Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C.C(Cl)Cl>[CH2:19]([O:18][C:16]([C:12]1([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:15][CH2:14][CH2:13]1)=[O:17])[CH3:20]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)C1(Br)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1(Nc2ccc3[nH]ncc3c2)CCC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 17.3 %

Procedure:
A mixture of 1H-indazol-5-ylamine (5.0 g, 37.6 mmol), ethyl 1-bromocyclobutane carboxylate (7.78 g, 6.08 mL, 37.6 mmol) and triethylamine (7.60 g, 10.5 mL, 75.1 mmol) in ethanol (5 mL) was heated at 100° C. for 3 days, then at 140° C. for 2 days. The reaction mixture was cooled to ambient temperature, and after 7 days the mixture was diluted with DCM (50 mL) and filtered. The filtrate was concentrated in vacuo then purified by chromatography (silica, 2 to 10% of a 9:1 MeOH:NH4OH solution in DCM) to give 1-(1H-indazol-5-ylamino)-cyclobutanecarboxylic acid ethyl ester (1.68 g, 6.49 mmol, 17%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:21])=[C:9]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27].Cl.N1C=CC=CC=1>>[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:21])=[C:9]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(F)c(OCCN3CCOCC3)cc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(F)c(OCCN4CCOCC4)cc23)c(Cl)cc1Cl

Procedure:
Following the procedure of Reference Example 8, a mixture of 4-chloro-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile (136 mg, 0.41 mmol), 2,4-dichloro-5-methoxyaniline (90.5 mg, 0.47 mmol) and pyridine hydrochloride (95 mg, 0.82 mmol) provides, after preparative thin layer chromatography eluting with 7% methanol in dichloromethane, 58 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile, mp 166-168° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([B:10]([OH:12])[OH:11])=[C:8]([CH3:13])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>O>[CH:1]([C:4]1[C:9]([B:10]([OH:12])[OH:11])=[C:8]([CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)C)c1B(O)O
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc(C(C)C)c1B(O)O
Temperature: -35 °C
Reaction time: 0.25 h

Procedure:
6-Isopropyl-2-methylbenzeneboronic acid (8 g) is added portionwise over 1 hour to 90% HNO3 (50 mL) at −40° C., maintaining an internal temperature below −30° C. After addition, the mixture is stirred at −40 to −30° C. for 15 min, then poured onto ice, and diluted with water. The solid is collected by filtration, washed with water and dried to give 6-isopropyl-2-methyl-3-nitrobenzeneboronic acid as a white solid. 1H NMR (DMSO-d6) 7.78 (d, 2H), 7.30 (d, 2H), 2.85 (m, 1H), 2.38 (s, 3H), 1.15 (d, 6H).
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.[CH:27](N(C(C)C)CC)(C)C.CNCCC>C(#N)C>[CH3:4][N:5]([CH2:6][CH2:7][CH3:27])[C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: CCCNC
Agent: [I-]
Solvent: CC#N
Product: CCCN(C)C(=O)/N=c1\sc(C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (50 mg, 0.10 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.13 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added N-methylpropan-1-amine (8 mg, 0.11 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[C:6]([O:10][C:11](=[O:34])[CH2:12][N:13]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:26])=[CH:20][N:21]=[C:22]2Cl)=[CH:17][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]>CC(O)(C)C>[C:6]([O:10][C:11](=[O:34])[CH2:12][N:13]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([Cl:26])=[CH:20][N:21]=[C:22]2[NH:4][C:3]([NH2:5])=[NH:2])=[CH:17][CH:16]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 50 °C
Yield: 11.1 %

Procedure:
N-Benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)methyl]glycine bistrifluoroacetate ##STR76## NaH (48.6 mg, 80% dispersion in mineral oil, 1.62 mmol) was added to t-BuOH (5 mL) and heated to 50° C. for 15 min. Guanidine hydrocloride (155 mg, 1.62 mmol) was added and heated at 50° C. for an additional 20 min. N-Benzyl-N-[(1,4-dichloro-7-isoquinolinyl)methyl]glycine t-butyl ester (40 mg, 0.09 mmol) added and the mixture was then heated at 95° C. for 20 h. The cooled mixture was evaporated in vacuo and the residue purified by column chromatography on silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5), followed by trituration with hexane and crystallisation with i-Pr2O, to give N-benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)methyl]glycine t-butyl ester (5 mg, 0.01 mmol) as a white solid.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].CON(C)[C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[O:14]>C(OCC)C>[CH3:8][CH:7]([CH3:9])[CH2:6][CH2:5][C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[O:14]
Reactant: CC(C)CCBr
Reactant: CON(C)C(=O)c1ccsc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
Magnesium powder (1.49 g, 61.3 mmol) was added to dry diethyl ether (100 ml) under nitrogen atmosphere. One iodine crystal (catalytic) was added, followed by 1-bromo-3-methylbutane (6.3 ml, 52.6 mmol). The reaction was initiated by sonication at 30° C. and was allowed to spontaneously reflux. Once the exothermic reaction had subsided, the mixture was added by cannulation to a solution of thiophene-3-carboxylic acid methoxy-methyl-amide (7.50 g, 43.8 mmol) in dry diethyl ether (10 ml). Once addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with saturated ammonium chloride (2×150 ml), dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by silica gel chromatography to yield the title compound as a colourless oil (1.55 g, 19%). 8H (d6 DMSO): 0.88 (6H, d), 1.49 (2H, q), 1.56 (1H, m), 2.90 (2H, t), 7.49 (1H, d), 7.59 (1H, d), 8.50 (1H, s).
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O=P(Cl)(Cl)[Cl:28]>>[CH2:9]([O:8][C:6]([C:5]1[C:4]([Cl:28])=[C:17]2[CH:16]=[N:15][N:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccccc1)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1Cl
Temperature: 130 °C
Yield: 65 %

Procedure:
A solution of 2-[(2-benzyl-2H-pyrazol-3-ylamino)-methylene]-malonic acid diethyl ester (7.0 g, 0.020 mol) in POCl3 (50 mL) was heated at reflux (130° C.) for 8 hours. The excess of POCl3 were distilled off and the reaction mixture cooled to 0° C., before careful addition of water (100 mL) and then aqueous NaOH (3N) until pH reached 7. The product was extracted with CH2Cl2 several times, and the combined orgnic phase were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/Heptane 1/6) afforded 4.10 g (65%) of the title product as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18](Br)([CH3:20])[CH3:19]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CC(C)Br
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(I)c2c(N)ncnc21
Yield: 72 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 0.0077 mol) and K2CO3 (4.2 g, 0.031 mol) in DMF (50 ml) was brought to 80° C. under an argon atomosphere. Isopropylbromide (1.0 g, 0.0084 mol) was added with a syringe. Reaction was refluxed under argon atmosphere for 2 hours. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 ml) was added and reaction was extracted with EtOAc. Organic phases concentrated in vacuo and purified using silica gel column chromatography [MeOH—CH2Cl2, 5:95] yielding BA12 (1.68 g, 72% yield). ESI-MS (M+H)+ m/z calcd 304.0, found 304.1.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]([F:25])[CH:14]=2)(O)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:25][C:15]1[CH:14]=[C:13]([C:10]2[CH2:11][CH:8]([C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH:9]=2)[CH:18]=[CH:17][C:16]=1[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)CNC(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1

Procedure:
A solution of Example 20, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid isobutyl-amide (3.71 g, 10.64 mmol) in trifluoroacetic acid (20 mL) and 1,2-dichloroethane (120 mL) was refluxed for 21 h and concentrated to give 8.6 g of crude 3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-isobutylcyclobut-2-enecarboxamide trifluoroacetate salt and residual TFA as a dark red-brown oil. Diagnostic 1H NMR signals: (CDCl3) δ 7.48 (t, J=7.7 Hz, 1H), 7.23 (d, partially obscured by CHCl3 signal, 1H), 7.09 (dd, J=10.3, 1.5 Hz, 1H), 6.38 (d, J=0.8 Hz, 1H), 4.33 (d, J=5.0 Hz, 1H), 3.77 (br s, 2H), 3.68 (d, J=4.6 Hz, 1H), 3.20-3.07 (m, 3 h), 2.98 (br s, 2H), 2.83 (dd, J=13.3, 1.7 Hz, 1H), 2.19-2.07 (m, 4H), 0.90 (d, J=7.1H, 6H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:40])[C:19]2[O:25][C:24]3[C:26]([Cl:36])=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:38])(=[O:37])[C:20]=2[CH:39]=1)=[O:15].C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:40])[C:19]2[O:25][C:24]3[C:26]([Cl:36])=[CH:27][C:28]([N:30]4[CH2:31][CH2:32][N:33]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:34][CH2:35]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:37])(=[O:38])[C:20]=2[CH:39]=1)=[O:15]
Reactant: CCCCCCCCCC=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCCCCCCN1CCN(c2cc(Cl)c3c(c2)CS(=O)(=O)c2cc(C(=O)OC)cc(C)c2O3)CC1
Temperature: 10 °C

Procedure:
Decanaldehyde (0.071 g, 0.45 mmol) was added with stirring to a solution of Example 104k (0.2 g, 0.45 mmol) in dry methanol (5 mL). Titanium isopropoxide (0.12 g, 0.45 mmol) was added and the reaction mixture was cooled to 10° C. Sodium cyanoborohydride (0.057 g, 0.9 mmol) was added and the reaction mixture was refluxed for 2 h. It was concentrated, treated with water and extracted with n-butanol. The organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, MeOH/CHCl3) to obtain the title compound. Yield.: 0.120 g (46%); 1H NMR (CDCl3): δ 0.90 (s, 5H, CH3CH2), 1.20 (m, 12H, 6CH2), 2.28 (s, 4H, 2CH2), 2.30 (t, 2H, CH2), 2.70 (t, 3H, CH3), 3.20 (t, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.80 (s, 2H, CH2), 6.80 (s, 1H, Ar), 7.00 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.4 (s 1H, Ar); MS: m/e (EI+) 577 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][Mg]Cl.Cl.C(OCC)C>C1COCC1.C(CC(=O)C)(=O)C.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C[Mg]Cl
Agent: [Fe+3]
Agent: Cl
Solvent: CC(=O)CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cnc(Cl)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-methoxypyrimidine (10 g) was dissolved in THF (100 ml), and while cooling, iron(III) acetylacetone (1.97 g), methyl magnesium chloride (3.0 M: 22.4 ml) were then added to the solution. The obtained mixture was stirred at room temperature overnight. Thereafter, iron(III) acetylacetone (1.97 g), and methyl magnesium chloride (3.0 M: 22.4 ml) were added to the reaction solution further twice. Thereafter, a 1 N hydrochloric acid aqueous solution was added to the reaction mixture, and diethyl ether was then added to the reaction solution to carry out liquid separation and extraction. The organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (6.6 g).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:29][CH2:30]2)[CH:24]=1
Reactant: CC(C)Oc1ccc(Cl)cc1N1CCNCC1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)Oc1ccc(Cl)cc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.241 g, 1.02 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.382 g, 1.13 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.583 g, 2.75 mmol, 2.67 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (100% EtOAc) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.219 g, 25%). MS: APCI: M+1: 473.2 (Exact Mass: 472.22).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].[OH-].[Na+].Br[CH2:54][CH2:55][OH:56]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:54][CH2:55][OH:56])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CCO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 20 h

Procedure:
N,N'-bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(1,3-dihydroxyprop-2-ylaminocarbonyl)-phenyl]urea (0.27 g, 0.2 mmol) from Example 4 was dissolved in water (7 ml) containing 2M aqueous NaOH (1.0 ml) and 2-bromoethanol (0.084 ml, 1.2 mmol). After stirring for 20 h, the solution was neutralized with a strongly acidic cation exchange resin and evaporated to dryness. The residue was purified by preparative HPLC. Yield 138 mg (50%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[C:22](O)(=[O:26])[C@H:23]([CH3:25])[OH:24].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:22](=[O:26])[C@@H:23]([OH:24])[CH3:25])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: C[C@H](O)C(=O)O
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A solution of 0.47 g (1.69 mmol) (S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one in 15 ml tetrahydrofurane was treated at 0° C. with 0.17 g (1.86 mmol) L-lactic acid, 0.26 g (1.69 mmol) 1-hydroxybenzotriazole hydrate, 590 μl (3.38 mmol) N-ethyldiisopropylamine and 0.33 g (1.69 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) yielded 0.50 g (84%) (S)—N—((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-hydroxy-propionamide as white solid; MS: m/e: 351.4 (M+H+), [α] 589=−131° (1% in MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6](I)[N:5]=1)[CH3:2].[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1nc(I)ccc1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CCOc1nc(C#N)ccc1OC
Temperature: 150 °C

Procedure:
To a solution of 2-ethoxy-6-iodo-3-methoxypyridine (10-2, 100 mg, 0.36 mmol, 1 equiv) in DMF (675 uL) was added copper cyanide (39 mg, 0.43, mmol, 1.2 equiv). The reaction mixture was heated in a microwave reactor at 150° C. for 20 minutes, and then was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was extracted with DCM (3×25 mL), and the organic phase was dried over Mg2SO4, concentrated and purified by normal phase column chromatography (20-50% EtOAc in hexanes) to yield the title compound (10-3) as a white solid. ESI+MS [M+H]+ C9H11N2O2: 179.1 found, 179.2 required.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[F:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1F
Reactant: Oc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2ccccc2)cc1F
Temperature: 120 °C
Yield: 57.6 %

Procedure:
Mix under argon atmosphere (4-bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester (2.12 g, 7.0 mmol), phenol (1.32 g, 14 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (129 mg, 0.7 mmol), and cesium carbonate (4.56 g, 14 mmol) in anhydrous NMP (15 mL). Degas the flask, fill with argon and add copper(I) chloride (346 mg, 3.5 mmol) quickly. Degas the flask then fill with argon and heat at 120° C. for 5 h. Cool to ambient temperature, dilute with EtOAc and filter. Wash the mixture sequentially with 0.5N aqueous HCl, 0.5N aqueous NaOH and brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 3:1) to obtain the desired intermediate (1.28 g, 58%). GC-MS m/z: 260 [(M-C4H9)+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=1[S:19]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: O=C1CNCCN1
Product: O=C1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using piperazin-2-one and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.43-8.35 (d, J=2.3, 1H), 7.99-7.89 (d, J=8.2, 1H), 7.77-7.65 (dd, J=8.3, 2.3, 2H), 6.95 (s, 2H), 3.99 (s, 3H), 3.73-3.58 (t, J=5.3, 3H), 3.51-3.42 (m, 3H), 1.36-1.04 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.ClC1C=CN=CC=1.[Li+].CC([N-]C(C)C)C.[CH:24](OCC)=[O:25]>C([O-])(O)=O.[Na+].C(Cl)Cl.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:24]=[O:25]
Reactant: Clc1ccncc1
Reactant: CCOC=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cnccc1Cl
Temperature: -78 °C
Reaction time: 4 h

Procedure:
4-Chloropyridine (3.1 g, 27.3 mmol, after drying over Na2SO4) was extracted from a mixture of 4-chloropyridine hydrochloride in 5% NaHCO3 with methylene chloride, dissolved in THF (50 mL), and cooled to −78° C. under dry nitrogen, followed by addition of LDA (1.5 M in cylclohexane, 18.2 mL). After 4 hours at −78° C., excess ethyl formate was added quickly. After 3 hours at −78° C., the reaction was allowed to warm to ambient temperature overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, chromatographed (20% EtOAc in hexanes), and dried under high vacuum to give 1.47 g of the aldehyde. MS m/e 142 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 7.44 (d, 1H, J=6 Hz), 8.69 (d, 1H, J=6 Hz), 9.06 (s, 1H), 10.51 (s, 1H).