Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[F:7][C:8]1[CH:9]=[C:10]([C@H:14]([C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17]2)[OH:15])[CH:11]=[CH:12][CH:13]=1.Cl.[F:30][C:31]1[CH:32]=[C:33]([C@@H:37]([C@@H:39]2[O:44][CH2:43][CH2:42][N:41]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:40]2)[OH:38])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2]([O:15][C@H:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1)[C@H:16]1[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1)(=[O:4])=[O:3].[CH3:1][S:2]([O:38][C@@H:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=1)[C@@H:39]1[O:44][CH2:43][CH2:42][N:41]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:40]1)(=[O:4])=[O:3]
Reactant: O[C@@H](c1cccc(F)c1)[C@H]1CN(Cc2ccccc2)CCO1
Reactant: O[C@H](c1cccc(F)c1)[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@@H](c1cccc(F)c1)[C@H]1CN(Cc2ccccc2)CCO1
Product: CS(=O)(=O)O[C@H](c1cccc(F)c1)[C@@H]1CN(Cc2ccccc2)CCO1
Reaction time: 1 h
Yield: 90 %

Procedure:
Methanesulphonyl chloride (1.01 g, 8.9 mmol) was added dropwise over 5 min to a stirred solution of (R)-[3-fluorophenyl][(2S)-4-benzylmorpholin-2-yl]methanol hydrochloride and (S)-[3-fluorophenyl][(2R)-4-benzylmorpholin-2-yl]methanol hydrochloride (1.50 g, 4.44 mmol) and triethylamine (1.79 g, 17.8 mmol) in dry dichloromethane (30 ml) at room temperature under nitrogen atmosphere. After 1 h, water (30 ml) was added, stirred vigorously and then the dichloromethane layer separated. The solution was dried over sodium sulphate, filtered and evaporated to a colourless oil. The oil was purified by chromatography on silica eluting with diethyl ether:hexane 3:1 to give (R)-[3-fluorophenyl][(2S)4-benzylmorpholin-2-yl]methyl methanesulphonate and (S)-[3-fluorophenyl][(2R)-4-benzylmorpholin-2-yl]methyl methanesulphonate as a colourless oil (1.51 g, 90%)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([N:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[C:23](=[O:30])[C:22]1=[O:31])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[OH:30][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:22]1=[O:31]
Reactant: CCCCCN1C(=O)C(=O)c2cnccc21
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 152 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (0.27 g, 1.90 mmol) in THF (10.0 mL) was added iso-propylmagnesium chloride (0.97 mL, 2 M solution in THF, 1.90 mmol) slowly at 0° C. The mixture was allowed to stir at ambient temperature for 1 hour followed by the addition of 1-pentyl-1H-pyrrolo[3,2-c]pyridine-2,3-dione (0.21 g, 0.96 mmol). The resulting mixture was stirred at ambient temperature overnight, quenched with saturated ammonium chloride (20.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, ½) to give the title compound (0.52 g, 40%) as a white solid: mp 193-195° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.30 (d, 1H), 7.88 (s, 1H), 7.22 (s, 1H), 7.04 (d, 1H), 6.64 (s, 1H), 6.21 (s, 1H), 5.93-5.87 (m, 2H), 3.70-3.50 (m, 2H), 1.63-1.48 (m, 2H), 1.36-1.23 (m, 4H), 0.84 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 151.4, 150.6, 148.5, 147.3, 143.4, 140.0, 128.6, 119.6, 107.1, 104.6, 101.2, 97.8, 73.9, 28.9, 26.8, 22.4, 14.4; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]4[C:26](=[CH:27][CH:28]=2)[C:25](C(O)=O)=[CH:24][C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.N#N.CO.O>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[CH:27]1[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[C:15]([C:13]2[C:12]3[C:7]([CH:6]=[C:5]4[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:28]=1
Reactant: O=C(O)c1cc2ccccc2c2cc(-c3c4ccccc4cc4ccccc34)ccc12
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: N#N
Solvent: CO
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: c1ccc2c(-c3ccc4ccc5ccccc5c4c3)c3ccccc3cc2c1

Procedure:
40 g (94 mmol) of 6-anthracen-9-ylphenanthrene-9-carboxylic acid are suspended in 250 ml of quinoline, the suspension is saturated with N2, 11.8 g (38 mmol) of copper chromite are added, and the mixture is heated at the boil for eight hours. The mixture is subsequently poured into 1 l of MeOH/water, and the black solid is filtered off with suction, washed with MeOH and subjected to Soxhlet extraction with CHCl3. Removal of the solvent leaves a greyish solid, which is recrystallised twice from dioxane. The yield is 30.6 g (92%).
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22])(=O)OC.O.[NH2:27][NH2:28]>>[C:21]([C:20]1[N:27]=[N:28][C:3]2[C@@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([C:4]=2[CH:19]=1)[CH2:6][CH2:7]3)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)C(C)(C)C)OC
Reactant: NN
Solvent: O
Product: CC(C)(C)c1cc2c(nn1)[C@]1(C)CC[C@H]2C1(C)C

Procedure:
light yellow oil. MS (ESI): 245.2 (MH+). Prepared from (1R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate. Minor product, regioisomer of compound of example 24, isolated and purified by silica gel chromatography.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[Cl:7]Cl.C[C:10]([CH3:12])=O.C(O)C>>[CH2:5]([O:4][CH:1]([O:3][CH2:10][CH3:12])[CH2:2][Cl:7])[CH3:6]
Reactant: ClCl
Reactant: CC(C)=O
Reactant: C=COC(C)=O
Solvent: CCO
Product: CCOC(CCl)OCC
Temperature: 0 °C

Procedure:
To a mixture of 5 g of vinyl acetate and 27 ml of ethanol acetone cooled on dry ice 5 g of dry chlorine gas are added, then it is left standing for a night at room temperature. The reaction is poured onto 50 g of ice-water. The product is extracted with 30 ml of chloroform, the extract is washed with a sodium hydrogen carbonate solution and water, then dried on magnesium sulfate and distilled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: CC(C)CBr
Reactant: Cc1cc(F)ccc1N=C1N[C@@H](CC(C)C)CS1
Product: Cc1cc(F)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Fluoro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-fluoro -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-fluoro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH2:7][CH:8]([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:3][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)CCOCCCCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)CCOCCCCBr
Reaction time: 18 h

Procedure:
6.1 cc (0.0636 mol) of phosphoric tribromide are added dropwise at 0° over the course of 20 minutes and while stirring, to a solution of 27.5 g (0.172 mol) of 4-isopentyloxy-butanol (production: see Example 15) and 1.36 g (0.0172 mol) of pyridine in 150 cc of absolute chloroform. The cooling bath is removed, the mixture is then heated to 60° for 1 hour and stirred at this temperature for 18 hours. The reaction mixture is poured into ice-cold sodium bicarbonate solution, the chloroform phase is removed in a separating funnel, washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is filtered with hexane/ethyl acetate (98:2) on silica gel. The evaporated filtrate is fractionally distilled and pure 1-bromo-4-isopentyloxy-butane is obtained. B.P.: 96°-97°/12 mm Hg.
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].Cl.[Br:6][C:7]1[N:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[C:10]2O.O.C(OCC)(=O)C>N1C=CC=CC=1>[Br:6][C:7]1[N:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[C:10]2[NH:4][O:3][CH2:1][CH3:2]
Reactant: CCON
Reactant: O=c1cc(O)c2nc(Br)ccc2[nH]1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCONc1cc(=O)[nH]c2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of EtONH2.HCl (1.05 g, 10.8 mmol) in pyridine (5 ml) was added 6-bromo-4-hydroxy-1H-1,5-naphthyridin-2-one (324 mg, 1.34 mmol) and stirring was continued for 17 h at 100° C. The mixture was allowed to cool to ambient temperature then water and ethyl acetate were added followed by separation of phases. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/MeOH, gradient, afforded 6-bromo-4-(ethoxyamino)-1H-1,5-naphthyridin-2-one.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:23]=1.C([O-])(=O)C.[K+].[CH3:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.C(#N)C.O>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>[CH:20]([N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:9]1[S:8][C:7]2[C:6]3[N:23]=[C:2]([C:35]4[C:30]([CH3:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)([CH3:22])[CH3:21]
Reactant: Cc1ncccc1B(O)O
Reactant: CC(C)n1ccnc1-c1cc2c(s1)-c1nc(Cl)ccc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ncccc1-c1ccc2c(n1)-c1sc(-c3nccn3C(C)C)cc1CCO2
Temperature: 140 °C

Procedure:
To a solution of 9-Chloro-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (63 mg, 0.18 mmol), Potassium acetate (60.2 mg, 0.613 mmol), 2-methylpyridine-3-boronic acid, (32.2 mg, 0.235 mmol) and Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) in Acetonitrile (2 mL, 30 mmol) and Water (2 mL, 100 mmol) was degassed. The reaction was heated in the microwave at 140° C. for 20 minutes. The reaction was cooled to r.t., then extract with ethyl acetate. The combined organics were concentrated and purified by reverse phase HPLC to give 304. MS: (ESI+)=403.1. 1H NMR (400 MHz, DMSO) δ 8.55-8.47 (m, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.50-7.43 (m, 2H), 7.36 (dd, J=7.7, 4.9 Hz, 1H), 7.29 (s, 1H), 7.00 (s, 1H), 4.82 (dt, J=13.3, 6.5 Hz, 1H), 4.43 (t, J=4.6 Hz, 2H), 2.65 (s, 3H), 1.44 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.[OH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([N:11]4[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[CH2:12]4)[C:10]=3[C:2]([C:34]3[CH:35]=[C:30]([CH2:29][OH:28])[CH:31]=[CH:32][CH:33]=3)=[CH:3]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(CO)c3)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Temperature: 150 °C
Yield: 146.6 %

Procedure:
A mixture of 5-bromo-7-[(4-methylphenyl)sulfonyl]-4-[(3S)-3-methylpiperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (C15) (0.225 g, 0.501 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.104 g, 0.684 mmol), sodium carbonate (0.159 g, 1.50 mmol) and dichlorobis(triphenylphosphine)palladium(II) (36 mg, 51 μmol) in acetonitrile (2 mL) and water (2 mL) was heated to 150° C. under microwave irradiation for 15 minutes. The reaction was concentrated in vacuo to afford the product (0.35 g, >100%), which was used directly in the following step without additional purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCC(F)(F)F)nc1
Temperature: 200 °C
Yield: 43.1 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol), 2,2,2-trifluoro-ethylamine (940 mg, 9.45 mmol) and N,N-diisopropylethylamine (1.64 mL, 9.45 mmol) in 1-methyl-pyrrolidin-2-one (10 mL) in a sealed tube was heated by microwave at 200° C. for 10 minutes. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (Isco 120 g column, 40% ethyl acetate/hexanes) to give (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (300 mg, 43%) as a yellow solid. LCMS calcd for C7H6F3N3O2 (m/e) 221, obsd 222 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:16][C:15]2=[CH:17][N:12]([CH:13]=[N:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C@H:5]([CH:18]([CH3:20])[CH3:19])[NH:4][C:3]1=[O:21].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[NH2:34][C@@H:35]([CH2:43][C:44]1[CH:45]=[N:46][C:47]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[CH:48][CH:49]=1)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[C:54]([O:53][C:51]([NH:50][C:47]1[N:46]=[CH:45][C:44]([CH2:43][C@H:35]([NH:34][C:22]([NH:1][C@@H:2]2[CH2:16][C:15]3=[CH:17][N:12]([CH:13]=[N:14]3)[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C@H:5]([CH:18]([CH3:19])[CH3:20])[NH:4][C:3]2=[O:21])=[O:23])[C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:49][CH:48]=1)=[O:52])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cn1
Reactant: CC(C)[C@H]1COCCCCn2cnc(c2)C[C@@H](N)C(=O)N1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COCCCCn2cnc(c2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A solution of 56 mg (190 μmol) of (8S,11R)-11-amino-8-isopropyl-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-10-one from step D in 5 ml of DMF was cooled to 0° C. and, while stirring, 32 mg (194 μmol) of 1,1′-carbonyldiimidazole were added. The mixture was stirred for 30 min, and then 64 mg (190 μmol) of tert-butyl (S)-2-amino-3-(6-tert-butoxycarbonylaminopyridin-3-yl)propionate were added, and the mixture was warmed to RT. After standing overnight, the same amount of 1,1′-carbonyldiimidazole was again added, and the mixture was stirred for a further 24 h. It was then concentrated and purified by preparative HPLC. 27 mg of the desired compound were obtained.
Reaction SMILES: O[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CCN(S(F)(F)[F:16])CC.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:16][CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(CO)C(=O)OCC
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(CF)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of ethyl 2-(hydroxymethyl)acrylate (5 g, 38 mmol) in 50 mL of methylene chloride was added DAST (6.0 mL, 46.1 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, then warmed up to room temperature and continuously stirred overnight. 20 mL of saturated NaHCO3 aqueous solution and 20 mL of ethyl acetate were added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 ml×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue (2.8 g, yield: 56%). MS (m/z): 131 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].ClCCl.CO>C1(C)C=CC=CC=1>[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16](=[NH:17])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1cccc(I)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: N=C(Nc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 mL 3-neck round bottom flask was added aniline (3.13 g, 33.6 mmol) and 150 mL of toluene. The solution was cooled in an ice bath under nitrogen. Next trimethylaluminum solution in toluene was added dropwise via dropping funnel (2.0 M, 23.5 mL, 47.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. Next 3-iodobenzonitrile (10 g, 44 mmol) in 50 mL of toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and then poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol. The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid which was triturated with hexane, filtered, and washed with more hexane and dried (7.84 g, 73%).
Reaction SMILES: [C:1](=[O:17])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:18][C:19](=[NH:49])[C:20]1[CH:48]=[CH:47][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]3[CH:46]=[CH:45][C:41]([C:42]([NH2:44])=[NH:43])=[CH:40][CH:39]=3)[CH2:30][CH2:29]2)=[CH:22][CH:21]=1.C(Cl)(Cl)Cl.[OH2:54]>CN(C)C=O>[NH2:49][C:19](=[N:18][C:1]([O:2][CH2:3][CH:4]([CH3:5])[CH3:6])=[O:17])[C:20]1[CH:48]=[CH:47][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([NH2:44])=[N:43][C:1]([O:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[O:54])=[CH:45][CH:46]=3)[CH2:30][CH2:29]2)=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)N)cc3)CC2)cc1
Reactant: CC(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)COC(=O)N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NC(=O)OCC(C)C)cc3)CC2)cc1
Reaction time: 17 h

Procedure:
Into a solution of 1.82 g of isobutyl 4-nitrophenyl carbonate in 15 mL of N,N-dimethylformamide, 1.50 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine was added at room temperature, and the solution was left reacting at the same temperature for 17 hours. Chloroform and water were added to the reaction mixture. The organic layer was separated, washed with water, a 5% potassium carbonate aqueous solution and a saturated sodium chloride aqueous solution successively, and dried over anhydrous magnesium sulfate, followed by solvent removal by evaporation under reduced pressure. The obtained residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=4:1). The obtained residue was dissolved in chloroform, washed with a 5% potassium carbonate aqueous solution and a saturated sodium chloride aqueous solution successively, and dried over anhydrous magnesium sulfate. After removing the solvent by evaporation under reduced pressure, 1.43 g of 4-{3-[4-(3-{4-[amino(isobutoxycarbonylimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-(isobutoxycarbonyl)benzamidine was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[Br-:13].[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:11])[CH:2]1[CH3:1])([OH:21])=[O:20]
Reactant: O=C(O)CCCCCBr
Reactant: CC1=Nc2ccccc2C1(C)C
Product: CC1[NH+](CCCCCC(=O)O)c2ccccc2C1(C)C
Product: [Br-]

Procedure:
N-(5-carboxypentyl)-2,3,3-trimethylindolinium bromide was prepared by the process set forth in Example IA with 2,3,3-trimethylindolenine and 6-bromohexanoic acid to produce 2.43 grams (71.2 percent yield) of yellow crystals. 1H and 13C NMR spectra indicated the following:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:22])[CH2:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[C:15]([Cl:21])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=[O:24].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:21][C:15]1[N+:14]([O-:24])=[C:13]([CH2:12][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:22])[C:18]([C:19]#[N:20])=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(Cl)[n+]([O-])c1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Another batch was prepared as follows: To a suspension of (6-chloro-3-cyano-pyridin-2-yl)-acetic acid 4-nitro-phenyl ester (157 mg, 0.5 mmol) and sodium percarbonate (157 mg, 1.0 mmol) in anhydrous acetonitrile (4 mL), cooled in an ice-water bath, was added trifluoromethanesulfonic anhydride dropwise (253 μL, 1.5 mmol). The reaction mixture turned into a translucent light yellow solution. After stirring for 3 hrs in ice-water bath, the reaction mixture was poured into saturated sodium carbonate solution (30 mL) and cooled in an ice-water bath. The reaction vial was rinsed with DCM and poured into the sodium carbonate solution. After stirring for 25 min in the ice-water bath, the organic layer was separated. The aqueous layer was further extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate. After rotary evaporation of most solvent, the concentrated solution was loaded on a preparative silica TLC (2 mm, 20×20 cm) and developed with EtOAc/Hexane (1:1). The title compound was obtained as a light yellow solid (108 mg, 65%). 1H-NMR (300 MHz, CDCl3) δ 8.29 (d, 2H), 7.68 (d, 1H), 7.51 (d, 1H), 7.31 (d, 2H), 4.40 (d, 2H).