Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCCS(=O)(=O)c1ccccc1Br
Product: CCCS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(propylsulfonyl)benzene. MS (ESI): mass calcd. for C19H18FN3O2S, 371.11; m/z found, 372.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.14 (d, J=1.2, 1H), 8.08 (dd, J=7.8, 1.1, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.72 (m, 1H), 7.48 (dd, J=7.4, 1.1, 1H), 7.38 (dd, J=12.4, 1.4, 1H), 7.32 (dd, J=8.0, 1.6, 1H), 2.94-2.81 (m, 2H), 1.49-1.32 (m, 2H), 0.79 (t, J=7.4, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH3:19])=[CH:7]2.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.Cl.CCN(CC)CC>C1(C)C=CC=CC=1.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>[CH3:19][C:8]1[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:25](=[O:27])[CH3:26]
Reactant: Cc1cc2cccc(Br)c2nc1Nc1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc2cc(C)c(Nc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A solution of 8-bromo-3-methyl-N-phenylquinolin-2-amine (182.0 mg, 0.581 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Inc., Wake Forest, N.C.; 0.216 mL, 0.639 mmol), and Pd(PPh3)4 (33.6 mg, 0.029 mmol) in toluene (3.0 mL) was sparged with argon and stirred under argon at 100° C. for 16 h. The mixture was then concentrated in vacuo, and the residue was taken up in THF (3.0 mL). HCl (concentrated, aq.; 0.073 mL, 0.872 mmol) was added, and the resulting mixture was stirred at 60° C. for 15 min. Et3N (0.243 mL, 1.743 mmol) was added, and the mixture was concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/hexanes) furnished 1-(3-methyl-2-(phenylamino)quinolin-8-yl)ethanone (161 mg, 0.583 mmol, 100% yield) as a yellow oil: 1H NMR (400 MHz, CD Cl3) δ ppm 7.79 (1H, s), 7.76 (1H, d, J=7.2 Hz), 7.64-7.72 (3H, m), 7.38 (2H, t, J=7.8 Hz), 7.29 (1H, t, J=7.5 Hz), 7.11 (1H, t, J=7.4 Hz), 6.52 (1H, br. s.), 2.76 (3H, s), 2.44 (3H, s). m/z (ESI, +ve) 277.1 (M+H)+.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C([Si]([O:32][CH2:33][CH2:34]I)(C)C)(C)(C)C>ClCCl.CCCCCC.C(OCC)(=O)C.O.C(COC)OC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:34][CH2:33][OH:32])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCO)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
Process 2: Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 4.62 ml, 7.26 mmol) was added to a dimethoxyethane solution (50 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (2.00 g, 6.60 mmol) obtained in Example 5. The temperature of the resulting mixture was elevated to room temperature, and stirring was performed for 15 minutes. After cooling the reaction mixture to −78° C., a dimethoxyethane solution (5 ml) of t-butyl-(2-iodoethyloxy)dimethylsilane (2.08 g, 7.26 mmol) was added thereto. The resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, followed by extraction with ether. The extracts were combined, washed successively with water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to short silica gel chromatography (hexane:ethyl acetate=7:1) to remove high-polarity impurities. The resulting oil was dissolved in tetrahydrofuran (50 ml), and to the resulting solution was added tetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 14.5 ml, 14.5 mmol). After stirring for 2 days, the solvent was distilled off. The residue thus obtained was dissolved in dichloromethane, followed by successive washing with 1N hydrochloric acid, water, and brine, driying over magnesium sulfate and concentration. The residue thus obtained was subjected to chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated, whereby the title compound (2.07 g, 5.82 mmol, 88%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[F:15][CH:16]([F:37])[O:17][C:18]1[CH:19]=[C:20]2[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:21]2=[N:22][CH:23]=1.[H-].[Na+]>CN(C=O)C>[F:37][CH:16]([F:15])[O:17][C:18]1[CH:19]=[C:20]2[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:32][CH:31]=3)[C:21]2=[N:22][CH:23]=1
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC(F)F)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(OC(F)F)cc21
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (62 mg) and 6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and the mixture was stirred at 180° C. under microwave irradiation for 30 min. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and recrystallized from AcOEt/hexane to give 6-(difluoromethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (56 mg) as white crystals.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Yield: 56.5 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.297 g, 0.000674 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.221 g, 0.000741 mol), sodium carbonate (0.179 g, 0.001684 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(O) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.185 g, 0.000381 mol): 1H NMR (DMSO-d6, 400 MHz) 8.79 (s, 2H), 8.24 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.81 (m, 1H), 1.55-2.56 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.23.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[BrH:16].N([O-])=O.[Na+].S(=O)(=O)(O)O.Cl>CO>[Br:16][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: COC(=O)C(C)c1c(F)cc(N)cc1F
Reactant: Br
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C(C)c1c(F)cc(Br)cc1F
Yield: 69.8 %

Procedure:
A solution of compound (29b) (6.7 g, 31.3 mmol) in 40% hydrobromic acid (18.4 mL, 125 mmol) was treated with an aqueous solution (38 mL) of sodium nitrite (2.4 g, 33.8 mmol), CuBr (2.5 g, 17.5 mmol), and 96% sulfuric acid (0.1 mL) in the same manner as in (i) above. The obtained product was further dissolved in methanol (100 mL), and a catalytic amount of concentrated hydrochloric acid (0.2 mL) was added thereto and treated in the same manner. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 6.1 g (70%) of compound (30b) as pale yellow liquid matter.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.[C:28](OC)(=O)[CH2:29]CC.C(C1C(NC2C=C(NC(=O)OC(C)(C)C)C=CC=2)=NC(SC)=NC=1)=O>>[CH2:28]([C:11]1[C:10](=[O:13])[N:9]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:17]=[CH:18][CH:19]=2)[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1)[CH3:29]
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: CCCC(=O)OC
Agent: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Product: CCc1cc2cnc(SC)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O

Procedure:
This compound (720 mg, 1.75 mmol, 31% yield) obtained as an off-white solid was prepared according to procedure described for Intermediate 51, using methyl butanoate (1.89 mL, 16.65 mmol) and tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (2.00 g, 5.55 mmol) as the starting materials. m/z (ESI, +ve ion) 413.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, s), 7.47-7.55 (2H, m), 7.39-7.46 (1H, m), 7.29 (1H, d, J=1.4 Hz), 6.92 (1H, dd, J=7.8, 1.0 Hz), 6.57 (1H, br. s.), 2.66 (2H, q, J=7.4 Hz), 2.19 (3H, s), 1.50 (9H, s), 1.23-1.31 (3H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=397.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].N1C=CC=CC=1.[C:17](Cl)(Cl)=[O:18].C1(C)C=CC=CC=1>C(Cl)Cl>[O:18]=[C:17]=[N:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C(C)C
Temperature: 0 °C

Procedure:
A mixture of L-valine methyl ester hydrochloride (10.0 g, 59.9 mmol), DCM (300 mL), and pyridine (19.3 mL, 240 mmol) was cooled in an ice/salt bath and a solution of 20% phosgene in PhMe (35.6 mL, 719 mmol) added dropwise, maintaining the reaction temperature below 5° C. during the addition. A white suspension resulted and after 1.5 hours, the reaction mixture was poured into ice-cold 1M HCl and extracted with DCM (2×500 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and evaporated. Flash column chromatography on silica (95 hexanes/5 EtOAc) gave the title compound as a colorless oil (6.43 g). 1H NMR (CDCl3 500 MHz) δ 3.94 (d, J=4.0 Hz, 1H), 3.82 (s, 3H), 2.24 (m, 1H), 1.03 (3, J=7.0 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:22]C(=O)C1C=CC=CC=1)=[N:10]2.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:20])([F:19])[F:21])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-Difluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (2.00 g) was dissolved in methanol (250 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.53 g) was added, and the solution was heated to reflux (heating block temperature 80° C.). After 3 h, the reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4, evaporated, and the residue purified by silica gel column chromatography (0% to 50% EtOAc in hexanes) to afford the title compound (1.42 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (dd, J=13.6, 3.8 Hz, 1 H), 3.15 (dd, J=13.8, 3.2 Hz, 1 H), 3.27-3.42 (m, 1 H), 3.93 (dd, J=8.2, 1.9 Hz, 1 H), 4.39-4.78 (m, 4 H), 6.96-7.25 (m, 3 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][C:37]([O-])=[O:38])[C:25]([C:40]([F:43])([F:42])[F:41])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[NH4+].C[N:48](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:48][C:37](=[O:38])[CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][CH2:28][C:26]1[C:25]([C:40]([F:42])([F:43])[F:41])=[CH:24][N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[N:27]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
The crude lithium 2-(2-(2-(2-((4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I97) was dissolved in DMF (2 mL) and ammonium chloride (210 mg, 3.92 mmol), HATU (149 mg, 0.392 mmol) and DIPEA (68.0 μL, 0.392 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, then concentrated. The residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL); the aqueous phase was extracted with further ethyl acetate (2×50 mL) and the combined ethyl acetate phases washed with brine (3×50 mL), dried over sodium sulfate and evaporated. The residue was chromatographed (4 g silica cartridge, 20-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C., then 0-5% gradient methanol/1% isopropylamine in ethyl acetate) to give a residue which was chromatographed (12 g silica cartridge, 80-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I98) (34 mg, 29% yield over two steps from ester) as a white foam; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.62 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.29-7.20 (m, 8H), 5.38 (s, 2H), 3.73 (s, 2H), 3.49 (s, 2H), 3.46-3.39 (m, 4H), 3.16-3.04 (m, 4H), 2.44-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.08 min; m/z 599.1 [M+H]+, 499.1 [M-Boc+2H]+; m/z 597.2 [M−H]−.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH2:25][C:26]([NH2:28])=[O:27])=[C:10]([CH3:24])[N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)C.[OH-].[Na+:31]>C(O)C>[Na+:31].[NH2:28][C:26](=[O:27])[CH2:25][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:5][C:4]([O-:29])=[O:3])[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10]=1[CH3:24]
Reactant: CCOC(=O)COc1cccc2c1c(CC(N)=O)c(C)n2Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(CC(N)=O)c2c(OCC(=O)[O-])cccc2n1Cc1cccc(Cl)c1
Yield: 88 %

Procedure:
A mixture of 155 mg (0.39 mmol) of [[3-(2-amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid ethyl ester and 4 mL of 1N NaOH in 10 mL of ethanol was heated 0.5 hours, allowed to cool and the precipitate filtered to give 140 mg (88% yield) of [[3-(2-amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid sodium salt, mp, >250° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7](=[CH2:26])[C:6]2([CH3:28])[CH3:27].[CH:29](OC)=[O:30]>>[CH:29]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7](=[CH2:26])[C:6]2([CH3:27])[CH3:28])=[O:30]
Reactant: C=C1N(CCCCCCCCCCCCCC)c2ccc(CN)cc2C1(C)C
Reactant: COC=O
Product: C=C1N(CCCCCCCCCCCCCC)c2ccc(CNC=O)cc2C1(C)C
Temperature: 55 °C
Yield: 68 %

Procedure:
5-aminomethyl-3,3-dimethyl-2-methylene-1-tetradecyl-indoline (14.88 g, 38.75 mmol) was dissolved in methyl formate (75 ml) and heated to reflux (55° C.) under argon for 24 hours. The solution was then cooled to room temperature and the methyl formate evaporated. The residue was recrystallized from hexane to yield 5-(N-formylaminomethyl)-3,3dimethyl-2-methylene-1-tetradecyl-indoline (4) (10.85 g, 68%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:26]=[CH:25][C:24]2[NH:23][C:22](=[O:27])[C:21]3[NH:28][CH:29]=[CH:30][C:20]=3[C:19]=2[CH:18]=1.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:27]=[C:22]1[C:21]2[NH:28][CH:29]=[CH:30][C:20]=2[C:19]2[CH:18]=[C:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:26]=[CH:25][C:24]=2[NH:23]1.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(-c3ccccc3)cc2c2cc[nH]c12
Temperature: 110 °C
Reaction time: 20 h
Yield: 19.2 %

Procedure:
17 mg (0.025 mmol) of dichlorobis(triphenylphosphine)-palladium (II), 45 mg (0.37 mmol) of phenylboronic acid and 0.6 mL (1.2 ml) of a 2M aqueous solution of potassium carbonate are added to a degassed solution of 100 mg (0.25 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 5 mL of anhydrous dioxan. The reaction mixture is stirred at 110° C. for 20 hours. Water is added and the product is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2) then triturated in methanol to give 16 mg (19%) of 4-oxo-8-phenyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][C@@H:18]2[CH2:20][C@@H:19]2[F:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:22])[C:3]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:4]1[C:3]([Cl:23])=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[C@@H:18]2[CH2:20][C@@H:19]2[F:21])=[CH:6][N:5]=1
Reactant: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1cnc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
6.6 g (0.017 mol) of ethyl 2-(4,5,6-trichloronicotinoyl)-3-[(1R,2S)-2-fluorocyclopropyl]aminoacrylate are stirred with 2.7 g (0.019 mol) of potassium carbonate in 35 ml of DMF at room temperature overnight. Ice-water is added to the mixture and the product is isolated.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=[O:15])[C:10]([C:11](O)=[O:12])=[C:5]2[N:4]=[C:3]1[CH3:17]>C(OC(=O)C)(=O)C>[CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:14](=[O:16])[O:15][C:11](=[O:12])[C:10]3=[C:5]2[N:4]=[C:3]1[CH3:17]
Reactant: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2n1C
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c3c(ccc2n1C)C(=O)OC3=O
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A mixture of 1,2-dimethyl-4,5-benzimidazoledicarboxylic acid (1.00 g, 4.27 mmol) and acetic anhydride (10 mL) is stirred 4 hours at reflux temperature, allowed to stand overnight at room temperature and filtered to afford the title product as yellow crystals (0.830 g, 89.8%), mp 295° C. (dec).