Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][O:10][C:11](=[O:25])[CH2:12][C:13](=[O:24])[CH2:14][O:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][O:10][C:11](=[O:25])[C:12]([C:13](=[O:24])[CH2:14][O:15][CH2:16][CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C(COCCC1CCCCC1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C(COCCC1CCCCC1)C(=Cc1cccc(Cl)c1)C(=O)OCCC(c1ccccc1)c1ccccc1

Procedure:
1.23 g (2.90 mmol) of 4-(2-cyclohexylethoxy)-3-oxobutanoic acid 3,3-diphenylpropyl ester, 0.33 ml (2.91 mmol) of 3-chlorobenzaldehyde, 0.05 ml (0.51 mmol) of piperidine and catalytic amount of p-toluenesulfonic acid were refluxed in 20 ml of benzene removing water for 1.5 hours. After adding ethyl acetate, the organic layer was washed with 1 N hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([I:19])[C:3]=1[NH2:4].[Cl:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].O>CN1C(=O)N(C)CC1>[Cl:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:4][C:3]1[C:2]([I:1])=[CH:8][C:7]([C:9]([F:18])([C:10]([F:13])([F:12])[F:11])[C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[I:19])=[O:24]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1I
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1I)c1cccc([N+](=O)[O-])c1Cl
Temperature: 135 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
To a solution of 40.0 g (78.0 mmol) of 2,6-diiodo-4-(heptafluoropropan-2-yl)aniline in 100 ml of DMI was added 20.6 g (94.0 mmol) of 2-chloro-3-nitrobenzoyl chloride, followed by stirring at 135° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into 1000 ml of water. After extraction with the addition of 1000 ml of ethyl acetate, the organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was washed with hexane to prepare 56.2 g (yield 99%) of a target compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:34][CH3:35])=[CH:20][C:21]([CH:23](OC(=O)C)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CO>C1COCC1.[Pd]>[CH2:23]([C:21]1[CH:20]=[C:19]([O:34][CH3:35])[C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[N:11][C:12]=2[CH:22]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OC(C)=O)c3ccccc3)cc(OC)c21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Yield: 91.3 %

Procedure:
A solution of 150 mg (0.317 mmol) acetic acid[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-phenyl-methyl ester in 8 ml THF:MeOH=1:2 is hydrogenated in the presence of 50 mg Pd/C (Engelhard 4505). Then the catalyst is filtered off and the filtrate is concentrated in vacuo to afford 120 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5](O)[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C(O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([N:64]=[N+:65]=[N-:66])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(O)CCCNC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
2-Hydroxy-5-(t-butyloxycarbonylamino)pentanoic acid ethyl ester, (11, 26.1 g, 0.1 mol), triphenylphosphine (26.2 g, 0.10 mol), diethylazodicarboxylate (17.4 g, 0.1 mol), and diphenylphosphorylazide (27.5 g, 0.1 mol) is dissolved in THF (500 mL) and heated to reflux and maintained there for 8 hours. The reaction is cooled to room temperature, evaporated to an oil, and the product isolated by column chromatography using dichloromethane:ethanol as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[Cl:16].CI.[C:19]([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[CH3:19][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([Cl:16])[CH:4]=1
Reactant: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzamide (10.40 g, 30.88 mmol) in THF (200 mL) was added methyl iodide (5.77 mL, 13.15 g, 92.7 mmol) and Cs2CO3 (30.19 g, 92.7 mmol) at −5° C. After 1 h at this temperature, the mixture was heated at 40° C. and stirred over night. Water was added and the mixture was extracted three times with MTBE. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by filtration over a short plug of silica gel to give the title compound (8.25 g), which was used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:30])[CH2:22][NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>C1(C)C=CC=CC=1.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>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:30])[CH2:22][NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 25 °C
Yield: 12 %

Procedure:
N-2-(4-(4-t-butoxycarbonylaminophenyl)phenyl)propyl 2-propane-sulfonamide: A degassed solution of 0.9 g (2.9 mmol) of material from Example 39, 1.4 g ( 2.8 mmol) of material from Preparation 51 and 0.2 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 mL of toluene was heated to reflux for 5 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. Chromatography (100 g of silica gel, 30% ethyl acetate/hexane) of the residue afforded 0.15 g (12%) of the title compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].[Cl:15][C:16]1[C:24]2[O:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][C:20]=2[CH:19]=[C:18]([CH:30]=[O:31])[C:17]=1[Cl:32].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[Cl:15][C:16]1[C:24]2[O:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][C:20]=2[CH:19]=[C:18]([CH:30]([C:14]2[N:10]([CH2:9][O:8][CH2:6][CH3:7])[N:11]=[CH:12][CH:13]=2)[OH:31])[C:17]=1[Cl:32]
Reactant: CCOCn1cccn1
Reactant: CCOC(=O)C1Oc2cc(C=O)c(Cl)c(Cl)c2O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCn1nccc1C(O)c1cc2c(c(Cl)c1Cl)OC(C(=O)OCC)O2
Reaction time: 1 h
Yield: 28.8 %

Procedure:
1.25 ml of 1.6M n-butyl lithium in n-hexane is added dropwise to a solution of 252 mg of 1-ethoxymethyl-pyrazole in 5 ml of tetrahydrofuran at -60° to -50° C. 0.4 ml of hexamethylphosphoric triamide is added to the mixture and the mixture is stirred at the same temperature for 1 hour. The mixture is added to a solution of 582 mg of ethyl 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate in 10 ml of tetrahydrofuran at -60° to -50° C. and the mixture is stirred at the same temperature for 5 minutes. An aqueous saturated ammonium chloride solution is added to the mixture and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform-acetone-ethanol) to give 240 mg of ethyl 4,5-dichloro-6-((1-ethoxymethyl-pyrazol-5-yl)-hydroxymethyl)-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2F)=N/O)ccc1=O
Temperature: 100 °C

Procedure:
To a solution of 5-(3-(4-bromophenyl)-3-(2,4-difluorophenyl)propanoyl)-1-methyl-pyridin-2(1H)-one (0.2 g, 463 μmol) in ethanol (5 mL) and water (0.2 mL) was added hydroxylamine hydrochloride (80.4 mg, 1.16 mmol) and sodium hydrogencarbonate (77.7 mg, 925 μmol) and the resulting colourless suspension was heated at reflux (100° C. oil bath temperature) for 4.5 hours. After cooling down the reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colourless foam (0.205 g, 99%). MS (ESI+): m/z=449.1 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:33]=[C:32]([CH:34]=O)[S:31][CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:33]=[C:32]([CH2:34][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[S:31][CH:30]=3)[S:28][C:19]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C=O)c4)sc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(CN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
Morpholine (50 μL, 0.57 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.43 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (460 mg, 2.17 mmol) is added. After stirring at 0° C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 169 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 209-212° C.; MS 531.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([CH:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[N-:22]=[N+:23]=[N-].[Na+]>CS(C)=O>[N:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([CH:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:22]=[N-:23]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1C1CCC(O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(C1CCC(O)CC1)C2=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
A mixture of 2.9 g (0.01 mol) of 4-(3-nitrophthalimidyl)-cyclohexanol and 0.9 g (0.013 mol) of sodium azide in 20 ml of dimethylsulphoxide is stirred for 6 hours at 80° C. and then evaporated in vacuo at the same temperature. The residue is diluted with 20 ml of water. The product which has separated out is filtered off with suction, washed with 5 ml of water and dried for 24 hours at 80° C. in a drying cabinet. 2.6 g (91% of theory) of 4-(3-azidophthalimidyl)-cyclohexanol are obtained; melting point 155° C. (with decomposition). IR spectrum (KBr): 1775 cm-1 and 1710 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=O.[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([CH2:17][C:18]#[N:19])=O)=[CH:13][CH:12]=1.C(=O)([O-])[O-:23].[K+].[K+]>ClC(Cl)C(Cl)Cl>[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]2[C:3]3[CH2:4][CH:5]4[CH2:8][CH:1]([CH2:7][CH2:6]4)[C:2]=3[NH:19][C:18](=[O:23])[CH:17]=2)=[CH:13][CH:12]=1
Reactant: O=C1CCC2CCC1C2
Reactant: O=C([O-])[O-]
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=c1cc(-c2ccc(F)cc2)c2c([nH]1)C1CCC(C2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Bicyclo[3.2.1]octan-2-one (2 g) and 4-fluorobenzoylacetonitrile (2.6 g) are dissolved in 1,1,2,2-tetrachloroethane (5 ml) and thereto is added 75% polyphosphoric acid (25 g). The mixture is stirred at 80° C. for 30 minutes, at 100° C. for 1 hour, and further at 130° C. for 30 minutes. After cooling, the reaction mixture is poured into ice-water and neutralized with potassium carbonate. The precipitated crystals are collected by filtration and washed successively with water and ethyl acetate. The resultant is recrystallized from methanol to give the desired product (2.7 g), m.p.>300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH3:20])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(OC)c1

Procedure:
3,4-Dimethoxyphenylacetic acid (3 g, 0.0153 mol) was dissolved in methanol (50 ml) and, thereafter, conc. sulfuric acid (0.05 ml) was added to the resulting solution, followed by heating at the reflux temperature for 2 h. Thereafter, the solvent was evaporated and the residue was neutralized with an aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic extract was dried with sodium sulfate, followed by evaporation of the solvent and drying under vacuum to yield the oil compound methyl 3,4-dimethoxyphenylacetate (3.2 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].ClC(Cl)(O[C:13](=[O:19])OC(Cl)(Cl)Cl)Cl.C(Cl)Cl.[OH-].[NH4+:25]>>[NH:1]([C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])[C:13]([NH2:25])=[O:19]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: [NH4+]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)N[C@@H]1CCCC[C@H]1O

Procedure:
Trans-2-amino-cyclohexanol (Aldrich) is treated with triphosgene in methylene chloride (1/3 equivalent). To the resulting solution, excess ammonium hydroxide is added to give after work up the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:23][O:24][CH2:25][CH2:26][Br:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1>O>[CH:1]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:23][O:24][CH2:25][CH2:26][Br:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NOCCBr)c1csc(N)n1
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOCCBr)c1csc(NC=O)n1
Temperature: 50 °C
Yield: 61.6 %

Procedure:
A mixture of acetic anhydride (15.9 g.) and formic acid (7.15 g.) was stirred at 50° C. for an hour. After cooling, ethyl 2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 25 g.) was added to the solution and stirred at room temperature for an hour. The resultant solution was poured into water and extracted with ethyl acetate twice. The extracts were washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate (three times) and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the solution in vacuo, the oily residue was triturated with a mixture of diisopropyl ether and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 16.75 g.), mp. 95° to 98° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[N:16]1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(-n2cccn2)cc1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-n3cccn3)cc2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and art-known 4-pyrazol-1-yl-benzenesulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: [P:1]([O-:43])([O-:42])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2].O>C(#N)C.C(O)(=O)C>[P:1]([OH:43])([OH:42])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c(=O)c1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
A solution of di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (20) (350 mg, 0.557 mmol) in acetonitrile (7 mL), acetic acid (7 mL), and H2O (7 mL) was stirred at 70° C. and the deprotection reaction followed by HPLC. Deprotection was complete after 1.5 hours. The reaction mixture was partially concentrated to remove the bulk of the acetonitrile then toluene (100 ml) was added and the mixture evaporated to azeotropically remove water and acetic acid. To the resulting suspension was added heptane (10 ml) and the suspension distilled down to 2-3 volumes (1 ml). Heptane (2 ml) was added and the suspension further stirred at room temp and filtered. The collected solid was dried in vacuo to afford [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (9) (254 mg, 88.4%) as off-white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 2H), 10.77 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.26-7.19 (m, 1H), 7.09 (dd, J=10.9, 7.6 Hz, 2H), 6.98 (s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.43 (dd, J=7.5, 2.1 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6) δ −2.35 (t, J=9.6 Hz, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:19])([C:5]([F:18])([F:17])[CH2:6][O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]=O.FC(F)(C1C=CC=CC=1)/C=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]([F:19])([C:5]([F:18])([F:17])[CH2:6][O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[CH:3]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Reactant: O=CC(F)(F)C(F)(F)COC/C=C/c1ccccc1
Product: CCOC(=O)/C=C/C(F)(F)C(F)(F)COC/C=C/c1ccccc1
Yield: 70 %

Procedure:
Obtained from Intermediate 38 (1.37 g, 4.96 mmol) by the procedure described in Intermediate 20. Purification by column chromatography with silica gel using n-hexane/ethyl acetate (15:1) as eluent gave the title compound (1.2 g, 70%) as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C(OCC)(=O)C.CCCCCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][O:15][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Reactant: C1=COCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and cam phorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×100 ml), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil (750 mg, 2.4 mmol, 80%).