Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13](Br)=[CH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH3:29])[C:20]3[C:25]([S:26][C:27]=2[CH:28]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3.[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C:33](=[O:39])[CH2:32]2>O.C1COCC1>[OH:39][C:33]1([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([CH3:29])[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:34]2[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]2)[CH2:32]1
Reactant: CN1c2ccccc2Sc2cc(C=C(Br)Br)ccc21
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN1c2ccccc2Sc2cc(CCC3(O)CN4CCC3CC4)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
In an atmosphere of argon, a hexane solution of n-butyl lithium (1.65M, 10.1 ml, 16.7 mmol) was added at -78° C. to a THF (25 ml) solution of 3-(2,2-dibromovinyl)-10-methylphenothiazine (3.13 g, 7.94 mmol), and the mixture was stirred for 1 hour and then at room temperature for 1 hour. The reaction mixture was again cooled at -78° C., and a THF (8 ml) solution of 3-quinuclidinone (1.09 g, 8.70 mmol) was added dropwise. The mixture was stirred at -78° C. for 1 hour and then with ice-cooling for 30 minutes. Water (5 ml) was added to the reaction mixture and the mixture was concentrated under a reduced pressure. A potassium carbonate aqueous solution was added and the reaction product was extracted with chloroform which was heated at about 50° C. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethanol-chloroform to give the title compound (1.75 g, 4.83 mmol, 61%) as yellow crystals.
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(C#Cc2ccc(CC(=O)OC)cc2)cc1C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 mmols) in triethylamine (8 mL) was treated with copper(I)iodide (67.0 mg, 0.35 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 0.35 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-7% EtOAc-hexanes) afforded 270.0 mg (53%) of the title compound as a pale-yellow oil.
Reaction SMILES: C([N:4]1[C:8]2=[CH:9][C:10]([CH3:12])=[N:11][N:7]2[C:6]([C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:40])[C:23]3[CH:28]=[C:27]([N:29]=[N:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH:26]=[CH:25][C:24]=3[OH:39])[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])=[N:5]1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO.O>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([NH:21][C:22](=[O:40])[C:23]2[CH:28]=[C:27]([N:29]=[N:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[CH:26]=[CH:25][C:24]=2[OH:39])=[CH:14][C:13]=1[C:6]1[N:7]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[NH:4][N:5]=1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc(OC)c(-c4nn(C(C)=O)c5cc(C)nn45)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc(OC)c(-c4n[nH]c5cc(C)nn45)c3)c2)cc1
Reaction time: 0.25 h

Procedure:
N-[3-(1-Acetyl-6-methyl-1H-pyrazolo[3,2-c]-s-triazol-3-yl)-4-methoxyphenyl]-2-hydroxy-5-(4-methoxyphenylazo)benzamide (1.4 g) was dissolved in methanol (100 ml) and a solution of sodium hydroxide (1.0 g) in water (30 ml) added. After stirring for 15 minutes the solution was acidified with glacial acetic acid when a gelatinous precipitate of the product appeared. This was removed by filtration, washed with water and crystallized in aqueous pyridine (850 mg; 66%), m.p. 295°-6°, λmax (methanol) = 350 nm.
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: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
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: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)c(C)c1

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (commercially available) (1.0 eq.) in EtOH (0.3 M) was added thionyl chloride (1.5 eq.) and heated to reflux for 2 hours. The solvent was concentrated en vaccuo, and the residue was diluted in ether and neutralized with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to give ethyl 4-bromo-3-methylbenzoate.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])=[N+:8]=[N-:9]>C1(C)C=CC=CC=1>[CH3:6][O:5][C:1]([C:2]1[N:9]=[N:8][N:7]([CH:10]([CH3:18])[C:11]([OH:13])=[O:12])[CH:3]=1)=[O:4]
Reactant: CC(N=[N+]=[N-])C(=O)OC(C)(C)C
Reactant: C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(C(C)C(=O)O)nn1
Temperature: 100 °C

Procedure:
To a solution of 1.87 g (22.3 mmol) of methyl prop-2-ynoate in 40 mL of toluene was added 1.9 g (11 mmol) of tert-butyl 2-azidopropanate. The reaction mixture was heated at 100° C. for 3 h then cooled to ambient temperature. All volatiles were removed under reduced pressure and the crude residue purified by column chromatography on silica gel eluting with a 5 to 25% acetone in hexanes gradient to afford the title compounds.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([NH:39][C@@H:40]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:41]([O:43]C)=[O:42])=[O:38])[C:34]4([CH3:50])[CH3:49])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:54])[CH3:53])(=O)C.[OH-].[Na+]>CO.C1COCC1>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([NH:39][C@@H:40]([CH2:45][CH:46]([CH3:47])[CH3:48])[C:41]([OH:43])=[O:42])=[O:38])[C:34]4([CH3:50])[CH3:49])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:53])[CH3:54]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a stirred solution of (S)-methyl 2-((1S,3R)-3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate (Example 41, 0.190 g, 0.253 mmol) in MeOH:THF (2:1) (7.5 ml) 2N NaOH (2.5 ml) was added at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the reaction mixture was acidified with 1N HCl, extracted with EtOAc, dried over Na2SO4 then the organic layer was concentrated and dried under vacuum to afford the title compound as an off white solid. Wt: 0.100 g: Yield: 56.7%; 1H NMR (300 MHz, DMSO-d6): δ 7.69 (d, 1H, J=8.1 Hz), 7.54 (d, 1H, J=6.6 Hz), 4.62 (s, 1H), 4.51 (s, 1H), 4.29-4.18 (m, 2H), 3.95-3.84 (m, 1H), 3.01-2.88 (m, 2H), 2.34-2.18 (m, 3H), 1.91-1.72 (m, 3H), 1.69-1.10 (m, 31H), 0.96-0.58 (m, 23H); Mass: [M+1]+694 (10%), [M+Na]+ 717 (100%); IR (KBr, cm−1): 3454, 2950, 1726, 1634, 1523, 1466, 1369, 1266, 1207, 1195, 1157, 1044, 1009, 922, 882, 722; M.R: 192.4° C.-213.8° C.; HPLC: 95.97%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[N:10]([NH:17][CH2:18]C=O)[CH:9]=[C:8]([C:21]([O:23]CC)=[O:22])[C:7]2=[O:26].C(O)(=O)C>C(O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[N:10]([NH:17][CH3:18])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:26]
Reactant: CCOC(=O)c1cn(NCC=O)c2c(OC)c(F)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
4.5 ml (0.0045 mole) of a 1N aqueous solution of sodium hydroxide were added to a solution of the whole (0.0015 mole) of the ethyl 6,7-difluoro-1-(N-formylmethylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVII, R10 =methyl) [prepared as described in Step (D3) above] dissolved in 10 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. At the end of this time, addition of acetic acid gave rise to crystals, which were collected by filtration to give 0.35 g of 6,7-difluoro-8-methoxy-1-(methylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIb, R10 =methyl) as a colorless powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(OCC)(=O)C>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reactant: NCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCN1CCCC1)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reaction time: 1 h
Yield: 26.4 %

Procedure:
4-(7-Chloro-4-quinazolinylamino)benzene sulphonyl chloride, hydrochloride (3.5 g, 0.011 mole) was added portionwise to a well-stirred mixture of sodium carbonate (11.5 g) in water (120 ml) and N-(2-aminoethyl)-pyrrolidine (1.26 g, 0.01 mole) in chloroform (120 ml) at about 10° C. After 1 hour at room temperature, the mixture was filtered. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give a gum. Trituration from ethyl acetate gave a white solid (1.14 g) which could be crystallised from ethanol-water, m.p. 203°-204.5° C.
Reaction SMILES: [C:1](=[O:26])([O:23][CH2:24]Cl)[O:2][CH2:3][CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[I-:27].[Na+]>C(#N)C>[C:1](=[O:26])([O:23][CH2:24][I:27])[O:2][CH2:3][CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate (3.88 g, 10 mmol) in acetonitrile (50 mL), was added sodium iodide (7.50 g, 50 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH1Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure, to give 4.51 g 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.[C:44](O)([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[CH3:41][C:40]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:31]1[CH:30]=[C:29]([C:27]2[CH2:26][C:25](=[O:42])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:45][CH2:44][C:46]([F:49])([F:48])[F:47])=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccncc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M212) (304 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (180 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:28])[CH2:37][CH2:36]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
10.9 g of N,N'-carbonyldiimidazole were added to a solution of 25.0 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 200 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 10.9 g of 1-(2-hydroxyethyl)piperazine in 50 ml of dry acetonitrile was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 45 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, after which it was diluted with 800 ml of ethyl acetate. The dilute solution was washed, in turn, with water (200 ml, three times) and an aqueous solution of sodium chloride (150 ml, once). The resulting ethyl acetate solution was concentrated by evaporation under reduced pressure to a volume of 100 ml, and the crystals which precipitated were collected by filtration, to give 28.6 g of the title compound as colorless crystals, melting at 140°-141° C.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].CC(C)=[O:12].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CO.O>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]([OH:12])=[O:5]
Reactant: CC(C)=O
Reactant: CCCC[C@H](C)CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CCCC[C@H](C)CC(=O)O
Reaction time: 0.25 h

Procedure:
To 10 g. of 3-(S)-methyl-1-heptanol in 175 ml. of acetone was added over 45 minutes 90 ml. of Jones reagent dropwise at 15°-20° C. After 15 minutes, 15 ml. of isopropanol was added and stirring continued for 30 minutes. The reaction was poured into water and the product extracted with ether. The extracts were combined, washed with water, a sodium bisulfite solution and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 10 g. of the product as a liquid, b.p. 84°-88° C./0.4 torr, [alpha]D =-4.46 (CH3OH C=0.105 g/ml.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[C:7]([O:35]C)=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2/[CH:27]=[CH:28]\[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])(=[O:19])=[O:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].CN(C)C1C=CC=CC=1.O>C(Cl)Cl>[Br:5][C:6]1[C:7]([OH:35])=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2/[CH:27]=[CH:28]\[CH2:29][N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])(=[O:18])=[O:19])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(O)c1C(=O)OC
Yield: 100 %

Procedure:
Aluminium chloride (0.303 g) was added to a stirred solution of (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-methoxybenzoate (Intermediate 161, 0.528 g) and N,N-dimethylaniline (0.915 g) in DCM (20 ml). The resultant mixture was stirred for 3 hours then a mixture of ice, water and DCM were added. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-6% to give (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-hydroxybenzoate (0.514 g) as a pale purple oil.
Reaction SMILES: [CH2:1]([C:3](=[N:10][NH:11]C(OC(C)(C)C)=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([CH:3]([NH:10][NH2:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCCCC(CC)=NNC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCC(CC)NN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
34.84 g (135.9 mmol) of tert-butyl N′-(1-ethyl-heptylidene)-hydrazinecarboxylate are dissolved in a mixture of 100 ml of THF and 150 ml of methanol and, after 9.93 g (157.6 mmol) of sodium cyanoborohydride have been added, the mixture is stirred for 2 hours at room temperature. 97 ml of 6N HCl are added dropwise and, after the addition has ended, the mixture is refluxed for 1.5 hours. It is neutralized with 6N NaOH solution, then, after the non-aqueous solvents have been removed, extracted three times with dichloromethane, and, after the mixture has been dried over sodium sulphate, the solvent is removed in vacuo. This gives 19.78 g (92%) of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[CH2:11].[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:17]([OH:22])[OH:18])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.2 %

Procedure:
Ref Li, W., Nelson, D. P., Jensen, M. S., Hoerrner, R. S., Cai, D., Larsen, R. D., Reider, P. J. J. Org. Chem., 2002, 67, 5394-5397. A solution of 1-bromo-2-(but-3-en-1-yl)benzene (9.46 g, 44.8 mmol) in dry THF (44.8 ml) was cooled (−78° C.) and treated with 2.5 M n-BuLi in hexanes (19.7 ml, 49.3 mmol). The mixture was stirred for 20 min, and then treated with triisopropyl borate (51.5 ml, 224 mmol). After 90 min, the reaction mixture was warmed to room temperature over 1 h. Then, the reaction was quenched with 2.0 N aq. HCl (240 mL), diluted with Et2O (120 mL), and the layers were stirred vigorously for several minutes. The resulting white precipitate was removed by filtration and then the filtrate layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated, affording a pale yellow oil which partially solidified upon standing. These solids were triturated with hexanes and then dried under vacuum. The decantate was concentrated to an oil, dissolved in fresh hexanes (˜15 mL) and stored (−40° C.) for 16 h. A second crop of solid was collected, washing with a small volume of hexanes, and dried under vacuum Both crops were combined to afford the desired product (5.46 g, 31.0 mmol, 69.2% yield) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ 8.24 (dd, J=7.8, 1.3 Hz, 1H), 7.52 (td, J=7.5, 1.4 Hz, 1H), 7.30-7.36 (m, 2H), 5.96 (ddt, J=17.0, 10.3, 6.5 Hz, 1H), 5.04-5.10 (m, 1H), 5.02 (dd, J=10.2, 1.6 Hz, 1H), 3.29-3.40 (m, 2H), 2.50 (td, J=7.9, 6.6 Hz, 2H). LCMS (M−H)=175.11.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:31](Cl)(Cl)[C:32](Cl)=[O:33].P(Cl)(Cl)(Cl)=O>[Cu].[Zn].C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][C:32](=[O:33])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C(CCCCCCCCCCCCCCCCCC)COCc1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture containing 7.18 g (18 mmol) of the compound prepared in (a) above, 75 ml of anhydrous diethyl ether and 1.4 g of zinc-copper couple was blanketed with nitrogen and treated dropwise at room temperature with a solution containing 3.63 g (20 mmol) of trichloroacetyl chloride and 3.06 g (20 mmol) of phosphorus oxychloride. After stirring the mixture at room temperature for 48 hours, the salts were filtered off and the filtrate concentrated in vacuo. The residue was then chromatographed on silica gel employing a mixture of petroleum ether and methyl-t-butyl ether in a ratio of 9:1 as the eluent to yield a yellow oil.