Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9])#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:26][N:25]=[N:24][N:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccccc1Br
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1nnn[nH]1
Temperature: 93 °C
Yield: 15.4 %

Procedure:
A mixture of 2-cyanophenyl bromide (1.00 g, 5.49 mmol), dibutyltin oxide (90.4 mg, 0.549 mmol) and trimethylsilyl azide (1.26 g, 10.98 mmol) in toluene (10.9 mL) were heated at 93° C. for 72 hours. The solvent was removed under reduced pressure and chased with methanol. The residue obtained was partitioned between ethyl acetate (25 mL) and 10% sodium bicarbonate solution (25 mL). The organic phase was extracted with an additional aliquot of 10% sodium bicarbonate solution. The combined aqueous extracts were acidified to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (190 mg. 74%) as a white solid. 1H NMR (CD3OD, 300 MHz) δ7.48-7.6 (m, 2H), 7.70 (dd, J=2 Hz, 7 Hz, 1H), 7.84 (dd, J=1 Hz, 6 Hz, 1H). HRMS (DCl/NH3) m/e, calcd for C7H6N479Br: 224.9776, found 224.9762. IR (KBr) 3440, 2600, 1602, 1056, 748 cm-1. Anal calc for C7H6N4Br: C, 37.36; H, 2.24; N, 24.90. Found: C, 37.44; H, 2.25; N, 24.77.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[CH3:31][N:32]1[CH:36]=[C:35]([C:37]2[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[NH2:40])[CH:34]=[N:33]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:40][C:39]3[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH:38]=3)=[O:29])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Cn1cc(-c2cc(N)cc(C(F)(F)F)c2)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4cnn(C)c4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) and 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (58.6 mg, 0.243 mmol) in pyridine (2 mL) was added T3P® (0.5 mL, 0.243 mmol) at 27° C. under N2. The mixture was stirred at 27° C. for 30 min. LCMS showed the reaction was completed. Then the mixture was put onto ice (5 g). The mixture was concentrated to give the residue. The residue was purified by preparative TLC (DCM/MeOH=10:1, Rf=0.6) to yield a light yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide (138 mg, 0.217 mmol, 89% yield): 1H NMR (400 MHz, CD3OD) δ 8.09-7.93 (m, 2H), 7.87-7.76 (m, 2H), 7.69-7.52 (m, 2H), 7.49-7.33 (m, 4H), 7.23 (dd, J=7.8, 16.4 Hz, 2H), 6.91 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.38-5.15 (m, 2H), 4.15 (d, J=7.1 Hz, 2H), 3.94-3.60 (m, 8H), 1.42 (t, J=6.8 Hz, 3H). ES-LCMS m/z 635 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH:26]([CH3:30])[CH2:25]3)=[N:22][NH:23][C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.COC[C@@H](NC(NC1N=CC2C(N3CCO[C@@H](C)C3)=NNC=2C=1)=O)C1C=CC=CC=1>CO>[CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][C@H:26]([CH3:30])[CH2:25]3)=[N:22][NH:23][C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC[C@@H](NC(=O)Nc1cc2[nH]nc(N3CCOC(C)C3)c2cn1)c1ccccc1
Agent: COC[C@@H](NC(=O)Nc1cc2[nH]nc(N3CCO[C@@H](C)C3)c2cn1)c1ccccc1
Solvent: CO
Product: COC[C@@H](NC(=O)Nc1cc2[nH]nc(N3CCO[C@H](C)C3)c2cn1)c1ccccc1
Yield: 33.3 %

Procedure:
The enantiomers of 1-((S)-2-Methoxy-1-phenylethyl)-3-(3-(2-methylmorpholino)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (38 mg, 0.072 mmol) were separated by SFC (Berger Multigram II SFC, column: Chiral Technology IC-H 2.1×25 cm, 5 uM, mobile phase: 39% to 61% MeOH+0.25% dimethyl ethylamine in CO2(1), flow rate: 70 mL/min, 6 min run time). The fractions were collected and the solvent evaporated in vacuo to afford 1-[(1S)-2-methoxy-1-phenylethyl]-3-{3-[(2R)-2-methylmorpholin-4-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}urea (9.91 mg, 0.024 mmol, 67%) and 1-[(1S)-2-methoxy-1-phenylethyl]-3-{3-[(2S)-2-methylmorpholin-4-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}urea. MS ESI calc'd. For C21H26N6O3 [M+1]+ 411. found 411. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 9.09 (s, 1H), 8.82 (s, 1H), 8.09 (br s, 1H), 7.39 (s, 1H), 7.35-7.31 (m, 4H), 7.26-7.21 (m, 1H), 5.00-4.93 (m, 1H), 3.91-3.83 (m, 1H), 3.78 (d, J=12.0 Hz, 1H), 3.74-3.65 (m, 3H), 3.55 (d, J=5.4 Hz, 2H), 3.25 (s, 3H), 2.91-2.82 (m, 1H), 2.59-2.51 (m, 1H), 1.15 (d, J=6.2 Hz, 3H) (Example 39). MS ESI calc'd. For C21H26N6O3 [M+1]+ 411. found 411. 1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 9.35-9.16 (br s, 1H), 9.11 (s, 1H), 8.83 (s, 1H), 8.18-8.09 (br s, 1H), 7.38 (s, 1H), 7.35-7.29 (m, 4H), 7.27-7.20 (m, 8.7, 1H), 5.02-4.90 (m, 1H), 3.93-3.83 (m, 1H), 3.78 (d, J=11.8 Hz, 1H), 3.74-3.64 (m, 3H), 3.55 (d, J=5.4 Hz, 2H), 3.25 (s, 3H), 3.10-3.01 (m, 1H), 2.93-2.82 (m, 1H), 2.60-2.51 (m, 1H), 1.14 (d, J=6.0 Hz, 3H) (Example 40).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:37])[C@@H:6]([NH:25][C:26](=[O:36])[C:27]1[C:32]([F:33])=[CH:31][C:30](Br)=[CH:29][C:28]=1[F:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].O.[CH3:39][N:40](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:4][C:5](=[O:37])[C@@H:6]([NH:25][C:26](=[O:36])[C:27]1[C:32]([F:33])=[CH:31][C:30]([C:39]#[N:40])=[CH:29][C:28]=1[F:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(C#N)cc1F
Temperature: 85 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a suspension of (S)-2-(4-bromo-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (5.78 g, 10 mmol), zinc cyanide (940 mg, 8 mmol), and tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) in DMF (40 mL, distilled and degassed) at room temperature. The resulting solution was heated to 85° C. and stirred for 24 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and it was poured into water (100 mL) to afford a cloudy suspension. Then, the organic compound was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified using an ISCO (150 g) column chromatography to afford 5.2 g (99% yield) of (S)-2-(4-cyano-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H26F2N4O5(M+H)+ 525.1944, found 525.1942.
Reaction SMILES: [OH:1][CH:2]([P:17](=[O:22])([O:20]C)[O:18]C)/[CH:3]=[C:4](\[CH3:16])/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].N1C(C)=CC(C)=CC=1C.C[Si](Br)(C)C>ClCCl.C1(C)C=CC=CC=1>[OH:1][CH:2]([P:17](=[O:18])([OH:22])[OH:20])/[CH:3]=[C:4](\[CH3:16])/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14]
Reactant: COP(=O)(OC)C(O)/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C(O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl [1-hydroxy-(E,E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]phosphonate (67 mg, 0.203 mmol) and 2,4,6-collidine (0.107 ml, 0.81 mmol)in dichloromethane (3 ml) under argon at 0° C., was added trimethylsilyl bromide (0.107 ml, 0.8 mmol) and the resulting mixture stirred at 0° C. for 30 min and then at r.t. for 5 hrs. The resulting white suspension was diluted with toluene (10 ml) and the solvent evaporated in vacuo, the resulting white solid was dissolved in ethylacetate and water and the pH was adjusted to pH=3 by the addition of 1M HCl solution. The organic layer was separated, dried (MgSO4) and evaporated to afford a pale yellow solid. The-solid was washed with dichloromethane (2×5 ml) and the white solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:9]([O:8][C:6]([C@@H:4]1[CH2:5][C@H:3]1[CH2:1][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])[CH3:10]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1CN1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Under N2 atmosphere, ethyl 2-formyl-1-cyclopropanecarboxylate (3.0 g, 21.1 mmol, 1.2 eq) and piperidine (1.5 g, 17.6 mmol, 1.0 eq) were dissolved in DCM (45 mL); after 2 hours at room temperature, the mixture was cooled at 0° C. and sodium triacetoxyborohydride (5.6 g, 26.4 mmol, 1.5 eq) was added dropwise. The mixture was stirred at room temperature for 2.5 hours, then the organic phase was washed with NaOH aq and water to give 3.3 g of the title product (yield 89%).
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH:9]([C:10]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:13]=[CH:12][C:11]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C=O
Yield: 70.1 %

Procedure:
This reaction was conducted in accordance with the procedure described by H. B. Hass and M. L. Bender in J. Am. Chem. Soc., 71 1767 (1949). Sodium (1.6 grams, 0.07 mole) was dissolved in 50 ml. of absolute ethanol. Subsequently, 2-nitropropane (8.1 grams, 0.09 mole) and 5-(bromomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (20 grams, 0.07 mole) were added. The resulting reaction mixture was refluxed for two hours, then cooled and the solvent removed in vacuo. The residue was taken up in ether, washed with water, washed with 1N sodium hydroxide, washed with saturated brine, and dried using sodium sulfate and filter paper. The solvent was removed in vacuo and the residue was distilled at 110° C. at 1.6 mm mercury pressure, yielding 11 grams of the 5-formyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@H:4]([CH2:36][CH2:37][S:38][CH3:39])[NH:5][C:6](=[O:35])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:10]([CH2:20][O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:9][C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].Cl.COC(=O)[C@H](CCSC)N.N>>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:20][C:10]2[C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:40])=[O:2])[CH2:36][CH2:37][S:38][CH3:39])=[O:35])=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH:9]=2)[CH:23]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cc(-c2ccc(C)cc2)c(COc2cccnc2)cc1-c1ccccc1C
Agent: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: N
Product: CSCC[C@H](NC(=O)c1cc(-c2ccc(C)cc2)c(COc2cccnc2)cc1-c1ccccc1C)C(=O)O

Procedure:
The desired compound was prepared by saponification of the compound of Example 343A, followed by coupling with methionine methyl ester hydrochloride and saponification of the methyl ester as described above. 1H NMR (300 MHz, CDCl3) δ 8.31 (1H, d, J=9 Hz), 8.19 (1H, d, J=3 Hz), 7.90 (1H, d, J=4 Hz), 7.42 (1H, s), 7.40-7.20 (10H, m), 6.07 (1H, d, J=9 Hz), 5.08 (2H, m), 4.62 (1H, m), 2.40 (3H, s), 2.25-2.10 (5H, 2.02 (3H, s), 2.00-1.55 (2H, m). MS (DCI, NH3) m/e 541 (M+H)+. Anal calcd for C32H32N2O4S.0.50H2O: C, 69.92; H, 6.05; N, 5.10. Found: C, 69.94; H, 6.20; N, 4.90.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([N:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)O)cc2OCC3)n(C(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)N4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a suspension of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid from Example 45 (0.0922 mmol) in DMF (2 mL) were added DIPEA (47 ul, 0.277 mmol), 1-methylpiperazine (31 uL, 0.277 mmol), HOBt (19 mg, 0.138 mmol) and EDCI (27 mg, 0.138 mmol) and the reaction mixture was stirred at RT for 2 h. Additional EDCI (50 mg) was added and the reaction mixture was stirred at RT for 18 h. The mixture was then partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 250 as a white solid (28 mg, 60% over three steps). LCMS: RT 2.92 min [M+H]+ 494.1. 1H NMR (DMSO, 400 MHz): δ 8.29 (1H, d, J=8.97 Hz), 7.83 (1H, s), 6.64 (1H, dd, J=8.98, 2.60 Hz), 6.42 (1H, d, J=2.57 Hz), 5.88-5.76 (1H, m), 4.47 (4H, s), 3.75-3.44 (4H, m), 2.24 (3H, s), 2.19 (2H, s), 2.06-1.94 (5H, m), 1.58 (6H, s), 1.44 (6H, d, J=6.59 Hz)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:34]5[CH2:35][CH2:36][N:31]([C:28](=[O:30])[CH3:29])[CH2:32][CH2:33]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
30 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 was coupled to 1-acetylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 16.8 mg of 267. MS (Q1) 491.8 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[O:31])[CH:3]=1
Reactant: COC(=O)c1ccccc1Sc1cc(Cl)ccc1C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)c1ccccc1S(=O)c1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Dimethyl 4-chloro-2,2'-thiodibenzoate (6.72 g) was dissolved in methylene chloride. To the solution was added m-chloroperbenzoic acid (4 g) and the solution was stirred at room temperature for 6 hours. The reaction mixture was poured into a 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the filtrate was evaporated to give a product. The product was suspended into a 20% aqueous sodium hydroxide solution and heated at 60° C. for 3 hours. After cooling, the solution was acidified with 6N HCl to give a precipitate. Recrystallization from aqueous methanol gave 4-chloro-2,2'-sulfinyldibenzoic acid (compound No. 25) in an amount of 4.5 g (yield: 70%). m.p. 279-281° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 58 mg, 52%). mp 171-173° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.81 (m, 1H) 8.05 (s, 1H), 8.12 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 434 (M+H)+, 451 (M+NH4)+. Anal. calc. for C21H21F2N3O3S.0.25H2O: C, 58.19; H, 4.88; N, 9.69. Found: C, 57.69; H, 5.01; N, 9.18.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>CN1CCCC1.[Cu]Cl>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[O:19][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ccc(C#N)cc4)c3)cc21
Reaction time: 0.75 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-179, 70 mg, 0.23 mmol) and Cesium carbonate (73.5 mg, 0.23 mmol, 1.0 eq) in N-Methylpyrrolidine (1 ml) was stirred at 23 deg C. for 45 min. 4-Bromobenzonitrile and Copper (I) Chloride were added and the resulting mixture was irradiated in a microwave at 150 deg C. for 5 min. LC/MS analysis showed very little conversion, so the reaction was capped and heated in an oil bath at 175 deg C. for 16 h. The resulting crude, dark mixture was run through a filter disk, then purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present), providing 4-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}benzonitrile (4-1) as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J=8.7 Hz), 7.48-7.47 (m, 2H), 7.30-7.28 (m, 2H), 7.08 (s, 1H), 7.08-7.02 (m, 4H), 3.69 (s, 2H), 3.47 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C26H25N3O2(M+H) 412.5, found 412.3.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23](C=O)[CH2:22][CH2:21]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2].[ClH:33]>O1CCOCC1>[ClH:33].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCN(C=O)CC4)CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCNCC4)CC3)cc21
Yield: 85 %

Procedure:
A solution of the N-formylquinolone from Example 18, (1.0 g, 2.25 mmol) in dioxane (20 mL) and aqueous hydrochloric acid (1N, 20 mL) was heated at 100° C. for 31/2 hours. The solvent was removed and the residue was recrystallized from methanol to give the product as a white crystalline solid (0.85 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(F)cc2F)nc1

Procedure:
In Scheme D, Ra, Ra′, Rc, Rc′, Re, Rg and X are as previously defined. In Scheme D (step 1), the halide can be displaced by either a nucleophilic aromatic substitution or transition metal catalyzed reaction. For example, methyl-6-chloronicotinate and 2,4-difluorophenol is dissolved in a suitable solvent such as DMF. To the reaction mixture is added a suitable base such as potassium carbonate monohydrate and the heated at reflux for a period of 2 to 18 hours to yield [6-(2,4-Difluoro-phenoxy)-nicotinic acid methyl ester. The reaction is concentrated and purified according to techniques well known in the art. These resulting esters formed in Scheme E, Step 1 can be further elaborated to final compounds using the procedures described in Scheme B, step 2 and 3.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([N+:18]([O-])=O)=[CH:10][C:9]=1[N+:21]([O-])=O)C(=O)C)(=O)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH3:2][C:1]1[NH:4][C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([NH2:18])=[CH:10][C:9]=2[N:21]=1
Reactant: [H][H]
Reactant: CC(=O)N(C(C)=O)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc2cc(N)cc(C(F)(F)F)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.63 g I.11 (N-acetyl-N-(2,4-dinitro-6-trifluoromethyl-phenyl)-acetamide) and 0.2 g Pd/C 10% in 20 ml glacial acetic acid was stirred for 5 h at 80° C. under a pressure of hydrogen of 50 psi. The catalyst was filtered and the solvent was evaporated. To the residue, 30 ml glacial acetic acid were added and the mixture was stirred for 2 h at reflux. The solvent was removed. The residue was treated with 50 ml 4 N aqueous hydrochloric acid and stirred for 1 h at reflux. The reaction mixture was cooled down to ambient temperature and the pH was adjusted to ˜7 with potassium carbonate. The resulting precipitate was filtered, washed with 30 ml water and dried.