Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([Br:15])=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].Br[CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])=[O:19].C1CCN2C(=NCCC2)CC1.CO>C1(C)C=CC=CC=1.CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18](=[O:19])[NH:20][C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[C:8]([Br:15])=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(Br)nc1C(F)(F)F
Reactant: Cc1cc(C)c(NC(=O)CBr)c(C)c1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(Br)n1CC(=O)Nc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 2-bromo-5-trifluoromethyl-3H-imidazole-4-carboxylic acid ethyl ester (3.00 g, 10.45 mmol) and 2-bromo-N-(2,4,6-trimethyl-phenyl)-acetamide (2.94 g, 11.50 mmol) in a mixture of toluene (16 mL) and acetone (8 mL) was added DBU (1.72 mL, 11.50 mmol). The resulting solution was stirred at room temperature for 5 days. Methanol (10 mL) was added to dissolve the precipitate formed, followed by the addition of silica gel (25 g). The solvent was removed under reduced pressure to dryness and the residue was applied to a silica gel-packed column. The isolation of the product was achieved by column chromatography (hexanes-ethyl acetate 4:1). Yield—4.25 g (88%). LC/MS: tR=1.62 min., MS: [M+H]=462.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH2:3]1.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39](=O)[O:40]C1C=CC=CC=1>C1COCC1>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:16]2[CH:15]=[C:14]3[C:19]([C:20]4[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:39]([NH:38][C:34]6[S:33][CH:37]=[CH:36][N:35]=6)=[O:40])[CH2:3]5)=[CH:9][CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]=4[NH:13]3)=[CH:18][CH:17]=2)=[O:22])[CH2:24][CH2:25]1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](N)C4)c23)CC1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](NC(=O)Nc5nccs5)C4)c23)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
A solution of (R)-4-(3-aminopiperidin-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 17-1, 23 mg, 0.053 mmol) and TEA (0.015 mL, 0.106 mmol) in THF (3 mL) was treated with phenyl thiazol-2-ylcarbamate (17.49 mg, 0.079 mmol). The mixture was stirred at 60° C. for 1.5 h, then at 70° C. for 2 h, then was concentrated and purified by preparative HPLC. The isolated TFA salt was partitioned between DCM and NaHCO3 (aq), and the organic phase was dried and concentrated to provide (R)-7-(4-methylpiperazine-1-carbonyl)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-9H-carbazole-1-carboxamide as a white solid (14 mg, 43%). 1H NMR (400 MHz, methanol-d4) δ 8.27 (1H, d, J=7.9 Hz), 7.87 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=1.1 Hz), 7.28 (1H, d, J=7.9 Hz), 7.18 (1H, br. s.), 6.93 (1H, d, J=3.7 Hz), 6.87 (1H, d, J=8.3 Hz), 4.25 (1H, br.), 3.82 (2H, br.), 3.41-3.68 (3H, m), 3.19 (3H, br.), 2.36-2.63 (4H, m), 2.33 (3H, s), 1.84-2.20 (3H, m), 1.71 (1H, br. s.). Mass spectrum m/z 561.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O.[O:18]([CH2:25][C:26]([OH:28])=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N+]([O-])(O)=O.[O:33]([CH2:37][CH2:38][NH2:39])[N+:34]([O-:36])=[O:35]>O1CCCC1>[O:33]([CH2:37][CH2:38][NH:39][C:26](=[O:28])[CH2:25][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N+:34]([O-:36])=[O:35]
Reactant: O=C(O)COc1ccccc1
Reactant: NCCO[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: O=C(COc1ccccc1)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
1.5 ml of triethylamine and 0.7 ml of diethyl cyanophosphate were added to a suspension of 0.65 g of phenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate in 20 ml of tetrahydrofuran with ice-cooling. The mixture was stirred at room temperature for 2 hours and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluent; hexane: ethyl acetate=1:1) and then recrystallized from diisopropyl ether to give 0.27 g of the title compound as colorless needles.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[CH3:35][N:36]1[CH2:40][CH:39]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:38]=[N:37]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(c2cn(S(=O)(=O)c3ccccc3)c3ncnc(N4CCC(NC(=O)c5ccccc5)CC4)c23)C=N1
Temperature: 25 °C

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D6 (400 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (185 mg, 0.89 mmol, commercially available from Maybridge, Sigma-Aldrich and Fluorochem), potassium phosphate trihydrate (590 mg, 2.22 mmol), palladium tetrakis (26 mg, 0.022 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml) and stirred under nitrogen at 90° C. overnight. Cooled to room temperature and the solvent removed in vacuo. Water (30 ml) was added and extracted with EtOAc (3×30 ml). The combined extracts were washed with brine and dried over MgSO4, concentrated to give crude product which was purified by silica gel column eluting with EtOAc to give 160 mg of desired product D27. LCMS [MH+] 542.2@1.56 min (5 min run)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(N2CCCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (172 mg, 0.492 mmol), 3-(methoxycarbonyl)phenylboric acid (177 mg, 0.984 mmol) and molecular sieves 4 Å (400 mg) were suspended in dichloromethane (10 mL). To this suspension, copper (II) acetate (188 mg, 0.984 mmol) and triethylamine (0.344 mL, 2.46 mmol) were added and the mixture was stirred at room temperature for 8 hours. Subsequently, the reaction mixture was filtered through Celite, followed by addition of a saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=20:1->2:1) gave 88.2 mg (37%) of the desired compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[N:7]1[CH:2]=[CH:3][N:4]=[CH:5][C:6]=1[NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)CNc1cncc(Cl)n1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CNc1cnccn1
Reaction time: 18 h
Yield: 77.1 %

Procedure:
Ethyl 2-(6-chloropyrazin-2-ylamino)acetate (23.6 g, 109 mmol) was dissolved in non-denatured ethanol (250 mL) and potassium carbonate (15.13 g, 109 mmol) was added. The reaction was put under nitrogen and palladium hydroxide (3.84 g, 5.47 mmol) was added. The reaction was stirred under an atmosphere of hydrogen for 18 h. Additional palladium hydroxide (3.84 g, 5.47 mmol) was added and the reaction was charged with additional hydrogen and allowed to stir overnight. The reaction was filtered through Celite and the solvent was removed under reduced pressure to afford the title compound (15.13 g, 84 mmol, 76% yield). MS (ESI) m/z 182.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH2:31][CH2:30][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 99.7 %

Procedure:
To a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Intermediate B120, 10.0 g, 23.27 mmol) and 1,4-dioxane (400 mL) was added MeOH (˜100 mL) to enhance solubility. Methyl vinyl sulfone (6.1 mL, 69.8 mmol) and Na2CO3 (7.4 g, 69.8 mmol) were added and the resultant mixture was heated at 80° C. overnight. The solvent was evaporated and the residue was taken up in DCM (300 mL) and filtered to remove salts. The filtrate was concentrated in vacuo to afford 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-[2-(methylsulfonyl)ethyl]piperazine (9.9 g, >95%) which was carried forward with no further purification. MS (ES+, m/z) 427 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: Brc1cncnc1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cncnc2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 5-Bromopyrimidine instead of 3-bromopyridineto yield the final compound as a off-white solid, MS (ISP): m/e=354.1 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[CH3:26])[C:13](=[O:27])[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:27]
Reactant: Cc1cnccc1NCCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1cnccc1NCCN1CCNCC1=O
Yield: 61.1 %

Procedure:
4-[2-(3-Methylpyridin-4-ylamino)-ethyl]-3-oxo-piperazine-1-carboxlic acid benzyl ester (0.20 g, 0.54 mmol) is dissolved in anhydrous ethanol (20 mL) and hydrogenated at 50 PSI with 10% Pd/C overnight. After filtration, the filtrate is concentrated. The residue is treated with Pd black in 5% HCO2H/CH2Cl2 (10 ml) for 10 minutes. Filtration and concentration gives crude residue, which is purified by chromatography using NH4OH/MeOH/CH2Cl2 (1:5:95) to give the title compound as a clear syrup (0.078 g, 0.33 mmol). 1H NMR (CDCl3, 300 MHz) δ8.17 (d, 1H), 8.03 (s, 1H), 7.35 (s, 5H), 6.36 (d, 1H), 5.30 (b, 1H), 3.74 (t, 2H), 3.53 (s, 2H), 3.38 (m, 4H), 3.08 (t, 2H), 2.02 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:8]([Cl:17])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1>[Cl:17][C:8]1[C:9]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(OCC2CCC2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OCC2CCC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-cyclobutylmethoxy-pyridine-2-carboxylic acid methyl ester (339 mg, 1.33 mmol) in THF (10 mL) was added sodium hydroxide solution (2.65 mL, 1 N). The resulting solution was stirred at room temperature for 2 hours, and afterwards acidified with hydrochloric acid (10 mL, 1N) and poured into ethyl acetate (50 mL). The phases were separated and the water phase was extracted with additional ethyl acetate; the organic portions were combined, dried over Na2SO4, filtered and concentrated. The crude material (286 mg, 89%) a white solid, was sufficiently pure to be used in the next step without further purification. MS (ESI, m/z): 240.1 (M−H−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][CH2:26][F:27])[C@H:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[H][H]>CO.[Pd]>[F:27][CH2:26][CH2:25][CH2:24][N:8]([C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCF)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCF)[C@H]1CCNC1

Procedure:
To a solution of (S)-benzyl 3-(tert-butoxycarbonyl(3-fluoropropyl)amino)pyrrolidine-1-carboxylate (611 mg, 1.6 mmol) in methanol (6.5 mL) was added ammonium formate (1.1 g, 18 mmol) followed palladium on carbon (10% w/w, 479 mg, 0.22 mmol). The reaction mixture was stirred at ambient temperature under a balloon of hydrogen for 1 hour, then degassed and filtered over a pad of celite. The filtrate was concentrated in vacuo to afford a residue, which was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=[O:21])[C@H:12]([NH:22]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH2:22][C@@H:12]1[CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:13]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ylcarbamate from Step F (135 mg, 0.320 mmol) in CH2Cl2 (5 mL) was added CF3CO2H (2.5 mL). After 30 min, the solution was concentrated in vacuo and azeotroped with toluene (2×). Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound. MS: m/z=323 (M+1).
Reaction SMILES: C([O-])(=O)C.[K+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23].C(OC(=O)C)(=O)C.C(O[N:41]=O)CC(C)C>C1C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][N:41]=[C:21]2[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)CCON=O
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(C)OC(=O)c1n[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A mixture of potassium acetate (1.34 g), isopropyl 2-amino-5-benzyloxyphenylacetate (3.9 g) and acetic anhydride (4.0 g) in benzene (40 ml) was stirred at 80° C. After 30 minutes, isopentylnitrite (2.3 g) was added dropwise to the mixture over 15 minutes and then the mixture was stirred at same temperature for 4 hours. After cooling, insoluble mass was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol (30 ml) containing conc. sulphuric acid (0.5 ml) and the mixture was stirred at 80° C. for 3 hours. After cooling to room temperatures the resulting crystals were collected by filtration and washed with isopropyl ether to give isopropyl 5-benzyloxy-1H-indazole-3-carboxylate (2.4 g).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([O:4][C:5]([NH:7][C@H:8]([C:19]([NH:21][C@@H:22]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])=[O:6])[CH3:3].CN1CCOCC1.[CH2:44]([O:51][C:52](Cl)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CCCCCC>C(Cl)Cl>[CH3:36][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:19]([NH:21][C@@H:22]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:53])=[CH:12][C:11]=1[CH3:18])=[O:6])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(OC(=O)OCc2ccccc2)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Temperature: -20 °C
Yield: 98.1 %

Procedure:
To N[(1,1-dimethylethoxy)carbonyl]-2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide (1.0 g, 2.0 mmol) dissolved in 75 ml of CH2Cl2 and cooled to -20° C. was added 264 mg (0.3 mmol) of N-methylmorpholine. The reaction was then cooled to -78° C. and maintained under an argon atmosphere. Benzylchloroformate (445 mg, 2.5 mmol) was then added to the stirred reaction mixture. The reaction was allowed to slowly warm to room temperature an stir overnight. The mixture was then filtered and the filtrate diluted with CH2CL2 (150 ml). This filtrate was washed 3 times with 75 ml aliquots of 0.5N KHSO4 and once with 75 ml of brine before it was dried over Na2SO4. The organic layer was then stripped of all solvent under reduced pressure to yield a pale yellow solid which by TLC was a mixture of product and starting material. This material was redissolved in 40 ml of CH 2 CL2 and then retreated with N-methylmorpholine and benzylchloroformate in a manner identical to the reaction disclosed above. This second reaction was worked up as described for the original reaction yield a pale yellow solid which was then triterated with hexane containing 5% diethylether to give 1.24 g of the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:55][C@H:56]1[CH2:60][NH:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:59]1[CH2:60][C@H:56]([OH:55])[CH2:57][C@H:58]1[C:61]([O:63][CH3:64])=[O:62])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (2 g, 6.6 mmole), synthesized using Scheme 1, in dichloromethane (20 mL) was added DIPEA (11.5 mL, 33.0 mmole), HATU (2.7 g, 7.2 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.3 g, 7.2 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude (2S,4R)-methyl 1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate. The crude product was taken to the next step without further purification (2.2 g, 80%). MS: MS m/z 427.2 (M++1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24]2.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>COCCOC.CO>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:2]1[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=1)[CH:25]=[CH:24]2
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: COc1ccc2cc(-c3n[nH]c4ccc(C#N)cc34)ccc2c1
Temperature: 45 °C
Yield: 48 %

Procedure:
The title compound was prepared as described in Example 161, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.500 g, 1.6 mmol), in ethylene glycol dimethyl ether (30 mL), 6-methoxynaphthalene-2-boronic acid (0.395 g, 2.0 mmol), [1,1′-bis(diphenyl phosphino-ferrocene] complex with dichloromethane (1:1) (0.133 g, 0.16 mmol) and potassium phosphate (3.5 g, 16.3 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (silica gel, 20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45° C. for 5 h. One half of the methanol was evaporated, water was added and the solid filtered and dried in a vacuum oven to afford the title compound (0.230 g, 47% yield over 2 steps): ES-MS (m/z) 300 [M+1]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C)c3)c(=O)n(C3CCCC3)c12
Yield: 72.2 %

Procedure:
1-Cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (29 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 402 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.46 (s, 1H), 7.77 (d, 1H), 7.53 (t, 1H), 7.46 (d, 1H), 7.32 (s, 1H), 7.16 (d, 1H), 7.14 (d, 1H), 6.83 (d, 1H), 5.06 (p, 1H), 4.12 (s, 3H), 2.41 (m, 2H), 2.32 (s, 3H), 1.98 (m, 4H), 1.32 (m, 2H) ppm.