Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([N+:30]([O-])=O)=[C:20](Cl)[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[CH3:36][NH:37][CH2:38][C:39](OC)=[O:40].C(N(CC)CC)C>CO>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[NH:30][C:39](=[O:40])[CH2:38][N:37]([CH3:36])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CNCC(=O)OC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(Cl)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CC(=O)Nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc21
Temperature: 80 °C
Yield: 64.2 %

Procedure:
In a microwave vial were added tert-butyl(1-(4-(6-chloro-5-nitro-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.417 mmol), methyl 2-(methylamino)acetate hydrochloride (58 mg, 0.417 mmol) and triethylamine (58 μl, 0.417 mmol) in methanol (2 ml). The solution was heated to 80° C. under microwave irradiation for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 100:0 to 0:100) to afford the title compound (103 mg, 65%). 1H NMR (500 MHz, CDCl3): 8.29 (1H, s), 7.25-7.38 (7H, m), 7.15-7.23 (2H, m), 5.05 (1H, br s), 4.39 (2H, s), 3.83 (3H, s), 3.11 (3H, s), 2.25-2.65 (4H, m), 2.05-2.20 (1H, m), 1.80-1.95 (1H, m), 1.10-1.50 (9H, br).
Reaction SMILES: [C:1]1([C:7]2([NH:10][C:11](=[O:13])[CH3:12])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH2:16][Cl:17]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:17][CH2:16][C:4]1[CH:5]=[CH:6][C:1]([C:7]2([NH:10][C:11](=[O:13])[CH3:12])[CH2:8][CH2:9]2)=[CH:2][CH:3]=1
Reactant: COCCl
Reactant: CC(=O)NC1(c2ccccc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of N-(1-phenylcyclopropyl)acetamide (5.0 g) in methylene chloride (35 ml) was added titanium tetrachloride (6.26 ml) under ice-cooling and to this solution was added dropwise a solution of methoxymethyl chloride (4.33 ml) in methylene chloride (15 ml) over 10 min under ice-cooling. The mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into ice water and extracted with chloroform (50 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (3.71 g) as white crystals, m.p.=124-127° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:20]#[N:21])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](B2OC(C)(C)C(C)(C)O2)=[C:27]([NH:29]C(=O)OC(C)(C)C)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.C(Cl)Cl.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>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]2=[C:2]3[C:3](=[C:20]([NH2:21])[N:29]=[C:27]2[CH:28]=1)[N:4]=[CH:5][C:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)=[CH:7]3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: CCCOc1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-(4-propoxyphenethyl)picolinonitrile (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol %), and 2N aqueous sodium carbonate solution (3.0 eq.) in toluene (0.2 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM. The two phases were separated. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give 8-methyl-2-(4-propoxyphenethyl)benzo[f][1,7]naphthyridin-5-amine. 1H NMR (Acetone-d6): δ 8.74 (s, 1H), 8.67 (s, 1H), 8.24 (d, 1H), 7.41 (s, 1H), 7.15-7.17 (m, 3H), 6.81 (d, 2H), 6.5 (br, 2H), 3.87 (t, 2H), 3.18 (t, 2H), 3.04 (t, 2H), 2.44 (s, 3H), 1.73 (m, 2H), 0.99 (t, 3H). LRMS [M+H]=372.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH:26]([C:28]1[NH:32][N:31]=[N:30][N:29]=1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:26][C:28]1[NH:32][N:31]=[N:30][N:29]=1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: O=Cc1nnn[nH]1
Product: CC1=C(CCON=Cc2nnn[nH]2)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 5-formyltetrazole by the method of Example 1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].[NH:35]1[C:43]2[C:38](=[N:39][C:40]([NH2:44])=[CH:41][CH:42]=2)[N:37]=[CH:36]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:44][C:40]2[N:39]=[C:38]3[N:37]=[CH:36][NH:35][C:43]3=[CH:42][CH:41]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc2[nH]cnc2n1
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4[nH]cnc4n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 217a (158 mg, 0.30 mmol), 1H-imidazo[4,5-b]pyridin-5-amine (80 mg, 0.60 mmol), Pd2(dba)3 (27 mg, 0.030 mmol), XantPhos (35 mg, 0.061 mmol), cesium carbonate (200 mg, 0.60 mmol), and 1,4-dioxane (5 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 100° C. for 6 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 217b (40 mg, 23%) as a yellow solid. MS-ESI: [M+H]+ 579.4
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[C:4](=[O:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[BH4-].[Na+].Cl>CO>[F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[CH:4]([OH:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: CC(CF)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(CF)(CF)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
130.5 g (0.395 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-2-butanone were dissolved in 800 ml of methanol, and 21 g (0.55 mol) of sodium borohydride were added in portions. The reaction solution was subsequently stirred for 15 hours and was then adjusted to a pH value of 3 with concentrated hydrochloric acid. The mixture was then stirred for 2 hours. After distilling off the solvent in vacuo, water/sodium bicarbonate were added to the residue and the mixture was extracted by shaking with 600 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was crystallized with diisopropyl ether. 112 g (86% of theory) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 97°-102° C. were obtained. ##STR77##
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[N:25]=1)[C:20]([OH:22])=O>CCOC(C)=O>[Cl:26][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([Cl:16])[N:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)nc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2,6-dichloro-isonicotinic acid (CAS RN 5398-44-7) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system eluting with EtOAc (isocratic). The product-containing fractions were pooled and evaporated to give a colorless foam. The foam was dissolved in EtOAc and washed three times with 2M aqueous Na2CO3 solution and brine, dried over MgSO4, filtered and evaporated. Colorless foam (13%). MS (ESI): m/z=372.07 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)C=CC=CC=1.NC1C2C(=CC=CC=2)CCC1.[CH2:32]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([F:49])=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH:40]1[NH2:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>CS(C)=O.O>[CH2:32]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([F:49])=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH:40]1[NH:50][C:8]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2)=[O:20])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC1CCc2cc(F)ccc2C1Cc1ccccc1
Reactant: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Agent: NC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccc2cnccc12)NC1CCc2cc(F)ccc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isoquinolin-5-yl-carbamic acid phenyl ester 2-1 (0.005 mole, 1.32 g) was dissolved in 15 mL of DMSO (dimethylsulfoxide) followed by the addition of the aminotetralin 2-2, 1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine (0.0044 mole, 1.12 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was poured into 50 mL of water containing 10 mL of 1N NaOH (sodium hydroxide). The precipitated solid was collected by filtration. This solid was chromatographed on silica gel eluting with methylene chloride, 3% methanol. Subsequently the product was further purified by recrystallization from ethyl acetate. The title compound 38, (1-(1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea) was obtained as an off-white solid (1.25 g, 0.00295 mole). MS (MH+): 426; 1H NMR (MeOH): δ 1.35 (m, 1H), 1.9 (m, 1H), 2.1-2.2 (m, 1H), 2.9-3.1 (m, 4H) 3.45 (m, 1H), 4.1-4.2 (m, 1H), 6.7 (t, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 5H), 7.85 (t, 1H), 8.1 (d, 1H), 8.25 (d, 1H), 8.35 (d, 1H), 8.6 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[O:14](S(C(F)(F)F)(=O)=O)[S:15]([C:18]([F:21])([F:20])[F:19])(=O)=[O:16]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[S:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])(=[O:16])=[O:14]
Reactant: O=Cc1ccc(O)c(C(F)(F)F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a mixture of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (500 mg, 2.7 mmol), TEA (805 mg, 8.0 mmol) in anhydrous DCM (10 mL) was added Tf2O (820 mg, 2.9 mmol) drop wise at 0° C., and stirred at the same temperature for 30 mins. Followed a standard aqueous/EtOAc workup and purified by column chromatography (PE:EtOAc=10:1) to give product (560 mg, 66% yield).
Reaction SMILES: [OH-].[Na+].O[C:4](=[CH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:14][C@H](C([O-])=O)CC([O-])=O>>[CH:13]1[C:9]([CH2:8][C@H:4]([NH2:14])[C:5]([OH:7])=[O:6])=[CH:10][S:11][CH:12]=1
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Reactant: O=C(O)C(O)=Cc1ccsc1
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](Cc1ccsc1)C(=O)O
Yield: 39.3 %

Procedure:
The procedure was largely as in Example 8. However, solution 1 contained only 20 g of hydroxy-3-(3-thienyl)acrylic acid and 19 g of L-aspartate. The product concentration was 11.5 g/l (58%) after the reaction. After ion-exchange chromatography, 7.9 g (40%) of L-3-(3-thienyl)alanine (2B) were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:29])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:29])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)/C=C/c2ccc(F)c(F)c2)c2cc(O)ccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1c(C(=O)CCc2ccc(F)c(F)c2)c2cc(O)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
General Procedure H. To a solution of (E)-1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)prop-2-en-1-one (Compound 30, 25 mg, 0.058 mmol) in MeOH (2.0 ml) was added Pd—C (10%, 3.0 mg, 0.0029 mmol). The suspension was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 2 h. The mixture was filtered through a pad of silica gel and concentrated. The residue was purified by PTLC (30% EtOAc-hexanes) to yield 1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)propan-1-one (Compound 31) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=3)[N:3]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2nc(Cl)nc(N3CCOCC3)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCOCC3)c2cc1OC
Yield: 52 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-4-morpholin-4-yl-quinazoline (3.10 g, 10.01 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 10.01 mmol, 1.0 equiv; commercially available), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.25 g, 0.40 mmol, 0.04 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.20 mmol, 0.02 equiv) and KOtert-Bu (1.35 g, 12.01 mmol, 1.2 equiv) in toluene (10 mL) was heated under Ar by microwave irradiation to 100° C. for 2 h. The crude reaction mixture was filtered through Hyflo Super Cel, a sat. solution of sodium chloride (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate to provide 2.45 g (52%) of the title compound. MS (ISP): 474.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:12]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C@@H:3]([CH2:4][C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)[C:2]([NH2:1])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)Cc1ccc(Br)nc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
(S)-tert-Butyl 1-amino-3-(6-bromopyridin-3-yl)-1-oxopropan-2-ylcarbamate (1.5 g) was dissolved in DCM (20 mL) and to the solution was added TFA (10 mL). The reaction mixture was stirred for 0.5 h then concentrated in vacuo. Crude material was dissolved in methanol and loaded onto an SCX cartridge. Non-basic impurities were washed off with methanol, then product was eluted with 10% ammonia in methanol to give the sub-title compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:38][CH2:37][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:19][CH2:18]2)=[O:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl[CH2:40][C:41]([N:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])=[O:42].C(=O)([O-])O.[Na+].O>CN(C=O)C>[CH2:44]([N:43]([CH2:47][CH2:48][CH3:49])[C:41]([CH2:40][O:7][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:18][CH2:19][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:37][CH2:38]2)=[O:16])=[CH:12][C:2]=1[Cl:1])=[O:42])[CH2:45][CH3:46]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)c(Cl)c4)CC3)N2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C(=O)COC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1Cl
Temperature: 60 °C

Procedure:
A solution of [2-Chloro-4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (step 2) (4.82 g, 8.52 mmol) in DMF (70 ml) was treated with 2-chloro-N,N-dipropyl-acetamide (3.18 g, 17.9 mmol) followed by sodium hydrogen carbonate (2.26 g, 26.9 mmol) and the resulting suspension heated to 60° C. overnight. Water (500 ml) was added to the reaction mixture and the product extracted with EtOAc (1000 ml). The organic extracts were washed with water (500 ml) and brine (500 ml), dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-12% 2N ammonia in ethanol in DCM followed by further purification by C18 reverse phase chromatography eluting with MeCN/water afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (1H, br s), 8.36 (1H, br s), 7.34 (1H, d), 7.14 (1H, dd), 7.02 (1H, s), 6.71 (2H, br s), 4.95 (2H, s), 4.89 (2H, s), 3.67-3.53 (2H, m), 3.39 (3H, br s), 3.19 (2H, t), 3.13 (2H, t), 2.75 (2H, t), 2.62 (2H, t), 1.65-1.41 (8H, m), 0.85 (3H, t), 0.80 (3H, t). LC-MS Rt 4.11 mins; 706.5 [M+H]+, Method 10minLC_v003.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>ClCCl.[Cl-].[Na+].O>[I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)nc1I
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 59A (1.3 g, 5 mmole) and diisopropyl-ethyl amine (1.3 mL, 7.5 mmole) in dichloromethane (20 mL) at ambient temperature was added 2-(trimethylsilyl)ethoxymethyl chloride (1.25 g, 7.5 mmole) dropwise. The solution was stirred overnight. Brine (20 mL) was added and the mixture was extracted with ethyl acetate. The mixture was dried with magnesium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with 25% ethyl acetate in hexane. The two regioisomers were isolated as a mixture. MS (DCI) m/e 397 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=[O:13])[C:10](O)=[O:11]>Cl>[NH:8]1[C:10](=[O:11])[C:9](=[O:13])[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1cccnc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cccnc2[nH]c1=O
Yield: 90.1 %

Procedure:
To a suspension of 2,3-diaminopyridine (20 g, 0.136 mol) in 4N aqueous HCl (200 ml) is added oxalic acid (20.7 g, 0.164 mol) and the reaction mixture is refluxed for 20 h. The reaction mixture is cooled and the solid precipitated is filtered, washed with water and dried under vacuum to afford 20 g (89%) of the title compound as a solid. HPLC (max plot) 98%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br.CCOC(C)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COC(CBr)OC
Reactant: CC(=O)c1ccc(O)c(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Temperature: 65 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
1-(2-Amino-3-chloro-4-hydroxyphenyl)ethanone (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65° C. for 24 h. Upon cooling to room temperature, EtOAc (1 L) and H2O (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1×400 ml). The combined organic layer was washed with aqueous 3% LiCl solution (2×1 L), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]-ethanone as a white solid (39 g, 67% yield).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11]>CC#N>[C:1]([NH:5][C:10]([NH:9][CH2:8][CH2:7][Cl:6])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C=NCCCl
Solvent: CC#N
Product: CC(C)(C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A solution of t-butylamine (6.00 g, 82 mmol) in MeCN (120 mL) was treated with 2-chloroethylisocyanate (9.00 g, 85 mmol), stirred at RT for 1 h, and the resulting solid was collected via filtration to afford 1-(tert-butyl)-3-(2-chloroethyl)urea (12.2 g, 83%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 5.89 (t, J=5.9 Hz, 1 H), 5.82 (s, 1 H), 3.53 (t, J=6.2 Hz, 2 H), 3.24 (q, J=6.1 Hz, 2 H), 1.19 (s, 9 H); MS (ESI) m/z: 179.1 (M+H+).