Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:68][CH2:67][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([CH:63]5[CH2:64][CH2:65][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:67][CH2:68]5)=[CH:59][CH:58]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)Oc1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1

Procedure:
7-(3-Isopropoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (100 mg, 0.4 mmol), N-Phenylbis(trifluoromethanesulphonimide) (146 mg, 0.408 mmol), N,N-Diisopropylethylamine (0.194 mL, 1.11 mmol), and N,N-Dimethylformamide (3 mL, 40 mmol) and stir at room temperature for half an hour. Add 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (139 mg, 0.594 mmol) and stir at 60° C. overnight. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were basified with saturated sodium bicarbonate, extracted with ethyl acetate, dried, filtered and collected as a yellow solid (47 mg, 30%). MP 233-235° C. LCMS (E/I+) 485 (M+H). NMR 1H (DMSO-d6)-9.43 (s, 1H), 8.97 (s, 1H), 7.82 (s, 1H), 7.73 (d, 2H, J=8.04 Hz), 7.66 (d, 1H, J=7.72 Hz), 7.43 (t, 1H, J=7.80 Hz), 7.14-7.22 (m, 5H), 6.98 (d, 1H, J=8.17 Hz), 6.94 (d, 1H, J=4.50 Hz), 4.70-4.75 (m, 1H), 2.87-2.95 (m, 4H), 2.40-2.46 (m, 1H), 2.10-2.22 (m, 2H), 1.70-1.76 (m, 4H), 1.31 (d, 6H, J=5.79 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>CCO.O>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][S:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1
Reactant: OB(O)c1cc(CN2CCSCC2)cnc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCSCC4)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (312 mg, 0.811 mmol), 2-fluoro-5-(thiomorpholinomethyl)pyridin-3-ylboronic acid (249 mg, 0.973 mmol), Am-Phos (40 mg, 0.057 mmol), and potassium acetate (239 mg, 2.432 mmol) in EtOH (3.5 mL) and water (1.5 mL) was heated in a microwave at 100° C. for 30 min. The mixture was partitioned between EtOAc (20 mL) and 1 N NaOH (3 mL). The separated EtOAc layer was washed with brine, concentrated and purified on a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 30-70% EtOAc in hexanes to give 4-(2-fluoro-5-(thiomorpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (306 mg, 67.3% yield) as a yellow viscous oil. 1H NMR (400 MHz) δ 8.47 (dd, J=9.3, 1.9 Hz, 1H); 8.28 (s, 1H); 7.24 (d, J=8.4 Hz, 4H); 6.90 (t, J=8.5 Hz, 4H); 4.76 (d, J=4.9 Hz, 4H); 3.74 (s, 3H); 3.73 (s, 3H); 3.60 (s, 2H); 2.66-2.58 (m, 8H); 2.47 (s, 3H). m/z (ESI, +ve ion) 561 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:32][C:33]3([CH3:37])[CH2:36][O:35][CH2:34]3)[C:17]([NH:19][C:20]3[CH:31]=[CH:30][C:23]([C:24]([O:26]CC=C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.CNC1C=CC=CC=1>O1CCCC1.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:32][C:33]3([CH3:37])[CH2:34][O:35][CH2:36]3)[C:17]([NH:19][C:20]3[CH:31]=[CH:30][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: C=CCOC(=O)c1ccc(NC(=O)C(CC2(C)COC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CNc1ccccc1
Product: COc1cn(C(CC2(C)COC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25 mg (44 μmol) of allyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoyl}amino)benzoate (racemate) and 48.2 μl (445 μmol) of N-methylaniline were initially charged in 1 ml of tetrahydrofuran, and the resulting solution was degassed. 5 mg (4 μmol) of tetrakis(triphenylphosphine)palladium(0) were then added, and the mixture was stirred at room temperature for another 30 min. The reaction solution was purified directly by preparative HPLC (neutral) and the title compound was obtained after final preparative thin-layer chromatography (ethyl acetate/cyclohexane=1:1). Yield: 10.1 mg (purity 92%, 42% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[C:30]([O:33][C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37])(=[O:32])[CH3:31].C([O-])(O)=O.[Na+]>O1CCCC1>[C:30]([O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:37])(=[O:32])[CH3:31]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)c3ccccc3OC(C)=O)cc2C1
Reaction time: 0.17 h
Yield: 56 %

Procedure:
338 mg of (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) was dissolved in 15 ml of tetrahydrofuran, 0.83 ml of triethylamine was added dropwise and stirred for 10 minutes, and then 600 mg of acetylsalicylic chloride was added and stirred at room temperature for 24 hrs. The reaction solution was poured into saturated aqueous NaHCO3 solution (20 ml), extracted with ethyl acetate (50 ml×3), concentrated, evaporated, and subjected to flash column chromatography (petroleum ether:ethyl acetate=5:1), to obtain (S)-methyl 2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5 (4H)-yl)-2-(2-chlorophenyl)-acetate (I-5) (280 mg). Yield: 56%, ee=96.1% (chiral HPLC analysis conditions: Chiralpak IC 4.6 mm×250 mm; column temperature: 25° C.; mobile phase: 85% n-hexane/15% tetrahydrofuran/0.1% diethylamine; flow rate: 0.5 ml/min; and detection wavelength: UV 254 nm), [α]D20=+14.00° (c 0.50, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 2.79-2.81 (m, 2H), 2.90-2.93 (m, 2H), 3.54-3.66 (m, 2H), 3.72 (s, 3H), 4.93 (s, 1H), 6.37 (s, 1H), 7.14-7.36 (m, 4H), 7.39-8.15 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 20.93, 24.93, 48.04, 50.12, 52.12, 67.65, 112.61, 117.34, 118.97, 121.66, 124.09, 126.14, 127.12, 129.35, 129.45, 129.79, 129.92, 130.71, 132.12, 133.54, 134.71, 135.73, 149.32, 151.12, 161.32, 169.47, 171.17; ESI-MS m/z 500 [M+H]+, 522 [M+Na]+; HRMS Calcd for C25H23NO6SCl [M+H]+ m/z 500.0931. found 500.0935.
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]([C:15]2[N:19]=[C:18]([C@H:20]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:21][C:22](O)=[O:23])[O:17][N:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:51][NH2:52]>O1CCCC1.CO>[CH:28]1([CH2:27][CH2:26][CH2:25][C@@H:20]([C:18]2[O:17][N:16]=[C:15]([C:13]([NH:12][CH:10]3[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]3)=[O:14])[N:19]=2)[CH2:21][C:22]([NH:52][OH:51])=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3R)-3-[3-({[1-(tert-butoxycarbonyl)-3-azetidinyl]amino}carbonyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (Preparation 79) (350 mg, 0.75 mmol) and N-methylmorpholine (163 μl, 1.48 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0° C., treated with isobutyl chloroformate (116 μl, 0.89 mmol) and stirred under a nitrogen atmosphere for 2 hours. O-(Trimethylsilyl)hydroxylamine (272 μl, 2.22 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (2×25 ml) and brine (25 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of 98.75:1.25:0.13 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a glass.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:8]2)=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:10]([N:11]([CH3:27])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(Cl)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of ethyl 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.00 g), methyl iodide (0.17 ml), potassium carbonate (0.36 g) and N,N-dimethylformamide (10 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were subjected to basic silica gel column chromatography to give the title compound (0.80 g, yield 77%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 156-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:10]([O:19][Si:20](OC(C)(C)C)([CH3:22])[CH3:21])[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35](Cl)CCl.C1C=C[C:42]2N(O)N=N[C:43]=2[CH:44]=1.O>C(Cl)Cl>[O:19]([C@@H:10]([CH2:11][N:12]1[CH2:13][CH2:14][CH2:15][C:16]1=[O:17])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[Si:20]([C:43]([CH3:42])([CH3:44])[CH3:35])([CH3:22])[CH3:21]
Reactant: On1nnc2ccccc21
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](CNCCCC(=O)O)O[Si](C)(C)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](CN1CCCC1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.3 %

Procedure:
0.6 g (1.23 mmol) of 4-[[(2S,3S)-3-(1-t-butoxyformamido)-2-(t-butoxydimethylsiloxy)-3-(cyclohexylmethyl)propyl]amino]butyric acid was dissolved in 2 ml of methylene chloride and added dropwise at -20° to a solution of 285 mg of EDC and 200 mg of HOBT in 13 ml of methylene chloride. The reaction mixture was subsequently warmed to room temperature within 15 minutes, stirred at this temperature for 17 hours and subsequently poured into water and extracted with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate, evaporated under reduced pressure and the residue was chromatographed on 10 g of silica gel using a mixture of methylene chloride and isopropanol as the eluting agent, whereby there were obtained 480 mg of t-butyl [(1S,2S)-2-(t-butyldimethylsiloxy)-1-(cyclohexylmethyl)-3-(2-oxo-1-pyrrolidinyl)propyl]carbamate as an oil which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([OH:20])=O)[CH2:8][C:9]=1[NH:10]2.ClC(OCC(C)C)=O.Cl.[CH3:30][NH:31][O:32][CH3:33]>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:16])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([N:31]([O:32][CH3:33])[CH3:30])=[O:20])[CH2:8][C:9]=1[NH:10]2
Reactant: CNOC
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(C(=O)O)CC3
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
Step 1 A solution of 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid (Intermediate 49-3, 2 g, 5.93 mmol) and TEA (2.067 mL, 14.83 mmol) in THF (20 mL) was treated with isobutyl chloroformate (0.810 g, 5.93 mmol) at 0° C. The mixture was stirred for 10 min, then was treated with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.579 g, 5.93 mmol) in THF (2 mL) and water (1 mL). The mixture was stirred at 0° C. for 1 h, then was diluted with DCM, washed with NaHCO3 (aq) and water, dried and concentrated. The residue was triturated with DCM to provide 5-bromo-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide as a light yellow solid (1.73 g, 77%). Mass spectrum m/z 380, 382 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:40])[C:22]2[CH:27]=[N:26][C:25](S(C)(=O)=O)=[N:24][C:23]=2[N:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:40])[C:22]2[CH:27]=[N:26][C:25]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:24][C:23]=2[N:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:19])[CH3:16]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (50 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (80 mg, 63%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.44 (s, 1H), 7.56 (br, 1H), 7.43 (d, J=8.9 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 5.00 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.16 (t, J=4.9 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 2.30 (s, 3H), 1.94 (m, 4H), 1.76 (m, 1H), 1.62 (m, 2H), 1.42 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.21 (m, 1H).
Reaction SMILES: [C:1]([Cl:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Cl-:20].[C:34]1([P+:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: [Cl-]
Product: c1ccc(C(c2ccccc2)(c2ccccc2)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
6.0 parts of trityl chloride was dissolved in 100 parts of acetonitrile and 5.7 parts of triphenylphosphine was added thereto. The mixture was heated under reflux for 6 hr. The mixture was allowed to stand for cooling and then the solvent was removed to obtain a brown oil which was then crystallized from acetone. The resulting crystals were collected by filtration and washed with acetone to obtain 9.2 parts of triphenyl(triphenylmethyl)phosphonium chloride (compound No. 69).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) (1.0 equiv.) in dimethylformamide (0.10 M) 22° C. was added 60% dispersion of sodium hydride in mineral oil (1.5 euiv.) and the resulting mixture was allowed to stir for 30 min. At this point, ethyl 5-bromopentanoate (1.2 equiv.) was added to this mixture. The reaction mixture was then allowed to stir for 18 hours after which it was diluted with ethyl acetate and water. The biphasic layers were separated and the organic layer was washed twice with water. The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by RP-HPLC using a 10-50% MeCN in water gradient. The resulting trifluoroacetate salt was then converted to the free base form by utilizing a StratoSpheres™ PL-SO3H SPE ion exchange resin, delivering ethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)pentanoate as a solid. 1H NMR (Acetone-d6): δ 8.80 (s, 1H), 8.74 (s, 1H), 8.33 (d, 1H), 7.47 (s, 1H), 7.24 (d, 1H), 7.17 (d, 2H), 6.85 (d, 2H), 4.10 (q, 2H), 3.97 (t, 2H), 3.25 (t, 2H), 3.07 (t, 2), 2.50 (s, 3H), 2.37 (t, 3H), 1.74-1.84 (m, 4H), 1.21 (t, 3H). LRMS [M+H]=458.2
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C([C:14]2[CH:67]=[CH:66][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23](C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[CH3:92][N:93]([CH3:97])[CH2:94][CH2:95][OH:96].C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([O:96][CH2:95][CH2:94][N:93]([CH3:97])[CH3:92])=[CH:67][CH:66]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)CCO
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: CN(C)CCOc1ccc(OCc2ccccc2)cc1

Procedure:
Compound 75A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with 2-(dimethylamino)ethanol and 4-(benzyloxy)phenol, respectively: 1H NMR (DMSO-d6): δ 7.31-7.44 (m, 5H), 6.84-6.94 (m, 4H), 5.03 (s, 2H), 3.94-3.98 (m, 2H), 2.57 (d, J=5.93 Hz, 2H), 2.19 (s, 6H). ESI (+)/MS: 272 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([N:15](CC)C(C)C)(C)C.CN.O1CCCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:12])=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Br)ccc1C
Temperature: 2 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.325 mmol, 0.5 g) in dichloromethane (25 mL) under nitrogen was added N,N-diisopropylethylamine (0.75 g, 5.8 mmol). Reaction then cooled in an ice bath to 2° C. and the yellow solution treated with 2M methylamine in tetrahydrofuran (3.49 mL, 6.98 mmol) over 5 minutes, followed by 1-propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (2.08 mL, 3.49 mmol) added dropwise. The ice bath was then removed and stirring continued overnight. The mixture was purified on silica (15 g column on Isolera 4) eluting with 0-5% methanol in dichloromethane to afford 5-Bromo-N,2-dimethylbenzamide (0.5 g, 2.2 mmol).