Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH:10]=1)[CH2:8]Br.[C-:12]#[N:13].[Na+].[Br-]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH2:8][C:12]#[N:13])[CH:10]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: [C-]#N
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)c(CC#N)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
5-Methoxy-2-bromobenzyl bromide (72.8 g, 0.26 mol) is dissolved in EtOH (280 mL) and stirred at room temperature. Sodium cyanide (38.2 g, 0.78 mol) is dissolved in water and added to the solution of the bromide. The reaction mixture is heated to reflux temperature for 3 hours and then cooled to room temperature. Most of the ethanol is removed by rotary evaporator. A solid forms which is isolated by filtration and washed with water (500 mL). The crude material is purified using flash chromatography (CH2Cl2/hexanes, 1:1) to give 5-methoxy-2-bromophenylacetonitrile (53 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([NH:13][CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12].CO.[BH4-].[Na+]>O>[CH2:10]([N:13]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12]
Reactant: C=CCNCC=C
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCN(CC=C)Cc1ccccc1O
Temperature: 0 °C
Yield: 64 %

Procedure:
12 g of 2-hydroxybenzaldehyde was placed in a 500 ml round bottom flask with 100 ml of diallyl amine and 100 ml of methanol. The reaction mixture was then cooled to 0° C. 4 g of NaBH4 (powder) was slowly added within 2.5 hrs and the temperature was kept at 0-6° C. Water was then added to the reaction mixture to terminate the reaction. The reaction mixture was then concentrated, and extracted with ethyl acetate and water. The organic phase was collected and concentrated to obtain crude product. The obtained crude product was eluted and purified with mobile phase eluant of n-hexane:ethylacetate (EA)=4: 1 and solid phase of silica gel. 12.8 g of the product of formula (IX) was obtained and recovery yield was 64%.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.[OH-].[Na+].[CH3:34][CH:35]([O:42]S(C1C=CC(C)=CC=1)(=O)=O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(O)C>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:42][CH:35]([CH3:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(OCc2ccccc2)cc1
Yield: 97.3 %

Procedure:
Hydroquinone monobenzyl ether (50 g, 0.25 mol) was added to ethanol (250 ml), followed by adding to the solution, NaOH (12 g, 0.30 mol) and optically active p-toluenesulfonic acid 1-methyl-heptyl ester (78 g, 0.274 mol) prepared in Example 1 with stirring, refluxing the mixture for about 10 hours, distilling off ethanol, adding 6N-HCl (250 ml) and toluene (500 ml) to carry out extraction with toluene, washing the toluene layer with 2N-NaOH aqueous solution, then with water till the washing water became neutral, and distilling off the solvent to obtain optically active p-(1-methyl-heptyloxy)-phenol benzyl ether (76 g). This product (50 g, 0.16 mol) was dissolved in ethanol (100 ml) and reduced in the presence of Pd/C catalyst to obtain optically active p-(1-methylheptyloxy)-phenol (24 g) having a b.p. of 162°-165° C./6 mmHg.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]#N)=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[OH-:13].[K+].C[OH:16]>O>[Br:1][C:2]1[C:3]([C:11]([OH:16])=[O:13])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: COCc1ccc(Br)c(C#N)n1
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COCc1ccc(Br)c(C(=O)O)n1

Procedure:
To a solution of 3-bromo-6-methoxymethyl-pyridine-2-carbonitrile (300 mg, 1.32 mmol) in MeOH (6 ml) was added a solution of potassium hydroxide (1.48 g, 26.43 mmol) in water (4 ml). The mixture was refluxed for 3 hours. MeOH was removed in vacuo, the aqueous solution was neutralized with conc. HCl under cooling, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered and evaporated. The obtained product (276 mg, 85%) was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][N:23]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CCNCC3)CC2)n1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CC2)CCN(C(=O)CC#N)CC3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (238.1 mg, 0.6107 mmol) and 2-cyanoacetic acid (132.3 mg, 1555 mmol) in DCM (10 mL) and DMF (3 mL) were added HATU (703.4 mg, 17.94 mmol) and Et3N (225 mg, 2.201 mmol). The mixture was stirred at room temperature for 3 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V)=1/5) to give the title compound as a light yellow solid (203.1 mg, 72.8%).
Reaction SMILES: FC1C=CC(C=NO)=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:14][CH:13]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I>C1COCC1.O>[Cl:36][CH2:37][CH2:38][CH2:39][CH:24]1[C:23](=[O:27])[C:22]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)=[N:19][O:20][C:21]=2[CH2:26][CH2:25]1
Reactant: ClCCCI
Reactant: O=C1CCCc2onc(-c3ccc(F)cc3)c21
Agent: CC(C)[N-]C(C)C
Agent: ON=Cc1ccc(F)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(-c3ccc(F)cc3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 4-fluorobenzaldehyde oxime, the starting ketone is prepared. In 170 ml anhydrous THF was dissolved 4.0 g 6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 17.3 ml lithium diisopropylamide (1.50 molar in cyclohexane) was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 2.2 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and the layers were then separated. The aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 4.2 g of 5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Reaction time: 4 h
Yield: 71.1 %

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purin-6-amine (105 mg) was dissolved in methanol (2 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction mixture was stirred for 4 hours and stripped to dryness. Water (2 mL) and methanol (15 mL) were added to the residue and then neutralised by the addition of 2N sodium hydroxide solution. The above was stripped to near dryness (small volume of water remaining) and the solid thus obtained was filtered off under suction (transferred and washed with water (2 mL, 3 times)). The solid was dried under suction before being dried further in vacuo to afford the title compound as a white solid (71.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[C:15]([N+:24]([O-])=O)[CH:14]=2)=[C:7]([Br:27])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].CCCCCCC>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[C:15]([NH2:24])[CH:14]=2)=[C:7]([Br:27])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(OC)c([N+](=O)[O-])c2)c(Br)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(Br)c(Oc2cc(N)c(OC)c(C(C)C)c2)c(Br)c1
Yield: 44.2 %

Procedure:
Methyl[3,5-dibromo-4-(5-isopropyl-4-methoxy-3-nitrophenoxy)phenyl]acetate (1.1 g, 2.12 mmol) was dissolved in ethanol (50 mL) and sodium hydrosulfite (1.85 g, 10.6 mmol) was added. The reaction mixture was heated at reflux for 48 hours. The reaction monitored by TLC (65:35 n-heptane: EtOAc) and when complete, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified on column (silica gel, n-heptane/EtOAc 1:1) to yield methyl[3,5-dibromo-4-(3-amino-5-isopropyl-4-methoxyphenoxy)phenyl]acetate (457 mg, 44%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[NH2:14].BrCC(C)=C>C1COCC1>[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[NH:14][CH2:1][C:2]([CH3:5])=[CH2:3]
Reactant: Nc1cc(Cl)nnc1Cl
Reactant: CC(C)(C)[O-]
Agent: C=C(C)CBr
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CNc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
Potassium tert-butoxide (157.5 g) was charged portionwise to a stirred solution of 3,6-dichloro-pyridazin-4-ylamine (210 g) in THF (3.36 L). After 15 minutes, 3-bromo-2-methylpropene (141.8 mL) was added dropwise over a period of 30 minutes, maintaining the temperature <25° C. The solution was allowed to stir at room temperature for 16 h, after which time the reaction was concentrated and the residue partitioned between DCM (6 L) and water (6 L). The aqueous phase was extracted with DCM (2×5 L). The combined organic phases were washed (brine, 5 L), dried with magnesium sulfate, filtered and concentrated. Chromatography (Silica gel, eluting with 70:30 Heptane:-EtOAc) gave the title compound (211.7 g). 1H NMR (270 MHz, CDCl3): 6.49 (1H, s), 5.48 (1H, br s), 5.00 (1H, s), 4.91 (1H, s), 3.81 (2H, d, J ═6 Hz), 1.80 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])=[CH:28][CH:27]=1>ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([S:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:35])=[O:36])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cold, stirred solution of 0.2 g of piperidin-4-ylmethyl-carbamic acid tert-butyl ester and 0.2 mL of N,N-diisopropylethyl amine in 20 mL of dichloromethane was added 0.3 g of 2-(4-fluoro-phenyl)-ethanesulfonyl chloride. After stirring overnight, the mixture was diluted with 50 mL of chloroform, washed with 50 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure. Trituration with hexane gave a white solid:
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: OCc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(CO)cc2)C1

Procedure:
A mixture containing 3(R)-(+)-(1-cyano-1,1,-diphenylmethyl)-piperidine (0.28 g), 4- hydroxymethylphenethyl bromide (0.22 g), anhydrous potassium carbonate (0.28 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.21 g, m.p. 110-114° C., [α]D25 -16.2° (c, 1.0, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I-:22].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
To 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (28.6 kg, 1 mol eq, limiting reagent) was added sodium iodide (15.1 kg, 1.05 mol eq) and acetic acid (200.2 L, 7 rel vol). 90% Nitric acid (20.1 kg, 3.0 mol eq) was added dropwise. The reaction was heated to 50° C. and stirred until an HPLC assay showed reaction to be complete. The reaction was cooled and stirred. The precipitated product was collected by filtration, washed with water (171.6 L, 6 rel vol) and dried to constant weight to yield the title compound (19.2 kg, 45.4 mol, 68%); 1H NMR (CDCl3): δ 2.36 (s, 3H); 7.42 (d, 1H, J=8.1 Hz); 7.50 (s, 1H); 7.78 (t, 1H, J=7.8 Hz); 7.85 (d, 1H, J=7.9 Hz); 8.86 (s, 1H); 13.44 (s, 1H) ppm; LCMS: m/z 424.0 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42])=[O:35].N1C=CC=CC=1>ClCCl>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](=[O:43])(=[O:42])[NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])=[O:35]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. methyl-3-(chlorosulfonyl)thiophene-2-carboxylate (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, methyl-3-(N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (percentage yield: 86%), was obtained.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=O.C(CCCCC(O)=O)=O.[NH3:20].[H][H]>[Ni].[Co]>[NH2:20][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCCCC=O
Reactant: [H][H]
Reactant: N
Agent: [Co]
Agent: [Ni]
Agent: O=CCCCCC(=O)O
Product: NCCCCCC(=O)O

Procedure:
U.S. Pat. No. 4,730,040 uses methyl 5-formylvalerate as a starting material to produce caprolactam. In this process, methyl 5-formylvalerate is first hydrolyzed in the presence of an acidic catalyst at 30° to 200° C. to 5-formylvaleric acid, which is then reacted with excess ammonia and hydrogen in the presence of Raney nickel or Raney cobalt as a hydrogenation catalyst at 50° to 150° C. under superatmospheric pressure to form 6-aminocaproic acid. After the unreacted ammonia and hydrogen gas are removed, the aqueous mixture is heated to 150° to 370° C. under 100 bar to induce dehydrolyzation and cyclization of 6-aminocaproic acid to form caprolactam. Such process is very complicated and the yield is not high enough.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[C:19]1([S:25][CH2:26][S:27][CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][CH:9]2[N:8]([C:11](=[O:12])[CH:10]2[NH:13][C:29](=[O:30])[CH2:28][S:27][CH2:26][S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1]
Reactant: O=C(Cl)CSCSc1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSCSc3ccccc3)C2SC1

Procedure:
3.1 gms. of 7-aminocephalosporanic acid and 3.4 gms. of [[(phenylthio)methyl]thio]acetyl chloride are treated according to the procedure of Example 3 to obtain DL-3-[(acetyloxy)methyl]-7-[[[[(phenylthio)methyl] thio]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. For purification, this product is converted to its potassium salt with potassium ethyl hexanoate. The reaction mixture is acidified and extracted with ethyl acetate to obtain the purified free acid. This is dissolved in methylene chloride and petroleum ether is added to the solution. The product precipitates in amorphous solid form.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[C:10]=1[C@@H:11]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:12]1[C:13](=O)[O:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C(C)=CC=CC=1>[Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[C:10]=1[CH:11]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:12]1[C:13](=[S:38])[O:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCc1cc2c(c(O[Si](C)(C)C(C)(C)C)c1)[C@@H]1CCCC[C@H]1C(=O)O2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CCCCCc1cc2c(c(O[Si](C)(C)C(C)(C)C)c1)C1CCCCC1C(=S)O2

Procedure:
2.00 g (4.97 mmol) of (6aR*,10aR*)-1-(tert-butyldimethylsilyloxy)-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-6-one was heated under reflux at 140° C. for 17 h with 4.25 g (10.2 mmol) of Lawesson's reagent in xylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([N+:33]([O-:35])=[O:34])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1ccccc1OCCN
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1OCCNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 23 °C
Yield: 74.3 %

Procedure:
A mixture comprising 2-(2-methoxyphenoxy)ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) was cooled to 0° C. and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was allowed to warm to 23° C. over two hours, quenched with aqueous hydrochloric acid (3M, 20 mL), washed with water (3×20 mL), dried (Na2SO4) and concentrated in vacuo to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (14 g, 74% yield) an off white solid; MS (PB-PCI) C17H18N2O6 m/e calc 346.34; found 347 (MH+).
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([C@@:30]1([CH3:56])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N+:32]2[C@@H:50]([CH:53]3[CH2:55][CH2:54]3)[CH2:51][O:52][C:31]1=2)[CH:28]=[CH2:29]>O1CCCC1.O>[CH2:27]([C@@:30]1([CH3:56])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N:32]([C@@H:50]([CH:53]2[CH2:55][CH2:54]2)[CH2:51][S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:31]1=[O:52])[CH:28]=[CH2:29]
Reactant: CC(C)(C)S
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSC(C)(C)C)C2CC2)C1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-2-propanethiol (0.195 mL, 1.796 mmol, dried over activated 4 Å molecular sieves) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.8 mL, 1.8 mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature. The reaction mixture was heated at 60° C. After 15 minutes at 60° C., (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-α]pyridin-4-ium 4-methylbenzenesulfonate (1.00 g, 1.632 mmol, Example 1, Step F) was added as a solid. The reaction mixture was heated at 60° C. for 12 hours and then cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate thrice and the organics were pooled, washed with brine, dried over sodium sulfate, decanted and concentrated under a vacuum to provide a brown oil. Purification by flash chromatography (80 g SiO2 column, gradient elution of 10 to 60% ethyl acetate in hexanes provided the desired product as a colorless syrup.