Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]=O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH:16]([C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc2ccccc2o1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
92 ml of a 1 N solution of potassium tert-butoxide in tetrahydrofuran are added dropwise to a vigorously stirred mixture at 0° C. of 68.4 mmol of benzofuran-2-carboxaldehyde and 92 mmol of methyltriphenylphosphonium bromide in 200 ml of tetrahydrofuran and 150 ml of dimethylformamide. The medium is stirred for 2 h at room temperature, poured into 2 liters of ice-water and extracted with ether. After concentration of the solvents, the residue is taken up in 1 liter of petroleum ether and the precipitate is filtered off and washed with petroleum ether. The expected product is obtained by evaporation of the filtrate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: CNc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1

Procedure:
A solution of 0.61 g (3.3 mmol) of 4-bromo-N-methylaniline and 0.5 mL (3.92 mmol) of benzenesulfonyl chloride in 5 mL of pyridine was stirred for 12 h at rt. After that time the pyridine was removed by azeotropic distillation with heptane. The residue was purified by chromatography on silica (hexanes:EtOAc, 9:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:25][CH3:26])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23]C)[CH:15]=3)[CH:7]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:25][CH3:26])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=3)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(OC)cc3n2CC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(O)cc3n2CC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.65 g, 4.37 mmole) in DCM (20 mL) was added 1M BBr3 in DCM (13.12 mL) over a period of 20 min. The reaction mixture was stirred further 1 h at room temperature and then the solvents were removed under reduced pressure. The residue was dissolved in MeOH and then poured into cold water. The precipitate was collected by filtration and washed with hexane and dried in vacuo to afford [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.5 g, 98%).
Reaction SMILES: Br[C:2]([F:9])([F:8])[CH:3](F)[CH2:4][CH2:5]Br.[SH:10][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[F:8][C:2]([F:9])=[CH:3][CH2:4][CH2:5][S:10][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: Sc1nc2ccccc2o1
Reactant: FC(CCBr)C(F)(F)Br
Product: FC(F)=CCCSc1nc2ccccc2o1

Procedure:
To the solution of 4-bromo-1,1-difluorobut-1-ene prepared in Example 6 was added potassium carbonate (10.76 g) and 2-mercaptobenzthiazole (9.18 g). The mixture was stirred at 55° C. for 6 hours and then at room temperature overnight. Gas-liquid chromatography of a sample of the reaction mixture showed that a small amount of 4-bromo-1,1-difluorobut-1-ene remained. More potassium carbonate (1.0 g) was added and the mixture heated for another two and a half hours at 55° C., when all of the bromo compound had been consumed. The mixture was cooled to room temperature and filtered. The residue was washed with acetone and the filtrate and washings combined and evaporated under reduced pressure to give the crude product (16.18 g). This was dissolved in dichloromethane. The solution was filtered and washed with dilute sodium hydroxide (2×25 ml) and with brine (2×25 ml), dried over magnesium sulphate, filtered, the filtrate evaporated to give 2-(4,4-difluorobut-3-enyl)thiobenzthiazole, having a gas chromatographic retention time identical with that of an authentic sample. The yield was 63% based on the quantity of 1,4-dibromo-1,1,2-trifluorobutane used in step (b) of Example 1. 2-(4,4-Difluorobut-3-enyl)thiobenzoxazole was prepared in the same way, but using 2-mercapto benzoxazole instead of 2-mercapto benzthiazole.
Reaction SMILES: [Br:1][CH:2]=CC=C(C)CC(OC)OC.[CH2:13]([O:15][CH:16]([O:23][CH2:24][CH3:25])[CH2:17][C:18]([CH3:22])=[CH:19][CH:20]=O)[CH3:14]>>[Br:1][CH:2]=[CH:20][CH:19]=[C:18]([CH3:22])[CH2:17][CH:16]([O:23][CH2:24][CH3:25])[O:15][CH2:13][CH3:14]
Reactant: COC(CC(C)=CC=CBr)OC
Reactant: CCOC(CC(C)=CC=O)OCC
Product: CCOC(CC(C)=CC=CBr)OCC

Procedure:
6-Bromo-3-methyl-1,1-diethoxy-3,5-hexadiene is prepared under the conditions described earlier for the preparation of 6-bromo-3-methyl-1,1-dimethoxy-3,5-hexadiene. Starting with 5,5-diethoxy-3-methyl-2-pentenal (4.67 g; 25.1 mmol), 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene (5.1 g) is obtained in 77.5% yield. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]3([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(-c3ccccc3)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (250 mg, 0.59 mmol, prepared in Example 53A-E), phenylboronic acid (108 mg, 0.9 mmol), tetrakis(triphenylphosphine)palladium (68 mg, 0.06 mmol), and 2M Na2CO3 (885 μL, 2 mmol) were mixed in dioxane (4 mL). The reaction vessel was placed under an argon atmosphere and stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give the crude product. The crude product was purified by silica flash chromatography (0-100% DCM/hexane) to give the desired compound as a yellow solid (172 mg). MS (m/e)=366.2 (M+H-tBu)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[O:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>>[OH:32][CH2:31][C:30]([NH:29][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:14]2[O:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:15]=2)[CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[O:2][CH3:1])([CH3:34])[CH3:33]
Reactant: COc1cc(-c2cc3nccc(-c4ccccc4)c3o2)cc(C(=O)O)c1OC
Reactant: CC(C)(N)CO
Product: COc1cc(-c2cc3nccc(-c4ccccc4)c3o2)cc(C(=O)NC(C)(C)CO)c1OC
Yield: 28 %

Procedure:
Starting from 2,3-dimethoxy-5-(7-phenylfuro[3,2-b]pyridin-2-yl)benzoic acid (120 μmol) and 2-Amino-2-methylpropan-1-ol (123 μmol) the product is prepared analogously to “A43” and obtained as a yellow solid in a yield of 28%. HPLC (method A): Rt 2.64 min (purity 93.5%); LCMS (ESI+) (method E): Rt 1.9 min, M+H+ 447.2 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.61 (d, J=5.2, 1H), 8.21 (s, 1H), 8.13-8.08 (m, 2H), 7.89 (d, J=2.1, 1H), 7.82 (s, 1H), 7.78 (d, J=2.1, 1H), 7.70-7.63 (m, 3H), 7.61-7.55 (m, 1H), 3.98 (s, 3H), 3.90 (s, br, 1H), 3.86 (s, 3H), 3.46 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:10](C)=CC=C[C:3]=1C(O)=O.[CH3:12][C:13]([NH:15][C@@H:16]1[C:32]2[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH3:34])C([CH:31]=2)=O)[C:24]2[C:23]([O:35][CH3:36])=[C:22]([O:37][CH3:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=2[CH2:18][CH2:17]1)=[O:14]>>[CH3:34][O:33][C:28]1[CH:27]=[CH:26][C:25]2[C:24]3[C:23]([O:35][CH3:36])=[C:22]([O:37][CH3:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=3[CH2:18][CH2:17][CH:16]([NH:15][C:13]([CH:12]3[CH2:3][CH:2]3[CH3:10])=[O:14])[C:32]=2[CH:31]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reactant: Cc1cccc(C(=O)O)c1Cl
Product: COc1ccc2c(c1)C(NC(=O)C1CC1C)CCc1cc(OC)c(OC)c(OC)c1-2

Procedure:
The same method used in Example 25 was carried out to obtain the title compound 41 (95 mg, Yield: 76%) except that (−)-7-deacetyl-9-methoxy allocolchicine was used instead of (−)-thiodeacetyl colchicine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C1(C)C=CC(S(O[CH2:39][C@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:25]([O:24][C:22]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]2[C:18]([O:19][CH2:39][C@H:40]3[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]3)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=2[Cl:21])[CH3:12])=[CH:9]1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](c1c(OC[C@H]2COC(C)(C)O2)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 110 °C

Procedure:
A suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (82.9 mg, 0.176 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (77.8 mg, 0.272 mmol), and potassium carbonate (102.5 mg, 0.7416 mmol) in DMF (3 mL) was subjected to microwave heating [Biotage, 110° C.] for 90 min. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 g] and purified using the Teledyne/ISCO system [RediSepRf silica 12 gram GOLD column], eluting with a solvent system of 5-20% EtOAc:heptane. Fractions containing product were combined and concentrated in vacuo. The recovered material was dissolved in minimal MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions were combined and concentrated in vacuo, giving the title material as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=8.42 (d, J=2.3 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.91 (q, J=6.8 Hz, 1H), 4.01-4.18 (m, 2H), 3.81-3.89 (m, 1H), 3.78 (dd, J=7.7, 4.9 Hz, 1H), 3.73 (br s, 1H), 1.73 (d, J=7.1 Hz, 3H), 1.68 (s, 9H), 1.34 (d, J=14.9 Hz, 6H). MS (ES+): m/z 604.96/606.80/608.57 (21/100/24) [MH++Na]. HPLC: tR=4.13 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.087 g, 0.313 mmol) was reacted with N-(2-azidoethyl)palmitamide (0.102 g, 0.313 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-palmitamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), δ 6.78 (t, J=4.5 Hz, 1H), δ 6.41 (s, 1H), δ 6.19 (s, 2H), δ 4.39 (t, J=5.4 Hz, 2H), 83.67 (q, J=5.5, 4.8 Hz, 2H), δ 2.61 (t, J=6.9 Hz, 2H), δ 2.12 (t, J=6.5 Hz, 2H), δ 2.07 (t, J=7.5 Hz, 2H), δ 1.42 (m, 13H), δ 1.42 (m, 2H), δ 1.32 (m, 22H), 0.81 (t, J=5.4 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.8, 174.3, 173.9, 149.5, 148.3, 121.9, 106.4, 85.0, 67.2, 51.1, 49.5, 39.5, 39.1, 38.1, 36.8, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.3, 28.2, 27.9, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C33H59N7O3(M+) 601.4679. found 601.4671, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)palmitamide hydrochloride (0.155 g, 92% yield). 1H NMR (300 MHz, CD3OD) δ 8.59 (s, 1H), δ 6.53 (s, 1H), δ 4.72 (s, 2H), δ 3.75 (s, 2H), δ 2.90 (s, 2H), δ 2.54 (s, 2H), δ 2.16 (t, J=7.2 Hz, 2H), δ 1.80 (s, 2H), δ 1.69 (s, 2H), δ 1.51 (s, 4H), δ 1.28 (bs, 24H), δ 0.71 (t, J=6.3 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.7, 147.2, 145.6, 128.4, 127.6, 108.6, 67.2, 52.7, 37.4, 36.5, 35.8, 31.9, 29.7, 29.5, 29.4, 29.2, 28.0, 27.9, 27.8, 27.7, 25.8, 24.1, 23.6, 23.2, 22.6 ppm; HRMS (ESI) calcd for C28H51N7O (M+) 501.4155. found 501.4143.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][C@H:4]([CH3:18])[N:3]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][C@H:4]([CH3:18])[N:3]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(N)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D7) (2.62 g, 7.53 mmol) in MeOH (25 mL) and water (25 mL) heated to 80° C. was added iron powder (1.26 g, 22.54 mmol) and ammonium chloride (2.01 g, 37.58 mmol). The reaction was stirred vigorously at 80° C. for 1.5 h and then the iron residues removed by filtration through Celite®. The filtrate was concentrated and the residue partitioned between DCM and water. The aqueous layer was further extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product as a yellow foam (2.01 g). Column chromatography eluting with 0-100% Et2O/petroleum ether gave the title compound (1.694 g). δH (CDCl3, 400 MHz) 7.12 (2H, d), 6.64 (2H, d), 4.05 (2H, m), 3.64 (2H, br s), 3.36 (2H, s), 2.59 (2 h, d), 2.06 (2H, dd), 1.46 (9H, s), 1.27 (6H, d). MS (ES): MH+ 320.3, MNa+ 342.3.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][CH3:13])=[C:10]([Cl:14])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[N:7]2.[CH3:19][S:20](N)(=[O:22])=[O:21]>>[Cl:14][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[N:7]2)=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[C:11]=1[CH2:12][CH3:13]
Reactant: CS(N)(=O)=O
Reactant: CCc1c(Cl)cc2nc(OC)c(OC)nc2c1N
Product: CCc1c(Cl)cc2nc(OC)c(OC)nc2c1NS(C)(=O)=O
Yield: 47 %

Procedure:
5-Amino-7-chloro-6-ethyl-2,3-dimethoxyquinoxaline was converted to the methane sulphonamide derivative by the method of step (g) above. The product was obtained in 47% yield.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:3].[C:23]([C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([O:44][CH3:45])[N:38]=2)=[CH:34]\[CH2:35][OH:36])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:23]([C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([O:44][CH3:45])[N:38]=2)=[CH:34]\[C:35]([OH:3])=[O:36])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1nc(/C(=C/C(=O)O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
Dess-Martin reagent (770 mg) was added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-ol (601 mg) in chloroform (20 mL), and the mixture was stirred at room temperature for 30 minutes. A 10% sodium thiosulfate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Sodium dihydrogenphosphate (1.0 g) and chlorous acid (1.6 g) were added to a solution of the resulting residue and 2-methyl-2-butene (2.3 g) in tert-butanol (15 mL)-water (5 mL), and the mixture was stirred at room temperature for one hour. The reaction solution was ice-cooled and then adjusted to a pH of less than 2 with 1 M hydrochloric acid, followed by extraction with chloroform. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1). Thereafter, the resulting solid was washed with hexane and then dried to give the title compound as a colorless powder (434 mg, 69%).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[CH2:29](O)CC>>[CH2:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])[CH2:2][CH3:29]
Reactant: CCCO
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Product: CCCOCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 11.7 %

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (5 g., 12.9 mmoles) was refluxed in n-propanol (50 ml.) for 20 minutes. The solution was cooled and the precipitated brown solid was filtered off and discarded. The filtrate was treated with water (300 ml.) and the pH adjusted to 8.5 with aqueous sodium bicarbonate. The solution was extracted with ethyl acetate (2 × 20 ml.) and the extracts were discarded. The aqueous phase was acidified to pH 1.5 and extracted with ethyl acetate (3 × 20 ml.). After drying, the solution was removed and the residue dissolved in ethyl acetate (50 ml.), and ether (100 ml.) was added. The precipitated brown solid was filtered off and discarded, and the filtrate evaporated to dryness. The residue was twice recrystallised from aqueous ethanol to give the title compound as colourless needles (500 mg., 11.7%), m.p. 152°-154° (decomp) [α]D25 = 79.8° (c 1.0, tetrahydrofuran), λmax (pH6-phosphate buffer) 236 nm. (ε = 13,600), 260 nm. (ε = 8,700) (shoulder), νmax (Nujol) 3310 (--NH--), 1772 (β-lactam), 1724 (--COOH), 1665 and 1535 cm-1 (--CONH--). (Found: C, 51.3; H, 5.1; N, 6.9; S, 15.9. C17H20N2S2O5 requires: C, 51.5; H, 5.1; N, 7.1; S, 16.2%). N.M.R. (D2O-NaHCO3) 5.78, 6.60, 8.52, 9.13τ (--CH2OCH2CH2CH3), Rf 0.48 (System B); 0.54 (System C).
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[N+:9]([C:3]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])([O-:11])=[O:10]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 3-chloro-2-nitroaniline (CXXI) (2.00 g, 11.6 mmol, 1 eq) and piperidine (2.95 g, 34.7 mmol, 3 eq) in DMF (60 ml) was added K2CO3 (4.78 g, 34.4 mmol, 3 eq) in one portion and the mixture was stirred at 120° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with saturated NaHCO3 solution (50 mL). The organic phases were dried over Na2SO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc=5:1→1:1) to give 2-nitro-3-(piperidin-1-yl)aniline (CXXII) (1.8 g, 8.14 mmol, 70.3% yield) as a black solid. ESIMS found for C11H15N3O2 m/z 222 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C@H:6]2[CH2:11][C@@H:8]([CH2:9][CH:10]=1)[C:7]2([CH3:13])[CH3:12].C12BC(CCC1)CCC2.[O:23]1CCC[CH2:24]1>>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[C@H:10]([CH:24]=[O:23])[CH2:9][C@@H:8]2[CH2:11][C@H:6]1[C:7]2([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: COCCC1=CC[C@@H]2C[C@H]1C2(C)C
Agent: B1C2CCCC1CCC2
Product: COCC[C@H]1[C@H](C=O)C[C@@H]2C[C@H]1C2(C)C
Temperature: -35 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1S,5R)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (940 mg) in tetrahydrofuran (5 mL) was added dropwise 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 10.43 mL). The reaction mixture was heated to reflux overnight, then cooled to −35° C. and then placed under a CO atmosphere (1 atm). LiAl(OtBu)3H (1M in tetrahydrofuran, 5.21 mL) was added dropwise over 30 minutes. Following the addition, the reaction mixture was stirred for 1.5 hours under CO (1 atm), during which time the reaction temperature was increased to 0° C. The mixture was warmed to room temperature and stirred for 45 minutes, then the system was flushed with argon and a buffer solution (5.28 g NaH2PO4 and 6.86 g K2HPO4 in 20 mL water) was added. The flask was chilled in a −10° C. cooling bath and the reaction was quenched by dropwise addition of 30% aqueous H2O; solution (2.2 mL), then warmed to room temperature and stirred for 15 minutes. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×75 mL). The organic phase was then washed with 10% Na2S2O3 (3×50 mL) and brine (50 mL), then dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in hexanes to give the title compound.