Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:59][O:60][CH3:61])[C:11]([NH:13][CH:14]2[C:57](=[O:58])[N:16]3[C:17]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:18]([CH2:21][P+:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=[O:3].[OH-].[Na+].C(OCC)C>CC(C)=O.O>[CH:2]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:59][O:60][CH3:61])[C:11]([NH:13][CH:14]2[C:57](=[O:58])[N:16]3[C:17]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])=[C:18]([CH:21]=[P:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=[O:3]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Yield: 72.4 %

Procedure:
[7-{2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido}-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyltriphenylphosphonium chloride (syn isomer)(5.33 g) was dissolved in a mixture of acetone (60 ml) and water (10 ml), and the solution was adjusted to pH 11 with 2 N aqueous solution of sodium hydroxide, followed by extraction three times with ethyl acetate (100 ml). The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was pulverized with diethyl ether to obtain benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (syn isomer)(3.7 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:5]=12.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:13](=[O:14])C1.Cl.[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([O:35][C:36]2[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=2)[CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([NH:10][C:13]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:38]4[CH:46]=[CH:47][CH:48]=[C:36]([O:35][C:34]5[CH:49]=[CH:50][C:31]([Cl:30])=[CH:32][CH:33]=5)[CH:37]=4)[CH2:41][CH2:42]3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Clc1ccc(Oc2cccc(CN3CCNCC3)c2)cc1
Reactant: Nc1cccc2nccn12
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2nccn12)N1CCN(Cc2cccc(Oc3ccc(Cl)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.4 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-5-ylamine (56.0 mg, 0.421 mmol) in CH2Cl2 (2.0 mL) were added N,N′-disuccinimidyl carbonate (108 mg, 0.421 mmol) and DMAP (51.0 mg, 0.417 mmol). The reaction mixture was stirred at rt for 6 h, then treated with 1-[3-(4-chloro-phenoxy)-benzyl]-piperazine hydrochloride (158 mg, 0.420 mmol) and diisopropylethylamine (109 mg, 0.840 mmol) and stirred for an additional 16 h at rt. The reaction mixture was diluted with EtOAc and extracted with H2O then saturated aqueous NaCl. The organic layer was dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give 4-[3-(4-chloro-phenoxy)-benzyl]-piperazine-1-carboxylic acid imidazo[1,2-a]pyridin-5-ylamide (90.0 mg, 46%). MS (ESI+): calcd for C26H24ClN6O2 m/z 461.17, found 462.2 (M+H)+. 1H NMR (d6-DMSO): 9.21 (br s, 1H), 7.57 (s, 1H), 7.54 (d, J=1.2, 1H), 7.47-7.35 (m, 4H), 7.23 (dd, J=9.0, 7.2, 1H), 7.15 (d, J=7.6, 1H), 7.06-7.01 (m, 3H), 6.94 (dd, J=8.1, 1.9, 1H), 6.73 (d, J=7.1, 1H), 3.54 (s, 2H), 3.52-3.45 (m, 4H), 2.46-2.40 (m, 4H).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH2:14]([OH:16])C>>[CH:14](=[O:16])[C:6]1[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:11].[OH:11][C:5]1[CH:10]=[CH:9][C:8]([CH:14]=[O:16])=[CH:7][CH:6]=1
Reactant: CCO
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)cc1
Product: O=Cc1ccccc1O

Procedure:
Sen et al J. Indian Chem. Soc. 9 173 (1932) state that the use of chloroform in an ethyl alcohol solution in the Reimer-Tiemann reaction increases the yield of aldehyde. However, the only example describing the reaction of phenol with chloroform and sodium hydroxide in aqueous ethyl alcohol shows a combined yield for salicylaldehyde and p-hydroxybenzaldehyde of only 33%, based on the phenol reacted. The proportion of salicylaldehyde to p-hydroxybenzaldehyde in the product is about five to one, the same as for the conventional aqueous reaction.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16]1[C:17]([N:28](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:21]=1.C(N(CC)CC)C.Cl.O1CCOCC1>ClCCl>[S:7]1[C:8]([C:16]2[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:24][CH2:23]3)[N:21]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc4ccccc4s3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
Ethanesulfonyl chloride (25.43 mg, 18.74 μL, 0.1978 mmol) was added to a solution of tert-butyl N-[3-(benzothiophen-2-yl)-5-piperazin-1-yl-pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (92 mg, 0.1798 mmol) and triethylamine (36.39 mg, 50.12 μL, 0.3596 mmol) in dichloromethane (3.965 mL) at 0° C. and the resulting solution stirred at room temperature for 1.5 hours. The reaction was then treated with HCl in dioxane (224.8 μL of 4 M, 0.8990 mmol) and allowed to stir at ambient temperature overnight. The mixture was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (14.4 mg, 20% Yield). 1H NMR (DMSO) d 1.24 (3H, t), 2.51 (2H, q), 3.30 masked signal, 3.52 (4H, m), 5.91 (2H, br s), 7.36-7.40 (2H, m), 7.84-7.86 (1H, m), 7.92 (1H, s), 7.95 (1H, m), 8.06 (1H, s) ppm; MS (ES+) 404.02
Reaction SMILES: C(O[C@@H](C1C(C)=C([F:23])C2C(=CC=C(Cl)C=2)C=1O)C(OCC)=O)(C)(C)C.[C:26]([O:30][C@@H:31]([C:37]1[C:46]([CH3:47])=[CH:45][C:44]2[C:39](=[CH:40][C:41]([F:49])=[CH:42][C:43]=2[F:48])[C:38]=1[O:50]S(C(F)(F)F)(=O)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C@@H:31]([C:37]1[C:46]([CH3:47])=[C:45]([F:23])[C:44]2[C:39](=[CH:40][C:41]([F:49])=[CH:42][C:43]=2[F:48])[C:38]=1[OH:50])[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:27])([CH3:29])[CH3:28]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(F)cc(F)cc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(Cl)ccc2c1O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2c(F)cc(F)cc2c1O

Procedure:
(S)-ethyl 2-tert-butoxy-2-(4,5,7-trifluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-(6-chloro-4-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate in Example 7 except (S)-ethyl 2-tert-butoxy-2-(5,7-difluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:22]([NH:30][C:31]1[CH:43]=[C:42]([CH:44]=[CH2:45])[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:22]([NH:30][C:31]1[CH:43]=[C:42](/[CH:44]=[CH:45]/[C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:41]=[CH:40][C:32]=1[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: Oc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(O)cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
0.12 g of 4-iodophenol, 0.18 mL of tributylamine and 4.2 mg of palladium acetate were added do 2.4 mL of N,N-dimethylacetamide solution containing 0.12 g of tert-butyl 2-(benzamido)-4-vinylbenzoate sequentially at room temperature and stirred under nitrogen atmosphere at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 0.10 g of tert-butyl 2-(benzamido)-4-((E)-2-(4-hydroxyphenyl)vinyl)benzoate as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+]([O-])=O.[N+:25](C1C=CC=CC=1O)([O-])=O.[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]>C1(C)C=CC=CC=1>[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:25][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:47])=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COc1cc2nccc(Oc3ccccc3[N+](=O)[O-])c2cc1OC
Reactant: CCCCc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 50 %

Procedure:
6,7-Dimethoxy-4-(2-aminophenoxy)quinoline (56 mg), which was obtained, analogously to Example 49, by reducing 6,7-dimethoxy-4-(2-nitrophenoxy)quinoline obtained in the same manner as described in Example 48, except that 2-nitrophenol was used in place of 4-nitrophenol, was dissolved in toluene (3 ml) with heat, 4-n-butylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 30 minutes. The resulting residue was purified by chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 45 mg of the title compound (yield: 50%).
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[N:10]=[C:11]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]2[N:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[N:25]=1.[OH2:32]>C1COCC1>[CH3:2][CH:3]([CH3:7])[CH2:4][CH2:5][O:6][C:9]1[N:10]=[C:11]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]2[N:17]=[C:16]([O:32][CH2:5][CH2:4][CH:3]([CH3:7])[CH3:2])[N:15]=[C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[N:25]=1
Reactant: O
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: CC(C)CCO
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)CCOc1nc(N2CCCCC2)c2nc(OCCC(C)C)nc(N3CCCCC3)c2n1
Temperature: 25 °C
Yield: 63 %

Procedure:
Sodium metal (0.115 g, 5 mmol) was added to 3-methylbutan-1-ol (0.44 g, 5 mmol) in dry THF (5 ml) and stirred until all had dissolved. 2,6-dichloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) dissolved in dry THF (10 ml) was added to the alkoxide and the mixture heated under reflux for 72 hours. After cooling to room temperature, water (20 ml) was added and the product extracted into ethyl acetate (4×20 ml). The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo. Recrystallisation from methanol/water yielded the title compound as a yellow crystalline solid (0.148 g, 63%), m.p. 105-106° C. Found: C, 66.73; H, 8.80; N, 17.48. C26H42N6O2 requires C, 66.35; H, 8.99; N, 17.86%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#N.Br[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].Cl.C([O:18]CC)C>[Cl-].[NH4+]>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:18])[CH:4]=1
Reactant: CC(C)CCBr
Reactant: CCOCC
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)CCC(=O)c1cccnc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A solution of 3-cyanopyridine (26.0 g, 0.25 mole) in dry diethyl ether (200 ml) was added dropwise over the hour to the Grignard reagent prepared from 1-bromo-3-methyl butane (40.7 g, 0.27 mole) and magensium (6.8 g, 0.26 mole) in dry diethyl ether (50 ml) under nitrogen. The mixture was heated at 35°C. for eight hours, cooled to room temperature, and diluted with cold saturated aqueous ammonium chloride solution (200 ml) followed by concentrated hydrochloric acid (50 ml). The mixture was stirred for five hours, the ether layer separated, and the aqeuous layer boiled for two hours. The aqueous layer was neutralised to pH9 with aqueous sodium hydroxide solution and extracted with diethyl ether (3×100 ml. The organic phase was dried (magnesium sulphate), concentrated under reduced pressure and distilled to give 3-methylbutyl 3-pyridyl ketone.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[C:20]([O:23][C:24](C)([CH3:28])[C:25](=[O:27])[CH3:26])(=[O:22])[CH3:21].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:20]([O:23][CH:24]([CH3:28])[C:25](=[O:27])[CH2:26][CH:1]([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:22])[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)OC(C)(C)C(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CC(=O)C(C)OC(C)=O)OCC
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
A 3 l round-bottomed flask fitted with a mechanical stirrer under an atmosphere of N2 was charged with triethyl orthoformate (304 ml, 1.83 mol) and CH2Cl2 (1.30 l). The solution was cooled to −65° C. and BF3.Et2O (255 ml, 2.01 mol) was added over 30 min to provide a yellow solution. After an additional 15 min, the cold bath was removed and the flask contents were allowed to warm to 0° C. After ageing at 0° C. for 45 min, the mixture was cooled to −60° C. to provide a thin white slurry. A solution of 3-acetoxy-3-methyl-2-butanone (131.55 g, 0.912 mol) and CH2Cl2 (100 ml) was added over 17 min. After a 40 min age at −65° C., diisopropylethylamine (404 ml, 2.32 mol) was added over 30 min maintaining an internal temperature below −63° C. After an additional 45 min at −65° C., the mixture was warmed to room temperature over 45 min and aged at that temperature for 5 h. The reaction mixture was poured onto saturated aqueous NaHCO3 (800 ml) and stirred for 15 min. The layers were partitioned and the organic phase was washed with 1M H2SO4 at 5° C. (2×800 ml), water at 5° C. (2×800 ml) and then dried over Na2SO4. The solvent was removed under diminished pressure to provide 4-acetoxy-1,1-diethoxy-4-methyl-3-butanone as an oil (270 g, 57 wt % pure) which was used without further purification in the subsequent steps. An analytical sample was prepared by HPLC on a Zorbax C-8 preparative column with gradient elution from 30% acetonitrile, 70% 0.1% H3PO4/H2O to 70% acetonitrile, 30% 0.1% H3PO4/H2O over 20 min: 1H NMR (CDCl3, 400 MHz) δ 4.95 (1H, t, J 5.6), 3.69 (2H, m), 3.53 (2H, m), 2.79 (2H, d, J 5.6), 2.07 (3H, s), 1.47 (6H, s), 1.18 (6H, t, J 6.8); 13C NMR (CDCl3, 100.61 MHz) δ 205.7, 170.4, 100.8, 83.7, 63.2, 41.4, 22.9, 21.1, 15.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(Cl)cc2)ns1
Temperature: 80 °C

Procedure:
To a solution of 4-chlorobenzamide (0.25 g, 1.60 mmol) in toluene (10 ml) was added chlorocarbonylsulfenyl chloride (0.70 ml, 8.03 mmol). The resulting reaction mixture was refluxed at 80° C. for 3 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed twice with water, twice with 5% NaHCO3, again with water, and was dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.520 g) that was carried forward to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[C:31]1([CH:37]([NH2:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:39][CH:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:38])=[O:29]
Reactant: O=C(Br)CBr
Reactant: CC(N)c1ccccc1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC(C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-phenylethylamine
Reaction SMILES: [I:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CO.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Fe]>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[C:2]([I:1])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(N)cc1I
Temperature: 50 °C
Yield: 90.6 %

Procedure:
Into the reaction was added tert-butyl (2-iodo-4-nitrobenzyl)methylcarbamate (4.90 g, 12.5 mmol), methanol (85 mL), acetic acid (14.2 mL) and iron (4.19 g, 75.0 mmol) powder. The reaction solution was heated at 50° C. for 1.5 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and a saturated sodium carbonate solution. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (4.10 g, 91%). LCMS calculated for C13H191N2O2Na (M+H)+: m/z=385.1.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([CH2:21][C:22]([OH:24])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[NH:48]1)=[O:46].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[N:48]1[C:22](=[O:24])[CH2:21][N:13]1[C:14]2=[CH:15][N:16]=[C:17]([CH3:20])[CH:18]=[C:19]2[C:11]([C:8]([NH2:9])=[O:10])=[N:12]1)=[O:46]
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(C(N)=O)nn(CC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)Nc3cccc(OC(F)(F)F)c3F)c2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)acetic acid trifluoroacetate salt (3.87 g, 11.1 mmol; prepared as described in Scheme A27) in DMF (45 mL) were successively added (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoro methoxy-phenyl)-amide trifluoroacetate salt (5.00 g, 11.1 mmol), DIPEA (7.77 mL, 44.5 mmol) and HBTU (5.06 g, 13.3 mmol). The reaction mixture was stirred at 25° C. for 2 h and was then concentrated in vacuo. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 5% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined and volatiles were evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 8 to 9 by addition of an aqueous saturated solution of NaHCO3, and then was extracted with CH2Cl2 (×3). The combined organic extracts were dried (phase separator) and concentrated under vacuum to afford the title compound as a white solid. MS: 521 [M+H]+; tR (HPLC conditions c): 3.81 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 1-(4-nitro-phenyl)-cyclopentanecarboxylic acid (8.85 g) in dry dichloromethane (100 mL) was treated with oxalyl chloride (5.0 mL) and catalytic amount dry dimethylformamide (5 drops). The mixture was stirred at room temperature, under anhydrous conditions, for 16 hours then evaporated to give the title compound as an off white solid (100%), which was used without further purification.
Reaction SMILES: [CH2:1]([CH:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:5])[CH:2]=[CH2:3].[H][H]>C(O)C.[Pt]>[CH2:1]([CH:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:5])[CH2:2][CH3:3]
Reactant: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CCCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
30 g (0.135 mol) of 1-allyl sorbitol syrup (produced as in example 1) was dissolved in 300 ml ethanol. 1.0 g of platinum (5% weight on activated carbon) was added and the mixture was hydrogenated at room temperature with hydrogen pressure at 60 psi. The reaction was stopped until no hydrogen pressure drop was observed. The solid was filtered. The allyl group of the solution was completely converted to propyl group based on NMR.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4](=[O:10])([O:6][CH2:7][CH2:8][OH:9])[NH2:5].C(=O)([O-])[O-].[K+].[K+]>>[C:4](=[O:10])([O:6][CH2:7][CH2:8][OH:9])[NH2:5].[OH:3][CH2:2][CH2:1][N:5]1[CH2:8][CH2:7][O:6][C:4]1=[O:10].[O:6]1[CH2:7][CH2:8][NH:5][C:4]1=[O:10]
Reactant: C1CO1
Agent: NC(=O)OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCO1
Product: O=C1OCCN1CCO

Procedure:
In a pressure reactor 26 g of ethylene oxide (0.59 mole) and 60 g of 2-hydroxyethyl carbamate (0.57 mole) are contacted in the presence of 1 g of potassium carbonate (0.0072 mole) at 110° C. for two hours. This resulted in an 85.3 percent conversion of 2-hydroxyethyl carbamate to products, with a selectivity to N-hydroxyethyl-2-oxazolidinone of 9.7 percent and to 2-oxazolidinone of 84.4 percent.