Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:26]([OH:28])=[O:27])=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: Cn1ccc2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c2ccc(-c3ccc(C(C)(C)C)cc3)cc21
Yield: 10.7 %

Procedure:
6-(4-tert-Butyl-phenyl)-1-methyl-1H-indole-3-carboxylic acid was prepared from 6-(4-tert-butyl-phenyl)-1-methyl-1H-indole (0.541 g, 2.05 mmol), n-butyllithium (0.98 mL, 2.5 mmol), crushed dry ice (3 g, 70 mmol) in dry THF (10 mL) according to the procedure described in Example 60. Purification by flash chromatography using 10-50% ethyl acetate in hexane and 100% ethyl acetate as eluants afforded the title compound as a light yellow solid (0.0675 g, 10.7%), mp: 236-238° C. (dec.). Mass spectrum (−APCI, [M−H]−) m/z 306. 1HNMR (400 MHz, DMSO-d6): δ 12.8-13.0 (br s, 1H), 7.8 (s, 1H), 7.65-7.7 (m, 3H), 7.45-7.5 (m, 2H), 7.4 (dd, 1H, J=8.3 Hz and 1.6 Hz), 7.2 (d, 1H, J=0.75 Hz), 4.05 (s, 3H) and 1.35 ppm (s, 9H). Elemental Analysis for C20H21NO2: Calculated: C, 78.15; H, 6.89; N, 4.56. Found: C, 77.82; H, 6.89; N, 4.42.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:21]([O:22][CH3:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:4][CH3:5])[CH3:2].[CH3:25][S:26]([C:29]1[N:34]=[C:33]([CH3:35])[C:32]([NH2:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC(C)([O-])C.[K+].C1COCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:21]([O:22][CH3:23])=[C:20]([NH:36][C:32]3[C:33]([CH3:35])=[N:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Reactant: CCC(CC)OC(=O)N1CCC(Oc2ncnc(Cl)c2OC)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCC(CC)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)nc3C)c2OC)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 2.1 %

Procedure:
4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid 1-ethyl-propyl ester, (0.50 g, 1.40 mmol) and 6-methanesulfonyl-2-methyl-pyridin-3-ylamine (0.26 g, 1.40 mmol) and palladium acetate (0.062 g, 0.28 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.191 g, 0.559 mmol) were combined in 50 mL dioxane, purged with nitrogen and a 1M solution of potassium t-butoxide in THF (2.79 mL, 2.79 mmol) added dropwise. The reaction was heated to 100° C. and stirred for 2 hours, then was filtered, concentrated, acidified and purified by prep HPLC, the desired fractions partitioned between saturated sodium hydrogen carbonate and ethyl acetate, the organic phase washed with brine and dried with magnesium sulfate to yield (15 mg, 0.029 mmol, 2.11% yield) desired product, as a white solid. 1HNMR (CDCl3, 400 MHz) δ 0.91 (t, J=7.33 Hz, 6H), 1.54-1.64 (m, 4H), 1.77-1.87 (m, 2H), 1.99-2.08 (m, 2H), 2.65 (s, 3H), 3.19 (s, 3H), 3.39-3.46 (m, 2H), 3.78-3.85 (m, 2H), 4.00 (s, 3H), 4.67 (pent, J=6.32 Hz, 1H), 5.36-5.43 (hept, J=3.79 Hz, 1H), 7.31 (bs, 1H), 7.96 (d, J=8.34 Hz, 1H), 8.20 (s, 1H), 9.02 (d, J=8.59 Hz, 1H). Exact mass calculated for C23H33N5O6S: 507.22 found: 508.5 (MH+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[C:25]([CH:28]4[CH2:30][CH2:29]4)[CH:26]=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C>C1COCC1.[NH4+].[Cl-].O>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]3[N:23]([C:19]([C:16]4[CH:15]=[CH:14][C:13]5[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=5)[N:17]=4)=[N:20][N:21]=3)[CH:24]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.3 %

Procedure:
To a 0° C. solution of 8-(tert-butyldimethylsilyloxy)-2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (0.159 g, 0.382 mmol) in 4 mL THF was added solid TBAF hydrate (0.150 g, 0.573 mmol), causing the reaction mixture to turn cloudy. The reaction mixture was warmed to ambient temperature after 5 minutes and then stirred 17 hours, after which it was diluted with saturated NH4Cl and water, causing solids to form. The solids were isolated by vacuum filtration through a Buchner funnel, rinsed with water, and air dried in vacuo to give the title compound (0.072 g, 0.238 mmol, 62.4% yield) as a light pink powder.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([N:28]1[CH2:33][CH2:32][C:31]([CH2:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:30][CH2:29]1)/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]2[C:24](=[N:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:15]2.C(N(CC)CC)C.[C:47](=O)([O:49]C1C=CC=CC=1)[NH2:48]>CS(C)=O>[O:27]=[C:22]1[C:16]2([CH2:21][CH2:20][N:19]([C:47]([NH2:48])=[O:49])[CH2:18][CH2:17]2)[CH2:15][C:14]2[C:24](=[N:25][CH:26]=[C:12](/[CH:11]=[CH:10]/[C:9](=[O:8])[N:28]3[CH2:33][CH2:32][C:31]([CH2:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:30][CH2:29]3)[CH:13]=2)[NH:23]1
Reactant: NC(=O)Oc1ccccc1
Reactant: O=C(/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: NC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a stirred solution of (E)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydro pyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naph-thyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Compound 34) (150 mg, 0.26 mmol) in DMSO (2 mL) were added triethylamine (110 mg, 1.04 mmol) and phenyl carbamate (44 mg, 0.32 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (50 mL), obtained solid was filtered, washed with water and dried under vacuum to get the desired compound as a yellow solid (40 mg, 31%); 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.4 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.28-7.14 (m, 1H), 5.93 (s, 2H), 5.68-5.65 (m, 1H), 4.28-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.76-3.72 (m, 3H), 3.66-3.62 (m, 1H), 3.60-3.52 (m, 2H), 3.18 (t, J=10.0 Hz, 2H), 2.95 (s, 2H), 2.20-2.06 (m, 2H), 1.76-1.66 (m, 2H), 1.34-1.24 (m, 2H); ES-MS: 493.3 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:31])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([Br:31])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 517 (M+H)+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=1.O[CH2:47][CH2:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1>C(Cl)Cl>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:47][CH2:48][CH:49]2[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])[CH2:53][CH2:54]2)=[C:37]([C:42]([F:43])([F:44])[F:45])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
DIAD (33.5 g) was added dropwise to the solution of triphenylphosphine (43.5 g), 4-bromo-2-trifluoromethylphenol (40 g) and tert-butyl 4-(2-hydroxyethyl)-piperidine-1-carboxylate (31.7 g) in DCM (200 ml) at 0° C. during 15 minutes. The mixture was then stirred at room temperature for 20 hours. After removal of DCM under reduced pressure, to the residue was added ether (100 ml) and heptane (300 ml), solid was then filtered off. Filtrate was then washed with 1M sodium hydroxide (100 ml×3). Organic layer dried over sodium sulphate, solvent removed under vacuum, residue was then columned on silica gel using heptane:EtOAc (5:1) as eluant to give tert-butyl 4-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate as a colorless oil as product (61.3 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][C@@H:27]3[C:32]([NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[O:33])(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:28][C@@H:27]3[C:32]([NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[O:33])(=[O:24])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Oc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Yield: 107.2 %

Procedure:
Phenyl chloroformate (60 mg) in CHCl3 (1 ml) was added to (2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) in pyridine (0.5 ml) and CHCl3 (0.5 ml) dropwise with cooling on an ice bath. The reaction mixture was stirred at said temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with 5% aqueous citric acid, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 202 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-phenoxycarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:68][O:69][C:70]1[CH:71]=[C:72]([CH:74]=[CH:75][C:76]=1[O:77][CH3:78])[NH2:73]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:68][O:69][C:70]1[CH:71]=[C:72]([NH:73][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[S:19][C:18]5[C:13](=[N:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:74]=[CH:75][C:76]=1[O:77][CH3:78]
Reactant: Clc1ccc2ncc(-c3cc4ncccc4s3)n2n1
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5ncccc5s4)n3n2)cc1OC
Temperature: 110 °C

Procedure:
To a solution of 6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.174 mmol, 1.0 equiv), xantphos (20 mg, 0.0348 mmol, 0.2 equiv), palladium acetate (4 mg, 0.0174 mmol, 0.1 equiv), and potassium carbonate (482 mg, 3.49 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (32 mg, 0.209 mmol, 1.2 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 35 mg, of the yellow solid, 50%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:18](OCC)=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2].[H][H]>[Pd].O1CCOCC1>[CH3:14][NH:13][C:10]1[CH:9]=[C:8]2[C:7]([CH2:6][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])[C:18](=[O:19])[NH:15]2)=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C1Cc2ccc(NC)cc2NC1=O
Yield: 25.1 %

Procedure:
A mixture of 2.6 g of the diester (4), of 10% Pd on charcoal and 75 mL of dioxane were shaken under 50 psi of hydrogen for 17 hours at 50° C. The catalyst was removed by filtering through Celite and the solvent was removed. The residue was chromatographed on 200 g of silica gel eluting with 3:17 (v/v) acetone: CH2Cl2. Fractions 75-120 (17 mL/fraction) were combined and concentrated to yield 0.5 g of a white powder. Recrystallization from MeOH-H2O produced an analytical sample, m.p. 171°-172° C.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:33][OH:34]>CC(O)C>[OH:34][NH:33][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[S:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:19][CH2:20]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1)[C@@H]1OC(C)(C)OC1=O
Solvent: CC(C)O
Product: CC(C)C[C@H](C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.3 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-((1S)-3-methyl-1-{[4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1-piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one (9.0 mg; 0.019 mmol; 1.0 eq.) in iPrOH (0.20 mL) was added an aqueous solution of hydroxylamine (50%; 0.0029 mL; 0.098 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 2 h. Evaporation of the solvents gave the title product (2) as a colorless oil (9 mg; 100%). M−(ESI): 432.1; M+(ESI): 434.3. HPLC (Condition A): Rt: 3.1 min (HPLC purity: 79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][CH2:27][OH:28]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A stirred solution of 10.1 grams (0.038 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) and 8.0 grams (0.058 mole) of potassium carbonate in 150 mL of DMF was cooled to 0–4° C. and 3.7 mL (0.041 mole) of 3-bromopropan-1-ol was slowly added. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred during an 18 hour period. After this time water was added to the reaction mixture, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 11.8 grams of residual solid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:35]=[CH:34][C:33]5[O:32][CH2:31][O:30][C:29]=5[CH:28]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[Cl:45])[CH:40]=O>CO>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[Cl:45])[CH:40]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:35]=[CH:34][C:33]5[O:32][CH2:31][O:30][C:29]=5[CH:28]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc(CNCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Solvent: CO
Product: O=C(CNCc1ccc(Oc2ccc(N=Cc3ccc(Cl)c(Cl)c3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
2-{[(4-(5-aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (7.80 g, 16.4 mmol) was dissolved in methanol (400 mL), and to the resulting solution was added 3,4-dichlorobenzaldehyde (2.87 g, 16.4 mmol). This solution was refluxed for 16 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 10.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]4)[CH:12]=3)=[CH:10][C:3]=12.ClC1C=CN=C2N(S(C3C=CC(C)=CC=3)(=O)=O)C(C3C4=N[C:50](OC)=[C:51]([O:53]C)C=C4N(CCCN4CCC(O)CC4)C=3)=CC=12.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([CH2:50][CH2:51][OH:53])[CH2:29][CH2:28]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCC(O)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3[nH]1)cn2CCCN1CCC(O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3[nH]1)cn2CCCN1CCC(CCO)CC1

Procedure:
1-{3-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dimethoxypyrrolo[3,2-b]pyridin-1-yl]propyl}piperidin-4-ol can be prepared as in example 5, stage 5(d), but starting with 0.368 g of 1-(3-{3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxypyrrolo[3,2-b]pyridin-1-yl}propyl)-piperidin-4-ol and 0.857 g of potassium hydroxide in 25 cm3 of methanol. 0.188 g of 2-(1-{3-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dimethoxypyrrolo[3,2-b]pyridin-1-yl]propyl}piperidin-4-yl)ethanol is thus obtained with the following characteristics:
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=[CH2:1])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C1CCN(c2ccc(Cl)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
Methyltriphenylphosphonium bromide (1.429 g, 4.00 mmol) was suspended in THF (Ratio: 1.667, Volume: 2.5 ml) and cooled to −78° C. n-butyllithium (0.960 ml, 2.400 mmol) was added dropwise over 3 min and the resulting yellow suspension was stirred at −78° C. for 10 min. A solution of 1-(4-chlorophenyl)piperidin-4-one (0.419 g, 2 mmol) in THF (Ratio: 1.000, Volume: 1.5 ml) was added dropwise over 3 min and the dark red suspension was stirred at −78° C. for 10 min and then allowed to slowly warm to 5° C. over 1 h. The reaction was stirred at 5° C. for 4 h and was quenched with water (4 mL). This was extracted with ethyl ether (2×5 mL) and the extracts were washed with water (4×5 mL). The combined water washes were back-extracted with ethyl ether (5 mL) and the combined organic extracts were washed with brine (5 ml), dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (40 g SiO2, hexanes:ethyl acetate 9:1) afforded 1-(4-chlorophenyl)-4-methylenepiperidine (0.196 g, 0.944 mmol, 47.2% yield) as a clear yellow oil. [M+H] calc'd for C12H14Cl, 208; found, 208.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9]2)C.O=[C:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[C:16]1([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:3])=[O:22])=[CH:14][C:13]=3[NH:15][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cc1cc(N)c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=C1CCOCC1
Product: O=C(O)Cc1cc(NC2CCOCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-(2-Phenyl-7-amino-1H-indol-5-yl)-acetic acid ethyl ester prepared as an intermediate in the process of Example 31 and 4-oxo-tetrahydropyran were reacted according to the same procedures as Step B of Example 1 and Example 30 to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:14][C:15]([Cl:18])=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:18][C:15]1[S:14][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1ccc(Br)s1
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: COCCOC
Product: O=Cc1ccccc1-c1ccc(Cl)s1

Procedure:
4-Formylphenylboronic acid (1.37 g, 9.15 mmol), 2-bromo-5-chlorothiophene (1 mL, 9.15 mmol), 2M Na2CO3 (9 mL, 18.3 mmol) and Pd(PPh3)4 (0.53 mg, 0.46 mmol) in DME (30 mL) are heated to reflux for 4 h after which time the reaction mixture is concentrated in vacuo and taken up in EtOAc. The organic solution is washed with water (×2) then brine and dried over MgSO4, filtered and concentrated to dryness. The crude residue is purified by chromatography using 5% EtOAc/hexanes as the eluent to yield a yellow solid (1.8 g, 8.1 mmol) as the title compound. EI MS [M]+=222, 224, Cl pattern.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[I:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1cccc2cccnc12
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2cc(I)cnc12
Temperature: 62 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A stirred mixture of 8-nitroquinoline (100 g, 0.57 mol) in acetic acid (500 ml) was treated with N-iodosuccinimide (155 g, 0.69 mol) portionwise over 10 minutes, and warmed to 62° C. for 6 h. A further portion of N-iodosuccinimide (25 g, 0.14 mol) was introduced and the mixture stirred for a further 16 h before cooling to ambient temperature. The solvent was removed in vacuo, keeping the temperature below 35° C. The residue was dissolved in dichloromethane (2 L) and washed successively with saturated aqueous sodium bicarbonate solution (2×1 L), 10% aqueous sodium thiosulphate solution (1 L), water (1 L), brine (100 ml), then the organic phase was dried over magnesium sulphate. The mixture was filtered and the solvent removed to give a yellow solid which was recrystallised from ethyl acetate to give the title compound (D3) (168 g, 97%) as a yellow solid;