Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15](O)[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].P(C)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH:15]1[C:14]2[C:19](=[CH:20][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:9])=[O:10])=[CH:12][CH:13]=2)[O:18][CH2:17][CH2:16]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:32]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(3-Fluorobenzene-sulfonyl)-chroman-4-ol (3.0 g, 9.7 mmol) in THF (40 ml) and toluene (40 ml) was added HC(COOEt)3 (4.5 g, 19.5 mmol) and then PMe3 (19.5 ml of 1.0M THF solution). The mixture was cooled to −78° C. DIAD (4.0 g, 19.5 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 hour and then at RT for overnight. The next day the TLC showed that the reaction was complete. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with MgSO4, concentrated and purified with flash column to give 2-Ethoxycarbonyl-2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-malonicacid diethyl ester: 5.0 g, clear oil. MS: 545 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CC[C@@H](O)C5)c34)cc2C)cn1
Yield: 15 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-3-pyrrolidinol to give the title compound in 15% yield; NMR Spectrum: 1.50-1.55 (m, 1H), 1.91-1.96 (m, 1H), 2.19 (s, 3H), 2.41-2.44 (m, 1H), 2.44 (s, 3H), 2.55 (dd, 1H), 2.68 (dd, 1H), 2.82-2.90 (m, 3H), 4.17 (br s, 1H), 4.41 (t, 2H), 4.70 (br s, 1H), 6.95 (d, 1H), 7.17-7.25 (m, 2H), 7.62-7.65 (m, 2H), 8.16 (s, 1H), 8.30 (s, 1H), 8.34 (s, 1H); Mass Spectrum: 462 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)=[CH:17][CH:16]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: OB(O)c1ccc(Br)cc1
Product: CN1CCN(C2CCN(c3ccc(Br)cc3)CC2)CC1

Procedure:
1-[1-(4-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 1-methyl-4-piperidin-4-yl-piperazine (0.50 g, 2.7 mmol) and 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product isolated as a tan solid (0.077 g, 9%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.9 Hz, 2H), 6.79 (d, J=7.7 Hz, 2H), 3.72-3.65 (m, 2H), 2.85-2.35 (m, 14H), 2.00-1.90 (m, 2H), 1.73-1.60 (m, 2H). MS=338, 340 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH2:8].[N:9]#[C:10][Br:11]>>[BrH:11].[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]=[C:10]1[NH2:9]
Reactant: COCCNCCN
Reactant: N#CBr
Product: Br
Product: COCCN1CCN=C1N
Yield: 88.8 %

Procedure:
Reaction of N-(2-methoxyethyl)ethylenediamine (16.0 g, 0.135 mol) (R. C. F. Jones and J. R. Nichols, Tetrahedron Lett., 1990, 31, 1767-1770) with cyanogen bromide (14.34 g, 0.135 mol) as described in the preparation of intermediate 6 gave 26.86 g (88% yield) of the title product as large white prisms (ethanol); mp 143-145° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[NH2:21][C:22]1[CH:29]=[CH:28][C:27](C)=[CH:26][C:23]=1[C:24]#[N:25].[C:31](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCCCCC.C(OCC)(=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][C:22]=1[NH:21][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)#[N:25]
Reactant: CC(=O)O
Reactant: Cc1ccc(N)c(C#N)c1
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](Nc3cc(C)ccc3C#N)CC[C@H]2CN1C(=O)OC
Yield: 5.3 %

Procedure:
Following the procedures from Example 3A, and using 1.076 g (3.8 mmol) of ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g (10.0 mmol) of 2-amino-5-methylbenzonitrile, 0.67 mL (12 mmol) of glacial acetic acid, and 1.14 g (5.4 mmol) of sodium triacetoxyborohydride, flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 80 mg (10% yield) of the title compound.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:20][CH2:19][CH2:18][S:17]1(=[O:22])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[O:21]=[S:17]1(=[O:22])[CH2:18][CH2:19][CH2:20][C:16]1=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)c1ccc(C(Cl)C2CCCS2(=O)=O)cc1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)c1ccc(C=C2CCCS2(=O)=O)cc1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Ethyl 2-{4-[chloro-(1,1-dioxotetrahydro-1λ6-thiophen-2-yl)methyl]phenyl} propionate (420 mg) obtained in Example 39 was dissolved in benzene (7.0 ml), and to the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 ml), and the mixture was stirred for 3 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (300 mg, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>>[N:15]1([C:4]2[N:3]=[C:2]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: c1ccncc1
Reactant: Clc1cccc(Cl)n1
Reactant: C1CNCCN1
Product: c1cc(N2CCCC2)nc(N2CCNCC2)c1

Procedure:
A solution of 2,6-dichloropyridine (10 g) and piperazine (25 g) in pyridine (30 ml) is stirred at 65° for 3 h and at 20°-25° overnight. The reaction mixture is concentrated, the residue is partitioned between ether and aqueous potassium carbonate. The organic phase separated, washed with saline, dried over sodium sulfate and concentrated. The residue is added to pyrrolidine (15 g), pyridine (100 ml) and heated at 100° for 6 days. The reaction mixture is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is separated, dried and concentrated. The residue is chromatographed on silica gel, eluting with methanol/ammonium hydroxide/methylene chloride (15/1/84). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCLl3) 1.9, 2.9, 3.4, 5.75, 6.5, 7.3 δ.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[NH:7][CH2:8][CH3:9].[O:12]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:8]([NH:7][C:6]1[CH:10]=[C:2]([C:14]2[CH:15]=[CH:16][O:12][CH:13]=2)[CH:3]=[CH:4][C:5]=1[CH3:11])[CH3:9]
Reactant: CCNc1cc(Br)ccc1C
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCNc1cc(-c2ccoc2)ccc1C
Yield: 98 %

Procedure:
0.69 g (3.20 mmol) of 5-bromo-N-ethyl-2-methylaniline and 0.93 g (4.80 mmol) of 3-furan boronic acid pinacol ester were dissolved in 7 mL of THF. 1.56 g (4.80 mmol) of cesium carbonate and 370 mg (0.32 mmol) of tetrakis(triphenyl phosphine)palladium(0) were added thereto and heated under reflux for 22 hours. After completion of the reaction, filtration was conducted, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give N-ethyl-5-(furan-3-yl)-2-methylaniline (yield: 98%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:10][C:9](=O)[CH2:8]1)=[O:6].[N+:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[C-:13].C(O)(=[O:21])C>O1CCCC1>[CH:13]([NH:12][C:14](=[C:9]1[CH2:10][CH:7]([C:5]([O:4][CH3:3])=[O:6])[CH2:8]1)[C:15]([O:17][CH3:18])=[O:16])=[O:21]
Reactant: CC(=O)O
Reactant: COC(=O)C1CC(=O)C1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(NC=O)=C1CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (0.27 g, 6.63 mmol, 60% oil dispersion) in dry tetrahydrofuran (10 ml), was added dropwise with vigorous stirring a solution of 3-methoxycarbonylcyclobutanone (0.707 g, 5.52 mmol) and methyl isocyanoacetate (0.6 g, 6.07 mmol) in dry tetrahydrofuran (20 ml) over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0° C. and 10% aqueous acetic acid (20 ml) added dropwise. The organic solvent was removed in vacuo and the resulting solution extracted with dichloromethane (3×20 ml). The combined extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to give an oil. The crude product was purified by flash chromatography, eluting with ethyl acetate-hexane (1:1, 3:2), to give methyl N-formyl-α-(3-methoxycarbonylcyclobutylidene)glycinate as a colourless oil.
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][C:44]=3C(F)(F)F)=[CH:33][C:34]=2[C:36]#[N:37])[C@@H:29]2[CH2:49][NH:50][CH2:51][CH2:52][C@H:28]12.Br[C:54]1[C:55]([O:60]CC)=NC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:55]([O:60][C:40]1[C:39]([NH:38][C:32]2[CH:31]=[C:30]3[C:35](=[C:34]([C:36]#[N:37])[CH:33]=2)[N:27]([CH3:26])[C@H:28]2[CH2:52][CH2:51][NH:50][CH2:49][C@@H:29]32)=[CH:44][CH:43]=[CH:42][N:41]=1)[CH3:54]
Reactant: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21
Reactant: CCOc1ncccc1Br
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ncccc1Nc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a yellow solid (30 mg, 28%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 100 mg, 0.31 mmol), 3-bromo-2-ethoxypyridine (63 mg, 0.31 mmol) and Cs2CO3 (199 mg, 0.6 mmol). MS (ESI): 350 (base, M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(N(CC)CC)C.[CH3:22][N:23]1[C:27](=[O:28])[CH2:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24]1>C(O)C>[NH2:13][C:12]1[O:28][C:27]2[N:23]([CH3:22])[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]=2[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]=1[C:10]#[N:14]
Reactant: CN1N=C(c2ccccc2)CC1=O
Reactant: O=Cc1ccc(F)cc1
Reactant: N#CCC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1nc(-c2ccccc2)c2c1OC(N)=C(C#N)C2c1ccc(F)cc1
Reaction time: 0.02 h
Yield: 18.3 %

Procedure:
A mixture of the 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1-methyl-3-phenyl-1H-pyrazol-5(4H)-one (500 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 20 h in vacuo and washed with ethanol and hexanes, and re-crystallized from ethanol to give 6-amino-4-(4-fluorophenyl)-1-methyl-3-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (182 mg, 0.525 mmol, 18%) as a light yellow solid. 1H-NMR (400 MHz) DMSO: 7.50-7.48 (d, 2H), 7.22-7.18 (m, 5H), 7.11 (s, 2H), 7.05-6.98 (t, 2H) 5.04 (s, 1H), 3.78 (s, 3H), 13C-NMR (100 MHz) DMSO: 162.5, 159.1, 146.0, 144.6, 140.9, 133.1, 129.8, 128.5, 127.9, 126.5, 120.4, 115.5, 115.3, 95.5, 59.7, 37.4, 34.5; LC/MS-MS: 347.1→281.0 m/z; GS1 and GS2 at 30, DP=66, CE=31, CXP=14, tR=4.00 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Al](C)C.CCCCCC.[O:19]=[C:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([NH:34][C:35]2[CH:39]=[CH:38][S:37][C:36]=2[C:40](OC)=[O:41])=[O:33])[CH2:28][CH2:27]1.Cl>C(Cl)(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:36]2[S:37][CH:38]=[CH:39][C:35]=2[NH:34][C:32]([C@H:29]2[CH2:28][CH2:27][C@H:26]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][C:20]3=[O:19])[CH2:31][CH2:30]2)=[O:33])=[O:41])=[N:3][CH:4]=1
Reactant: COC(=O)c1sccc1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cn1)c1sccc1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloropyridine (179 mg) is dissolved in chloroform (5 ml), and there to is added dropwise 0.98 M trimethyl aluminum-hexane solution (1.42 ml) under ice-cooling. The reaction solution is stirred at room temperature for 0.5 hours, and thereto is added methyl 3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)-thiophene-2-carboxylate (170 mg), and the mixture is heated to reflux for 18 hours. After allowing to cool, to the reaction mixture is added 10% hydrochloric acid (4 ml), and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform) to give the title compound (172 mg). APCI-MS M/Z: 463/465[M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54](C)[CH3:55])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:32]=[C:31]3[C:22]([C:23]4[CH:24]=[CH:25][C:26]([C:33]5[CH:34]=[CH:35][C:36]6[N:40]=[C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](OC(C)(C)C)=[O:47])[NH:38][C:37]=6[CH:53]=5)=[CH:27][C:28]=4[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.O1CCOC[CH2:59]1.[CH3:64][O:65][C:66]([NH:68][C@H:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)C(O)=O)=[O:67].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CO>[CH3:64][O:65][C:66]([NH:68][C@H:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:41]1[C:39]1[NH:38][C:37]2[CH:53]=[C:33]([C:26]3[CH:25]=[C:24]4[C:23]([C:22]5[CH:21]=[CH:20][C:19]([C:16]6[NH:15][C:14]([C@@H:10]7[CH2:11][CH2:12][CH2:13][N:9]7[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]([CH3:55])[CH3:59])=[N:18][CH:17]=6)=[CH:32][C:31]=5[CH2:30][CH2:29]4)=[CH:28][CH:27]=3)[CH:34]=[CH:35][C:36]=2[N:40]=1)=[O:47])=[O:67]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Reactant: C1COCCO1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Temperature: 0 °C
Yield: 35.3 %

Procedure:
A solution of (S)-tert-butyl 2-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (30 mg, 0.04 mol), methanol (0.5 mL), and 4M HCl in dioxane (1 mL, 4 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after twenty minutes. The resulting residue was dissolved in a 4:1 dichloromethane:dimethylformamide solution (1.0 mL). One half of this solution was removed and used in the subsequent reaction. To this solution (˜0.5 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (4.2 mg, 0.02 mmol) and COMU (8.5 mg, 0.02 mmol) and the reaction was cooled to 0° C. Diisopropylethylamine (0.011 mL, 0.06 mmol) was added and the reaction was stirred at 0° C. for twenty minutes. The reaction was quenched by the addition of formic acid (0.05 mL) and thoroughly concentrated. The resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% HCO2H), followed by a second preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA) to yield methyl (S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (6 mg, 36%). LCMS-ESI+: calculated for C49H52N8O6: 848.99; observed [M+1]+: 850.2.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])C(=O)C=1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.BrCC(C1C=CC(CO)=CC=1)=O>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][N:39]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[O:17])[C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=C(CBr)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CO)cc1

Procedure:
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 15b (with acetonitrile as solvent) from 350 mg (1.58 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 19b) and 399 mg (1.74 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)[CH:3]=1.C(O)(=O)CCCCCC=C.N1CCC[C@H]1C(O)=O.C(C1N=C(C2C=C(O[CH:60]3[CH2:78][CH:77]4[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67]C[CH2:69][CH:70]=[CH:71][CH:72]5[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]4=[O:79])[CH2:73]5)[CH2:61]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:20]([C:18]1[N:19]=[C:15]([C:4]2[CH:3]=[C:2]([O:1][CH:60]3[CH2:78][CH:77]4[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:69][CH:70]=[CH:71][CH:72]5[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]4=[O:79])[CH2:73]5)[CH2:61]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: C=CCCCCCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinoline (28), oct-7-enoic acid and intermediate 5 following the procedure (Step D-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=633 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[OH:17])=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:23]=1[CH2:24][N:25]([C:38]1[S:42][N:41]=[CH:40][N:39]=1)[S:26]([C:29]1[CH:34]=[C:33]([F:35])[C:32](F)=[CH:31][C:30]=1[F:37])(=[O:28])=[O:27]>CN(C)C=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17][C:32]3[C:33]([F:35])=[CH:34][C:29]([S:26]([N:25]([CH2:24][C:23]4[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:22]=4[O:21][CH3:20])[C:38]4[S:42][N:41]=[CH:40][N:39]=4)(=[O:27])=[O:28])=[C:30]([F:37])[CH:31]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(Cl)cc1-c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4[nH]cnc4c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a mixture of 2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenol (0.110 g, 0.45 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (0.020 g of a 60% w/w dispersion in mineral oil, 0.50 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. N-(2,4-Dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.210 g, 0.47 mmol) was added and the reaction mixture was stirred for 16 h at ambient temperature. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (10 mL). The organic phase was washed with water (2 10 mL) and brine (2 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient of ethyl acetate in hexanes to afford 4-(2-(1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as an off-white solid in 34% yield (0.102 g): MS (ES+) m/z 669.7 (M+1), 671.7 (M+1).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:33]1[C:34]2[C:35]3[CH:48]=[CH:47][S:46][C:36]=3[C:37](=[O:45])[NH:38][C:39]=2[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]>>[CH2:8]([N:7]([CH2:6][C:5]1[CH:12]=[CH:13][C:2]([C:33]2[C:34]3[C:35]4[CH:48]=[CH:47][S:46][C:36]=4[C:37](=[O:45])[NH:38][C:39]=3[CH:40]=[CH:41][C:42]=2[O:43][CH3:44])=[CH:3][CH:4]=1)[CH2:10][CH3:11])[CH3:9]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CCN(CC)Cc1ccc(Br)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CCN(CC)Cc1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 17.8 %

Procedure:
Following General Procedure E, N-(4-bromobenzyl)-N-ethylethanamine (200 mg, 0.83 mmol) was reacted with bis(pinacolato)diboron (230 mg, 0.91 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (260 mg, 0.83 mmol) to afford the desired product (58 mg, 25%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=8.2 Hz, 2H), 7.60-7.54 (m, 2H), 7.46-7.43 (m, 2H), 7.41 (d, J=9.1 Hz, 1H), 5.99 (d, J=5.4 Hz, 1H), 4.50 (s, 2H), 3.75 (s, 3H), 3.41-3.32 (m, 4H), 1.44 (t, J=7.3 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].C(OC(O)C)C>[Pd].[Pt]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Pt]
Agent: CCOC(C)O
Product: Nc1ccc(-c2nc3cc(N)ccc3o2)cc1

Procedure:
The process of claim 17 wherein the 2-(4-nitrophenyl)-5-nitrobenzoxazole is reduced by hydrogen and palladium or platinum over carbon in the presence of ethoxyethanol under such conditions to form 2-(4-aminophenyl)-5-aminobenzoxazole.