Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[Cl:14][CH2:15][CH2:16][CH2:17]Br.CC(C)=O>O>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:7]1[C:6]([O:12][CH3:13])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[C:9]([OH:10])[CH:8]=1
Reactant: COc1cc(C(C)=O)c(O)cc1O
Reactant: ClCCCBr
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)c(O)cc1OCCCCl
Yield: 70.3 %

Procedure:
A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K2C3 (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) and acetone (25 mL) was stirred and refluxed under N2 for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H2O, brine) dried (MgSO4) and concentrated to yield 1.4 g of an off-white solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99°-101° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH2:10](N)[CH2:11][NH2:12]>O.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:10][CH2:11][NH:12]1
Reactant: Oc1ccccc1
Reactant: NCCN
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCNO2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts toluene and 595 parts of 50% formalin. A uniform toluene-water dispersion is maintained with agitation. The temperature of the reaction mixture is adjusted to 25° C. and maintained below 30° C. while 144 parts of ethylene diamine are added slowly. The reaction mixture is stirred for 2 hours at 30° C. after the amine addition is complete. The reaction mixture is heated to 46° C. under reduced pressure and refluxed for 3 hours. After 3 hours the distillate is passed through an oil water separator in the distillate return line. The toluene is continuously returned to the reactor while the water is removed. Azeotropic water removal is continued while the batch temperature is increased to 69° C. and the pressure is gradually reduced to about 5.0 kPa. The reaction mixture is essentially water free. It is cooled while 150 parts of 2-butoxyethanol are added and mixed in. The clear pale yellow solution is filtered. The product had the following composition and properties: Percent closed dihydrobenzoxazine 66%; equivalent wt. 224; solids 55.2%; Brookfield viscosity 12 cps @25° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][C:16]#[N:17]>CN(C=O)C.CCOC(C)=O.Cl>[C:16]([CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])#[N:17]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: N#CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCCn1cnc2c(N)ncnc21
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a suspension of 57% NaH in mineral oil (0.962 g, 22.8 mmol) in dry DMF (100 mL) was added 10 (3.40 g, 24.9 mmol) under nitrogen and the mixture was heated at 80° C. for 1.0 h. A solution of 3-bromopropionitrile (2.81 g, 21.0 mmol) in DMF (5.0 mL) was added at 25° C. and the reaction was heated at 65° C. for 17 h. It was then diluted with EtOAc (250 mL) and 5% aqueous HCl solution (150 mL). The organic layer was separated and then washed with water (4×100 mL). It was dried over MgSO4 (s) and concentrated under reduced pressure. Purification of the residue was carried out by use of column chromatography (EtOAc/hexanes=7.5:2.5) to afford compound 15 (3.510 g, 18.67 mmol) in 75% yield: mp 148-150° C.; Rf(hexanes/EtOAc=1:2) 0.38; UV (EtOH) λmax 260 (ε 13,900); 1H NMR (CD3OD) δ 2.92 (t J=5.8 Hz, 2 H, CH2CN),3.43 (t, J=5.8 Hz, 2 H, CH2N), 8.35 (s, 1 H, HC2), 8.69 (s, 1 H, HC8); MS m/z 188 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:18][C:17]1[C:12]([Cl:11])=[C:13]([O:19][CH3:20])[CH:14]=[CH:15][C:16]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 31.55 g of p-fluorobenzoyl chloride, 32 g of 2,3-dichloroanisole and 35.22 g of AlCl3 combined in 1,2-dichloroethane and reacted. The resultant crude product is triturated with warm hexane, cooled and filtered to yield 2,3-dichloro-4-methoxy-4'-fluorobenzophenone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was cooled to 0° C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146–149° C. Analysis: Calculated for C27H35N5O3S: % C, 63.63; % H, 6.92; % N, 13.74. Found: % C, 62.96; % H, 7.03; % N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Yield: 75 %

Procedure:
To a solution of methyl 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinoline-6-carboxylate (2.0 g, 4.8 mmol) in tetrahydrofuran (50 mL) was added sodium borohydride (729 mg, 19.2 mmol). After being refluxed for 60 hours, the reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of the crude product.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Br)c1O
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask vanillin (Aldrich, 33.3 g, 0.22 moles) was dissolved in glacial acetic acid (100 mL) with stirring. A solution of bromine (Baker, 35.0 g, 0.43 mol, 11.2 mL) in glacial acetic acid (100 mL) was added to the solution of vanillin. After 5 min a precipitate formed but the reaction was allowed to stir for an additional 15 min. The solid was collected by filtration giving 18.2 g, 35%. The filtrate was then slowly added to water (300 mL) and allowed to stand overnight. The resulting solid was filtered and dried under vacuum giving additional product (18.4 g, 35%, total yield 36.6 g, 70%), mp 159°-163° C. (lit, 163°-164° C.), 1H NMR (CDCl3) δ3.99 (s, 3H), 6.61 (bs, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 9.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)CCBr
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCBr)cc1
Yield: 96.2 %

Procedure:
A suspension of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (Curran et al., J. Med. Chem. 17, 273 (1974)) (75.0 g, 0.369 mol) and 3-bromoproionylchloride (100 g, 0.583 mol) in toluene (800 ml) was stirred under reflux for 16 hours. The reaction mixture was allowed to cool and the solid product collected, dried and stirred with water (500 ml) for 30 minutes. The crude product was collected, washed with water (500 ml) and dried to give 6-[4-(3-bromopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (120 g, 97%), m.p. 215°-217° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+]>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 ml) and formaldehyde (2.4 ml, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH is monitored every 15 min and adjusted to ˜7 with ACOH. After 45 min, the mixture was concentrated in vacuo and the residue is dissolved in EtOAc, washed with 6 N NaOH, 1 N NaOH, and 2 N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×). The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford 1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([Cl:9])=[N:7][CH:6]=[CH:5][N:4]=1.Br[CH2:11][CH:12](OCC)OCC.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[Cl:9][C:8]1[C:3]2[N:4]([CH:11]=[CH:12][N:2]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1Cl
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Clc1nccn2ccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HBr (48% in H2O) is added to a solution of 2-amino-3-chloropyrazine (1.2 g, 9.26 mmol) and BrCH2CH(OEt)2 (1.6 mL, 10 mmol) in MeOH and H2O (5 mL and 10 mL) at RT. The mixture is stirred for 24 h at RT and then heated to 40° C. for 48 h. The pH is adjusted to 7 with sat. Na2CO3. The mixture is extracted with CH2Cl2. The organic phase is dried over anhydrous Na2SO4. The product is purified by silica gel column chromatography (4% MeOH in CH2Cl2) to give the title compound as an off white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)O.[ClH:14].S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:17].[Cl:14][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:3][N:2]([CH3:13])[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCC(O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCC(Cl)c1ccccc1

Procedure:
(+-)3-dimethylamino-l-phenyl-1-propanol (10) (19 g) was dissolved in CH2Cl2 (200 ml). The solution was saturated with HCl (g). Thionyl chloride (17 ml) was added dropwise over 20 min. resulting in slight reflux. Subsequental reflux for 5 h resulted in the formation of a precipitate. Cooling and evaporation of the reaction mixture resulted in a yellowish crystalline mass, which was rinsed by several washings with acetone, resulting in colourless crystals of the title compound identified by 1H NMR.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br>C(O)(=O)C.Cl.O>[Br:14][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Yield: 109.9 %

Procedure:
To a stirred solution of the acetophenone prepared in Step 2 (11.91 g, 60.5 mmol) in glacial acetic acid (133 ml) and hydrochloric acid (0.11 ml) at ambient temperature, was added a soluton of bromine (8.22 g, 51.4 mmol) in glacial acetic acid (9.3 ml) over a period of three hours. The reaction mixture was diluted with water (500 ml) and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and concentrated in vacuo to give 15.66 g of crude 2-bromo-4′-(methylsulfonyl)acetophenone: 1H NMR (CDCl3) δ3.10 (s, 3H), 4.45 (s, 2H), 8.08 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H). The sample was used without further purification.
Reaction SMILES: [CH3:1][NH2:2].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.[BH4-].[Na+]>CO>[NH:3]1[C:11]2[C:6](=[C:7]([CH2:12][NH:2][CH3:1])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of methanamine (536 mg, 17.24 mmol) in MeOH (10 mL) was added 1H-indole-4-carbaldehyde (500 mg, 3.45 mmol). The reaction mixture was stirred at RT for 14 h. The reaction was cooled in an ice bath and NaBH4 (130 mg, 3.45 mmol) was added in several portions. The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h. The solvent was removed under reduced pressure to afford 300 mg (54.5%) of (1H-indol-4-yl)-N-methylmethanamine (116) which was used in the next step without further purification: MS (ESI) m/z=161.3 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared from 4-fluoronitrobenzene (2 g) and 1,2,4-triazole (1 g) as described in Description 61 to give a white solid (2.6 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:36][CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[I-].[Na+]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:36][CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C

Procedure:
In analogy to the procedure described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 110B]) in the presence of catalytic amount of sodium iodide to give 2-{4-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 102] to yield the title compound as white crystals of mp. 119.5–120.0° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>CO>[OH:13][CH:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]1[CH3:3]
Reactant: CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)c2ccccc2C1O
Temperature: 0 °C
Yield: 32.5 %

Procedure:
NaBH4 (566 mg, 14.91 mmol) was added to a stirring solution of 2-methyl-isoindole-1,3-dione (2.0 g, 12.42 mmol) in methanol (20 mL) at 0° C. Stirring at 0° C. was maintained for 1 hour, then the reaction was warmed to room temperature. Additional NaBH4 (566 mg, 14.91 mmol) was added in order to push the reaction to completion. The reaction was then quenched with acetic acid (5 mL) and partitioned between water and dichloromethane. The organic layer was washed several times with water and concentrated under vacuum to give 659-mg of the sub-title compound as a white solid. MS: ESI (positive): 164 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:35]>O.C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:35]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 5.7 %

Procedure:
10 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid containing 7.2% of ethanol were added to a solution of 2 g of sodium acetate in 7.5 ml of water and 20 ml of absolute ethanol and the mixture was stirred for 15 minutes, was treated with 1.5 g of activated carbon and was filtered. The filter was washed twice with 5 ml of a 9-1 ethanol-water mixture and the filtrate was added dropwise over 50 minutes with stirring at room temperature to 80 ml of ethanol which caused precipitation of the sodium salt. The mixture was stirred for 2 hours at 0° C. and was vacuum filtered. The crystals were washed with ethanol and dried under reduced pressure to obtain 8.45 g of the crystalline D form of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme- 4-carboxylate containing 5.7% of water.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.[BH4-].[Na+].[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 22.2 g (0.2 m) 4-fluoroaniline, and 17.6 ml (0.24 m) acetone in 120 ml (2 m) glacial acetic acid in the three neck 500 ml round bottom flask was stirred mechanically and cooled to approximately 10° C. in an ice bath. To this solution 9.4 g (0.25 m) sodium borohydride was added in parts while keeping the temperature below 20° C. It was allowed to stir at 20° C. for 30 minutes and one hour at room temperature. The mixture was poured into 500 ml ice water. The aqueous solution was made alkaline by dropwise addition of 120 ml 50% aqueous sodium hydroxide solution below 25° C. The product was extracted with hexane, (2×100 ml) which was washed with saturated sodium chloride solution, dried on anhydrous magnesium sulfate and evaporated to give a clear liquid. The product was distilled to give a clear colorless liquid product, 21.8 g B.P. 40°/0.5 mm. Yield 71%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCO
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C2OCCO2)nc1
Yield: 82.4 %

Procedure:
A mixture of 2-pyridinecarboxaldehyde (300 g), 300 mL of ethylene glycol, 3 L of toluene and 100 g of p-toluenesulfonic acid in a 5 L 3 neck-flask equipped with a Dean-Stark head was refluxed for 4 h, separating the water formed. The mixture was concentrated in vacuo to 1/2 of its volume, and poured into a 5 L flask containing a cold (5° C.) sodium bicarbonate solution. The aqueous layer was extracted with methylene chloride (3×500 mL), the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to yield a dark oil. The oil was distilled (1 mm/100°-110° C.) to afford 349.1 g (82.4%) of 2-(1,3-dioxolan-2-yl)pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl 5-hydroxyisophthalate (1 eq.) in DMF (0.5 M) at 0° C. was added portionwise NaH (1.2 eq.) and stirred for 30 min at 0° C. Benzyl bromide (1.2 eq.) was added and the reaction was stirred at rt for 1.5 h. The reaction was then quenched with water ( 1/7 volume), and the resulting precipitate was filtered and washed with hexane. The filtrate was diluted with ether and washed several times with water and brine. The organic extract was dried over MgSO4 and concentrated in vacuo to give a solid which was combined with the filtered precipitate to give dimethyl 5-(benzyloxy)isophthalate. This compound was subsequently dissolved in THF/MeOH (2:1, 0.5 M), and to this solution was added KOH powder. After stirring for 18 h at rt, the reaction was poured into a solution of ether/water. The two layers were separated and the ethereal layer was discarded. The aqueous layer was acidified to pH <1 with 3 N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](N1C=CN=C1)([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)=[S:8]>C(#N)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:7]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)=[S:8]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccs1
Solvent: CC#N
Product: S=C(Nc1nccs1)n1ccnc1
Yield: 89.1 %

Procedure:
35 g (349.5 mmol) of 2-aminothiazole and 62.3 g (349.5 mmol) thiocarbonyldiimidazole were stirred in 1300 ml acetonitrile for a total of four days at room temperature. Filtration of the precipitate formed and drying yielded 65.5 g of light yellow solid.