Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:5])[CH:3]=[CH2:4].I[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.CCN(CC)CC>CC#N.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:1]=[C:2]([CH3:5])[CH2:3][CH2:4][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C=CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CCC(C)=O)cc1

Procedure:
3-Hydroxy-1-butene (Aldrich) (2.15 mL, 25 mmol), ethyl 4-iodobenzoate (5.52 g, 20 mmol), Et3N (3.5 mL, 25 mmol) and Pd(OAc)2 (19 mg, 0.08 mmol) were combined in 6 mL CH3CN, sealed in a glass pressure tube and heated at 100° for 3 h. The mixture was cooled, diluted with Et2O, washed with water, 1N NaOH, 5% KHSO4, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% EtOAc/hexanes) provided 21-1 as a white crystalline solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[N:11]=1)(C)(C)C.[ClH:21]>CCOC(C)=O>[ClH:21].[ClH:21].[N:11]1[C:12]2[NH:13][CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=[CH:19][C:10]=1[CH2:9][CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCc1ccc2c(n1)NCCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCc1ccc2c(n1)NCCC2
Reaction time: 0.5 h

Procedure:
Through a solution of 10-6 (4.0 g, 16 mmol) in EtOAc (200 mL) at 0° C. was bubbled a stream of HCl gas for 10 minutes. After an additional 30 minutes, the mixture was purged with argon for 1 h and then concentrated. The residue was dissolved in acetonitrile and concentrated to give 10-7 as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1.[CH2:15]([C@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@H:17]([OH:19])[CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: CCC(CC)COc1cccc(Br)c1
Reactant: ClC[C@@H]1CO1
Product: CCC(CC)COc1cccc(C[C@@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-ethylbutoxy)benzene followed by addition to (S)-(+)-epichlorohydrin gave (R)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol. Yield (1.55 g, 59%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m, 3H), 5.13 (d, J=4.8 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (d, J=5.6 Hz, 2H), 3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=10.8, 5.6 Hz, 1H), 2.74 (dd, J=13.6, 5.2 Hz, 1H), 2.61 (dd, J=13.2, 7.4 Hz, 1H), 1.74-1.69 (m, 1H), 1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH2:15][C:16](=[O:21])[N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2].N>C(O)=O>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][C:16](=[O:21])[N:17]4[CH3:20])=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN1C(=O)Cc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Agent: N
Solvent: O=CO
Product: CN1C(=O)Cc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(N)CCOCC4)cc3)cc21
Temperature: 0 °C
Yield: 35.4 %

Procedure:
A solution of (S)-tert-butyl 4-(1-cyano-2-(4-(1-methyl-2-oxoindolin-6-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 21, step (ii), 35 mg) in formic acid (5 mL) was stirred at 50° C. for 30 min. The reaction mixture was poured into ice/water (50 mL) and basified to pH 8 with 0.880 aqueous ammonia solution. The mixture was extracted with ethyl acetate (2×40 mL) and the organics were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by reversed phase HPLC on a Waters' Sunfire column using methanol and aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the desired compound were evaporated to dryness to afford product which was further purified by chromatography on silica eluting with 3% 2M methanolic ammonia in dichloromethane. Pure fractions were evaporated to dryness to afford the titled compound (10 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)#[N:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]#[N:16])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Boc-4-hydroxypiperidine (20 g, 99.35 mmol) and 2-cyanophenol (11.82 g, 99.35 mmol) were added to mixture of triphenylphosphine (26.06 g, 99.35 mmol) and di-tert-butyl azodicarboxylate (19.56 mL, 99.35 mmol) in tetrahydrofuran (800 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was taken up in hydrochloric acid (4M in dioxane, 300 mL). The reaction mixture was stirred at room temperature for 18 hours and was then concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was separated and washed with ethyl acetate (2×100 mL). The aqueous solution was then basified with 2M sodium hydroxide solution and then extracted with diethyl ether (3×100 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid in quantitative yield. LRMS ESI m/z 203 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[NH:4][C@@H:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:24](O)(=O)C.C(N)=N>C(OCCO)C>[N+:21]([C:19]1[CH:18]=[CH:17][C:3]2[N:4]([C@@H:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:24]=[N:1][C:2]=2[CH:20]=1)([O-:23])=[O:22]
Reactant: CC(=O)O
Reactant: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1N)c1ccccc1
Agent: N=CN
Solvent: CCOCCO
Product: COC(=O)C[C@H](c1ccccc1)n1cnc2cc([N+](=O)[O-])ccc21
Temperature: 85 °C

Procedure:
To a solution of methyl (3R)-3-(2-amino-4-nitroanilino)-3-phenylpropanoate (2.10 g, 6.7 mmol) in 2-ethoxyethanol (65 mL) was added formamidine acetate (2.8 g, 26.6 mmol), and the mixture heated to 85° C. for 5 hours. The mixture was then cooled to room temperature, evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5) to afford a mixture of the title compound and the corresponding 2-ethoxyethanol ester, which was used directly without any additional purification. [LCMS (Method C, Mobile Phase I) RT=2.86 mins (broad), MH+ 326 (Me-ester) and 384 (EtOCH2CH2-ester)].
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:15][C:13]([NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]([NH:20][CH:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:26]([O:28][CH3:29])=[O:27])=[O:12])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Boc-Phe-OH (2 g, 13.77 mmol), H-Leu-OMe (11 g, 41.32 mmol), HOBt (5.58 g, 41.32 mmol), and HBTU (15.67 g, 41.32 mmol) were dissolved in DMF (69 mL) and then DIPEA (7.2 mL, 41.32 mmol) was added under argon. The reaction was stirred for 8 hrs at room temperature. The reaction was extracted by EtOAc and wash with 5% NaHSO3, sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, and concentrated by rotary evaporation. The crude was purified by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.3) to give methyl 2-(2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylamino)-4-methylpentanoate as white solid (4.5 g, 8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:9][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: Nc1ccc(Br)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)c(F)c1
Temperature: 195 °C
Yield: 43.3 %

Procedure:
4-bromobenzene-1,2-diamine (1.75 g, 9.39 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.39 mmol) were dissolved in polyphosphoric acid (70 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (1.5 g) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27].C(O)(=O)C(O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)C.C(Cl)Cl>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Br)nc2n1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Br)nc3n2)CC1
Temperature: 26 °C
Reaction time: 18 h
Yield: 8.3 %

Procedure:
The procedure described in Example 4 is followed but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (8 g.) in anhydrous dimethylformamide (240 cc.), sodium hydride (50% dispersion in mineral oil) (1.2 g.) and 1-chlorocarbonyl-4-methylpiperazine (4.1 g.) in anhydrous dimethylformamide (40 cc.). After stirring at 26° C. for 18 hours, the reaction mixture is poured into ice-water (1,500 cc.). The insoluble matter (7.3 g.) is filtered off and dissolved in a mixture (73 cc.) of methylene chloride and ethyl acetate (80-20 by volume). The solution obtained is passed through a column of silica gel (73 g.). Elution is first carried out with a mixture (5,750 cc.) of methylene chloride and ethyl acetate (80-20 by volume); the corresponding eluates are discarded. Elution is then carried out with pure ethyl acetate (1,250 cc.) and then with a mixture (1,250 cc.) of ethyl acetate and methanol (50--50 by volume); the corresponding eluates are combined and concentrated to dryness. A residue (3 g.) is obtained which is dissolved in ethanol (90 cc.). A solution of oxalic acid (0.53 g.) in ethanol (10.5 cc.) is added to the solution obtained. The mixture is stirred for 1 hour and the precipitate which forms is filtered off and washed with ethanol (6 cc.). A product (1.8 g.), melting at 260° C., is thus obtained and is treated with a saturated solution of sodium bicarbonate (50 cc.) and methylene chloride (40 cc.). The organic layer is isolated by decanting, dried over anhydrous potassium carbonate and concentrated to dryness. A residue weighing 1.2 g. is obtained and is recrystallised from ethanol (80 cc.). 2-(7-Bromo-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1yl)carbonyloxy-isoindolin-1-one (0.9 g.), melting at 225°-230° C., is thus obtained.
Reaction SMILES: C(O)(=O)C.C(O)C.[NH2:8][C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:52])[C@@H:21]([CH2:38][CH2:39][CH2:40][NH:41]C(OCC2C=CC=CC=2)=O)[NH:22][C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)=[O:10].C>[Pd].CO>[NH2:8][C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:52])[C@@H:21]([CH2:38][CH2:39][CH2:40][NH2:41])[NH:22][C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:14][CH:13]=1)=[O:10]
Reactant: NC(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CC(N)=O)cc1
Yield: 82 %

Procedure:
Prepared analogously to Example 1d) but using a mixture of glacial acetic acid and ethanol (1/1, v/v) as solvent instead of methanol, from (R)-N-[[4-(aminocarbonylmethyl)phenyl]methyl]-N2 -(diphenylacetyl)-N5 -(phenylmethoxycarbonyl)-ornithinamide by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 82% of theory. Colourless amorphous substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(OCCBr)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A reaction mixture of 4-hydroxybenzonitrile (1.19 g, 10 mmol), 1,2-dibromoethane (9.39 g, 50 mmol), and K2CO3 (4.14 g, 30 mmol) in DMF (20 mL) was stirred at 100° C. for 5 h and cooled to room temperature. To the reaction mixture was added ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford the 4-(2-bromoethoxy)benzonitrile (1.2 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12]2)=[O:9])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: O=[N+]([O-])O
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Temperature: 5 °C
Reaction time: 6 h

Procedure:
Under argon and at −10° C., 20 g (110.7 mmol) of (4-chlorophenyl)(cyclopropyl)methanone were added slowly to 60 ml of concentrated nitric acid. The reaction mixture was then slowly warmed to 5° C. and stirred at this temperature for 6 h. Carefully, the reaction solution was then added with stirring to about 100 ml of ice-water. This resulted in the precipitation of a white solid which was filtered off with suction and washed repeatedly with water. The solid obtained in this manner was then dried under high vacuum. This gave 24.3 g (97% of theory) of the desired product.
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C([Li])CCC.CCCCCC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>O1CCCC1>[CH3:1][Si:2]([C:5]1([Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C1=CC=CC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
14.7 g (0.106 moles) of trimethylsilylcyclopentadiene (obtained from Fluka) and 150 ml of tetrahydrofuran (THF) were placed in a reaction flask and cooled to 0° C. 47.4 ml of a solution of butyllithium in n-hexane (2.3 molar; total amount 0.109 moles) were added dropwise over 20 minutes. When the addition was complete, the yellow solution was stirred for a further one hour and the cooling bath was then removed. At room temperature the solution was stirred for a further one hour and then cooled to −20° C. 14.8 ml (0.117 moles) of trimethylsilyl chloride were then added dropwise over 10 minutes and the reaction mixture was stirred for two hours at −10° C. The cooling bath was then removed and the reaction solution was heated to room temperature and subsequently stirred for a further one hour. The reaction mixture was filtered through Celite; the filter was washed with hexane and the hexane was removed from the combined filtrates under vacuum. On distillation at 26° C. under 0.4 mbar, the crude product gave 19 g of pure compound 1 (85% of the theoretical yield). Boiling point and NMR data are consistent with the literature (J. Organometallic Chem. 29, (1971), 227; ibid. 30, (1971), C 57; J. Am. Chem. Soc. 102, (1980), 4429; J. Gen. Chem. USSR, Eng. Transl. 43, (1973), 1970; J. Chem. Soc., Dalton Trans. 1980, 1156). 1H NMR (400 MHz, C6D6): δ=6.74 (m, 2H); 6.43 (m, 2H); −0.04 (s, 18H).
Reaction SMILES: NC1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[H-].[Na+].IC.CC(O)=O.[CH3:17][N:18]([CH:20]=O)[CH3:19]>CCOC(C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:20]([N:18]([CH3:19])[CH3:17])=[N:3][CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(I)cn1
Reaction time: 14 h

Procedure:
To a solution of 2-amino-5-iodopyridine (1.00 g; 4.55 mmol) in 10 mL of DMF was added 545 mg of 60% NaH (13.6 mmol) and 0.85 mL of iodomethane (13.6 mmol). The mixture was stirred for 14 h, and the mixture was neutralized with 1M HOAc. The mixture was extracted with Et2O, the extract was washed with water and brine, dried with MgSO4, filtered, and concentrated. Chromatography (0–25% EtOAc in hexanes) provided 700 mg (2.82 mmol) of (5-iodo-pyridin-2-yl)-dimethyl-amine.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([Cl:12])[N:6]=1.CS(C)=O.[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18]>CO>[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21][O:11][C:10]1[C:5]([Cl:4])=[N:6][C:7]([Cl:12])=[CH:8][CH:9]=1)[CH3:18]
Reactant: Oc1ccc(Cl)nc1Cl
Reactant: CCN(CC)C(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCN(CC)C(=O)COc1ccc(Cl)nc1Cl
Temperature: 25 °C

Procedure:
A solution of 4.6 g of sodium methylate (0.2 mole) in 50 ml of absolute methanol is slowly added at room temperature to 33.4 g (0.2 mole) of 2,6-dichloropyridin-3-ol. There is then added, with gentle heating, 100 to 150 ml of dimethylsulphoxide until the cloudy solution becomes clear. The solution is then heated to 80°-90° and methanol is distilled off. The reaction solution is cooled and an addition is slowly made dropwise at 0°-10° C of a solution of 60 g (0.2 mole) of chloroacetic acid diethylamide (dissolved in 300 ml of dimethylsulphoxide). After the dropwise addition is completed, the reaction mixture is stirred at room temperature for a further hour. The solvent is distilled off under reduced pressure; the oil remaining is taken up in ether, washed with water, dried and freed from solvent to leave N,N-diethyl-(2,6-dichloro-3-pyridyl)-oxy-acetic acid amide, which boils at 137°/0.4 torr; yield: 35 g (62% of theory). Treatment with ethereal hydrochloric acid yields the hydrochloride, which is recrystallised from isopropanol.
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:14].CN1C(=O)N(C)CCC1.Br[CH2:35][CH2:36][Cl:37]>C1COCC1>[CH2:13]([O:15][C:16](=[O:24])[CH:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:35][CH2:36][Cl:37])[CH3:14]
Reactant: CCOC(=O)CC1CCCCC1
Reactant: ClCCBr
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CCCl)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (2.71 ml, 1.1 eq.) was added to dry THF (10 ml) and cooled to -78° C. N-Butyllithium (11.01 ml of 1.6 Molar solution, 1.0 eq.) was added and the mixture stirred at -78° C. for 0.5 hour. To this mixture was then added dropwise a solution of ethyl-2-cyclohexylacetate (3.0 g, 1.0 eq.) in THF (20 ml) at -78° C. and stirred for 0.5 hour. DMPU (2.13 ml, 1.0 eq.) in THF (20 ml) was added dropwise and allowed to stir at -78° C. for 10 minutes. To this mixture was added 1-bromo-2-chloroethane (1.46 ml, 1.0 eq.) in THF (10 ml) and the mixture stirred at -5° C. for 15 minutes. The mixture was then warmed to room temperature and stirred for 1.0 hour. The mixture was cooled to 0° C., quenched with saturated ammonium chloride solution, extracted with ethyl ether and the ether layer was washed three times with water. The organic layer was separated, dried over K2CO3 and the solvent removed to provide 3.6 g of product. This was fractionally distilled to provide 3.0 g of product Boiling Point 66°-70° C. at 0.05 mmHg.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(Nc3nc(C)cs3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)c2c(CN)ncc(Nc3nc(C)cs3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To a solution of [6,8-dimethoxy-4-(4-methyl-thiazol-2-ylamino)-isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester (20 mg, 0.045 mmol) in 1 mL CH2Cl2 was added a 4.0 M HCl solution in dioxane (0.70 mL). After the reaction mixture was stirred at room temperature for 20 h, the resulting yellow solid was collected by suction filtration, and dried in vacuo to give (1-aminomethyl-6,8-dimethoxy-isoquinolin-4-yl)-(4-methyl-thiazol-2-yl)amine hydrochloride salt (9.0 mg, 53%). 1H-NMR (D2O): δ, 8.35 (s, 1H), 6.75 (s, 2H), 6.35 (s, 1H), 4.78 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 2.06 (s, 3H); MS: calculated for C16H19N4O2S (M−Cl) 331.0; found: 331.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH:17]3[CH:22]=[CH:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]3)=[C:12]([F:25])[CH:11]=2)[CH2:5]1.[F:26][CH:27]([F:33])[C:28](OCC)=[O:29].C(N(CC)CC)C>CO>[O:24]=[S:20]1(=[O:23])[CH:19]=[CH:18][CH:17]([C:13]2[C:14]([F:16])=[CH:15][C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:28](=[O:29])[CH:27]([F:33])[F:26])[O:8][C:7]3=[O:9])=[CH:11][C:12]=2[F:25])[CH2:22][CH2:21]1
Reactant: CCOC(=O)C(F)F
Reactant: NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(F)F
Yield: 80.9 %

Procedure:
(5S)-5-(aminomethyl)-3-[4-(1,1-dioxido-3,4-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one monohydrochloride from Step 1 (0.400 g, 1.02 mmol), ethyl difluoroacetate (0.633 g, 5.1 mmol), and triethylamine (0.284 ml, 2.04 mmol) in methanol (8 ml) were stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give white solid (0.36 g, 80%).