Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].O1CCCC1.[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>CC1C=CC=CC=1.C(O)(=O)C>[C:15]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]([C:25]2[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=2)([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:32])[CH2:22][CH2:23]1)(=[O:17])[CH3:16]
Reactant: Fc1ccc(Br)cc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(Br)cc2)CC1
Reaction time: 5 h

Procedure:
To a stirred and refluxing Grignard-complex previously prepared starting from 52.5 parts of 1-bromo-4-fluorobenzene, 7.5 parts of magnesium and 216 parts of tetrahydrofuran was added dropwise a solution of 94 parts of 1-acetyl-4-(4-bromo-benzoyl)piperidine in 450 parts of tetrahydrofuran. Upon completion, stirring was continued for 5 hours at reflux. The reaction mixture was cooled, poured onto a mixture of 300 parts of crushed ice and 40 parts of acetic acid and stirred for 15 minutes. 450 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated. The residue was taken up in methylbenzene and the whole was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 75 parts of 1-acetyl-α-(4-bromophenyl)-α-(4-fluorophenyl)-4-piperidinemethanol as a residue (intermediate 16).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=C[C:15](Cl)=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:5]1)=[N+:2]=[N-:3].[C:29](Cl)(=[O:31])[CH3:30].[CH:33]([Cl:36])(Cl)Cl.CO>C1C=CC=CC=1.[Ag]C#N>[C:29]([N:23]1[C:24](=[O:25])[C:26]([CH3:27])=[CH:28][N:20]([C@@H:6]2[O:7][C@H:8]([CH2:9][O:10][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[C:33]([Cl:36])[CH:17]=3)[C@@H:4]([N:1]=[N+:2]=[N-:3])[CH2:5]2)[C:21]1=[O:22])(=[O:31])[CH3:30]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)[nH]c1=O
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Cl
Agent: N#C[Ag]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)n1c(=O)c(C)cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(=O)c3cccc(Cl)c3)O2)c1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
To a mixture of 3'-azido-5'-O-(4-chlorobenzoyl)-3'-deoxythymidine (0.3 g, 0.74 mMol) and silver cyanide (0.4 g, 3.0 mMol) in 20 mL of benzene, excess acetyl chloride (2.6 g, 33 mMol) was added in several portions. The mixture was stirred at room temperature until the starting material disappeared (4 hours) as established by TLC CHCl3 /MeOH 20:1 (v/v). The reaction was filtered and the filtrate evaporated under reduced pressure to dryness. The resulting oily residue was chromatographed on silica gel eluted with chloroform/hexane 1:1 (v/v) followed by chloroform to give 0.21 g (64%) of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:13]([NH:14][CH:15]=[O:16])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[CH3:17]N(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].S(OC)(OC)(=O)=O>O.CC(C)CC(=O)C>[CH3:1][C:2]1[C:13]([N:14]([CH3:17])[CH:15]=[O:16])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1cc2c(cc1NC=O)N1CCN=C1S2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(=O)CC(C)C
Product: Cc1cc2c(cc1N(C)C=O)N1CCN=C1S2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5.5 parts of N-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)formamide and 80 parts of hexamethylphosphoric triamide are added portionwise 1.24 parts of sodium hydride dispersion 75.8%. After stirring for 2 hours at room temperature, there are added dropwise 4.9 parts of dimethyl sulfate. Upon completion, stirring is continued for 3 hours at 50° C. and overnight at room temperature. 4-Methyl-2-pentanone and water are added and the layers are separated. The aqueous phase is extracted twice with 4-methyl-2-pentanone. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 1.5 parts of N-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)-N-methylformamide; mp. 164.2° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH3:11])=[CH:4][CH:3]=1.[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH3:11])[CH:4]=[CH:3][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:9]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccc(N)c(C#N)c1C
Product: Cc1ccc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 53a from 6-amino-2,3-dimethylbenzonitrile and benzoyl isocyanate as a off-white solid (210 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.43 (s, 3H), 7.48 (d, J=6.4 Hz, 2H), 7.53 (t, J=8 Hz, 7.6 Hz, 2H), 7.65 (t, J=7.2 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 8.03 (d, J=7.6 Hz, 2H), 11.29 (s, 1H), 11.37 (s, 1H). MS 293 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:7]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[OH-].[NH4+]>C1C=CC=CC=1>[Cl:3][CH:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:7]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14]
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1Cl)C(c1ccccc1Cl)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Clc1ccccc1C(Cl)C(c1ccccc1Cl)n1ccnc1
Yield: 94.8 %

Procedure:
A solution of 6 g (0.05 mole) of thionyl chloride dissolved in 20 ml of benzene is added dropwise to a solution containing 11 g (0.033 mole) of 1-[2-hydroxy-1,2-di-(2-chlorophenyl)ethyl] imidazole and 150 ml of benzene at room temperature. The reaction mixture is heated to reflux for 3 hours and is then made basic with 10% ammonium hydroxide solution. The organic product is extracted with ether and the combined ether extracts are washed with water, saturated sodium chloride solution, and dried over magnesium sulfate. Solvent is evaporated to give 11 g of a brown oil. This material is further purified by converting to its hydrochloride salt and back neutralized to the free base to give 8.2 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].[CH2:25]([O:32][C:33]([N:35]([CH2:37][CH2:38]Cl)[CH3:36])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:38][CH2:37][N:35]([C:33]([O:32][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:34])[CH3:36])[C:12]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3NC(=O)[C@@H]2O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A mixture of 2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy- 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.42 g of powdered potassium hydroxide and 15 ml of dimethylsulfoxide is stirred at 50° C. for 30 minutes. A solution of 2.64 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride in 5 ml of dimethylsulfoxide is added to the mixture, and the mixture is stirred at 50° C. for 3 days. The mixture is poured into ice-water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform: ethyl acetate=10:1). 2.95 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[C:18]([CH3:19])[C:13]=2[O:12][C:11](=[O:27])[CH:10]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][CH2:4][C:5]([C:10]1[C:11](=[O:27])[O:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=[CH:15][C:14]=2[C:9]=1[OH:8])=[O:7])[CH3:2]
Reactant: Cc1c(OC2CCCCO2)ccc2c(O)cc(=O)oc12
Reactant: CCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOCC(=O)c1c(O)c2ccc(OC3CCCCO3)c(C)c2oc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.21 ml of ethoxy acetic acid is added to a solution containing 5.00 g of 4-hydroxy-8-methyl-7-[(tetrahydro-2H-pyran-2-yl) oxy]-2H-1-benzopyran-2-one, 7.30 g of 4-dimethylaminopyridine and 3.816 g of N-(3-dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride. This mixture is agitated for 16 hours at ambient temperature. After diluting with dichloromethane, washing is carried out with an aqueous solution of sodium dihydrogen phosphate then with brine. After drying over magnesium sulphate, filtering and evaporating to dryness, the product obtained is triturated in a hexane-ethyl acetate mixture (4-1). The product obtained is separated and dried. In this way 5.40 g of sought product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)[Cl:32]>[OH-].[Na+].[Cu]I>[ClH:32].[ClH:32].[C:23]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCCCC
Reactant: ClCCl
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCCCCCC#Cc1cncc(OC[C@@H]2CCCN2C)c1
Product: Cl

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272 mg, 0.1 mmol) in 6 mL of methylene chloride was added triethylamine (0.4 mL), Pd(II) (18 mg), CuI (a catalytic amount) and 0.3 mL of 1-octyne (0.2 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with methylene chloride, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The free was purified by chromatography, eluting with 1 to 2% methanol in methylene chloride. MS (CI/NH3) m/z 301 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.91 (μ, 3H), 1.32 (μ, 4H), 1.60 (μ, 2H), 1.90 (μ, 3H), 2.15 (μ, 1H), 2.42 (μ, 2H), 2.64 (σ, 3H), 2.98 (βρ σ, 1H), 3.34 (βρ σ, 1H), 4.04 (μ, 1H), 4.25 (μ, 1H), 7.22 (μ, 1H), 8.22 (μ, 2H). The salt was prepared by treatment with HCl in ether, as described above, to give 110 mg of the title compound. MS (CI/NH3) m/z 301 (M+H)+. 1H NMR (D2O, 300 MHz) δ8.45 (d, J=2.6, 1H), 8.42 (d, J=1.1, 1H), 8.07 (m, 1H), 4.63 (dd, J=3.0, 11.1, 1H), 4.47 (dd, J=5.9, 11.4, 1H), 3.97 (m, 1H), 3.78 (m, 1H), 3.27 (m, 1H), 3.05 (s, 3H), 2.51 (t, J=7.0, 2H), 2.42 (m, 1H), 2.23 (m, 1H), 2.10 (m, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 1.33 (m, 4H), 0.88 (m, 3H). Anal. Calcd for C19H28N2O·2.0 HCl: C, 61.12; H, 8.10; N, 7.50. Found: C, 60.99; H, 7.89; N, 7.28. [α]25D =-4.00° (c 1.75, MeOH).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].S1[C:10]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14][C:9]=2NC1.Cl[C:33]1C=CC=C(C(OO)=O)C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:5]=[S:2]1[C:1]2[CH:13]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:11]=[CH:10][C:9]=2[CH2:14][CH2:33]1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)SCN2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CS(=O)(=O)O
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)S(=O)CC2

Procedure:
The product from Example 54 is treated with one equivalent of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1F

Procedure:
13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300 ml of acetone. Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethyl sulfate are successively added. The mixture is stirred at reflux temperature for 20 h. The reaction mixture is then mixed with 300 ml of water and the acetone is removed in a rotary evaporator. Several extractions with dichloromethane are carried out. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then removed in vacuo. The remaining solid is used further without further purification. 16.1 g (84% of theory) of the title compound are obtained as a colorless solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:6]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH2:1][CH2:2][CH2:3][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:10][CH2:9][CH3:8].[C:10]1([CH:9]([C:3]2[C:2]([CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:8])=[C:1]([OH:7])[CH:6]=[CH:5][CH:4]=2)[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: Oc1ccccc1
Product: CC(c1ccccc1)c1cccc(O)c1C(C)c1ccccc1
Product: CCCCCCCCCCCCc1ccc(O)cc1
Reaction time: 20 h
Yield: 2 %
Yield: 5 %

Procedure:
A suspension of 188 parts of phenol, 125 parts of styrene and 5 parts of ion exchange resin is prepared in a stirred reactor at 80° C. and 1 bar pressure, the mixture being stirred at 700 rpm. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor 700 rpm. After 3 hours, 24.4 parts of phenol and 16.2 parts of styrene are introduced per hour at 80° C. and 1 bar pressure and correspondingly 40.6 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and are subjected to fractional distillation. After 100 hours' operation, 2,840 parts (92% of theory, based on starting material II) of 4-(α-phenylethyl)-phenol of boiling point 136°-139° C./4 millibars are obtained, in addition to 155 parts (5% of theory, based on starting material II) of 2-(α-phenylethyl)-phenol and 47.2 parts (2% of theory, based on starting material II) of di-(α-phenylethyl)-phenol. The conversion is 59% of theory, based on phenol employed, or practically 100%, based on starting material II.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:21][N:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=3)[CH2:19][CH2:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:17])=[CH:11][NH:12]3)[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:40][C@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]1>CN(C)C(=O)C>[CH:28]([C:24]1[CH:23]=[C:22]([N:20]2[CH2:19][CH2:18][C:2]3[N:7]=[C:6]([C:8]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:9]=4[C:10]([CH3:17])=[CH:11][NH:12]5)[N:5]=[C:4]([N:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C@@H:41]4[CH3:40])[C:3]=3[CH2:21]2)[N:26]([CH3:27])[N:25]=1)([CH3:29])[CH3:30]
Reactant: C[C@H]1CCCCN1
Reactant: Cc1c[nH]c2cccc(-c3nc(Cl)c4c(n3)CCN(c3cc(C(C)C)nn3C)C4)c12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2cccc(-c3nc4c(c(N5CCCC[C@@H]5C)n3)CN(c3cc(C(C)C)nn3C)CC4)c12
Temperature: 125 °C

Procedure:
To a solution of 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (50 mg, 0.123 mmol) in N,N-dimethylacetamide (1.5 mL), was added diisopropylethylamine (0.15 mL, 0.86 mmol) and (S)-2-methylpiperidine (37 mg, 0.37 mmol). The reaction was stirred and heated to 125° C. for 24 h. After cooling, the mixture was directly purified via HPLC ((0.1% ammonium hydroxide in acetonitrile)/water=35%-100%). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.23 (br. s., 1 H), 7.42 (d, J=8.1 Hz, 1 H), 7.33 (d, J=8.1 Hz, 1 H), 7.16-7.26 (m, 1 H), 7.04 (s, 1 H), 5.69 (s, 1 H), 4.06-4.16 (m, 1 H), 3.90-4.06 (m, 2 H), 3.67 (s, 3 H), 3.53 (d, J=13.4 Hz, 1 H), 3.29-3.40 (m, 2 H), 3.16-3.29 (m, 1 H), 3.10 (d, J=4.5 Hz, 2 H), 2.85 (dt, J=13.8, 6.9 Hz, 1 H), 2.10 (s, 3 H), 1.74-1.91 (m, 2 H), 1.65-1.74 (m, 2 H), 1.48-1.65 (m, 2 H), 1.22 (d, J=6.8 Hz, 6 H); MS (ESI+) m/z 484.4 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][O:13][CH2:14][C:15]1[C:20]([CH2:21][O:22][CH3:23])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:24].COCC1C(COC)=C([N+]([O-])=O)C=CC=1O>C(#N)C.O>[CH3:12][O:13][CH2:14][C:15]1[C:20]([CH2:21][O:22][CH3:23])=[CH:19][CH:18]=[C:17]([N+:8]([O-:11])=[O:9])[C:16]=1[OH:24]
Reactant: COCc1cccc(O)c1COC
Reactant: O=[N+]([O-])O
Agent: COCc1c(O)ccc([N+](=O)[O-])c1COC
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCc1ccc([N+](=O)[O-])c(O)c1COC
Reaction time: 0.67 h
Yield: 54.6 %

Procedure:
Acetyl nitrate obtained by mixing acetic anhydride (306 mg, 3.0 mmol) with fuming nitric acid (189 mg, 3.0 mmol) at 0° C. was dropped into a solution of 2,3-bis(methoxymethyl)phenol (483 mg, 2.65 mmol) in acetonitrile (5 ml) at 0° C. followed by stirring for 40 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom to provide a 2:1 mixture (329 mg; yield 54%) of 2,3-bis(methoxymethyl)-6-nitrophenol and 2,3-bis(methoxymethyl)-4-nitrophenol as yellow solid. This was used in the next reaction without separation and purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[CH3:27][O:28][CH2:29]C(Cl)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:24]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:12][N:8]1[C:6](=[O:7])[CH2:29][O:28][CH3:27])=[O:26])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: COCC(=O)Cl
Reactant: NCc1ccccc1
Product: COCC(=O)N1CC(=NOCc2ccc(OC)cc2)C[C@H]1C(=O)NCc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and benzylamine the title compound was obtained in 49% purity by LC/MS. MS(ESI+): m/z=426.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8](S)[O:9][C:5]=2[CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>ClC1C=CC=CC=1>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(S)oc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1ccc2nc(Cl)oc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 100 mg portion of 6-methoxy-2-mercaptobenzoxazole and 172 mg of phosphorus pentachloride were dissolved in 35 ml of chlorobenzene to carry out 8 hours of heating under reflux. The reaction solution was poured into 300 ml of ice water and extracted three times with 100 ml of dichloromethane. The resulting organic layers were combined, dehydrated with sodium sulfate, concentrated under a reduced pressure and then purified by a silica gel column chromatography (n-hexane:chloroform=1:1), to obtain 79 mg of 2-chloro-6-methoxybenzoxazole.
Reaction SMILES: CC(C)([O-])C.[Na+].CN(C)C=O.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]1([CH2:32]I)[O:29][CH2:28][C@@H:27]([CH2:30][OH:31])[CH2:26]1>CN(C)C1C=CN=CC=1.ClCCl.O>[N:12]1([CH2:32][C@@:25]2([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[O:29][CH2:28][C@@H:27]([CH2:30][OH:31])[CH2:26]2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: OC[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: OC[C@@H]1CO[C@@](Cn2cncn2)(c2ccc(F)cc2F)C1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
Added 4-dimethylaminopyridine (8.61 g) and sodium tertiary butoxide (339 g) to a mixture of dimethylformamide (2500 ml) and 1,2,4-triazole (243.6 g) and stirred the reaction mixture for 30-45 minutes at 25-35° C. ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl)methanol compound of formula-8 (250 g) was added to the reaction mixture. The reaction mixture was heated to 100-110° C. and stirred for 18 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35° C. and then poured into water. Added dichloromethane to the reaction mixture. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloro methane. The combined dichloromethane layers were extracted with 50% aqueous HCl and separating both the aqueous and organic layers then pH of the aq. layer was adjusted to 8-9 with 50% aqueous sodium hydroxide. Both organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by sodium chloride solution and then distilled to get title compound as a residue. The obtained residue containing the title compound of formula-9 was taken to next step without isolation.
Reaction SMILES: [C:1]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[N:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21]([O:25][C:26](=[O:44])[C@@H:27]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:28][NH:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:24])([CH3:23])[CH3:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:21]([O:25][C:26](=[O:44])[C@@H:27]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:28][NH:29][C:30](=[O:33])[CH2:31][NH:32][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:10]1[N:9]=[C:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:13]([NH2:14])=[CH:12][CH:11]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1nc(CCCC(=O)O)ccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)c1nc(CCCC(=O)NCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)ccc1N
Reaction time: 8 h

Procedure:
Acid 5-5 (144 mg, 0.51 mmol), amine 5-7 (202 mg, 0.56 mmol), NMM (226 μL, 2.1 mmol) and BOP (241 mg, 0.77 mmol) were combined in 2.6 mL DMF. After stirring overnight the solvent was evaporated, the residue was dissolved in EtOAc, washed with water, sat. NaHCO3, 5% KHSO4, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 10% CHCl3 /EtOAc) provided 5-8 as an off-white glass.