Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([OH:22])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(OCc3ccc(F)cc3)c2CC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Prepare a slurry of sodium hydride (60% in mineral oil; 99 mg, 2.5 mmol) in DMF (4 mL) and heat to 65° C. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.84 mmol) in DMF (5 mL) dropwise and stir for 1 h. Add a solution of 4-fluorobenzyl bromide (191 mg, 1.0 mmol) in DMF (1 mL), stir at 65° C. for 1.5 h and cool to ambient temperature. Add water (1 mL) and concentrate the mixture to an oily residue. Partition the residue between EtOAc/hexane (1:1) and water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, wash with 2N aqueous NaOH, dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1 and 7:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]O)([CH3:16])([CH3:15])[CH3:14].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:13]([O:17][C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[Cl:1])=[O:24])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: Oc1cccc2c(Cl)nccc12
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 1-chloro-5-hydroxyisoquinoline (539 mg, synthesized according to the method described in a reference (Georgian, V. et al., J. Org. Chem., 27, 4571 (1962))), (3-hydroxypropyl)carbamic acid tert-butyl ester (1.58 g, Tokyo Kasei Kogyo) and 1,1′-azobis(N,N-dimethylformamide) (1.55 g) in tetrahydrofuran (8 ml) was added with tri(n-butyl)phosphine (2.24 ml) with ice cooling and stirred at room temperature for 24 hours. The deposited solid was removed by filtration, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (860 mg) as white powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[CH:8]([OH:19])[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:4]=2[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].CS(C)=O.N1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:23]([O:19][C:8]1[C:7](=[O:20])[NH:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[S:10][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)(=[O:25])[CH3:24]
Reactant: COc1ccc(C2Sc3cc(Cl)ccc3NC(=O)C2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C2=C(OC(C)=O)C(=O)Nc3ccc(Cl)cc3S2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
A mixture of 8-chloro-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (36.0 g), acetic anhydride (50 ml), dimethylsulfoxide (100 ml), pyridine (3 ml) and toluene (100 ml) is stirred at room temperature for 3 days. Water is added to the mixture, and the mixture is extracted with ethyl acetate, and the extract is washed with water, and dried. The resultant is evaporated to remove the solvent, and diethyl ether is added to the residue. The precipitated crystal is collected by filtration to give 3-acetoxy-8-chloro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (24.5 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:5]=2[N:6]=1.C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:30][NH:31][O:32][CH3:33]>O.[OH-].[Na+]>[CH3:33][O:32][N:31]([CH3:30])[C:11]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)=[O:13]
Reactant: CNOC
Reactant: Cc1nc2cc(C(=O)O)ccc2o1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc2oc(C)nc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a flask containing 2-methylbenzo[d]oxazole-5-carboxylic acid (1.00 g, 5.64 mmol) was added DCM (40 mL) to give a suspension. Carbonyldiimidazole (1.01 g, 6.21 mmol) was added and the mixture remained homogeneous and was stirred at room temperature for 17 hours, then N,O-dimethylhydroxylamine hydrochloride (688 mg, 7.06 mmol) was added and the mixture was stirred at room temperature for 18 hours. The contents were diluted with water and 1 N NaOH and extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (10-40% EtOAc-DCM) gave the title compound as an amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](O)=[O:22])[CH:14]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](=[O:22])[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cccc(OCC(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Cool a solution of 4-aminobenzonitrile (0.48 g, 4.02 mmol) in pyridine (30 mL), to 0° C., and add 3-carboxymethoxy-benzoic acid methyl ester (0.79 g, 3.76 mmol) followed by phosphorous oxychloride (0.38 mL, 4.02 mmol). Stir the mixture at 0° C. for 2 h then dilute with water causing a solid to precipitate from solution. Collect the solid by filtration, wash with water, and dry on the filter pad to provide 1.01 g (81.0%) of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:16])=[C:4](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.CC([S@](N)=O)(C)C.BrC1C(Cl)=C(C=O)C=NC=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:16])=[C:4]([CH2:8][NH:9][S@@:10]([C:12]([CH3:14])([CH3:13])[CH3:15])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cncc(Br)c1Cl
Agent: CC(C)(C)[S@](N)=O
Agent: O=Cc1cncc(Br)c1Cl
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)[S@@](=O)NCc1cncc(Br)c1Cl

Procedure:
(R)-2-Methyl-propane-2-sulfinic acid 1-(5-bromo-4-chloro-pyridin-3-yl)-meth-(E)-ylideneamide, prepared from (R)-2-methylpropane-2-sulfinamide and 5-bromo-4-chloro-pyridine-3-carbaldehyde in analogy to procedure described for the preparation of intermediate A-35 [A], has been reduced with NaBH4 in MeOH in analogy to the procedure described for the preparation of intermediate A-35 [B] to give the title compound as a yellow oil. MS: 325.2 (M+H+).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1
Reactant: [I-]
Reactant: Cc1nnc(SCCl)s1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCI)s1
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (730 mg : 4 mMol.) in acetone (6 ml) is added sodium iodide (1.2 g : 2.0 equivalents : 8 mMol.), and the mixture is stirred at 55° C. for 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated to give 5-iodomethylthio-2-methyl-1,3,4-thiadiazole (1.05 g) as yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])C.O.[NH2:14][NH2:15]>C(O)C>[O:11]=[C:7]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[CH2:10][CH2:9][O:8]1
Reactant: NN
Reactant: CCOC(=O)CN1CCOC1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCOC1=O

Procedure:
As described for example 112a, (2-oxo-oxazolidin-3-yl)-acetic acid ethyl ester (Potts, Kevin T.; Bhattacharjee, Debkumar; Kanemasa, Shuji. Journal of Organic Chemistry (1980), 45(24), 4985-8) in ethanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 72 h. All volatiles were evaporated, the residue was chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=90:10:1) and the title compound was obtained as a white solid (yield: 77%). MS: m/e=160.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCCC1C=CC=[C:20]2[C:21]([NH:23]C(=O)C=12)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:1]1([C:7]#[C:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:20][CH2:21][NH2:23])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#CC1CCNCC1)c1ccccc1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NCCN1CCC(C#Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
4-(Phenylethynyl)piperidine (0.5 mmol, 92 mg) was dissolved in acetonitrile (anhydrous 4 Å, 4 mL) together with bromoethylphtalimide (0.5 mmol, 128 mg) and K2CO3 (2 mmol, 276 mg). The reaction mixture was heated to reflux for 3 hours, diluted with ethyl acetate (50 mL) and washed with HCl/aq (1M, 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The protection group was removed by stirring the compound in methylamine (33% in ethanol, 5 mL) for another 3 hours. The mixture was evaporated, diluted with ethyl acetate (50 mL) and washed with NaOH (1M, 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH:20]=1)#[CH:15].C(N(CC)CC)C>CN(C=O)C.O.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(Cc2cc(C)on2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Cn2cc(-c3cc4cnc(Br)cc4n3S(C)(=O)=O)cn2)no1
Temperature: 60 °C
Yield: 52.1 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (46 mg, 0.066 mmol) was added to a solution of N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (8) (0.5 g, 1.32 mmol), 3-((4-ethynyl-1H-pyrazol-1-yl)methyl)-5-methylisoxazole (32) (0.278 g, 1.48 mmol), triethylamine (0.7 g, 7 mmol) and copper iodide (13 mg, 0.065 mmol) in DMF (5 ml). The reaction mixture was heated for 1 h at 60° C. The reaction mixture was cooled to room temperature and diluted with water (20 ml) and dichloromethane (30 ml). The organic solution was dried and concentrated in vacuo. The crude product was purified by flash silica chromatography (10 to 20% ethyl acetate in hexane) to afford the product as a white powder (300 mg, 51.8%). 1H-NMR (500 MHz, CDCl3) 2.43 (s, 3H), 2.96 (s, 3H), 5.41 (s, 2H), 6.02 (s, 1H), 6.69 (s, 1H), 7.78 (s, 1H), 7.87 (s, 1H), 8.22 (s, 1H), 8.62 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:15][Si:16](Cl)([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:16]([CH3:23])([CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)c1ccccc1

Procedure:
The title compound was prepared from the compound of Example e and 1.1 eq dimethylphenylsilyl chloride according to General Method A. Purification by HPLC with 1:9 ethyl acetate/hexanes gave 6.3 g of the desired product as a clear oil, a 91% yield.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([C:13]1[CH:14]=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])[CH3:10]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(=O)c1cccc(-c2ccccc2)c1
Yield: 100.1 %

Procedure:
A suspension of 6.71 g (55 mmol) of phenylboronic acid, 9.95 g (50 mmol) of 3-bromoacetophenone, 30 mg (0.13 mmol) of palladium acetate, 17.28 g (125 mmol) of potassium carbonate and 16.12 g (50 mmol) of tetrabutylammonium bromide in 55 ml of water was vigorously stirred under a stream of nitrogen and then stirred at 70° C. under an atmosphere of nitrogen for 75 minutes. Water was added to the reaction mixture and the mixture was extracted with tert-butyl methyl ether. Then, the organic layer was dried and concentrated. The residue (10.23 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=7:1) to obtain 9.82 g of 3-acetylbiphenyl as oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[OH-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CO.O1CCCC1.O>[CH2:14]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
In a mixed solvent of methanol and tetrahydrofuran was dissolved 5.17 g of 4-hydroxy-3-chlorobenzoic acid, and a solution of 2.4 g of sodium hydroxide in 5 ml of water was added to the solution. Then, 10 ml of benzyl chloride was added to the mixture and the liquid was refluxed for 4 hours. Then, 1.2 g of sodium hydroxide was further added to the mixture, the liquid was refluxed for 2 hours, and the reaction liquid was put into 1N hydrochloric acid, and the precipitate was recovered by filtration, washed with water, methanol and n-pentane in succession and recrystallized from a mixed solvent of benzene and tetrahydrofuran to obtain 2.7 g of 4-benzyloxy-3-chlorobenzoic acid. Then, 15 g of thionyl chloride was added to 2.7 g of this 4-benzyloxy-3-chlorobenzoic acid, and the mixture was reacted under reflux and reacted for 3 hours. Unreacted thionyl chloride was removed by distillation under reduced pressure. Thus, 4-benzyloxy-3-chlorobenzoic acid chloride was quantitatively obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].II.[C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])#[N:14].Cl>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]([C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][CH:21]=1)[C:13]#[N:14])=[O:19]
Reactant: COc1ccccc1Br
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cccc(C#N)c1
Temperature: -75 °C
Yield: 79 %

Procedure:
30 g (0.16 mol) of 2-bromoanisole are added dropwise to a mixture of 3.85 g (0.16 mol) of magnesium, containing a crystal of iodine, in 75 ml of anhydrous tetrahydrofuran and the reaction mixture is then refluxed for 1 hour. The resulting solution is then added dropwise to a solution of 26.48 g (0.16 mol) of 3-cyanobenzoyl chloride in 75 ml of anhydrous tetrahydrofuran, cooled to -75° C. The temperature is allowed to rise to 20° C., the reaction medium is hydrolyzed with a 1N aqueous solution of hydrochloric acid and the expected product is then extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. 30 g of the expected product (yield: 80%) are obtained in the form of crystals.
Reaction SMILES: Cl.[C:2]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:25]#[C:26][NH2:27].C(=O)([O-])O.[Na+]>O>[NH2:27][C:26]1[N:25]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:11][CH2:12]2)[C:17]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:23]=1
Reactant: N#CN
Reactant: Nc1ccccc1C(=O)C1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(C2CCN(C(=O)c3ccccc3)CC2)c2ccccc2n1
Yield: 97.6 %

Procedure:
The titled compound was prepared by warming a mixture of 1-benzoyl-4-(2-aminobenzoyl)piperidine hydrochloride (17 g, 0.049 mol) and cyanamide (4.12 g, 0.098 mol). At about 50° C., vigorous exothermic reaction occurred. After the reaction was finished, the reaction mixture was cooled, water was added to the reaction mixture, and then added sodium hydrogencarbonate to make the mixture basic. The mixture was then extracted with dichloromethane. The organic layer was washed with aqueous solution of saturated sodium chloride, and then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the titled compound (15.9 g) as a foam.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]([O:18][CH2:19][C@:20]12[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:23]([O:24][CH2:25]1)[C@H:22]([N:35]1[CH:43]=[N:42][C:41]3[C:40](=O)[NH:39][CH:38]=[N:37][C:36]1=3)[O:21]2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(OCC)(=O)C>[C:10]([O:18][CH2:19][C@:20]12[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:23]([O:24][CH2:25]1)[C@H:22]([N:35]1[CH:43]=[N:42][C:41]3[C:36]1=[N:37][CH:38]=[N:39][C:40]=3[Cl:3])[O:21]2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OC[C@]12CO[C@@H]([C@H](n3cnc4c(=O)[nH]cnc43)O1)[C@@H]2OCc1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OC[C@]12CO[C@@H]([C@H](n3cnc4c(Cl)ncnc43)O1)[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (2.1 mL, 29 mmol) and DMF (1 mL) were added to a solution of compound 22 (1.24 g, 2.62 mmol) in dichloromethane. The mixture was stirred at 30° C. (oil bath) overnight, diluted with ethyl acetate (50 mL), washed with NaHCO3 (sat. aq., 100 mL) and water (2×50 mL), dried (Na2SO4), and concentrated under reduced pressure. A white solid residue was purified by column silica gel chromatography using 0 to 2% of methanol/dichloromethane as eluent. Yield: 1.2 g (93%) of compound 26 as a white solid material.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3([CH2:20][C:21]([NH:23][OH:24])=[O:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:27]OS([O-])=O.[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([C:14]3([CH2:20][C:21]([NH:23][OH:24])=[O:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:27])=[CH:11][CH:12]=2)=[CH:25][CH:26]=1
Reactant: O=S([O-])OO
Reactant: O=C(CC1(Sc2ccc(Oc3ccc(F)cc3)cc2)CCOCC1)NO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(CC1(S(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1)NO
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2-{4-[4-(4-Fluorophenoxy)phenylthio]-tetrahydropyran-4-yl}-N-hydroxyacetamide (500 mg) was dissolved in methanol (25 ml). OXONE (400 mg) in water (5 ml) was added. After stirring for 30 minutes, the mixture was partitioned between methylene chloride and water. Preparative TLC on silica gel and elution with 10% methanol/methylene chloride gave 2-{4-[4-(4-fluorophenoxy)phenylsulfinyl]-tetrahydropyran-4-yl}-N-hydroxyacetamide (402 mg, m.p. 120° C.).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1([C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[N:11]1.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.ClCCl.C(OCC)(=O)C>[N:10]1([C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=C/C=C/c1ccc(-n2cccn2)nc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc(-n2cccn2)nc1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
DIBAL (1.0 M solution in toluene, 3.10 mL, 3.10 mmol) was added dropwise to a suspension of the compound from step B (350 mg, 1.53 mmol) in toluene (10 mL) and dichloromethane (4 mL) at −78° C. and the mixture was stirred for 2 h at that temperature. Methanol (1 mL) was added and the mixture was poured into a stirring mixture of ethyl acetate (20 mL) and 10% aq. potassium sodium tartrate (20 mL) and stirred for 1 h at RT. The organic layer was washed with brine (20 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 185 mg (59%) of the title compound. MS 202 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:7]=1
Reactant: O=C1CCCCC1Cl
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCCC1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (120.0 g), 2-chloro-1-cyclohexanone (108.0 g), potassium carbonate (163.3 g), and DMF (1.2 l) was stirred at 70° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give Compound IId-a (138.5 g, 78.3%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1.[C@@H:20]12[CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:24][CH2:23][CH2:22][NH:21]2>CN(C)C=O.C(#N)C>[Cl:12][C:11]1[C:2]([N:27]2[CH2:28][C@@H:20]3[C@@H:25]([CH2:24][CH2:23][CH2:22][NH:21]3)[CH2:26]2)=[N:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(Cl)ncc2c1=O
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3C[C@@H]4CCCN[C@@H]4C3)ncc2c1=O

Procedure:
200 mg (0.67 mmol) of 7,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acid are stirred with 190 mg (1.5 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane in a mixture of 1.7 ml of dimethylformamide and 1.7 ml of acetonitrile under argon overnight. The precipitate is isolated and washed with acetonitrile. The crude product is purified on silica gel (eluent: dichloromethane/methanol/aqueous ammonia solution 75:20:25).