Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]([CH2:7][CH3:8])=O)([CH3:4])([CH3:3])[CH3:2].[C:9]([O:13][C:14](=[O:17])[NH:15][NH2:16])([CH3:12])([CH3:11])[CH3:10]>CO.C(O)(=O)C>[C:9]([O:13][C:14]([NH:15][N:16]=[C:5]([CH2:7][CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCC(=O)C(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CCC(=NNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tert-butylethylketone (5 g) was mixed with tert-butylcarbazate (6.4 g, 1.1 eq.) in 30 mL of methanol with 3 drops of acetic acid at room temperature. A solid formed within one hour; more methanol was added, and the mixture was stirred at room temperature for three days to produce N′-(1-ethyl-2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3, 500 MHz) δ (ppm): 7.5 (br, 1H), 2.23 (q, 2H)), 1.51 (s, 9H), 1.15 (s, 9H), 1.1 (t, 3H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1.CCCCCC>[CH3:8][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([CH3:11])=[CH:3][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(C)c(Br)cc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)cc1C
Temperature: -62.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of 4-bromo-2,5-dimethylanisole (5, 172 g, 0.8 mol) in anhydrous THF (800 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 352 mL, 0.88 mol, 1.1 equiv) in hexane at −60–−65° C. under N2. The resulting reaction mixture was stired at −60–65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (165.44 g, 203.2 mL, 0.88 mol, 1.1 equiv) at −60 to −65° C. The reaction mixture was stirred at −60 to −65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (750 mL) at −60 to −65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 400 mL). The combined organic extracts were then washed with H2O (400 mL), and saturated NaCl solution (400 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (500 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×200 mL), dried in vacuo at 40–45° C. for overnight. The crude product (6, 116.7 g, 144.0 g theoretical, 81%) was obtained as a white powder.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][NH2:34])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(O)(=O)C>CO.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][NH2:34])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: [Pd]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN

Procedure:
In 50 ml of MeOH is dissolved 250 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH2, and following addition of 0.1 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filteredoff, the filtrate is dissolved in a small amount of 1 N-aqueous acetic acidand the solution is put on a column of Sephadex LH-20(2.5×120 cm). Elution is carried out with 1 N-aqueous acetic acid and fractions from 310ml through 335 ml are pooled and lyophilized. 95 mg (38%); [α]D22 +20.5° (c=0.2, MeOH); Rf2 =0.22; amino acid analysis (hydrolyzed with HCl): Gly, 1.00; Ala, 1.05; Tyr, 0.89; Phe,1.01; mean recovery rate 81%.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([O:17][C:18](=O)[CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:17])[CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2c(-c3ccccc3)cc(=O)[nH]c21
Temperature: 110 °C
Yield: 15 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (4.0 g, 20.7 mmol) in AcOH (20 mL) was added 3-oxo-3-phenyl-propionic acid ethyl ester (3.5 g, 20.7 mmol). The reaction was then heated to 110° C. for 14 hr, at which time the reaction was cooled to room temperature and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography using a 75 g short Biotageo column, eluting with a gradient of 5%, 10% EtOAc/hexanes. The product-containing fractions were collected and concentrated to give the title compound (1.0 g, 15% yield) as a colorless solid. Rf=0.31 (20% EtOAc/hexanes); LRMS m/z (APCl) 322 (M+1); 500 MHz 1H NMR (CDCl3) δ 7.46-7.44 (m, 3H), 7.38-7.36 (m, 2H), 6.17 (s, 1H), 3.16 (dddd, J=7.9, 7.9, 7.9, 7.9 Hz, 1H), 2.17-2.11 (m, 2H), 1.76 (s, 9H), 1.71-1.67 (m, 4H); 125 MHz 13C NMR (CDCl3) δ 163.1, 151.0, 147.5, 141.8, 138.5, 128.9, 128.4, 128.2, 112.5, 110.6, 105.7, 59.7, 34.2, 29.2, 27.6, 18.4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>CO>[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[N:18]([C:2]1[CH:3]=[C:4]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16]2
Reactant: C1CN2CCC(CC2)N1
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of methyl 2-chloro-5-nitroisonicotinate (Intermediate 26A) (0.1 g, 0.46 mmol) in methanol (3 mL) under nitrogen was added 1,4-diazabicyclo[3.2.2]nonane (0.18 g, 0.55 mmol) and triethylamine (7 mg, 0.69 mmol), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 10 g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinate.
Reaction SMILES: [C:1]([N:8]([CH3:15])[C@H:9]([CH2:13][OH:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].[K+].[Br-].Cl[O-].[Na+]>ClCCl.O>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([CH:13]=[O:14])[CH:10]([CH3:11])[CH3:12])[CH3:15])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)[C@@H](CO)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
To a solution of 10.5 g Boc-N-methyl-valinol (48.3 mmol) in 50 ml dichloromethane was added a solution of 1.63 g NaHCO3 (19.3 mmol) and 0.58 g KBr (4.8 mmol) in 50 ml deionized water. The reaction mixture was cooled to 0° C. and after the addition of 77 mg 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO, 0.48 mmol), 36.6 g 10.3% aqueous sodium hypochlorite (53.1 mmol Cl2) were added under stirring over 2.5 h at 0-5°. After additional stirring for 30 min the excess of NaOCl was destroyed by the addition 38% aqueous sodium bisulfite and the reaction mixture was warmed up to 20°. The aqueous layer was extracted with 50 ml dichloromethane and the organic layers were washed with 50 ml 10% brine and dried (Na2SO4). Removal of the solvent by rotary evaporation afforded 9.9 g (95%) crude product as a light orange oil, [α]D=−130 (CHCl3; c=1). 1H-NMR:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:34])[CH2:16][NH:17][C:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[CH:22]2)=[CH:11][C:10]=1[NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:33][C:18]([NH:17][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:37])[CH:11]=1)[OH:34])([CH3:32])[CH2:19][CH2:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[CH:22]1
Reactant: [H][H]
Reactant: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
0.10 g palladium (5% on activated charcoal) were added to. a solution of 0.30 g (0.41 mmol) (R)—N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl)phenyl)-benzenesulphonamide in 15 mL ethanol. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at ambient temperature for 3 h. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%) (R)—N-(5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-2-hydroxy-phenyl)-benzenesulphonamide was obtained as a colourless solid.
Reaction SMILES: CI.[NH2:3][C:4]1[C:8]([NH:9][C:10]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=S)=[CH:7][S:6][CH:5]=1.Cl.CC(C)=O>C(O)C.C(OCC)(=O)C>[ClH:19].[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[NH:9][C:8]2=[CH:7][S:6][CH:5]=[C:4]2[N:3]=1
Reactant: Nc1cscc1NC(=S)Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Solvent: CI
Solvent: CCOC(C)=O
Product: Clc1cccc(Cl)c1Nc1nc2cscc2[nH]1
Reaction time: 6 h

Procedure:
2.5 g of methyl iodide were added to a suspension of 0.951 g of N-(3-amino-4-thienyl)-N′-(2,6-dichlorophenyl)thiourea in 40 ml of anhydrous ethanol and the mixture was boiled on a reflux condenser for 6 hours. After the solvent had been distilled off on a Rotavapor, the residue was admixed with water, made alkaline using an aqueous saturated sodium hydrogencarbonate solution and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulfate and treated with activated carbon, and the solvent was distilled off on a Rotavapor. The residue was then purified by column chromatography on silica gel using a mixture of 10 parts by volume of dichloromethane and 1 part by volume of methanol. After the solvent had been distilled off, a brown oily-amorphous product was obtained. It was dissolved in a little ethyl acetate, made strongly acidic using a hydrogen chloride gas-saturated ether solution, and, after adding a little acetone, boiled until complete crystallization. M.p. >300° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc(Nc2cc(Nc3cccc(O)c3)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3cccc(OCCCN(C)C)c3)ncn2)c1
Yield: 16 %

Procedure:
Using an analogous procedure to that described in Example 27, 4-(3'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine (0.5 g) was reacted with 3-dimethylaminopropyl chloride to give 4-[3'-(3-dimethylaminopropoxy)anilino]-6-(3'-methylanilino)pyrimidine in 16% yield, m.p. 142°-144° C.;
Reaction SMILES: [Cl:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][S:4]([N:7]=[C:8]=[O:9])(=[O:6])=[O:5].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=1>ClCCl>[CH3:28][C:23]1[CH:24]=[C:25]([CH3:27])[N:26]=[C:21]([NH:20][C:8]([NH:7][S:4]([CH:3]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:2]2[Cl:1])(=[O:5])=[O:6])=[O:9])[N:22]=1
Reactant: CCCCCCCCCCC(Cl)CS(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2CCCCCCCCCCC2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
15.4 g (0.05 mole) of 2-chlorododecylsulfonyl isocyanate in 100 ml of dichloromethane were initially introduced and 6.2 g (0.05 mole) of 2-amino-4,6-dimethylpyrimidine were added in portions at 0° C. The mixture was initially stirred at 0° C. for 2 hours and then at room temperature for 18 hours and was then worked up in analogy to Example 5. 15.2 g (71% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-chlorocyclododecylsulfonamide were obtained (pale yellow solid material, melting point 84° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]
Reactant: Oc1cccc(Br)c1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of 3-bromophenol (14) (2.0 g, 11.56 mmol), N-(2-hydroxyethyl)phthalimide (2.21 g, 11.6 mmol) and triphenyl phosphine (3.03 g, 11.6 mmol) in anhydrous THF (25 mL) was added diethyl azodicarboxylate (2.57 g, 12.7 mmol) slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight. After concentration under reduced pressure, 50% EtOAc-hexanes (100 mL) was added and the mixture was warmed to 60° C. After cooling to room temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (10% EtOAc-hexanes) gave bromide 17 as a white solid. Yield (1.92 g, 48%): 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.88 (m, 4H), 7.19 (t, J=8.4 Hz, 1H), 7.06-7.09 (m, 2H), 6.87-6.90 (m, 1H), 4.22 (t, J=5.6 Hz, 2H), 3.93 (t, J=5.6 Hz, 2H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[K])C.Cl[CH2:13][CH:14]=[CH2:15]>C(O)C>[CH2:15]([S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:14]=[CH2:13]
Reactant: Sc1ncccn1
Reactant: C=CCCl
Agent: CCO[K]
Solvent: CCO
Product: C=CCSc1ncccn1
Yield: 90 %

Procedure:
10 mmole of 2-mercaptopyrimidine was dissolved in 20 ml of ethanol in stirring. 10 mole of EtOK was added to the solution, stirred for 5 minutes. At last, about 20 mmole (Not more than 30 mmole) of 3-chloropropylene was added, and stirred overnight. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The obtained viscous liquid was separated with a Si gel column (solvents: 1 ethylacetate/3 hexane). 1H NMR (CD3Cl): δ(ppm) 8.39 (2H, d, JH-H=4.74), 6.86 (1H, t, JH-H=4.74), 5.89 (1H, m), 5.20 (1H, d, JH-H=17.00), 5.00 (1H, d, JH-H=9.97), 3.71 (2H, d, JH-H=6.83). Yield: 90%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60]/[CH:61]=[CH:62]/[CH3:63].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:60]/[CH:61]=[CH:62]/[CH3:63])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C/C=C/COC(=N)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: C/C=C/COC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (115 mg in 3 ml 33% methylene chloride in cyclohexane) trans-2-butenyl trichloroacetimidate (48 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 35 minutes the reaction was quenchedby the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compounds (14 mg 4"-ether; 12 mg 3"-ether).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][C:28]1[C:29]([C:40]2[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=2)=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([CH:38]=O)[CH:34]=[CH:33]2>>[F:26][C:2]([F:1])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]4[C:37](=[C:28]([CH3:27])[C:29]([C:40]5[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=5)=[CH:30][CH:31]=4)[N:36]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: Cc1c(-c2cnn(C)c2)ccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Product: Cc1c(-c2cnn(C)c2)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate and 8-methyl-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbaldehyde. LCMS APCI (+) m/z 507 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].O1CCCC1.[BH4-].[Na+]>CO>[CH2:29]([O:28][C:7]1[C:8]2[C:9](=[O:27])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[CH:11]([OH:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=12)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)c(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.112 g, 0.24 mmol) was suspended in methanol (2 ml) and tetrahydrofuran (3 ml) added to dissolve the reactant. The reaction mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.027 g, 0.72 mmol) added portionwise. Stirred under argon for 2-3 hours at 0° C. Further sodium borohydride was added to the reaction to push it to completion. The reaction mixture was evaporated to a solid and partitioned between EtOAc and ammonium chloride (saturated). The aqueous layer was extracted with EtOAc (×2) and the combined organics washed with brine and dried over MgSO4. Solvent was evaporated to give the title product as a gummy residue, which was triturated with hexane to afford a solid (0.111 g, 0.23 mmol).
Reaction SMILES: [N:1]#[N:2].C([O:6][C@H:7]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@@H:8]1[S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([OH:105])=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]1[O:96][C@H:95]([CH2:97][O:98]C(=O)C)[C@@H:90]([O:91]C(=O)C)[C@H:85]([O:86]C(=O)C)[C@@H:80]1[O:81]C(=O)C)=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]1[O:59][C@H:58]([CH2:60][O:61]C(=O)C)[C@@H:53]([O:54]C(=O)C)[C@H:48]([O:49]C(=O)C)[C@@H:43]1[O:44]C(=O)C)=[O:30])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@H:8]1([S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([OH:105])=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]2[O:96][C@H:95]([CH2:97][OH:98])[C@@H:90]([OH:91])[C@H:85]([OH:86])[C@@H:80]2[OH:81])=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:53]([OH:54])[C@H:48]([OH:49])[C@@H:43]2[OH:44])=[O:30])[O:9][C@H:10]([CH2:21][OH:22])[C@@H:11]([OH:17])[C@H:12]([OH:13])[C@@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N#N
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(=O)O
Yield: 88.7 %

Procedure:
A solution of 4 (2.0 g) in methanol-water-triethylamine 5:4:1 (v/v/v, 20 ml) is kept overnight at room temperature, and evaporated in vacuo to a residue that is put on a column of silica gel and eluted with chloroform-methanol-water 60:40:10 (v/v/v). The desired fractions are combined and evaporated to dryness. A solution of this compound in water (15 ml) is lyophilized to give 5 (1.2 g, 90%): mp 95°-100° C.; [α]D27 +115±0.9° (c 1.1, H2O); NMR (D2O) δ: 5.37 (s, 1H, H-1), 5.34 (s, 2H, H-1), 4.36, 4.19 (q,q, α-CH), 3.24 (m, ε-CH2), 2.95 (m, SCH2), 2.71 (t, 2H), 2.61 (t, 4H) (SCH2CH2), 1.33-1.92 (CCH2CH2CH2C).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)=O>C(O)C.Cl.[Pd]>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH:2]([CH3:14])[CH3:1]
Reactant: CC(C)C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)Cc1ccccc1N
Reaction time: 2 h
Yield: 27.3 %

Procedure:
To a cooled solution of 5.7 g (29.5 mmol) of 2-methyl-1-(2-nitrophenyl)propan-1-one in 35 mL of ethanol and 7 mL of concentrated hydrochloric acid is added under inert atmosphere, 0.7 g of 10% palladium on activated carbon. The mixture is hydrogenated at 50° C. under 4 bar for 2 hours. The suspension is filtered over celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in water, alcalinized to pH 9 with a concentrated solution of sodium hydroxide and extracted 3 times with ethyl acetate. The organic phases are combined, washed with water then with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily yellow residue (5 g) is purified over 150 g of silica gel (eluant heptane/ethyl acetate 2/1) to give 1.2 g (27%) of 2-isobutylaniline as an oil.