Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].II.[CH2:15]([C:18](=[CH2:22])[C:19]([OH:21])=[O:20])[CH2:16][CH3:17].C(N(CC)CC)C.S(=O)(=O)(O)O>O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](/[CH:22]=[C:18](\[CH2:15][CH2:16][CH3:17])/[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: C=C(CCC)C(=O)O
Reactant: COc1ccc(S(=O)[O-])cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC/C(=C\S(=O)(=O)c1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Sodium 4-methoxyphenylsulfinate (10.0 g, 51.49 mmol) was dissolved in water (50 ml). This solution was shaken with iodine (8.7 g, 34.29 mmol) in dichloromethane (60 ml). The dichloromethane layer turned from deep pink to orange. The dichloromethane layer was dried over magnesium sulfate and filtered into a flask containing 2-propylacrylic acid (2.0 g, 17.52 mmol). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (7.3 ml, 51.49 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. Sulphuric acid (2M, 50 ml) was added to quench the reaction. The organic phase was washed with 10% aqueous sodium bisulphite (50 ml), then extracted with sodium hydroxide (1 g) in water (50 ml). The aqueous layer was washed with MTBE (20 ml) and the acidifed with sulphuric acid (2M, 10 ml). The product was extracted into dichloromethane (2×30 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound in 90% yield. This yellow solid was recrystallised from hot solvent (ethyl acetate:heptane:glacial acetic acid 1:1:0.2) to give the title compound as white crystals (4.02 g, 80%).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7]([O:13]C(=O)C)=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:31]1([C:2]2[O:6][C:5]3[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=3[C:3]=2[C:17](=[O:30])[C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (30 mg, 0.063 mmol) and imidazole (60 mg, 0.88 mmol) in a mixture of toluene:triethylamine (3 mL: 2 drops) was refluxed for 4 hours (tlc). Solvent was distilled under vacuum and the crude residue was purified by PTLC (eluent=ethyl-acetate: 1% triethylamine) to give the title compound as a yellow solid; (8 mg, 30%); 1H NMR (300 MHz, CDCl3) δ 8.24 (bs, 1H), 7.52 (b, 1H), 7.19 (b, 1H), 7.06 (s, 2H, benzoyl Hs), 6.99 (d, 1H, J=8.60 Hz), 6.93 (d, 1H, J=8.66 Hz), 3.96 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.76 (s, 6H, 2×OMe).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([CH2:15][C:16]2[CH:17]=[C:18]([OH:26])[C:19]3[CH:20]=[CH:21][N:22]([CH3:25])[C:23]=3[CH:24]=2)=[CH:10][N:9]=1.[CH3:27][CH:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CN(C)C=O>[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH3:25])=[C:18]([O:26][S:30]([CH:28]([CH3:29])[CH3:27])(=[O:32])=[O:31])[CH:17]=2)=[CH:10][N:9]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1ccc2c(O)cc(Cc3cnc(N)nc3N)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Oc1cc(Cc2cnc(N)nc2N)cc2c1ccn2C
Yield: 37.4 %

Procedure:
Potassium tert-butylate (150 mg, 1.31 mmol) was added at 0° C. (ice bath) to a solution of 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-methyl-1H-indol-4-ol (Example 4; 293 mg, 1.09 mmol) in N,N-dimethylformamide (33 mL). After 30 min the solution was treated with propane-2-sulfonyl chloride (190 mg, 1.31 mmol), and the ice bath was removed. After 2.5 h the reaction mixture was poured into ice water, set to pH 9-10 with 25% aqueous ammonia solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), and evaporated. Column chromatography (SiO2; CH2Cl2/MeOH/NH4OH19:1:0.05) afforded the title compound (153 mg, 37%). White solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([C:16]1[O:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C(O)C>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[O:20][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(N3CCOCC3)cc2)o1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
The reaction flask was flushed with nitrogen and charged with 4-(4-bromo-phenyl)-morpholine (2.134 g, 8.81 mmol), 5-formyl-furan-2-boronic acid (1.832 g, 13.10 mmol) and sodium carbonate (3.016 g, 28.46 mmol). A mixture of 1,2-dimethoxyethane (35 mL), ethanol (10 mL) and water (13 mL) was added and the reaction mixture was stirred for 10 min under a nitrogen atmosphere. Dichlorobis(triphenylphosphine) palladium(II) (0.205 g, 0.29 mmol) was added and the mixture was stirred and heated at 80° C. for 18 h. The mixture was cooled to room temperature and partitioned between ether (250 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash Silica (100 mL, 20% ethyl acetate in hexanes) to afford 5-(4-morpholin-4-yl-phenyl)-furan-2-carbaldehyde (1.36 g, 60%). 1H NMR (400 MHz, CDCl3): δ 3.26 (2H, dd, J=5.2, 3.6 Hz), 3.87 (2H, dd, J=5.2, 3.6 Hz), 6.69 (1H, d, J=4.0 Hz), 6.93 (2H, m), 7.26 (1H, s), 7.30 (1H, d, J=4.0), 7.74 (2H, m), 9.58 (1H, s). ESI-MS: 258.0.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]#[N:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].[OH-].[K+]>C(O)C>[C:1]1([C:7]2[O:11][C:10]([C:12](=[N:15][OH:16])[NH2:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2ccccc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2ccccc2)o1
Temperature: 25 °C

Procedure:
A mixture of 10 g (0.059 mole) of 5-phenyl-2-furonitrile, 4.1 g (0.060 mole) of hydroxylamine hydrochloride, 4.0 g (0.060 mole) of potassium hydroxide, and 150 ml of absolute ethanol was refluxed for 21/2 hours, cooled to room temperature, and then added to 750 ml of ice/H2O. the resulting solid was washed in water and dried at 60° to yield 10 g (84%), m.p. 118°-120°.
Reaction SMILES: II.C1(=O)C2C(=CC=CC=2)CC1.BrC/C=C/C(OC)=O.Cl.[CH:22]1([CH:31]=[CH:32][CH2:33][CH2:34][OH:35])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>O1CCCC1.CO.[H][H].[Pd].[Zn].ClCCl.CCOCC>[CH:22]1([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: OCCC=CC1CCc2ccccc21
Agent: [Pd]
Agent: COC(=O)/C=C/CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: OCCCCC1CCc2ccccc21
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A suspension of activated zinc (40 g) in dry tetrahydrofuran (150 ml) was heated to reflux and a few crystals of iodine was added. A solution of 1-indanone (50 g) and methyl 4-bromo-crotonate (100 g) in 400 ml of dry tetrahydrofuran was added dropwise followed by reflux for 1 h. After cooling, ice was added and the pH adjusted to 1 with concentrated hydrochloric acid followed by extraction with dichloromethane. Concentration of the organic phase left a viscous oil which was dissolved in methanol (400 ml). Concentrated hydrochloric acid (100 ml) was added and the mixture stirred for 30 min. Removal of solvents in vacuo, addition of water, and extraction with ether gave, after drying over magnesium sulfate and removal of solvent in vacuo, an oil (34 g). The oil was dissolved in 300 ml of dry ether and added dropwise to a suspension of lithium aluminium hydride (21 g). After reflux for 2 h, the reaction mixture was hydrolyzed with water. Filtration and removal of solvent in vacuo gave a mixture of isomers from which 4-(1-indanyl)-but-3-en-1-ol (6 g) could be isolated by column chromatography (silica gel, eluent:dichloromethane/ether =9:1). The remaining mixture of isomers (9 g) was dissolved in 150 ml of methanol and hydrogenated at 3 atm of hydrogen pressure in is a conventional Parr apparatus in the presence of 5% palladium on charcoal (6 g) for 12 h. Filtration and removal of solvent in vacuo gave 6 g of 4-(1-indanyl)-1-butanol. The alcohol was converted to the title compound, 28, via the corresponding methanesulfonate following the procedures described in EXAMPLE 2 using spiro[isobenzofuran-1(3H),4'-piperidine], mp: 114°-15° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN1CCc2sccc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CN1CCc2sccc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:39][O:40][C:41]1[CH:47]=[C:46]([C:48]2[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH:53]=2)[C:45]([N+:55]([O-:57])=[O:56])=[CH:44][C:42]=1[NH2:43]>CC(O)CCC>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:43][C:42]4[CH:44]=[C:45]([N+:55]([O-:57])=[O:56])[C:46]([C:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH:49]=5)=[CH:47][C:41]=4[O:40][CH3:39])[N:20]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Yield: 69.2 %

Procedure:
A mixture of 1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole (Intermediate 10, 384 mg, 0.95 mmol), p-toluene sulphonic acid monohydrate (271 mg, 1.43 mmol) and 2-s methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) was heated in 2-pentanol (12 mL) at reflux under N2 for 24 h. Further p-toluene sulphonic acid monohydrate (0.090 g, 0.48 mmol) was then added and the mixture was heated at reflux for a further 6 h. The mixture was then concentrated in vacuo and the resulting reside was dissolved into a mixture of CH2Cl2, CH3OH and EtOAc (10 mL, 3 mL and 3 mL). This solution was concentrated in vacuo onto silica. Purification by FCC, eluting with 4-10% CH3OH in CH2Cl2 gave the title compound (415 mg, 56%) as a yellow foam; 1H NMR: 2.29 (1.95H, s), 2.52 (0.7H, m), 2.73 (2.6H, s), 3.18 (1.4H, m), 3.57 (2H, s), 3.96 (3H, s), 5.68 (1H, s), 7.00 (1H, s), 7.11 (1.3H, d), 7.26 (1H, m), 7.44 (1H, m), 7.49 (1.3H, d), 7.64 (2H, t), 7.73 (1H, m), 8.01 (1H, d), 8.07-8.15 (2H, m), 8.19 (1H, d), 8.64 (2H, d), 8.70 (1H, s), 8.97 (1H, s); (the spectrum seems to appear to show a mixture of rotamers, arising due to restricted rotation of bonds within the molecule) m/z: ES+ MH+ 631.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C>O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1

Procedure:
Alternatively to a solution of 5.0 g of the compound prepared in Example 4 in 100 mL of water was added 2.2 g of sodium benzoate. The mixture was heated on a steam bath until homogeneous. Charcoal (approximately 2 g) was added and this mixture was filtered through Celite® washing with 20 mL of water. Crystallization began immediately. After cooling for 2 h, the solids were collected and washed with water. After drying the solids for 3 days in a vacuum oven at 50° C., 3.9 g (67%) was collected. 1H NMR confirmed the salt as a 1:1 ratio of benzoic acid and methyl (2R,3R)-2-{3-[amino(imino)methyl]benzyl}-3-{[4-(1-oxidopyridin-4-yl)benzoyl]amino}butanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:16](=[O:36])[N:15]2[CH3:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][C@H:39]([CH2:41][O:42][CH3:43])[CH3:40]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C@@H:39]([CH3:40])[CH2:41][O:42][CH3:43])[N:20]=3)=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:16](=[O:36])[N:15]2[CH3:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(S(C)(=O)=O)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC[C@H](C)N
Solvent: Cc1ccccc1
Product: COC[C@H](C)Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C)n2C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-3-oxo-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester, 12, (6 g, 12 mmol) in toluene (30 mL) is added (S)-2-amino-3-methoxypropane (2.14 g, 24 mmol). After stirring at 90° C. for 2 hours, the reaction mixture is cooled to room temperature and then concentrated in vacuo. Purification over silica (50% EtOAc/hexane) affords the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[CH2:5][CH2:6][C:7]=1[CH:8]=O)[CH3:2].CO[CH2:13][CH2:14][O:15]C>>[O:15]=[C:14]([CH2:2][CH2:1][CH2:3][CH2:7][CH3:6])/[CH:13]=[CH:8]/[C:7]1[CH2:6][CH2:5][C:4](=[O:10])[C:3]=1[CH2:1][CH3:2]
Reactant: CCC1=C(C=O)CCC1=O
Reactant: COCCOC
Product: CCCCCC(=O)/C=C/C1=C(CC)C(=O)CC1
Reaction time: 2 h
Yield: 80 %

Procedure:
1.7 g (0.035 mole) of a 50% NaH dispersion is transferred into a dry 500 ml 3-neck flask equipped with an addition funnel, overhead stirrer and septum. The NaH was covered with 175 ml of DME and a solution of 10.1 g (0.045 mole) dimethyl (2-oxoheptyl) phosphonate in 12 ml of DME is added dropwise over a 10 minute period. The mixture is stirred for 1 hour at room temperature to form the sodium salt of the phosphonate. A solution of the crude aldehyde 5 supra [from oxidation of 7.0 g (0.05 mole) of the vinyl compound 4] in 25 ml of DME was added over a twenty-minute period, and the mixture was stirred an additional two hours. The reaction was terminated by the addition of 2.5 ml glacial acetic acid followed by 175 ml water. The reaction mixture was extracted with CHCl3, and the combined organic extracts washed with water and dried over sodium sulfate. The CHCl3 was removed under reduced pressure to yield 12.6 g of crude product. This material was chromatographed over silicic acid using ethyl acetate-cyclohexane for elution to give 6.7 g (80%) of a yellow liquid Ic. The spectral characteristics of this compound were similar to Ia and Ib with the ##STR6## group evident in the nmr spectrum, --(CH2)4CH3 at δ0.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][OH:23])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]=[C:26]=[O:27].O.C(OCC)(=O)C>CN(C)C=O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][O:23][C:26]([NH:25][CH3:24])=[O:27])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)OCC(COc1noc2ccc(Cl)cc12)NC(=O)OC(C)(C)C

Procedure:
To a solution of 0.50 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole in 5 ml of N,N-dimethylformamide is added 0.14 g of cuprous chloride. To this solution is added a solution of 0.13 g of methyl isocyanate in 5 ml of methylene chloride at 20°-25° C., and they are further subjected to reaction at the same temperature for 30 minutes. Water and ethyl acetate are added to the reaction mixture, and after shaking, the organic layer is separated. The separated organic layer is washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure, to obtain 3-(2-tert-butoxycarbonylamino-3-methylaminocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.9 %

Procedure:
To a solution of 4-chlorobenzylamine (2.83 g, 20.0 mmol) and 4-isopropylbenzaldehyde (2.96 g, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for three days. Water (5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and aqueous 1 M KOH (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 5.80 g of crude product as a white semicrystalline oil. The product was used in the subsequent reaction step without further purification.
Reaction SMILES: [N:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:8].CN(C)[CH:11]=[CH:12][CH:13]=O.C(=O)([O-])[O-].[Na+].[Na+]>>[N:1]1[C:6]2[C:5](=[CH:11][CH:12]=[CH:13][N:7]=2)[CH:4]=[CH:3][C:2]=1[NH2:8]
Reactant: CN(C)C=CC=O
Reactant: Nc1cccc(N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ccc2cccnc2n1
Temperature: 120 °C
Yield: 20.9 %

Procedure:
Pyridine-2,6-diamine (0.30 g, 2.8 mmol), 3-dimethylaminoacrolein (90%, 0.30 g, 2.8 mmol), and polyphosphoric acid (PPA) (2.7 mL) were combined and the reaction mixture was heated to 120° C. for 10 hours. Then, the reaction mixture was poured on ice water and neutralized with solid sodium carbonate. The resulting aqueous mixture was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, concentrated, and purified by column chromatography (EtOAc/hexanes) to give [1,8]-naphthyridin-2-ylamine Yield 85 mg (21%). LCMS (ESI): calc. C8H7N3=145; obs. M+H=146.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:11]1[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=1)\[CH3:21])[CH3:16]
Reactant: Cc1ccc(O)cn1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(C)nc1
Temperature: 23 °C
Yield: 56.2 %

Procedure:
Potassium t-butoxide (10.4 g, 0.092 mol) was added to a stirred solution of 6-methyl-pyridin-3-ol (5.00 g, 0.046 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 6.80 g, 0.046 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (5.72 g, 56%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[OH:10].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH3:13]
Reactant: OCc1ccc(O)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
A mixture of 2-bromo-4-(hydroxymethyl)phenol (3.00 g, 14.7 mmol), iodoethane (4.60 mL, 44.3 mmol) and potassium carbonate (6.12 g, 44.3 mmol) in ethanol (30 mL) was stirred at room temperature for 2 days. The obtained reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was applied to silica gel chromatography (ethyl acetate). The solvent was evaporated under reduced pressure to give (3-bromo-4-ethoxyphenyl)methanol (2.98 g) as a white solid.
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.[S-:19][C:20]#[N:21].[K+].FC(F)(F)S(O)(=O)=O.O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]#[N:21])[CH2:15][S:14][C@H:9]12
Reactant: N#C[S-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (40 g) and potassium thiocyanate (15.7 g) in acetonitrile (200 ml) was added dropwise trifluoromethanesulfonic acid (40 ml) below 15° C. under cooling in an ice-bath and stirring, which was continued for 30 minutes at 5° to 15° C. and for 40 minutes at ambient temperature. The reaction mixture was poured into cold water (400 ml) and stirred for 30 minutes. The resulting precipitate was filtered, washed with water and acetone and dried to give 7-amino-3-cyanothiomethyl-3-cephem-4-carboxylic acid (26.2 g), mp. 175° to 180° C. (dec.).