Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=2[CH3:27])=[N:14]1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])=[N:14]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Yield: 45 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-bromo-1,3-thiazole-4-carboxylic acid (0.909 g, 4.37 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (1 g, 3.64 mmol). The product was purified by Flash-chromatography. Yield 45.0%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.61 (s, 3H), 4.29 (dd, 1H), 4.45 (dd, 1H), 4.60 (m, 1H), 6.46 (d, 1H), 7.51 (d, 1H), 7.57 (dd, 1H), 7.61 (dd, 1H), 7.98 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:17](=[C:19]([C:23]([O-:25])=O)[CH:20]=[CH:21][CH:22]=3)[N:18]=2)[CH2:10][CH:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.Cl.[CH3:30][N:31]1[CH:36]2[CH2:37][CH2:38][CH2:39][CH:32]1[CH2:33][CH:34]([NH2:40])[CH2:35]2>>[CH3:26][CH:9]1[CH2:10][N:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:25])[NH:40][CH:34]4[CH2:33][CH:32]5[N:31]([CH3:30])[CH:36]([CH2:37][CH2:38][CH2:39]5)[CH2:35]4)[C:17]=3[N:18]=2)[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CC1CN(c2nc3c(C(=O)[O-])cccc3o2)CCN1C(=O)OC(C)(C)C
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Agent: [Li+]
Product: CC1CN(c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)CCN1C(=O)OC(C)(C)C

Procedure:
Following general procedure GP-C1, lithium 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate and 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine dihydrochloride were coupled to provide tert-butyl 2-methyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamoyl)benzoxazol-2-yl)piperazine-1-carboxylate. MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:7]1[CH:6]=[C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2[OH:14])[CH:4]=[CH:3][C:2]=1[Cl:1])([O-:18])=[O:17]
Reactant: Oc1cc(Cl)nnc1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(-c2nnc(Cl)cc2O)ccc1Cl
Temperature: 0 °C

Procedure:
3-(4'-Chlorophenyl)-4-hydroxy-6-chloropyridazine (12 g, 0.04978 mol) was introduced into cooled, highly-concentrated nitric acid in the course of 15 minutes at a temperature of 0°-5° C. The mixture was stirred for 30 more minutes at 0° C., and the reaction mixture was then stirred into ice-water. The resulting yellow solid product was isolated, washed with water and reprecipitated using NH4OH/HCl. After drying, 11 g, 0.0385 mol, of 3-(3'-nitro-4'-chlorophenyl)-4-hydroxy-6-chloropyridazine of m.p. 204°-209° C. were obtained, which corresponds to a crude yield of 77.25%. According to TLC analysis (SiO2 /10% ethanol/chloroform), the sample proves to be largely uniform. Recrystallized from ethanol, the compound melts at 208°-211° C.
Reaction SMILES: [CH3:1][O-].[Na+].C[O:5][C:6](=O)[CH:7]([CH:13]([CH3:15])C)[NH:8][S:9]([NH2:12])(=[O:11])=[O:10]>CO>[CH2:13]([CH:7]1[NH:8][S:9](=[O:11])(=[O:10])[NH:12][C:6]1=[O:5])[CH2:15][CH3:1]
Reactant: C[O-]
Reactant: COC(=O)C(NS(N)(=O)=O)C(C)C
Agent: [Na+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Reaction time: 6 h
Yield: 184053 %

Procedure:
A solution of freshly prepared sodium methoxide (6.41 g, from 2.3 g of Na) in 100 ml of methanol was added to a solution of N-(aminosulfonyl)-DL-valine methyl ester (10.5 g; 0.05 mmol) in methanol (150 ml) and the resulting reaction mixture was stirred for 6 hours. The mixture was cooled, neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin, and filtered. The filtrate was concentrated in vacuo to yield a solid residue which was crystallized from methanol/hexane to afford 16.4 g of a crude 4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H R2 =isopropyl, R3 =H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]2[CH2:20][CH2:19][O:18]2)[C:12]2[C:7]1=[N:8][C:9]([C:21]1[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[N:22]=1)=[N:10][CH:11]=2.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:9]2[N:8]=[C:7]3[C:12]([N:13]([CH2:16][CH:17]4[CH2:20][CH2:19][O:18]4)[C:14](=[O:15])[NH:6]3)=[CH:11][N:10]=2)=[N:22]1
Reactant: COc1ccc(Cn2c(=O)n(CC3CCO3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC1CCO1
Yield: 48.9 %

Procedure:
476 mg (0.82 mmol) of the compound from example 86A were dissolved in 15 ml of trifluoroacetic acid, 953 mg (8.20 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 173 mg of the title compound were obtained (49% of theory).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C:7]2[C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[N:11]([CH2:22][CH3:23])[C:10](=[O:24])[CH2:9][N:8]=2)=[CH:3][CH:2]=1>[Pd].CO.C(Cl)Cl>[CH2:22]([N:11]1[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH2:13][CH2:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:6][CH:5]=2)=[N:8][CH2:9][C:10]1=[O:24])[CH3:23]
Reactant: CCN1C(=O)CN=C(c2ccc(-c3ccccc3)cc2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCN1C(=O)CN=C(c2ccc(CCc3ccccc3)cc2)c2cc(OC)c(OC)cc21
Yield: 65.4 %

Procedure:
Leave the following under hydrogen pressure (Patm) for 48 hours: 80 mg of 5-(1,1′-biphenyl-4-yl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbp), 16 mg of 10% palladium on charcoal (20% by weight of product to reduce), in 30 ml of methanol and 1 ml of CH2Cl2. Filter on celite, rinse several times with methanol. Evaporate to dryness. Purify by silica chromatography (AcOEt 1/hexane 1). Recrystallize in ether. One obtains 28 mg of the abovenamed product in the form of a white powder. Yield: 35%. M: 148–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.27 (t, 3H, —CH3), 3.00 (s, 4H, 2×—CH2). 3,37–3,40 (m, 2H, CH2), 3.45–3.65 (m, 4H, —OCH3+1H NCH2), 3.92 (s, 3H, OCH3), 4.21–4.48 (m, 1H, NCH2), 6.22 (d, 1H Ar), 6.77 (d, 1H Ar), 7.19–7.39 (m, 9H Ar).
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[OH-].[NH4+:19]>>[Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:19])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Yield: 99 %

Procedure:
4-(2-Bromo-tetrafluoroethoxy)benzoic acid prepared as in Example 1 (26.6 g, 0.083 mol) is transferred to a 250 mL round-bottomed flask along with 150 mL of methylene chloride. Oxalyl chloride (11.64 g, 0.92 mol) is added and the mixture is stirred under nitrogen overnight to form a turbid solution which is concentrated by rotary evaporation and distilled at 80°-90° C./0.1 mmHg to yield 20.88 g of 4-(2-bromotetrafluoroethoxy)benzoyl chloride as a colorless liquid, leaving 6.16 g of unreacted acid (76.8% conversion, 96.5% yield). The benzoyl chloride is added slowly with stirring to 8 mL of cold ammonium hydroxide (0.12 mol). The product amide precipitates as fine white needles which are filtered and dried under vacuum to yield 14.74 g of 4-(2-bromotetrafluoroethoxy)benzamide (75% conversion, 99% yield, m.p. 150.5°-151.5° C.), along with 4.8 g of 4-(2-bromo-tetrafluoroethoxy)benzoic acid which is recovered from the mother liquor (24.3% recovery).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:18]([CH3:25])([CH3:26])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCNC1
Yield: 84.4 %

Procedure:
A mixture of 1-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (690 mg, 1.83 mmol), ammonium formate (461 mg, 7.31 mmol), 10% Pd/C (100 mg) in methanol (10 ml) and water (1 ml) was refluxed overnight. The mixture was filtered through celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with brine and dried over MgSO4. Evaporation of solvent provided the title compound as oil (444 mg, 84%).
Reaction SMILES: [CH:1]([C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture of 3-formyl-2-methyl-7-nitrobenzo[b]furan (1.83 g) and sodium borohydride (200 mg) in methanol (40 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water. The separated oil was extracted with dichloromethane. The extract was washed with brine, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 3-hydroxymethyl-2-methyl-7-nitrobenzo[b]furan (1.38 g) as a solid.
Reaction SMILES: Cl.[CH:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH:6]12[O:9][CH:2]([CH2:8][CH2:7]1)[CH2:3][N:4]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)[N:14]=1)[CH2:5]2
Reactant: O=C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To an aqueous solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (66 mL) was added 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one (2.7 g, 11 mmol) as a suspension in acetone (40 mL). To the mixture was added solid sodium carbonate (2.5 g, 24 mmol). The suspension was stirred at 80° C. for two hours and then allowed to cool to room temperature. The title compound was collected by filtration, washed with water, and dried under vacuum; MS (ES+) 324.4 (M+H)+
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]([CH3:26])[C:17]([C:19]1[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].O>CN(C)C=O>[CH3:15][N:16]([CH3:26])[C:17]([C:19]1[C:20]([S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: SCc1ccccc1
Reactant: CN(C)C(=O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
A solution of 25.0 g (223 mmol) of potassium t-butoxide in 100 ml of dimethylformamide was cooled to 0° C. and 22 ml (186 mmol) of benzyl mercaptan added dropwise at 0° C. After addition was complete, the reaction mixture was allowed to warm to 25° C. and stirred at this temperature for 15 minutes. The reaction mixture was then re-cooled to O° C. and 34.0 g (186 mmol) of N,N-dimethyl-2-(chloro)-3-pyridinecarboxamide added in one portion. After an exotherm to 50° C., the mixture was heated at 80° C. for 1.5 hour. The mixture was cooled, poured into 100 ml of water and extracted with ether. The combined organic extracts were washed twice with water, then brine and dried over sodium sulfate. Concentration gave 19.2 g of a viscous yellow oil. IR (Nujol) 1640 (CONMe2) cm-1.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][C:9]1[N:14]=[C:13]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OCc1cccc(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
A solution of acetic acid 6-tert-butoxycarbonylamino-pyridin-2-ylmethyl ester (0.85 g, 3.18 mmol) in dichloromethane (30.00 ml) was cooled to 0° C. and trifluoroacetic acid (2.40 ml) was added dropwise. After stirring at room temperature for 3 h, further trifluoroacetic acid (1.50 ml) was added and stirring was maintained for further 2 h. The reaction mixture was basified with 1 N sodium bicarbonate (54.00 ml) to a pH 8. The organic phase was separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated to yield pure acetic acid 6-amino-pyridin-2-ylmethyl ester (0.54 g, 100%) as a white solid, MS (ISP): m/e=167.4 (M+H+).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH2:52][C:53]([O:55]C(C)(C)C)=[O:54])/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH2:52][C:53]([OH:55])=[O:54])/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnnn4N)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 37.5 %

Procedure:
A solution of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (4.80 g, 5.6 mmol) in trifluoroacetic acid (48 ml) was stirred at room temperature for 40 minutes. Trifluoroacetic acid was removed by evaporation and the residue was washed with ether. To the residue was added 80% formic acid (10 ml) and the mixture was stirred at room temperature for 40 minutes. Then the mixture was treated in a manner similar to that described in Example 6, (d) to give pale brown powder of crude 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.17 g).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH:7]([OH:10])[CH2:8][OH:9]
Reactant: OCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: OCC(O)C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
Dihydropyran (18.25 mL, 200 mmol) was added dropwise to a cold (0° ) mixture of ethylene glycol (55.92 mL, 1 mol) in 500 mL CH2Cl2 containing 3.8 g (20 mmol) of dissolved p-toluene sulfonic acid monohydrate over 2 hrs. The mixture was allowed to stir for an additional 2 hrs at this temperature, and then was allowed to warm to rt. Stirring continued for 2 days, after which the mixture was poured into a separating funnel and allowed to separate. The lower organic layer was removed and saved, and the upper layer was extracted with 100 mL CH2Cl2. The combined CH2Cl2 layers were washed six times with 100 mL portions of sat'd NaCl, and dried over Na2SO4. The solution was filtered and reduced, and the residue was purified by chromatography with the same silica as above. The column was eluted isocratically with 3:2 EtOAc:hexane which contained 1% triethylamine (TEA). Fractions which contained pure product, rf 0.5 (using the same TLC system as above) were pooled and evaporated to give 9.7 g (33% yield) of a colorless oil. 1H NMR (300 mHz, CDCl3, PPM) 5.6-5.5, m, 1H. 4.0-3.9, m, 1H. 4.8-4.65, m, 4H. 3.6-3.5, m, 1H. 1.9-1.7, m, 2H. 1.65-1.5, m, 4H.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.[Cl-].[NH4+].Cl>O1CCCC1.C(OC)(C)(C)C.O>[CH2:6]([O:8][CH2:9][N:10]1[C:14]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:13][CH:12]=[N:11]1)[CH3:7]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCOCn1cccn1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCOCn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Butyl lithium (2.5 M in hexanes, 32.4 mL, 0.0811 mol) was added slowly via syringe to a solution of 1-(ethoxymethyl)-1H-pyrazole (Preparation 338, 9.3 g, 0.074 mol) in anhydrous tetrahydrofuran (100.0 mL) at 0° C. and stirred under nitrogen for 15 minutes and then at room temperature for 30 minutes. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.5 mL, 0.0811 mol) was added via syringe. The mixture was warmed to room temperature and stirred under nitrogen for 60 hours. Saturated aqueous ammonium chloride solution (50.0 mL) was added followed by water (150.0 mL). The mixture was poured into tert-butylmethylether (200.0 mL) and the biphasic mixture stirred vigorously for 30 minutes. The aqueous layer was acidified to pH 6 with hydrochloric acid (6.0 M aqueous solution) and extracted with tert-butylmethylether (3×200.0 mL). The combined organics were washed with saturated aqueous sodium chloride solution (100.0 mL) and then stirred with activated charcoal (1 g) for 30 minutes. Magnesium sulphate was added and the mixture filtered through a pad of Celite™, washing with tert-butylmethylether (1 L). Concentration in vacuo afforded the title compound as a brown oil, 14.5 g, 78% yield.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([NH2:6])=[O:5])C.[Cl:10]O>C(OCC)(=O)C>[Cl:10][NH:6][C:4](=[O:5])[CH:3]([CH3:1])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(CC)C(N)=O
Reactant: OCl
Solvent: CCOC(C)=O
Product: CCCC(C)C(=O)NCl
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A stirred suspension of 2-ethyl valeramide (33.0 g, 286 mmol) in 220 ml of ethyl acetate was cooled to 0° and hypochlorous acid (55.25 g of 27.67% solution, 291 mmol) was added over 15 minutes. The cooling bath was removed and stirring continued for 1/2 hour. The organic phase was collected and dried (MgSO4) and the solvent was removed on a rotary evaporator to yield 32.8 g of N-chloro-2-methyl valeramide as a clear yellow liquid.
Reaction SMILES: [C:1]([CH:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH:4]=O)#[N:2].Cl.[NH2:20][CH:21](C(OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(=O)C.[Na+].[O-]CC.[Na+]>CO.O>[NH2:2][C:1]1[C:3]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[CH:4][NH:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(C#N)C=O)CC1
Agent: CC(=O)[O-]
Agent: CC[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOC(=O)c1[nH]cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
The tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (757 mg, 3.0 mmol) obtained in Step 4 of Example 1 was dissolved in methanol (6 mL) and water (2 mL), diethyl aminomalonate hydrochloride (952 mg, 4.5 mmol) and sodium acetate (492 mg, 6.0 mmol) were added, followed by stirring at room temperature for 18 hours. The reaction liquid was concentrated under a reduced pressure and dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (1.53 g) was dissolved in ethanol (6 mL), and then sodium ethoxide (510 mg, 7.5 mmol) was added, followed by heating under reflux for 3 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=100:1→50:1) to give tert-butyl 4-[4-amino-5-(ethoxycarbonyl)-1H-pyrrol-3-yl]piperidine-1-carboxylate (466 mg, 46.0%) as a pale yellow amorphous.
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:35][C:36]1[CH:37]=[C:38]([CH2:42][CH2:43][C:44](O)=[O:45])[CH:39]=[CH:40][CH:41]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:13][C:44](=[O:45])[CH2:43][CH2:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([I:35])[CH:37]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CCc1cccc(I)c1
Reactant: CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)OCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)CCc1cccc(I)c1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
1-Octanoyl-3-O-trityl-rac-glycerol (414 mg, 0.90 mmol), 3-(m-iodophenyl)propanoic acid (250 mg, 0.91 mmol) and DMAP were dissolved in CH2Cl2 (8.3 ml). DCC (206 mg, 1.00 mmol) was added and the mixture was stirred overnight. The mixture was then diluted with CH2Cl2. The organic and aqueous phases were separated and washed twice with 1 N HCl, once with saturated NaHCO3, once with H2O, and once with brine. The organic layer was then dried over MgSO4 and evaporated. Purification by chromatography on 12 g silica gel and with a hexanes:ethyl acetate (8:1) solvent yielded pure compound 44, 1-octanoyl-2-[3-(m-iodophenyl)propanoyl]-3-O-trityl-rac-glycerol (473.5 mg. 73% Yield).