Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([O:6][CH3:7])=[O:5].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([C:11]1[S:12][C:8](/[C:3](=[CH:2]\[O:1][CH3:26])/[C:4]([O:6][CH3:7])=[O:5])=[C:9]([CH:16]=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:10]=1)([CH3:15])[CH3:14]
Reactant: COC(=O)C(=CO)c1sc(C(C)C)nc1/C=C/c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CO/C=C(/C(=O)OC)c1sc(C(C)C)nc1/C=C/c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CO/C=C(/C(=O)OC)c1sc(C(C)C)nc1C=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The product of Step G was dissolved in 20 ml of acetone and then 3 ml of methyl iodide and 4 g of potassium carbonate were added. The mixture was stirred for 16 hours at 20° C. After bringing the mixture to dryness, the residue was chromatographed on silica, eluting with a hexane--ethyl acetate mixture (8-2) to obtain 1.3 g of the desired product. Thin layer chromatography; Rf=0.20 [eluant: hexane--ethyl acetate (8-2)].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.F[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(C(=O)NCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 160 °C
Reaction time: 6 h
Yield: 3.9 %

Procedure:
N-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide hydrochloride (198 mg, 0.513 mmol) and methyl 2-fluorobenzoate (0.0653 mL, 0.513 mmol) were dissolved in dimethylsulfoxide (5 mL). To this solution, potassium carbonate (142 mg, 1.03 mmol) was added and the mixture was stirred for 6 hours at 160° C. Subsequently, the mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 9.80 mg (4%) of the desired compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C(Cl)Cl>[CH3:16][S:17]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:3]([CH3:15])([CH3:2])[CH2:4]1)(=[O:19])=[O:18]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)CN(S(C)(=O)=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 3,3-dimethyl-6-nitroindoline hydrochloride (2.9 g, 12.8 mmol) in CH2Cl2 (75 mL) was added TEA (4.48 mL, 32.2 mmol) and methanesulfonyl chloride (1.1 mL, 13.5 mmol) at 0° C. The resulting mixture was stirred at RT for 4 h and water was added. Mixture was extracted with CH2Cl2, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford 1-Methanesulfonyl-3,3-dimethyl-6-nitro-2,3-dihydro-1H-indole as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].[CH2:25]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:26]>>[CH2:25]([C:27]1[CH:33]=[CH:32][C:30]([N:31]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:21]([C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)(=[O:23])=[O:22])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4cccs4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 405.12 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)) thiophene-2-sulfonyl chloride and 4-ethyl-aniline.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:26]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cc(F)ccc1OCc1ccccc1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCc3ccccc3F)n2)c1

Procedure:
Example 30 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {5-fluoro-2-[(2-fluorobenzyl)oxy]phenyl}boronic acid (Combi-Blocks Inc.). The batch was purified by preparative TLC. 1H NMR (400 MHz, CDCl3, 300K) δ=8.84 (s, 1H), 7.79 (br, 1H), 7.63 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.27 (m, 1H), 7.09 (m, 5H), 5.22 (s, 2H), 4.23 (s, 2H), 2.78 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][C:16]=1[O:17][CH3:18].C(N(CC)C(C)C)(C)C>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:13]2[CH:14]=[N:15][C:16]([O:17][CH3:18])=[C:11]([F:10])[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: COc1ncc(B(O)O)cc1F
Reactant: Nc1ncc(Cl)nc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ncc(Nc2ncc(Cl)nc2Br)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.5 %

Procedure:
A mixture of 3-bromo-5-chloropyrazin-2-amine (780 mg, 3.74 mmol, Ark Phar. Inc., Libertyville, Ill.), 5-fluoro-6-methoxypyridin-3-ylboronic acid (1919 mg, 11.23 mmol, Anichem), N,N-diisopropylethylamine (1.953 mL, 11.23 mmol, Aldrich, St. Louis, Mo.) and copper (II) acetate (1.12 g, 5.61 mmol, Aldrich, St. Louis, Mo.) in dichloromethane (30 mL) was stirred at room temperature for 72 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 3-bromo-5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrazin-2-amine (218 mg, 0.654 mmol, 17.47% yield). 1H NMR (300 MHz, CDCl3) δ 4.03 (s, 3H) 7.00 (s, 1H) 7.82 (dd, J=11.25, 1.75 Hz, 1H) 8.04 (d, J=9.06 Hz, 2H). m/z (ESI, +ve ion) 331.9 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ocnc2C(N)=O)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ncoc1-c1cccc(O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
5-(3-Methoxyphenyl)-4-oxazolecarboxamide (1.29 g, 5.9 mmol) was dissolved in dichloromethane (120 mL) and cooled to about 0° C. under N2. Boron tribromide solution (29 mL of 1 M in dichloromethane) was added dropwise and the solution stirred about 18 hours at room temperature. Methanol (10 mL) was added dropwise {caution: reacts vigorously}, and after being stirred 10 min the solution was concentrated onto SiO2 and chromatographed (elution with 20% methanol/ethyl acetate) to give the phenol 848 mg (70%), mp 202°-204° C.IR (KBr, cm-1) 3398, 3188, 3132, 1684, 1608, 1572, 1254, 1190, 866, 694, 618. 1H NMR (300 MHz, DMSO-d6)δ 6.82 to 6.85 (1H, m), 7.26 (1H, t, J=8.0 Hz) 7.56 to 7.69 (4H, m), 8.49 (1H, s), 9.66 (1H, s). 13C NMR 75 MHz, DMSO-d6) ppm 114.62, 116.95, 118.59, 128.08, 129.04, 129.52, 149.87, 151.10, 157.22, 162.80. m/e 205 (MH+).
Reaction SMILES: COC1C=CC([CH2:9][CH2:10][N:11]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)[C:12](=[O:25])[NH:13][C:14]2[S:15][C:16]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])=[CH:17][N:18]=2)=CC=1.[CH2:33]([O:40]CCN(C1CCC(C)CC1)C(=O)NC1SC(SCC(O)=O)=CN=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][CH2:9][CH2:10][N:11]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)[C:12](=[O:25])[NH:13][C:14]1[S:15][C:16]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])=[CH:17][N:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(S(=O)CC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Reactant: CC1CCC(N(CCOCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: C[C@H]1CC[C@H](N(CCOCc2ccccc2)C(=O)Nc2ncc(S(=O)CC(=O)O)s2)CC1

Procedure:
The compound was prepared as previously described for {2-[3-[2-(4-methoxy -phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfinyl}-acetic acid using {2-[3-(2-benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.O1CCCC1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1nccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nccc2c(N)cccc12
Yield: 88 %

Procedure:
1-Methyl-5-nitroisoquinoline (prepared according to Rathelot, P. et al. Eur. J. Med. Chem. 1995, 30, 503-508.) (2.19 g, 11.64 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL) in a 250 mL stainless steel pressure bottle to which was added 5% Pd—C (0.438 g, 4.12 mmol). The reaction mixture was stirred for 2 h under 30 psi hydrogen at ambient temperature. The mixture was filtered through a nylon membrane and the volatiles evaporated in vacuo. The resulting grayish solid was triturated with 1:1 hexanes-CH2Cl2 (50 mL) and the title compound (1.62 g, 10.24 mmol, 88%) was collected as an off white solid. MS (DCI/NH3) m/z 159 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([Li])CCC.[CH3:40][C:41]1[S:42][C:43]([C:47]([C:49]2[N:53]([CH3:54])[N:52]=[N:51][CH:50]=2)=[O:48])=[C:44]([CH3:46])[N:45]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:47]([C:43]3[S:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])([C:49]3[N:53]([CH3:54])[N:52]=[N:51][CH:50]=3)[OH:48])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3sc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.02 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (500 mg, 116 mmol, Intermediate 47: step d) was added THF (15 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 0.45 mL, 1.13 mmol) was added drop wise. The color of the solution became a dark brown. After 1 minute, (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (275 mg, 1.24 mmol in 2 mL THF, Intermediate 48: step b) was introduced and the color of the mixture went from dark brown to greenish to light orange color all within 1 minute. The mixture was allowed to warm to 0° C. over 45 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The mixture was diluted further with water and extracted with EtOAc, 3×45 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light orange foam. The crude was chromatographed on silica gel (initially using 10% CH3CN-toluene then changing to 80% CH3CN-DCM) to afford the title compound as an off white solid. MS m/e 574.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.14 (d, J=2.1 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.56-7.48 (m, 3H), 7.39 (d, J=8.1 Hz, 2H), 7.21-7.13 (m, 1H), 4.44-4.64 (m, 1H), 4.34 (s, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H). Example 79A was separated into its individual enantiomers using the following conditions: Chiralpack OD, 80% heptanes: 20% ethanol; wavelength=242 nM to provide the two enantiomers. The first eluting enantiomer was Example 79B and the second eluting enantiomer was Example 79C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:15]=1[O:16][C:17]1[C:22](=[O:23])[N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)[C:20]([CH2:39][CH2:40][CH3:41])=[N:19][C:18]=1[CH2:42][CH3:43]>C(OCC)(=O)C>[F:13][C:14]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:15]=1[O:16][C:17]1[C:22](=[O:23])[N:21]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)[C:20]([CH2:39][CH2:40][CH3:41])=[N:19][C:18]=1[CH2:42][CH3:43]
Reactant: CCCc1nc(CC)c(Oc2cc(F)ccc2F)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cc(F)ccc2F)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogen carbonate (0.5 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[5-(2,5-difluorophenoxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.29 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.19 g, 57%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24]2.ClCCl.P([O-])([O-])([O-])=[O:38].[K+].[K+].[K+].Cl>COCCOC.CO>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:2]1[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:38])[CH:9]=3)[NH:4][N:3]=1)[CH:25]=[CH:24]2
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(C(N)=O)cc34)ccc2c1
Temperature: 45 °C
Yield: 45.3 %

Procedure:
The title compound was prepared as described in Example 408 using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.500 g, 1.6 mmol), in ethylene glycol dimethyl ether (30 mL), 6-methoxynaphthalene-2-boronic acid (0.395 g, 2.0 mmol), [1,1′-bis(diphenyl phosphino-ferrocene] complex with dichloromethane (1:1) (0.133 g, 0.16 mmol) and potassium phosphate (3.5 g, 16.3 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (silica gel, 20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45° C. for 5 h. One half of the methanol was evaporated, water was added and the solid filtered and dried in a vacuum oven to afford the title compound (0.230 g, 47% yield over 2 steps): ES-MS (m/z) 300 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncccn2)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
110 mg 4-hydroxy-4-pyrimidin-2-yl-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 2.5 mL pyridine and 0.18 ml phosphoroxychloride was added. The reaction mixture was stirred at RT for one day. The reaction was decomposed with water and extracted with DCM. The organic layer was dried and the solvent was removed to yield 84 mg of the desired compound. Rt: 1.31 min (method B), (M+H)+: 262
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 4-bromoaniline (1.0 eq) in dichloromethane, triethylamine (2.2 eq) was added at 0° C. and stirred for 15 min. To this mixture was added acetic anhydride (1.0 eq) in dichloromethane at 0° C., after addition the reaction was continued at room temperature for 5 hrs. Water was added and the organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-(4-bromophenyl)acetamide. (Yield=65%)
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: OB(O)c1ccncc1Cl
Reactant: Nc1ncc(Br)c(NC2CCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccncc2Cl)c(NC2CCCC2)n1
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To a solution of 2 (2.57 g, 10.0 mmol) in dioxane (75 mL) were added 3-chloropyridine-4-boronic acid (4.72 g, 10.0 mmol), trans-dichlorobis(triphenylphosphine)-palladium(II) (702 mg, 1.0 mmol), and sodium carbonate (3.82 g, 36 mmol, in 36 mL of water). The mixture thus obtained was purged with N2 for 10 min and heated at 120° C. in a sealed tube for 22 h. The reaction mixture was diluted with water and the product was extracted with chloroform. The organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 2.5% methanol in dichloromethane to give the title compound (3) as a white solid (2.31 g, 80%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, s), 8.50 (1H, d, J=4.9 Hz), 7.51 (1H, s), 7.34 (1H, d, 1H, J=4.9 Hz), 6.21 (2H, d, 1H, br s), 5.97 (1H, d, J=7.6 Hz), 4.43 (1H, p, J=7.4 Hz), 1.84 (2H, m), 1.62 (2H, m), 1.40-1.49 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 290.0, Calculated 290.1.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35].C(N([CH2:42][CH3:43])CC)C.O>S(Cl)(Cl)=O.ClCCl>[CH2:25]([O:8][C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:3][CH2:2][CH2:1][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:42]=[CH2:43])=[O:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)=[O:9])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Reactant: C=CCCCCCCCCCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: C=CCCCCCCCCCOC(=O)c1ccc(-c2ccc(-c3ccc(C(=O)OCCCCCCCCCC=C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of [1,1′;4′,1″]terphenyl-4,4″-dicarboxylic acid (6.37 g, 20 mmol) in 100 ml of thionyl chloride was heated at reflux for 12 h then thionyl chloride was evaporated by azeotropic distillation. The crude yellow residue obtained therefrom was mixed with 10-undecen-1-ol (7.49 g, 44 mmol) in dichloromethane (300 ml) and triethylamine (8.9 g, 88 mmol) was added dropwise to the resulting mixture. The reaction mixture was stirred at 6 h at room temperature, then poured into water (300 ml) and extracted with dichloromethane (2×400 ml). The combined organic extracts were washed with saturated NaCl solution (500 ml), dried over magnesium sulphate, filtered and evaporated to dryness to give a brownish residue which was recrystallised from acetone/dichlorometane: 9/1 to afford pure [1,1′;4′,1″]terphenyl-4,4″-dicarboxylic acid diundec-10-enyl ester as white crystalline material. Yield 8.97 g.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([CH:12]=O)=[CH:11][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][NH:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:21][NH:22][C:23](=[O:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:12][C:10]3[CH:9]=[C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:20])[NH:4][C:5]=4[CH:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(-c5ccccc5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 349A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.82 Hz, 3H) 2.51-2.57 (m, 4H) 2.73 (d, J=4.55 Hz, 3H) 3.18-3.29 (m, 4H) 3.48 (s, 2H) 4.70 (q, J=6.65 Hz, 1H) 6.90-6.96 (m, 4H) 7.32-7.37 (m, 1H) 7.41-7.46 (m, 2H) 7.51-7.56 (m, 2H) 7.66-7.72 (m, 2H) 8.13 (q, J=4.38 Hz, 1H) 10.71 (s, 1H). ESI-MS: m/z 471.4 (M+H)+. mp=184.9-188.9° C.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[N:12]([O-])=O.[Na+]>>[C:1]([N:9]=[N+:10]=[N-:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: [N-]=[N+]=NC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
Nicotinic acid hydrazide (18 g) was added in small portions with ice cooling to 22 ml concentrated hydrochloric acid, and 30 ml of aqueous solution of 18 g sodium nitrite was then added dropwise while maintaining the temperature at 0° C. or lower. The mixture was stirred at 0° C. for 15 minutes and extracted with ether, the extract was washed with an aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate, and the solvent was distilled off from the dried solution, giving 16 g of nicotinic acid azide.