Br:13][C:14]1[C:20]([CH3:21])=[CH:19][C:17]([NH:18][C:2]([NH:46][NH:45][C:43](=[O:44])[CH2:42][C@@H:39]2[CH2:40][CH2:41][N:37]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH2:38]2)=[O:4])=[C:16]([F:22])[CH:15]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)c(F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(NC(=O)NNC(=O)C[C@@H]2CCN(C(=O)C3CC3)C2)c(F)cc1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a round bottom flask was added triphosgene (2.57 mmol) and dichloromethane (20 mL) under nitrogen, and the solution was cooled to −78° C. In a separate vial, 4-bromo-2-fluoro-5-methylaniline (7.35 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (18.4 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. After 10 min, analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (4.41 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and stirred for 20 min. Analysis by LCMS indicated desired product formation. The reaction was poured into a separatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to an oil. The residue was purified by silica gel chromatography (0-15% isopropanol/ethyl acetate). The desired fractions were combined and concentrated to afford the title product as an oil (1.9 g, 59%). MS(ES)+ m/e 441.0, 442.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)[C:18]2=[O:25].FC1C=C2C(=CC=1)NC(=O)C2=O>>[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[C:19](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:18]2=[O:25]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(I)ccc2-n2c1nc1ccccc1c2=O
Yield: 31 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-iodoisatin for 5-fluoroisatin gave the title compound in 31% yield: mp 296.5°-297.3° C.; 1H NMR (300MHz, DMSO-d6) δ 8.16-8.36 (m, 4H) 7.96 (2, H) 7.70-7.83 (m, 1H); MS (M+H)+ 374.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1I.N#N.[CH3:12][CH2:13][OH:14].[Li][CH:16](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:12][C@H:13]([OH:14])[CH3:16]
Reactant: CCO
Reactant: Fc1ccc(Br)c(I)c1
Reactant: [Li]C(C)CC
Agent: FB(F)F
Agent: N#N
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)Cc1cc(F)ccc1Br
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A solution of 1-bromo-4-fluoro-2-iodobenzene (6.02 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.52 in EtOAc/hexane 3:7) to give (2R)-1-(2-bromo-5-fluorophenyl)propan-2-ol (1.67 g, 35%) as white solid. 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 4.14 (m, 1H), 2.78-2.96 (m, 2H), 1.45 (d, J=4.53 Hz, 1H), 1.29 (d, J=6.24 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:5][C:6]([Br:9])=[CH:7][N:8]=1.CO.C[O-].[Na+].[CH:15](O)=[O:16]>C(OCC)=O>[Br:9][C:6]1[S:5][C:4]([CH2:3][NH:2][CH:15]=[O:16])=[N:8][CH:7]=1
Reactant: O=CO
Reactant: NCc1ncc(Br)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC=O
Solvent: CO
Product: O=CNCc1ncc(Br)s1
Temperature: 48 °C
Reaction time: 5 h

Procedure:
2-Aminomethyl-5-bromothiazole hydrochloride (350 g) was dissolved in 7 L of ethyl formate. To this solution were added 296 ml of a 28% methanol solution of sodium methoxide and 173 ml of a formic acid solution. The mixture was then stirred at an internal temperature of 48° C. for 5 hr. The solvent was removed by evaporation under the reduced pressure. When precipitate occurred, ethanol was added to dissolve the precipitate. The solvent was again removed by evaporation under the reduced pressure until crystal was formed. The solution was stirred under ice cooling overnight. The precipitated crystal was then collected by filtration, was then washed with cold ethanol and hexane, and was dried under the reduced pressure to give 189 g of 5-bromo-2-formylaminomethylthiazole. Further, the filtrate was concentrated, and the concentrate was crystallized from ethanol to give 58 g of secondary-crystal.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:2].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:19])[C@@H:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Product: CCCCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxononyl)-2-oxazolidinone (10.09 g), prepared in Referential Example 71, and tert-butyl bromoacetate (30 ml), the desired compound (12.62 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:22]/[C:23](/[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)=[CH:24]\[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:39]3[CH:40]=[C:35](/[C:23](/[F:22])=[CH:24]/[C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=4)[CH:36]=[CH:37][CH:38]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(/C=C(\F)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(/C=C(\F)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 41.6 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol) and (Z)-methyl 4-(2-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)vinyl)benzoate (150 mg, 0.39 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (64 mg, 0.6 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give (Z)-methyl 4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoate (70 mg, 42%) as a yellow sold. 543 [M+H]+, tR=1.88 min.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][OH:15]>>[C:1]1(=[N:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: NO
Product: ON=C1CCCCCCCCCCC1

Procedure:
reacting cyclododecanone with hydroxylamine in an aqueous solution in the presence of an excess amount of cyclododecanone or a solvent to produce cyclododecanone oxime (hereinafter, referred to as an “oxime-forming step”);
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[I:12]
Reactant: Cc1cc(F)cc(I)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cc(F)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 11.8 %

Procedure:
A solution of 4-fluoro-2-iodo-6-methyl-benzoic acid (8.87 g, 31.8 mmol) in acetone (80 mL) was treated with anhydrous K2CO3 (6.91 g, 50 mmol) followed by methyl iodide (2.72 mL, 40 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography of the resulting material using 10% ethyl acetate in hexanes afforded 4-fluoro-2-iodo-6-methyl-benzoic acid methyl ester (1.1 g, 12%).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:19][CH2:20]2)=[O:14])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccc(O)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
1-[1-(4-Benzyloxybenzoyl)-4-piperidinyl]-3,4-dihyrocarbostyril (4.76 g) is dissolved in methanol (100 ml) and thereto is added 5% palladium-carbon (1 g). The mixture is stirred at room temperature under 1 atm. under hydrogen atmosphere. After the completion of the reaction, the catalyst is filetered off and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1) and further recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2.5 g) as white powder, m.p. 182°-183° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.[C:28]([O:36][CH3:37])(=[O:35])[C:29]#[C:30][C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C.Cl[C:46](=[O:52])[C:47]([O:49][CH2:50][CH3:51])=O>C(Cl)Cl.CCOC(C)=O>[CH2:50]([O:49][C:47]1[C:46](=[O:52])[N:25]([C:24]2[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=2)[CH:30]([C:31]([O:33][CH3:34])=[O:32])[C:29]=1[C:28]([O:36][CH3:37])=[O:35])[CH3:51]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COC(=O)C#CC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC1=C(C(=O)OC)C(C(=O)OC)N(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 53 %

Procedure:
To a stirred solution of triphenylphosphine (262 mg, 1.00 mmol) and 4-fluoroaniline (111 mg, 1.00 mmol) in CH2Cl2 (5 mL) was added dimethyl but-2-ynedioate (142 mg, 1.00 mmol) dropwise. The reaction mixture turned brown and was stirred for 1 h before triethylamine (139 μL, 1.00 mmol) and ethyl 2-chloro-2-oxoacetate (150 mg, 1.10 mmol) were added. The reaction mixture was stirred at rt for 14 h, concentrated and the residue was purified by ISCO, eluting with Hex/EtOAc (0-20% B over 15 min) to Intermediate 12 (180 mg, 0.530 mmol, 53.0% yield) as a white solid. HPLC/MS (Method L) RT=1.75 min, [M+H]+ 337.9.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[O:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:29][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Reactant: NOc1ccccc1
Agent: Cl
Product: O=C(NOc1ccccc1)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluoro-benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ; 8.82 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.24 (d, 2H, J=7.9 Hz), 7.38–7.33 (m, 2H), 7.07–7.01 (m, 2H), 6.88–6.74 (m, 3H), 5.57 (s, 2H). LCMS (API-ES, M+H+): 363.1. HRMS calcd for C20H16FN4O2 (M+H) 363.1257. found 363.1256. HPLC: >85% purity.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[K+].Cl[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(C)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNCC(=O)O
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN(CC(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
In a 250 ml three-necked flask equipped with a magnetic stirrer, a thermometer, a dropping funnel and a condenser, a mixture of sarcosine (4.45 g; 50 mmol) and KOH (8.47 g; 151 mmol) in 70 ml of isopropanol is prepared by heating the mixture to 50° C. The medium remains cloudy after 30 minutes then chlorodiphenylmethane (10.7 ml; 60 mmol) is added over 30 minutes at 50° C. The mixture is heated for 5 hours at this temperature. The mixture is then left to cool down to ambient temperature. After the addition of 100 ml of water, the pH is adjusted to 10 and the chlorodiphenylmethane which has not reacted is recovered after extraction with CHCl3. The pH is adjusted to 5-6 with concentrated HCl and the mixture is extracted once again with chloroform in order to produce 2.23 g of product (Yield=18%) in the form of colourless gum.