Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:14][CH2:13][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CCO)c(Cl)cc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCBr)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a solution of 2-(2-chloro-5-methoxy-4-nitrophenyl)ethanol (0.85 g, 3.67 mmol) in DCM (20 mL), triphenylphosphine (1.54 g, 5.9 mmol) and carbon tetrabromide (1.46 g, 4.4 mmol) were added. The reaction mixture was maintained for 7 hours at room temperature then partitioned between water (50 mL) and EtOAc (80 mL). The separated aqueous phase was extracted with EtOAc (80 mL), then the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The product was purified by column chromatography on neutral silica gel using 5-15% EtOAc in hexane to give the title compound (0.9 g, 83%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of 6-chloro-7-hydroxychroman-4-carboxylic acid (99 g, 433 mmol) in ethanol (650 mL) was added sulfuric acid (1.2 mL) and the reaction was stirred at 60° C. for 24 hours. The reaction was cooled to ambient temperature and the resulting solids were removed by filtration and discarded. The filtrate was diluted with ethyl acetate (700 mL), washed with water, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a solvent system of 20% ethyl acetate/hexanes to give ethyl 6-chloro-7-hydroxychroman-4-carboxylate (46 g, 41%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16])([CH3:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].S(=O)(=O)(O)O>>[CH3:7][C:4]1([CH3:5])[CH2:3][C:2]([CH3:1])([CH3:8])[C:9]2[C:10](=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:16]1
Reactant: Cc1ccc(C(C)(C)CC(C)(C)O)c(O)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc2c(c1)OC(C)(C)CC2(C)C

Procedure:
To 2.16 g (11.7 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl) 5-methyl-phenol (Compound 45) was added under nitrogen 50 ml of 20% aqueous sulfuric acid. The reaction mixture was heated at reflux for 13 h and then cooled. The organic layer was separated and the aqueous layer was extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCO3 solution, water again and saturated NaCl solution and then dried (MgSO4) The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDCl3): & 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s), 2.26 (3H, s), 6.63 (1H, s), 6.72 (1H, d, J~7.9 Hz), 7.15 (1H, d, J~7.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:4]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:16]=[S:17])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(N2CCOCC2)c1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N=C=S)c(N2CCOCC2)c1

Procedure:
Reaction of 4-methoxy-2-morpholinoaniline (4.7 g) and thiophosgene (2.9 ml) in dioxan (25 ml) and water (75 ml) for 30 minutes at 0° C. and 3 hours at room temperature yielded a residue which was extracted with dichloromethane to give 4-methoxy-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)#[CH:20].[I-]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#Cc1cncnc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (719 mg, 2.01 mmol) and triethylamine (3 mL, 0.015 mmol) in N,N-dimethylformamide (3 mL) was treated with 5-ethynyl-pyrimidine (230 mg, 2.21 mmol). The resulting reaction mixture was degassed with argon for 10 min and then treated with cooper iodide (92 mg, 0.48 mmol) and bis(triphenylphosphine)palladium (II) chloride (169 mg, 0.24 mmol). The reaction was stirred at 25° C. for 18 h and then heated at 67° C. for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid methyl ester (440 mg, 66%) as an orange oil: EI-HRMS m/e calcd for C21H22N2O2 (M+) 334.1681, found 334.1681.
Reaction SMILES: ClC1C=CC([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:13][C:11]=3[N:12]=2)=CC=1.[C:22]([Cl:25])(=O)[CH3:23]>>[C:10]([O:21][C:17]([C:23]1[CH:16]=[CH:15][CH:14]=[CH:13][C:22]=1[Cl:25])([C:14]1[CH:15]=[CH:16][C:10]2[O:9][CH:8]=[N:12][C:11]=2[CH:13]=1)[C:18]([OH:20])=[O:19])(=[O:9])[CH3:11]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(O)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Product: CC(=O)OC(C(=O)O)(c1ccc2ocnc2c1)c1ccccc1Cl

Procedure:
A mixture of 2-p-chlorophenyl-5-benzoxazolylglycolic acid (4 g.) and acetyl chloride (50 ml.) was heated under reflux for 24 hours. The residue on evaporation was crystallised to give pure α-acetoxy-2-chlorophenyl-5-benzoxazolylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[NH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1
Reactant: NN1CCCC1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: COc1ccc(C(=O)NN2CCCC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluormethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 1-aminopyrrolidine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: N#CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 67.5 %

Procedure:
Potassium cyanide (2.6 g) was added to a stirred, two-phase mixture of 4-(chloromethyl)biphenyl (2.02 g) and tetrabutyl ammonium hydrogen sulphate (200 mg) in dichloromethane (50 ml). The reaction mixture was stirred at ambient temperature for 36 hours. The organic layer was separated and washed with water (10 ml), dried (MgSO4) and evaporated to give a solid residue which was crystallised from n-hexane to give 4-(cyanomethyl)biphenyl (1.3 g) as a solid, m.p. 95° C.; microanalysis, found: C, 86.3; H, 5.7; N, 7.2%; C14H11N .0.1H2O requires C, 86.2; H, 5.7; N, 7.18%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16]([NH:33]N)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Ni]>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16]([NH2:33])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
A suspension of 2,4-di(N-benzylpiperazinyl)-6-hydrazino pyrimidine (19.7 g, 43 mmol) and Raney Ni (5 g) in EtOAc (250 mL) was shaken in a Parr hydrogenator at 50 psi H2 for 16 hours. The resulting suspension was filtered through celite and the filtrate was concentrated to give 18 g (94%) of the title compound as a foam. 1H NMR (CDCl3) δ 2.47 (m, 8H, piperazine), 3.51 (m, 8H, piperazine), 3.77 (m, 4H, CH2), 4.30 (bs, 2H, NH2), 5.04 (s, 1H, C5H), 7.3 (m, 10H, Ar).
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([C:62]([CH3:65])([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56]>>[CH3:53][O:54][C:55]([NH:57][C@H:58]([C:59]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[C:5](=[O:6])[C@H:4]([N:3]([CH2:1][CH3:2])[CH2:51][CH3:52])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:20][CH:19]=2)[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:25][CH:26]=1)=[O:32])=[O:60])[C:62]([CH3:63])([CH3:64])[CH3:65])=[O:56]
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 59 %

Procedure:
The product from Example 81A (0.042 g, 0.060 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (0.013 g, 0.066 mmol) were processed as in Example 81A to give 0.031 g (59%) of the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.88 (t, J=7.10 Hz, 6 H) 0.95 (s, 9 H) 1.76-1.89 (m, 4 H) 1.93-2.00 (m, 2 H) 2.02-2.10 (m, 1 H) 2.10-2.18 (m, 1 H) 2.40-2.47 (m, 2 H) 2.56-2.65 (m, 2 H) 3.52 (s, 3 H) 3.61 (dd, J=17.24, 7.48 Hz, 2 H) 3.73-3.80 (m, 2 H) 4.20 (d, J=9.00 Hz, 1 H) 4.37 (dd, J=7.93, 4.27 Hz, 1 H) 4.42 (dd, J=7.78, 5.19 Hz, 1 H) 4.54 (s, 4 H) 4.66 (s, 1 H) 6.63 (dd, J=9.31, 4.43 Hz, 2 H) 6.90 (t, J=8.85 Hz, 2 H) 7.07 (d, J=8.85 Hz, 1 H) 7.17 (dd, J=8.47, 3.89 Hz, 4 H) 7.26 (t, J=7.17 Hz, 1 H) 7.32 (t, J=7.40 Hz, 2 H) 7.39 (d, J=7.17 Hz, 2 H) 7.50 (dd, J=8.39, 6.10 Hz, 4 H) 9.95 (s, 1 H) 9.99 (s, 1 H); MS ESI+ m/z 876.5.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:18][C:17]2[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=2)=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(O)cc1
Reactant: N#Cc1ncc(Cl)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Oc2cnc(C#N)c(C#N)n2)cc1
Yield: 41.5 %

Procedure:
2,3-Dicyano-5-chloropyrazine (0.83 g; 0.005 mole) was dissolved in 25 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.54 g (0.005 mole) of p-cresol, 0.21 g (0.005 mole) of sodium hydroxide, 1 ml of water and 15 ml of acetone was added dropwise over the period of 15 minutes. The mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the solvent was removed by concentration under reduced pressure. The residue was extracted with 100 ml of chloroform. The chloroform solution was washed with 30 ml of a 1 N aqueous solution of sodium hydroxide and 30 ml of water and dried over anhydrous calcium chloride. Then, the solvent was distilled off. Recrystallization of the crude product from ethanol afforded 0.49 g (yield 41%) of 2,3-dicyano-5-(p-methylphenoxy)pyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N1C=CC=CC=1>C(#N)C>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(Cl)cc2)cc1
Yield: 89.5 %

Procedure:
4-Chlorothiophenol (21.6 g) was dissolved in dry acetonitrile (500 ml) and a solution of 4-acetoxybenzoyl chloride (29.7 g) in acetonitrile (50 ml) was added. The mixture was stirred at room temperature whilst pyridine (12.1 ml) was added rapidly dropwise. When the reaction was complete the bulk of the solvents was removed by evaporation in vacuo and the residue partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulphate, and evaporated to afford the desired thioester as a pale yellow solid (41.0 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(#N)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(N)cc1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCc1ccc(NC(=O)CCCCl)cc1
Temperature: 50 °C
Yield: 52.2 %

Procedure:
17.9 gm (0.1 mol) of p-aminophenethyl acetate were dissolved in 180 ml of acetonitrile, 27.6 gm (0.2 mol) of potassium carbonate were added to the solution, and then, while stirring, 17.0 gm (0.12 mol) of 4-chlorobutyric acid chloride were added dropwise. The resulting mixture was stirred for 2 hours at room temperature, thereafter heated to 50°C and then vacuum-filtered to remove precipitated inorganic salts. The solvent was distilled out of the filtrate in vacuo, and the residue was recrystallized from isopropanol, yielding 14.8 gm (52.2% of theory) of p-(4-chlorobutyramido)-phenethyl acetate, m.p. 83°C.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:1]([C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: O=C1CCCC1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C1(O)CCCC1
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (3.30 mL; 3.30 mmol; 1.10 equiv) was reacted with cyclopentanone (252 mg; 3.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 9.09 mL, 3.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as colorless oil (353 mg, 92%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH2:35])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:35][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:43])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add acetic anhydride (43 μL, 0.44 mmol) to a solution of (2R,3S,5R)-5-[(1S,2S)-1-Hydroxy-2-amino-3-(3-propoxy-5-fluorophenyl)-propyl]-2-(3-fluoro-2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (231 mg, 0.44 mmol) and triethylamine (92 μL, 0.65 mmol) in dichloromethane (4.6 mL) and stir at room temperature for 30 minutes. Concentrate reaction mixture under a stream of nitrogen and subject residue to silica gel chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[Si:16]([O:23][CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(N(C)C)=O>[Si:16]([O:23][CH:24]1[CH2:25][CH2:26][C:27]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:28][CH2:29]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(O[Si](C)(C)C(C)(C)C)CC1)N2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (100 mg, 0.450 mmol), 4-{[tert-butyl(dimethyl) silyl]oxy}cyclohexanone (0.339 mL, 1.35 mmol), CSA (10.5 mg, 0.0450 mmol), MgSO4 (108 mg, 0.900 mmol) in anhydrous DMA (1.5 mL) was stirred at 90° C. for 1 h. The mixture was partitioned between EtOAc (20 mL) and aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 30:70 hexane/EtOAc to EtOAc) to give 4-{[tert-butyl(dimethyl)silyl]oxy}-6′-(5-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclohexane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of methyl 5-chloro-2-(3-hydroxyazetidin-1-yl)nicotinate (D62) (50 mg, 0.206 mmol) and triethylamine (0.057 ml, 0.412 mmol) in dimethylformamide (0.26 ml) cooled at 0° C., methansulfonyl chloride (0.016 ml, 0.206 mmole) was added dropwise and the reaction mixture stirred at the same temperature for 1 h. After solvent evaporation the obtained residue was purified by SPE-Si (5 g) eluting with a mixture petroleum ether/ethyl acetate from 90/10 to 70/30. Collected fractions, after solvent evaporation, afforded the title compound (D63) (53 mg)
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:6])=O.[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[C:9]=1[C:10]([O:12][CH3:13])=[O:11].N>C(O)(=O)C>[C:22]([NH:21][S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:8]([NH:7][CH:4]([CH3:6])[CH3:3])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:20])=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1c(N)cccc1S(=O)(=O)NC(C)(C)C
Reactant: CC(C)=O
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(NC(C)C)cccc1S(=O)(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At a temperature of 5-10° C., 925 mg (24.4 mmol) of sodium borohydride are stirred into 14 ml of acetic acid. After 1 h, this mixture is admixed first with 1.42 g (24.4 mmol) of acetone and then with 700 mg (2.44 mmol) of methyl 2-amino-6-[(tert-butylamino)sulfonyl]benzoate and stirred at 5-10° C. for 2.5 h. For work-up, the reaction mixture is poured into ice-water, neutralized with aqueous ammonia solution and extracted with dichloromethane. The organic phase is concentrated and the residue that remains is triturated with diisopropyl ether. After filtration with suction and drying, 700 mg (89% of theory) of methyl 2-[(tert-butylamino)sulfonyl]-6-(isopropylamino)benzoate remain as a white solid of m.p. 110-112° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>O>[NH2:8][C:7]1[C:2]([NH:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[N:5][C:6]=1[Cl:9]
Reactant: NCc1ccc(CO)o1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccc(CO)o1
Reaction time: 10 h
Yield: 76.6 %

Procedure:
A mixture of 16.3 parts of 4,6-dichloro-5-pyrimidinamine, 14 parts of 5-(aminomethyl)-2-furanmethanol, 12 parts of N,N-diethylethanamine and 200 parts of water was stirred for 10 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 19.5 parts (76.6%) of 5-[[(5-amino-6-chloro-4-pyrimidinyl)amino]methyl]-2-furanmethanol; mp. 136.7° C. (interm. 17).
Reaction SMILES: CC(O[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.[CH3:19][C:20]1[N:24]([CH3:25])[C:23]([SH:26])=[N:22][N:21]=1.Cl>O.CC(C)=O.C([O-])(O)=O.[Na+]>[CH3:19][C:20]1[N:24]([CH3:25])[C:23]([S:26][CH2:5][C:6]2[CH2:15][S:14][C@@H:9]3[CH:10]([NH2:13])[C:11](=[O:12])[N:8]3[C:7]=2[C:16]([OH:18])=[O:17])=[N:22][N:21]=1
Reactant: Cc1nnc(S)n1C
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1C
Yield: 60 %

Procedure:
To a solution of NaHCO3 (4.2 g., 0.05 mol.) in water (50 ml.) was added 7-ACA (6.8 g., 0.025 mol.), water (50 ml.) and acetone (25 ml.). The resulting solution was warmed to 45° and then a solution of 3,4-dimethyl-5-mercapto-1,2,4-triazole (5.0 g., 0.038 mol.) in acetone (50 ml.) and 5% NaHCO3 (10 ml.) was added. The reaction was refluxed until the reaction was completed as determined by the disappearance of the acetoxy carbonyl band in the infrared absorption spectrum. During this time the pH was maintained at ca. 7.6. The solution was cooled to 10° and adjusted to pH 3.5 with 3N HCl. The precipitated product was collected, washed with acetone, and dried to give a 60% yield of 3-(3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl)-7-amino-3-cephem-4-carboxylic acid.