Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([OH:16])=[C:11]([NH2:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].Cl[C:21](=[N+:23]([CH3:25])[CH3:24])Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]2[O:16][C:21]([N:23]([CH3:25])[CH3:24])=[N:17][C:11]=2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)c(O)c(Br)c1
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)c1nc2cc(CNC(=O)OC(C)(C)C)cc(Br)c2o1

Procedure:
A mixture of tert-butylN—(3-amino-5-bromo-4-hydroxybenzyl)carbamate (300 mg, 0.95 mmol) and dichloromethylenedimethylammonium chloride (phosgene iminium chloride, 240 mg, 1.48 mmol) in 10 mL of dry CH2Cl2 was refluxed for 6 h. After cooling the solution was extracted with EtOAc, washed with NaHCO3, brine and dried (MgSO4). After purification by column chromatography (1% MeOH in CH2Cl2) 192 mg (55%) of tert-butylN-{[7-bromo-2-(dimethylamino)-1,3-benzoxazol-5-yl]methyl}carbamate were obtained. 1H NMR (CDCl3) δ 7.14 (s, 1H, H-6); 7.04 (s, 1H, H-4); 5.11 (bs, 1H, NH); 4.31 (d, 2H, J=5.6 Hz, CH2); 3.23, 3.22 (s, 6H, NCH3 2×); 1.48 (s, 9H, (CH3)3C); 13C NMR (CDCl3) δ 163.3 (C-2), 156.2 (CO), 146.6 (C-7a), 145.1 (C-3a), 137.0 (C-5), 122.8 (C-6), 114.3 (C-4), 100.6 (C-7), 79.9 ((CH3)3C), 44.7 (CH2), 38.1 (NCH3×2), 28.8 ((CH3)3C).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si](C)(C)N[Si](C)(C)C.[Na].[S:19]1[C:23]2[C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[O:26][CH2:27][CH2:28][C:22]=2[CH:21]=[C:20]1[C:33](Cl)=[O:34]>C1COCC1>[Cl:8][C:7]1[C:2]([N:1]([CH3:9])[C:33]([C:20]2[S:19][C:23]3[C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[O:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)=[O:34])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Agent: [Na]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ncccc1Cl
Temperature: 0 °C

Procedure:
An ice water cooled solution of 2-amino-3-chloropyridine (0.200 g, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was reacted with a THF solution of 1 M sodium hexamethyldisilazane to give a clear solution. This reaction mix was stirred at cooled temperature for 30 minutes. Next, 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride (0.100 g, 0.378 mmol) was added portionwise as a solid. Reaction mix was stirred at room temperature with monitor for formation of desired product and concentrated in vacuo to a solid residue. This residue was taken into ethyl acetate and the organic was washed with water, then saline and dried (Na2SO4). The crude material was purified by MPLC on silica, eluting with 10% to 80% ethyl acetate/hexanes to give 128 mg N-(3-chloropyridin-2-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide, 34% of theoretical yield.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:7][C:6]([CH2:8][NH2:9])=[CH:5][CH:4]=1.C1N=CN([C:17]([N:19]2C=N[CH:21]=[CH:20]2)=[O:18])C=1.NC1C2[O:31][CH2:32][C:33](=[O:35])[NH:34][C:29]=2[CH:28]=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[O:35]=[C:33]1[NH:34][C:29]2[CH:28]=[CH:27][CH:26]=[C:20]([NH:19][C:17]([NH:9][CH2:8][C:6]3[O:7][C:3]([C:2]([F:10])([F:1])[F:11])=[CH:4][CH:5]=3)=[O:18])[C:21]=2[O:31][CH2:32]1
Reactant: NCc1ccc(C(F)(F)F)o1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)o2)N1
Temperature: 70 °C
Yield: 10 %

Procedure:
To a solution of [5-(trifluoromethyl)-2-furyl]methanamine (0.48 g, 2.91 mmol) in THF (20 mL) was added CDI (2.1 mol eq, 0.99 g) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×25 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (yellow oil, 1.68 g, quantitative yield). The oil obtained was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.57 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by crystallization from a mixture of MeOH/EtOAc to afford the product as a pale yellow solid (0.088 g, 10% Yield). 1HNMR (DMSO, 400 MHz) δ 4.37 (d, 2H, J=6), 4.60 (s, 2H), 6.46 (m, 2H), 6.77 (t, 1H, J=8), 7.16 (m, 1H), 7.37 (t, 1H), 7.72 (dd, 1H, J=2), 8.16 (s, 1H), 10.64 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[N:48]=[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:47])[C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:44])[CH3:43])[CH:37]=4)[CH:30]=[CH:31][C:32]=3[CH3:33])=[CH:25][N:20]2[N:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:45]([C:42]([C:38]1[CH:37]=[C:36]([C:35]([NH:34][C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([CH:28]=2)[O:26][C:24]2[CH:23]=[CH:22][C:21]3[N:20]([N:19]=[C:18]([NH:17][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:10])[N:48]=3)[CH:25]=2)=[O:47])[CH:41]=[CH:40][CH:39]=1)([CH3:44])[CH3:43])#[N:46]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C)cn3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 6-methylpyridine-3-carboxylic acid (252 mg, 1.84 mmol) in tetrahydrofuran (6 mL) were added oxalyl chloride (200 μL, 2.30 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (196 mg, 0.460 mmol) were dissolved in pyridine (7 mL), and the mixture was stirred at room temperature for 7 days. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→99.5/0.5), and fractions containing the desired product were concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (124 mg, 49%) as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([NH:17][C:18]([C:20]1([Br:27])[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][NH:21]1)=[O:19])([CH3:16])[CH3:15].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>C1COCC1>[CH3:16][C:14]([NH:17][C:18]([C:20]1([Br:27])[C:25]([CH2:26][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Cl:28])[CH:30]=2)=[CH:24][CH:23]=[CH:22][NH:21]1)=[O:19])([CH3:13])[CH3:15]
Reactant: Clc1cccc(CBr)c1
Reactant: CC1=CC=CNC1(Br)C(=O)NC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NC(=O)C1(Br)NC=CC=C1CCc1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Cool diisopropylamine dissolved in THF (60 mL) to 0°-5° C. Add n-butyl lithium(39 mL, 97.99 mmol.) and stir the reaction at that temperature for 30 min. Canulate this reaction mixture to a cooled solution of N-(1,1-dimethylethyl)-2-bromo-3-methyl pyridine carboxamide (9.91 g, 97.99 mmol) in dry THF (250 mL) (-70° C.). Stir for 0.5 h then add 3-chlorobenzyl bromide(11.4 g, 55.31 mmol) dissolved in 50 mL of THF. Stir the reaction mixture for 0.5 h. Quench the reaction with water and extract the products twice with EtOAc. Dry the organic phase over Na2SO4, filter and chromatograph on silica gel column eluting with 3% MeOH solution in CH2Cl2 to give the title compound (15 g, Yield 60%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:22][CH3:23])=[N:10][CH:11]=[C:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:22][CH3:23])=[N:10][CH:11]=[C:12]([N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH3:26])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(NC(=O)OC(C)(C)C)cc1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(N(C)C(=O)OC(C)(C)C)cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
970 mg of 3-benzyl-5-tert-butoxycarbonylamino-2-methoxypyridine was dissolved in 10 ml of N,N-dimethylformamide, followed by. adding 200 mg of 60% oily sodium hydride thereto. After stirring at room temperature, 0.192 ml of methyl iodide was added thereto in an ice bath. After the returned to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 920 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][CH2:26][C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:8]([NH:10][CH:11]2[C:22](=[O:23])[N:13]3[C:14]([C:19]([O-:21])=[S:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:44]([O:50][CH2:51]I)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46].C(OCC)(=O)C.O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][CH2:26][C:27]([O:29][CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:28])[C:8]([NH:10][CH:11]2[C:22](=[O:23])[N:13]3[C:14]([C:19]([O:21][CH2:51][O:50][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[S:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC1=C(C([O-])=S)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C(=S)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (4.0 g) in dimethylformamide (40 ml) was added a solution of pivaloyloxymethyl iodide (1.5 g) in dimethylformamide (4.5 ml) at 0° C. and the mixture was stirred for 15 minutes at the same temperature. Ethyl acetate (150 ml) and water (100 ml) were added to the reaction mixture. The separated organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (3.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23].[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][O:19][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCO[Si](C)(C)C(C)(C)C)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.8 %

Procedure:
To a solution of 2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (9) (400 mg, 1.06 mmol) in THF (anhydrous, 30 mL) were added TBDMS-Cl (193 mg, 1.28 mmol) and Et3N (0.178 mL, 1.28 mmol). The solution was stirred at room temperature for 2 days. The solution was filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 2.5%-20% EtOAc/hexanes gradient, to afford 420 mg (81% yield) of the title compound. 1H NMR 400 MHz (CDCl3) δ 10.4 (s, 1H), 7.83 (s, 1H), 7.76-7.68 (m, 2H), 7.40-7.33 (m, 1H), 6.30 (br s, 1H), 3.62 (br s, 2H), 3.48 (s, 2H), 3.02 (s, 3H), 0.89 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2O.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[Cl:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccc(Br)cc2c(O)c1S(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: Cc1nc2ccc(Br)cc2c(Cl)c1S(C)(=O)=O
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 18 %

Procedure:
6-Bromo-3-methanesulfonyl-2-methyl-quinolin-4-ol (example C.1) (6 g, 19 mmol) and N,N-dimethyl-p-toluidine (5.5 mL, 38 mmol) were dissolved in toluene (60 mL) and heated under argon to reflux. The phosphorous oxychloride (1.9 mL, 20.9 mL) was added and heating at reflux continued for 6.5 h. The product precipitated spontaneously upon cooling to 20° C., the crystals were filtered off and washed with little toluene. One obtained 4.19 g (66%) of light brown crystals. Since the product is somewhat soluble in toluene, the mother liquor was extracted with 3 N HCl (2×), sat. NaCl (2×). The residue was purified by chromatography on silica gel in dichloromethane. One obtained 1.17 g (18%) of additional material. MS: m/z=333/335 (M).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.[C:45](O)(=[O:47])C.[CH3:49][N:50]([CH3:55])[CH2:51][CH2:52][CH2:53][NH2:54].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[OH:47][CH2:45][CH2:55][NH:50][CH2:51][C@:52]12[CH2:53][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[CH3:49][N:50]([CH3:55])[CH2:51][CH2:52][CH2:53][NH:54][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: CN(C)CCCN
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and 3-(dimethylamino)propylamine (0.084 ml, 0.668 mmol). To the mixture was added sodium triacetoxyborohydride (0.177 g, 0.835 mmol) and it was stirred at rt for 72 h. After 72 h of stirring, the reaction was diluted with 7 ml of sat. NaHCO3 was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give the expected product, tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(dimethylamino)propylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate. The crude product was used in the next step with no additional purification. LCMS: m/e 685.6 (M−H)−, 2.92 min (method 6).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]=O)[S:7]/[C:6]/1=[CH:12]\[C:13]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])=[O:14])[CH2:2][CH2:3][CH3:4].[OH2:24].[N:25]1C=CC=CC=1>>[CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]=[N:25][OH:24])[S:7]/[C:6]/1=[CH:12]\[C:13]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccncc1
Reactant: O
Reactant: CCCCN1C=C(C=O)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Product: CCCCN1C=C(C=NO)S/C1=C\C(=O)c1cc(Cl)ccc1OC

Procedure:
A mixture of Example 19 (35 mg, 0.1 mmol) and NH2OH_HCl (10 mg, 0.15 mmol) in pyridine (2 mL) was stirred at room temperature for 14 hours. The mixture was poured into water and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed sequentially with water and brine, dried over MgSO4, Filtered, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate as an eluent to provide the title compounds as a mixture of E and Z isomers. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 3 H), 1.25-1.42 (m, 2 H), 1.73 (m, 2 H), 3.86 (s, 3 H), 4.01 (m, 2 H), 6.58 (s, 0.6 H), 6.64 (s, 0.4 H), 7.04-7.20 (m, 1H), 7.35-7.49 (m, 1 H), 7.57 (s, 1 H), 7.61-7.70 (m, 1 H), 7.88 (s, 0.6 H), 8.19 (s, 0.4H), 11.26 (s, 0.4 H), 11.72 (s, 0.6 H), MS (DCI) m/z 368 (M+H)+, 352 (M+H-16)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1coc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
3 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole and 1.5 g of triethylamine were dissolved in 50 ml of dichloromethane, to which a solution of 1 g of acetyl chloride in 20 ml of dichloromethane was added dropwise under ice cooling. After stirring at room temperature for 8 hours, the mixture was washed with water and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was treated by column chromatography to obtain 2.7 g of 4-acetoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 76.5%). n20D=1.4752.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C1[O:7]C1C.[C:8]1(=O)[O:15][C:13](=[O:14])[CH:11]([OH:12])[CH:9]1[OH:10]>>[O:14]=[CH:13][C@@H:11]([C@H:9]([C@@H:8]([C@@H:2]([CH2:1][OH:3])[OH:7])[OH:15])[OH:10])[OH:12]
Reactant: C1CO1
Reactant: O=C1OC(=O)C(O)C1O
Reactant: CC1CO1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 20 %

Procedure:
1 mol of glucose was addition-polymerized with 25 mol of ethylene oxide and 25 mol of propylene oxide, the obtained glucose-polyoxyalkylene glycol ether compound was reacted with 5 mol of tartaric anhydride to form a half ester, and the ester was reacted with 5 mol of N-hydroxyglutal imide to prepare crosslinking agent 5. ##STR12##
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6](SC)[S:7][CH3:8])(=[O:4])=[O:3].[CH3:11][NH2:12]>C(O)C>[CH3:11][NH:12][C:6](=[N:5][S:2]([CH3:1])(=[O:4])=[O:3])[S:7][CH3:8]
Reactant: CSC(=NS(C)(=O)=O)SC
Reactant: CN
Solvent: CCO
Product: CNC(=NS(C)(=O)=O)SC
Temperature: 53 °C
Reaction time: 8 h

Procedure:
A mixture of N-methylsulphonyl-bis(methylthio)methanimine (188 g) and ethanol (760 ml) was stirred and warmed to 53° C. and the resulting solution was treated dropwise at 45° C. with a solution of methylamine in ethanol (33% w/w; 115 ml) during 2 hours. The solution was then stirred at room temperature for 7 hours and allowed to stand overnight. The solution was concentrated in vacuo to low volume and crystallised from cold ethanol, to give N-methyl-N'-methylsulphonyl-S-methylisothiourea (162 g), m.p. 88°-91° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>CC#N.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccccn2)CC1
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnc3ccccn23)CC1
Yield: 59.5 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)-4-(2-(2-pyridinyl)hydrazino)carbonyl-piperidine (320 mg, 1.0 mmol) and dichlorotriphenylphosphorane (666 mg, 2.1 mmol) in CH3CN (10 mL) was added Et3N (0.42 mL, 3.0 mmol). After refluxing for 2h, the solution was diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration followed by flash chromatography eluting with 100% EtOAc, then 10% MeOH/CH2Cl2 afforded the title compound (180 mg) as a foamy solid. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 9H), 2.05˜2.11 (m, 4H), 3.03 (br s, 2H), 3.24 (m, 1H), 4.25 (br d, J=11.7 Hz, 1H), 6.86 (dt, J=6.9, 0.9 Hz, 1H), 7.25 (m, 1H), 7.78 (dt, J=9.4, 1.2 Hz, 1H), 7.95 (dt, J=6.8, 1.1 Hz, 1H), 7.79 (dd, J=7.3, 0.8 Hz, 1H).
Reaction SMILES: O[CH2:2][CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5].C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:39]([CH2:2][CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Solvent: Cc1ccccc1
Product: CCC(CN=[N+]=[N-])Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-hydroxymethyl-propyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine in toluene was added diphenylphosphoryl azide and 1,8-diazbicyclo[3,4,0]undec-7-ene at 0° C. The resulting mixture was stirred at rt for 30 min, then heated 75° C. overnight. The reaction mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, dried, concentrated and purified by silica gel Biotage using 1:1 methylene chloride/hexane to methylene chloride as eluent to give (1-azidomethyl-propyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid in-4-yl]-amine as a light yellow oil. The oil was reduced with triphenylphospine to give the title compound. 1H NMR (CDCl3) d 6.86(s, 2H), 6.11(s, 1H), 4.02(d, 1H), 3.40(q, 1H), 2.84(m, 2H), 2.28(s, 3H), 2.13(s, 6H), 2.06(s, 6H), 1.61 (m, 2H), 0.98(t, 3H)ppm