Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl.Cl.Cl[CH2:38][C:39]1[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:38][C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cn1cc(CCl)cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6cnn(C)c6)cc5C)ccc(F)c43)ccc21
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 4-(chloromethyl)-1-methyl-1H-pyrazole dihydrochloride (61.1 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (124.4 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and 72 h at 70° C. Another portion of 4-(chloromethyl)-1-methyl-1H-pyrazole dihydrochloride (124.4 mg) and potassium carbonate (124.4 mg) was added and the mixture was shaken again for 24 h at 120° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 10.1 mg; LC (method 23): tR=2.06 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH3:18])=[C:7]([C:19]([O:21]CC)=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>C(O)C>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]([CH3:18])=[C:7]([C:19]([OH:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccccc2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)cc(C(C)(C)C)n1CCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 300 mg portion of ethyl 5-tert-butyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate was suspended in 9 ml of ethanol, and 1.8 ml of a 8 M potassium hydroxide aqueous solution was added, followed by stirring overnight at 100° C. The reaction liquid was cooled to room temperature, adjusted to pH 1 by adding 6 M hydrochloric acid and 1 M hydrochloric acid under ice-cooling, and then stirred at the same temperature for 1 hour. The resulting solid was collected by filtration, washed with water and then dried at 90° C. under a reduced pressure to obtain 269 mg of 5-tert-butyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylic acid as a colorless solid.
Reaction SMILES: C(OCCS(C1C=CC(C([C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26](F)[CH:27]=[C:22]3[CH:21]=2)=CC(C)C)=CC=1)(=O)=O)C>[Pd].CO>[NH:29]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=[CH:20]1
Reactant: CCOCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: c1cnc2[nH]ccc2c1
Temperature: 50 °C
Yield: 334.1 %

Procedure:
A mixture of 2-{1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (160 mg, 0.38 mmol) and 10% palladium on activated carbon (70 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo to afford 2-{1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-3-methyl-butyl}-5-fluoro}-1H-pyrrolo[2,3-b]pyridine (150 mg, 93%) which was used in the next step without further purification: LC/MS m/e calcd for C22H27FN2O3S [M+H]+ 419.53, observed 419.0.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].[NH2:15][C:16](N)=[O:17]>O>[Br:10][C:9]1[CH:8]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:6]=[C:3]2[C:2]=1[NH:1][C:16]([OH:17])=[N:15][CH:4]2[OH:5]
Reactant: NC(N)=O
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1C=O
Solvent: O
Product: OC1=NC(O)c2cc(C(F)(F)F)cc(Br)c2N1
Yield: 187.7 %

Procedure:
2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde (1.74 g, 6.49 mmol, 1.00 eq) and urea (5.85 g, 97.4 mmol, 15.0 eq) were stirred at 190° C. for 3 h. The resulting solid was returned to ambient temperature, stirred in water (60 mL) for 20 min, and filtered. This was repeated for a total of three washes. The solid was dried in a desiccator to give 3.79 g of the desired product as an off-white solid. ES/MS m/z 311, 313 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[CH2:18](O)[CH2:19][OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:18][CH2:19][OH:20])=[O:15])[C:5]2=[O:17]
Reactant: OCCO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)cnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OCCO)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
6-Bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Intermediate 22, 1.7 g, 5.72 mmol), ethane-1,2-diol (1.91 g, 34.34 mmol) and triphenylphosphine (9.0 g, 34.34 mmol) were dissolved in tetrahydrofuran (100 mL). Diethyl azodicarboxylate (DEAD) (4.97 g, 28.61 mol) was added drop wise and the mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure, and water (100 mL) was added. The aqueous mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash column chromatography over silica gel (100-200 mesh) using eluent gradient of ethyl acetate/petroleum ether: 1:1 to 100:0 to afford 1.6 g (82%) of 2-hydroxyethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:53]1[C:57](=[O:58])[CH2:56][CH2:55][C:54]1=[O:59]>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[O:59]=[C:54]1[CH2:55][CH2:56][C:57](=[O:58])[N:53]1[O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trityl acid 8 (200 mg, 0.42 mM) in dry THF (6 mL) was added dicyclohexyl carbodiimide (DDC, 206 mg, 1 mM). The reaction mixture was stirred for 30 min at r.t., and N-hydroxysuccinimide (70 mg, 0.6 mM) and a catalytic amount of DMAP added and was allowed to stir for overnight. The solvent was removed under rotaevaporator and the solid obtained was dissolved in dry ether. The precipitated DCU was filtered and the solvent ether was evaporated. The crude solid obtained was separated by silica column chromatography using CH2Cl2. Yield: about 120 mg. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.70 (m, 2H), 1.9 (t, 2H), 2.9 (s, 4H), 3.5 (m, 2H), 3.9 (t, 2H), 4.0 (t, 2H), 6.85 (m, 4H), 7.25 (m, 4H), 7.32 (m, 5H), 7.51 (m, 3H), 8.09 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(#N)C>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=3)[C:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:6]2[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate and methanesulfonyl chloride followed the procedure of Example 1 Step 3 as a white solid: 1H NMR (DMSO-d6) δ 2.86 (s, 3H, 5.87 (s, 2H), 7.22 (d, J=8.4 Hz, 2H, 7.25 (dd, J=9.0, 2.1 Hz, 1H, 7.30-7.40 (m, 3H, 7.40-7.50 (m, 6H), 7.58-7.63 (m, 4H, 7.66 (d, J=9.0 Hz, 1H, 9.40 (s, 1H, 12.52 (br s, 1H; MS (ESI) m/z 495 [M-H]−; HRMS calcd for C29H25N2O4S: 497.1533; found (ESI+): 497.1524; Anal. calcd for C29H24N2O4S.0.5H2O.0.5 ACN: C, 68.49; H, 5.05; N, 6.66. Found: C, 68.05; H, 5.04; N, 7.04.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]3[CH:10]=[CH:11][S:12][C:6]=23)[CH2:15][CH2:16]1)(=[O:33])=[O:32]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (0.21 g, 0.72 mmol) (Example 3, Step 1) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) in methylene chloride (2 mL) was added methanesulfonyl chloride (0.083 mL, 1.1 mmol). The reaction was stirred at room temperature for 2 h. After dilution with sat. aq. NaHCO3 solution, the resulting mixture was extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.24 g, 90%). LCMS calculated for C14H18N3O5S2 (M+H)+: m/z=372.1. Found: 372.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][CH2:13][Cl:14])[N:6]=[CH:5]2
Reactant: ClCCBr
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCn1ncc2cc(Br)ccc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A mixture of 5-bromo-1H-indazole (900 mg, 4.57 mmol), 1-bromo-2-chloroethane (1.31 g, 9.14 mmol) and K2CO3 (1.89 g, 13 7 mmol) in DMF (40 mL) in a sealed pressure flask was heated at 40° C. for 10 h. Additional 1.3 g 1-bromo-2-chloroethane (1.31 g, 9.14 mmol), and K2CO3 (1.89 g, 13 7 mmol) were then added and heating was continued for 3 h. This was filtered, the solvent removed from the filtrate, and the residue chromatographed on silica gel (step gradient elution with hexane containing 0, 5, 10 and 20% EtOAc) afforded (in order of elution): 5-bromo-1-(2-chloroethyl)-1H-indazole (690 mg, 2.66 mmol, 58% yield). MS (ESI) m/z 260.95 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.99 (1H, s), 7.88 (1H, s), 7.46-7.52 (1H, m), 7.36 (1H, d, J=8.85 Hz), 4.67 (2H, t, J=6.26 Hz), 3.97 (2H, t, J=6.26 Hz). 5-bromo-2-(2-chloroethyl)-2H-indazole (360 mg, 1.39 mmol, 30% yield). MS (ESI) m/z 260.95 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.98 (1H, s), 7.85 (1H, s), 7.60 (1H, d, J=9.16 Hz), 7.37 (1H, d, J=9.16 Hz), 4.69-4.74 (2H, m), 4.02-4.07 (2H, m).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C[O:19][CH:20]=[C:21]([C:26](OC)=O)[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[C:20](=[O:19])[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][N:17]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccnc(N)c2)n1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: ClCCl
Product: COC(=O)c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 160 °C
Yield: 57.9 %

Procedure:
4-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-aminopyridine (497 mg) and dimethyl methoxymethylenemalonate (425 mg) were dissolved in methylene chloride, and stirred at 90°0 C. for 2 hours while the solvent was evaporated. The reaction mixture was added with propionic acid (0.5 ml) and heated at 160° C. for 10 hours with stirring. The reaction mixture was cooled, then added with ethyl acetate, washed with saturated sodium hydrogencarbonate and dried over sodium over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (416 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:27])([CH3:26])[CH2:15][N:16]3[CH2:20][CH:19]4[O:21]C(C)(C)[O:23][CH:18]4[CH2:17]3)[CH:11]=[CH:10][C:9]=2[NH:28][C:29]([C:31]2[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])=[CH:4][CH2:3]1.[ClH:39].C1COCC1>CCOC(C)=O>[ClH:39].[OH:21][CH:19]1[CH:18]([OH:23])[CH2:17][N:16]([CH2:15][C:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:28][C:29]([C:31]3[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=3)=[O:30])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:38])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)([CH3:27])[CH3:26])[CH2:20]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CN3CC4OC(C)(C)OC4C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cc(C(C)(C)CN3CC(O)C(O)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[2-(2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-1,1-dimethyl-ethyl]-phenyl}-amide (as prepared in Example 140, 42.0 mg, 0.0811 mmol) in 2 mL of 1:1 1N HCl/THF was stirred at 80° C. for 0.5 h. After cooling to RT, the mixture was treated with 40 mL of EtOAc and concentrated in vacuo to give the title compound (38.8 mg, 91%) as a colorless oil. 1H-NMR (1:1 CD3OD; 400 MHz): 8.29 (d, 1H, J=8.6 Hz), 8.00 (s, 1H), 7.43 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 4.17 (m, 2H), 3.64 (s, 2H), 3.31-3.37 (m, 2H), 2.98-3.07 (m, 2H), 2.34 (m, 2H), 2.09 (m, 2H), 1.61 (t, 2H, J=6.3 Hz), 1.51 (s, 6H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N5O3, 478.3 (M+H). found 478.3.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1>>[F:9][C:7]1[CH:8]=[C:2]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH3:11])[CH:3]=[C:4]([F:10])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Product: Cc1c[nH]c2ccc(-c3cc(F)c(N)c(F)c3)cc12
Yield: 54.9 %

Procedure:
The title compound (68 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (160 mg, 0.62 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.71 (s, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 2H), 7.28-7.21 (m, 2H), 7.09 (s, 1H), 5.12 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C)=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Br.N>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1cc(N)c(C(=O)c2ccccc2)cc1OC
Agent: Br
Agent: N
Solvent: O
Product: COc1cc(N)c(C(=O)c2ccccc2)cc1O
Temperature: 95 °C
Yield: 45 %

Procedure:
To 400 mg (1.55 mmol) of (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa), add dropwise 2.1 ml of HBr 40% by weight in water. Heat at 95° C. for 12 hours. At 0° C. add ammonia to pH=8.9. Add 100 ml H2O and extract three times with 100 ml of CH2Cl2. Dry on MgSO4, evaporate the CH2Cl2 and purify by silica chromatography (AcOEt 1/hexane 4 then 1/1). Yield: 45%. 1H-NMR (CDCl3, 200 MHz): d 3.92 (s, 3H, OCH3), 6.20 (s, 1H Ar), 7.00 (s, 1H Ar), 7.42–7.61 (m, 5H Ar).
Reaction SMILES: [I-].[C:2]([O:6][C:7]([NH:9][C@@H:10]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[O:17])[CH2:11][CH2:12][S+](C)C)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[NH4+].O>C1COCC1>[C:2]([O:6][C:7](=[O:8])[NH:9][C@@H:10]1[CH2:11][CH2:12][N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:16]1=[O:17])([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1ccc(CNC(=O)[C@@H](CC[S+](C)C)NC(=O)OC(C)(C)C)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of (R)-(3-((tert-butoxycarbonyl)amino)-4-((3,4-dimethoxybenzyl)amino)-4-oxobutyl)dimethylsulfonium, iodide salt (2 g, 3.7 mmol) in THF (50 mL) was added LHMDS (3.7 mL, 3.7 mmol) dropwise. The reaction was stirred at 0° C. for a further 2 hrs. Then was added saturated ammonium chloride solution and water. The mixture was extracted with 100 mL ethyl acetate. The layers were separated and the organic fraction was washed with water and brine. It was then dried over sodium sulfate, filtered, and evaporated. The residue was purified via silica gel chromatography using 50% ethyl acetate/petroleum ether. Yield 0.8 gms (R)-tert-butyl(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate. LCMS (method P) RT 0.82 min, m/z 351.2 (MH+); 1H NMR (400 MHz, chloroform-d) δ 1.45 (s, 9H), 1.78-1.86 (m, 1H), 2.57-2.60 (br s, 1H), 3.15-3.23 (m, 2H), 3.68 (s, 6H), 4.12-4.25 (br s, 1H), 4.40 (m, 2H), 5.14 (br s, 1H), 6.75-6.82 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([CH3:16])[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:5]2[OH:29].C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([CH3:16])[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:5]2[OH:29]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(Br)c(C(F)(F)F)nc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(Br)c(C(F)(F)F)nc21

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g) by treatment of tert-butyl 2-(6-bromo-4-hydroxy-1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 90 (d)) with TFA. MS (ESI, pos. ion) m/z: 425 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 13.02 (br. s, 1 H), 10.34 (s, 1 H), 8.81 (s, 1 H), 4.16 (d, J=5.7 Hz, 2 H), 3.65 (s, 3 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([F:23])([F:22])[F:21])[N:12]=[C:11]([NH2:24])[N:10]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26]>O1CCOCC1.CCOC(C)=O.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>[NH2:24][C:11]1[N:10]=[C:9]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([F:23])([F:22])[F:21])[N:12]=1
Reactant: Nc1nc(Cl)cc(N2CCCC2C(F)(F)F)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(N3CCCC3C(F)(F)F)nc(N)n2)cc1F
Temperature: 100 °C
Yield: 59.5 %

Procedure:
Potassium carbonate (129 mg, 0.934 mmol) and water (1.5 mL) were added to a stirring mixture of 4-chloro-6-[2-(trifluoromethyl)-1-pyrrolidinyl]-2-pyrimidinamine (83 mg, 0.311 mmol) and (4-cyano-3-fluorophenyl)boronic acid (61.6 mg, 0.374 mmol) in 1,4-dioxane (3 mL). After degassing, Pd(PPh3)4 (29 mg, 0.025 mmol) was added, and the vessel was seal and heated at 100° C. in an oil bath overnight. LCMS showed complete conversion. The mixture was diluted with EtOAc, and washed with water. The aqueous layer was back-extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) filtered and evaporated. Purification by silica gel chromatography (Analogix RS-4 g) eluting with 5-20% EtOAc—CHCl3 afforded the title compound (65 mg) as a white foam. The sample contained some PH3P/Ph3PO by NMR, but was suitable for subsequent reactions. LC-MS (ES) m/z=352 [M+H]+.
Reaction SMILES: I.I.[CH:3]1[N:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH2:13])[C:6]2=[N:5][CH:4]=1.[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][C:28]2([C:31](O)=[O:32])[CH2:30][CH2:29]2)=[O:26])=[CH:23][CH:22]=1)[CH3:19].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:3]1[N:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH:13][C:31]([C:28]3([NH:27][C:25](=[O:26])[C:24]4[CH:34]=[CH:35][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=4)[CH2:30][CH2:29]3)=[O:32])[C:6]2=[N:5][CH:4]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(C(=O)NC2(C(=O)N[C@@H]3CCc4ccccc4-n4ccnc43)CC2)cc1
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Add (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine dihydroiodide (650 g, 1.43 mol), 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid (427 g, 1.71 mol), and 1-hydroxybenzotriazole hydrate (262.5 g. 1.71 mol) to dichloromethane (3 L). Stir the mixture in an ice water bath and slowly add diisopropylethylamine (797 ml, 4.57 mol). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (333.6 g, 1.71 mol) over 10 minutes. Remove the ice water bath and allow the mixture to stir for approximately 16 hours at ambient temperature. Wash the reaction mixture with water (3×4 L). Dry the organic phase over sodium sulfate. Filter and concentrate the mixture under reduced pressure to approximately 1 L volume. Dilute the residue with ethyl acetate (4 L). Remove 2 L of solvent under reduced pressure. Allow mixture to stand 1 hour at ambient temperature. Isolate the resulting precipitate by filtration and wash the cake with hexanes (2×2 L) to give the title compound (569.9 g, 93%) as a pale tan solid: MS (m/z): 431 (M+1). H1 NMR (399.81 MHz, DMSO): 8.91 (s, 1H), 7.95-7.93 (d, J=7.5 Hz, 1H), 7.87-7.83 (d, J=8.7 Hz, 2H), 7.49 (d, J=1.4 Hz, 1H), 7.44-7.43 (d, J=7.6 Hz, 1H), 7.38 (m, 2H), 7.34-7.29 (m, 1H), 7.00-6.96 (d, J=8.7 Hz, 2H), 6.95 (d, J=1.3 Hz, 1H), 4.65-4.60 (m, 1H), 4.08 (q, J=7.0 Hz, 2H), 2.70-2.65 (m, 1H), 2.59-2.56 (m, 1H), 2.33-2.28 (m, 1H), 2.04-2.00 (m, 1H), 1.34-1.31 (m, 4H), 1.27-1.25 (m, 1H), 1.03-0.98 (m, 1H), 0.96-0.90 (m, 1H).