Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35][CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35][CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: O=C(O)C1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(C(=O)O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with isonipecotic acid. A yellow solid 106 was obtained (0.0225 g, 47%). 1H-NMR (CDCl3, 400 MHz) δ 1.90–1.99 (m, 2H), 2.09–2.16 (m, 2H), 2.68–2.77 (m, 1H), 3.43–3.50 (m, 2H), 3.83 (s, 3H), 4.14–4.20 (m, 2H), 6.95 (d, J=6.2 Hz, 1H), 6.99–7.05 (m, 3H), 7.06 (d, J=8.4 Hz, 1H), 7.45–7.52 (m, 3H), 7.84 (s, 1H), 8.20 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[N:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:18][CH2:17][C:15]1[N:16]=[C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[S:13][CH:14]=1
Reactant: O=C(NCc1ccccc1)Nc1nc(CN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1csc(NC(=O)NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyl-N′-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazol-2-yl}urea 20c (3 g; 7.64 mmol) was suspended in 50 ml of CH3OH and then, after addition of 2 g of hydrazine hydrate, stirred at RT for 2 h. The resulting solid was filtered off, and the resulting mother liquor was evaporated and triturated with 0.5 N HCl. Renewed filtration and concentration of the mother liquor led to enrichment of the required product, and this purification step was therefore repeated 3×. 0.78 g; ESI-MS [M+H+]=263.05
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][CH:13]=[C:12]2[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccnc4ccsc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
Thieno[3,2-b]pyridin-7-ol (203 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (4 mg, yield 1%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]([NH2:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:22][C@@H:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH3:21])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H](NCc1ccc(Cl)c([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde 1 (1.71 g, 9.2 mmol) and (R)-1-(3-chlorophenyl)ethanamine (1.115 g, 7.2 mmol) in DCE (15 mL) at room temperature was added acetic acid (2.0 mL, 35 mmol) and NaBH(OAc)3 (2.23 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 d, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave (R)—N-(4-chloro-3-nitrobenzyl)-1-(3-chlorophenyl)ethanamine 30 (2.03 g, 87% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.7 Hz, 3H), 3.66 (s, 2H), 3.77 (q, J=6.7 Hz, 1H), 7.18-7.32 (m, 5H), 7.44-7.48 (m, 2H), 7.83 (s, 1H). Mass spectrum: calculated for C15H14Cl2N2O2 324.0. found 325.1 (M++1).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH2:31][CH2:29][OH:30])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:20])[F:19])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Product: O=C(NCCO)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 18 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using ethanolamine instead of methylamine to the title compound (19 mg, 18%) which was obtained as a white solid. MS: m/e=426.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:17].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCCC1>[Br:1][C:2]1[C:3](=[O:17])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=1)[CH:5]=2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Temperature: 177.5 °C
Yield: 86 %

Procedure:
2,7-Dibromofluorene (20.00 g, 61.72 mmol), potassium permanganate (31.61 g, 200.0 mmol) and copper(II) sulphate pentahydrate (49.94 g, 200.0 mmol) were ground together to afford a fine powder. The powder was heated at 175-180° C. for 6 h. After cooling to room temperature, tetrahydrofuran (1 L) was added and the mixture was sonicated for 30 minutes before being filtered through celite. The solvent was removed under reduced pressure to afford a crude product, which was triturated with hot methanol (300 mL) and filtered before being dried under reduced pressure to afford 2,7-dibromofluorenone (1) (17.94 g, 86%) as a yellow solid, purity 100% (GC): 1H and 13C NMR spectra as expected; M+=338 (t).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[OH-].[Na+].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>O1CCOCC1.O>[C:11]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: NCCCS(=O)(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-amino-1-propanesulfonic acid (2.0 g, 14.4 mmol) was dissolved a NaOH (1.2 g, 30.2 mmol) solution in a mixture of 1,4-dioxane (5 mL) and water (15 mL). The mixture was cooled to 0° C. before pivaloyl chloride (2.8 mL, 21.6 mmol) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and it was stirred at 65° C. for 4 h. The solvent was evaporated under reduced pressure. The resulting solid was dissolved in water (30 mL), and treated with Dowex 50WX8 resin. The suspension was stirred for 5 minutes and the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The residual material was suspended in 20% EtOH/Acetone. The mixture was stirres at reflux for 30 seconds. The solid product was collected by filtration, and dried in vacuo, to afford compound DT (1.3 g, 41%). 1H NMR (D2O, 500 MHz) δ ppm 3.16 (t, 2H, J=6.8 Hz), 2.75 (t, 2H, J=7.8 Hz), 1.78 (m, 2H), 1.1 (s, 9H). 13C NMR (D2O, 125 MHz) δ ppm 182.75, 48.70, 38.57, 38.18, 26.65, 24.27. ES-MS 222 (M−1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH2:62]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:62][CH2:61][CH2:60][N:59]([CH3:63])[CH3:58])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethylethylenediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 2H) 1.27-1.51 (m, 2H) 1.51-1.86 (m, 6H) 2.17 (s, 6H) 2.39 (t, J=7.8 Hz, 2H) 3.31 (s, 3H) 3.38 (m, 2H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.48 (d, J=8.0 Hz, 1H) 7.52 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.28 (d, J=8.34 Hz, 1H) 8.35 (br. s., 1H). [M+H] calculated for C26H35F2N7O3, 532. found 532.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[CH:75]=[CH:74][C:73]([N:76]2[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]2)=[CH:72][C:54]=1[C:55]([NH:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[C:66]([CH3:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O>[CH3:71][C:66]1[CH:65]=[C:64]([C:61]2[N:62]=[CH:63][C:58]([NH:57][C:55]([C:54]3[CH:72]=[C:73]([N:76]4[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]4)[CH:74]=[CH:75][C:53]=3[NH:52][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH:11]=3)=[O:56])=[N:59][CH:60]=2)[CH:69]=[CH:68][C:67]=1[CH3:70]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)cn2)cc1C
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(C(=O)NCCOCCO)c3)cn2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid (189.3 mg, 0.7.5 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL), HATU (331.2 mg, 0.87 mmol, 3.50 equiv), N,N-diisopropylethylamine (160.6 mg, 1.24 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 44.8 mg (28%) of a light yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.36 (s, 1H), 11.06 (s, 1H), 9.38 (d, J=1.5 Hz, 1H), 9.03 (d, J=1.5 Hz, 1H), 8.74˜8.66 (m, 1H), 8.39 (s, 1H), 8.10˜8.01 (m, 3H), 7.92 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.66˜7.51 (m, 2H), 7.37 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 3.56˜3.34 (m, 13H), 2.32˜2.28 (m, 6H), 1.72˜1.61 (m, 6H). MS (ES, m/z): 637 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].IC.[CH2:23](C(C)=O)[CH3:24]>O>[CH2:23]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100% S) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CCO>[N+:13]([C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([O-:15])=[O:14]
Reactant: NCC1CCOCC1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28 g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75° C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1/hexanes:EtOAc as eluent. Yield: 2.53 g (88%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2H), 1.73 (d, J=1.76 Hz, 1H), 1.76 (d, J=1.95 Hz, 1H), 1.88-2.01 (m, 1H), 3.22 (dd, J=6.74, 5.57 Hz, 2H), 3.42 (td, J=11.86, 2.05 Hz, 2H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1H), 4.04 (d, J=3.51 Hz, 1H), 6.48 (br.s, 1H), 6.85 (d, J=9.37 Hz, 1H), 7.65 (br.s, 1H), 8.03-8.09 (m, 2H).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[N:13]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:12](=[O:26])[N:11]=1)[CH2:2]2.C(N(CC)CC)C.Cl[CH2:35][C:36]1[CH:44]=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1>CN(C=O)C>[O:40]1[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][CH:3]([NH:9][C:10]3[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=5)[N:13]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:12](=[O:26])[N:11]=3)[CH2:4]4)=[CH:37][C:38]=2[O:42][CH2:41]1
Reactant: O=c1nc(NC2CC3CCC(C2)N3)c2cc(Cl)ccc2n1CC(F)(F)F
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1nc(NC2CC3CCC(C2)N3Cc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 50 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
To a solution of 4-(8-aza-bicyclo[3.2.1]oct-3-ylamino)-6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazolin-2-one (149 mg, 0.320 mmol) in DMF (10 mL) was added triethylamine (0.3 mL) and 5-Chloromethyl-benzo[1,3]dioxole (0.061 mL, 0.480 mmol). The solution was heated to 50° C. and stirred for 6 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (gradient elution: 0→20% MeOH/dichloromethane) to provide 99 mg white solid (60%). 1H NMR (300 MHz, CDCl3) δ ppm 2.10 (m, 4H), 2.32 (m, 2H), 3.56 (m, 3H), 3.77 (s, 2H), 4.87 (m, 2H), 5.96 (s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.83 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.17 (m, 2H), 7.56 (dd, J=2.3, 8.9 Hz, 1H), 7.91 (s, 1H); MS (ESI+Q1MS) m/z 522 [M+2H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:35])([F:34])[F:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2C(F)(F)F)cc1
Yield: 39.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.031 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@@H:9]2[CH2:12][C@H:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)[CH:8]=1)([O-])=O.CCN(CC)CC.[C:31]1([CH2:41][C:42](O)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C.[Pd]>[C:31]1([CH2:41][C:42]([NH:1][C:4]2[N:5]=[CH:6][N:7]([C@H:9]3[CH2:12][C@H:11]([O:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH2:10]3)[CH:8]=2)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-Toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Preparation 4, Step 2; 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg) in ethyl acetate (30 mL). The mixture was then reacted under 50 psi H2 at room temperature for 6 h. The mixture was filtered through celite into a flame-dried flask which was kept under a nitrogen atmosphere. Et3N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution in ethyl acetate, 1.75 mmol). The mixture was stirred at room temperature for 1 h and was then diluted with ethyl acetate and was washed with water and brine. The organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo The resulting residue was purified by silica gel chromatography (50:1 chloroform-methanol) to afford 600 mg (72% yield) of trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester; 1H NMR (400 MHz, CDCl3) δ7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J 8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP/Cl): 476.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](B(O)O)[CH:38]=2)[C:33]([CH3:43])=[N:32]1.C([O-])([O-])=O.[K+].[K+].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.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:39]4[C:34]([C:33]([CH3:43])=[N:32][N:31]4[CH3:30])=[CH:35][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nn(C)c2cc(B(O)O)ccc12
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
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1,3-dimethyl-1H-indazol-6-ylboronic acid (76 mg, 0.4 mmol), Pd(PPh3)4 (23 mg, 20 μmol), and K2CO3 (83 mg, 0.6 mmol). De-gassed dioxane (1.6 mL) and water (0.4 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 30% EtOAc in hexanes) to give the product. LCMS-ESI+: calc'd for C31H33ClN3O3S: 562.2 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:25]3[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=3[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:25]4[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=4[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 4-chlorophenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 26).