Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 101 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.37–7.24 (m, 6H), 7.02–6.95 (m, 2H), 6.51 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.53–2.48 (m, 3H), 2.37–2.30 (m, 4H), 1.98–1.92 (m, 4H), 1.82–1.59 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 494.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccccc1NC(=O)c1c(N)ncnc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccccc1NC(=O)c1c(N)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Temperature: 150 °C
Yield: 36.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (97 mg, 0.36 mmol), 4-amino-6-chloro-N-(2-methoxyphenyl)pyrimidine-5-carboxamide (100 mg, 0.36 mmol), DIEA (400 μl, 2.3 mmol) and cesium fluoride (166 mg, 1.09 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 150° C. in a microwave oven for 35 min. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (30% to 70%, dichloromethane-ethyl acetate) to obtain 67 mg (37% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([OH:19])=O)[N:9]=[C:10]([C:11]3[NH:12][CH:13]=[CH:14][N:15]=3)[C:3]=12.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][NH:31][C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([N:31]3[CH2:32][CH2:33][CH2:34][C:35]4[N:27]([C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)[N:28]=[CH:29][C:30]3=4)=[O:19])[N:9]=[C:10]([C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)[C:3]=12
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Product: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The compound was prepared from 2-(4-amino-3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine above using General Method A. The product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (6.4 mg). 1H NMR (400 MHz, MeOH-d4) δ 8.35 (s, 1H), 8.15 (s, 1H), 7.54 (m, 2H), 7.27 (m, 4H), 5.70 (s, 2H), 4.00 (m, 2H), 2.91 (t, J=6.2 Hz, 2H), 2.18 (m, 2H); MS: (ES) m/z calculated for C22H20FN10O [M+H]+ 459.18, found 459.1.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:18])([N:15]=[C:16]=[O:17])[CH3:14])[CH:8]=1)([CH3:6])[CH3:5])=[C:2]=[O:3].[CH2:19]([CH:21]([NH:24][OH:25])[CH2:22][CH3:23])[CH3:20]>ClCCl>[C:9]1([C:13]([CH3:18])([NH:15][C:16]([N:24]([OH:25])[CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:17])[CH3:14])[CH:10]=[CH:11][CH:12]=[C:7]([C:4]([NH:1][C:2]([N:24]([CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[OH:25])=[O:3])([CH3:6])[CH3:5])[CH:8]=1
Reactant: CC(C)(N=C=O)c1cccc(C(C)(C)N=C=O)c1
Reactant: CCC(CC)NO
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)NC(C)(C)c1cccc(C(C)(C)NC(=O)N(O)C(CC)CC)c1
Yield: 88.8 %

Procedure:
A solution of 1,3-Bis(1-isocyanato-1-methylethyl)benzene (2.3 ml, 10 mmol) and dichloromethane (100 ml) was charged with N-(1-ethylpropyl)hydroxylamine (2.2 g, 21.3 mmol). A precipitate formed immediately and the resulting mixture was maintained overnight. The precipitate was recovered by filtration and dried in vacuo to yield 4.0 g of the desired product as a white powder. Recrystallization from N,N-dimethylformamide.backslash.water provided an analytically pure sample: MP: 170.5-172.0° C. ; 1H NMR (300 MHz, DMSO): δ 8.91 (s, 2H), 7.37 (s, 1H), 7.18 (apparent d, J=1.0 Hz, 3H), 6.53 (s, 2H), 3.75-3.65 (m, 2H), 1.57 (s, 12H), 1.51-1.30 (m, 8H), 0.80 (t, J=7.3 Hz, 12 H); 13C NMR (75 MHz, DMSO): δ 159.3, 147.7, 127.1, 122.2, 121.0, 59.5, 54.3, 29.8, 24.4, 11.2; IR (KBr): 3436, 3160, 2963, 2928, 2873, 1632, 1520, 1380, 1361, 1270, 1232, 1160, 790, 702 cm-1 ; Anal. calc'd for C24H42N4O4 : C, 63.97; H, 9.39; N, 12.43. Found: C, 63.81; H, 9.35; N, 12.48.
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH:38]3[CH2:43][CH2:42][N:41]([C:44](OC(C)(C)C)=O)[CH2:40][CH2:39]3)[CH:37]=2)O1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:3]2[C:2]([C:33]3[CH:34]=[N:35][N:36]([CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH:37]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:16])[N:8]3[C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:20]=1
Reactant: COC(=O)N1c2ccc(Br)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C

Procedure:
Methyl (S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from methyl (S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate, and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate according to the procedure outlined above for Example 58. 1H NMR (300 MHz, CDCl3) δ ppm 0.74-1.01 (m, 1H), 1.14 (d, J=6.74 Hz, 3H), 1.47-1.82 (m, 2H), 1.99-2.07 (m, 1H), 2.31 (br s, 1H), 2.44 (dt, J=17.00, 5.72 Hz, 1H), 2.52-2.72 (m, 1H), 2.77 (s, 3H), 3.16 (br s, 1H), 3.27-3.62 (m, 2H), 3.82 (s, 3H), 4.43 (br s, 1H), 4.57-4.84 (m, 2H), 4.85-5.10 (m, 1H), 6.68-6.75 (m, 2H), 6.86-6.98 (m, 2H), 7.27 (s, 1H), 7.41 (d, J=8.50 Hz, 1H), 7.57-7.78 (m, 2H). MS (ESI, pos. ion) m/z 479 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.CN(C)C(N(C)C)=N.[F:39][C:40]([F:47])([F:46])[C:41](OCC)=[O:42]>CO>[F:39][C:40]([F:47])([F:46])[C:41]([NH:22][C@@H:20]([CH3:21])[C@H:19]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=1)[N:10]=[CH:11]2)[C:23]1[CH:24]=[CH:25][C:26]([S:29][CH3:30])=[CH:27][CH:28]=1)=[O:42]
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine hydrochloride (9a) (150 mg, 0.34 mmol) was dissolved in MeOH (2 mL). 1,1,3,3-tetramethylguanidine (128 μL, 1.02 mmol) was added and the mixture was stirred for 5 min, ethyl trifluoroacetate (83 μL, 0.7 mmol) was added and the reaction mixture was stirred at r.t. for 2.5 h. The reaction mixture was evaporated and the residual material was purified by semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 20 min gradient of 20%-90% MeCN in water followed by isocratic final concentration until product had eluted. UV=254 nm was used for detection. Fractions with product was combined and lyophilized to afford the title compound as a colourless solid. Yield 128 mg (74%)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:17]2[S:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[C:20]([CH3:21])[C:16]=2[CH:15]=1.Cl>N1C=CC=CC=1>[Cl:13][C:14]1[CH:27]=[CH:26][C:17]2[S:18][C:19]([S:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)(=[O:23])=[O:24])=[C:20]([CH3:21])[C:16]=2[CH:15]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
Into 3 mL of pyridine was dissolved 60 mg of ethyl 4-aminobenzoate, and 123 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 2 hours of stirring at room temperature. After confirmation of disappearance of the starting material, 2 mol/L hydrochloric acid was added, followed by extraction with ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 80 mg of the title compound as light pink powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:24][CH:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:16])[O:15][CH:11]2[CH:10]([CH3:25])[CH2:9]1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>CCOC(C)=O>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]2[CH2:24][CH:12]3[N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:14](=[O:16])[O:15][CH:11]3[CH:10]([CH3:25])[CH2:9]2)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]
Reactant: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)CC2C1OC(=O)N2C(=O)OC(C)(C)C

Procedure:
Following Method 9, (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, (+/−)-tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate was obtained. LCMS (m/z): 549.2/551.2 (MH+), Rt=0.78 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, light brown solid (0.3 g, 40%), MS (ISP) m/z=341.4 [(M+H)+], mp 151° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (0.45 g, 2.38 mmol).
Reaction SMILES: Cl[CH:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]1[CH:17]=[O:18].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:11]1([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]([CH:17]=[O:18])[CH:2]2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: O=CC1c2cccnc2N(c2ccccc2)C1Cl
Product: O=CC1c2cccnc2N(c2ccccc2)C1N1CCNCC1
Yield: 63 %

Procedure:
2-Chloro-1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-3-carboxaldehyde is reacted with piperazine as described in Example 2 to give l-phenyl-2-(piperazin-1-yl)-1,3-dihydropyrrolo[2,3-b]pyridine-3-carboxaldehyde (63% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:24](C1(C)C(O)=C(C(C)(C)C)C=C(C)C1)(C)(C)[CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([CH:24]=[CH2:25])[CH:11]=3)[C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2cc(Br)ccc2c1=O
Reactant: CC1=CC(C(C)(C)C)=C(O)C(C)(C(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(=O)c(C(=O)OCC)cn(C3CCCCC3)c2c1
Temperature: 25 °C
Yield: 9385.9 %

Procedure:
A mixture of 1 g of ethyl 7-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 13ad)), 60 mg of palladium tetrakis-triphenylphosphine, 1.55 ml of tributyl-vinyl-stannate and 5 mg of 2,6-di-tert-butyl-4-methyl-cresol in 25 ml of toluene is heated at reflux for 1 hr. The reaction mixture is cooled to room temperature, treated with 100 ml of ethyl acetate and washed with 100 ml of 10% aqueous ammonia solution. The aqueous solution is extracted with 50 ml of ethyl acetate. The combined organic phases are washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with hexane/ethyl acetate 1:1. 0.646 g (75%) of ethyl 1-cyclohexyl-4-oxo-7-vinyl-1,4-dihydro-quinoline-3-carboxylate is obtained as a colourless amorphous solid. Mass spectrum (ISP): 326.3(M++H, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[H-].[Na+].[Br:29][C:30]1[C:35]([CH2:36]Br)=[C:34]([O:38][CH3:39])[C:33]([O:40][CH3:41])=[C:32]([O:42][CH3:43])[C:31]=1[O:44][CH3:45]>CN(C=O)C.O>[Br:29][C:30]1[C:31]([O:44][CH3:45])=[C:32]([O:42][CH3:43])[C:33]([O:40][CH3:41])=[C:34]([O:38][CH3:39])[C:35]=1[CH2:36][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)c1ccc(OCCCC(C(=O)OCC)C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCC(Cc2c(Br)c(OC)c(OC)c(OC)c2OC)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-5-(4-ethoxycarbonylphenoxy)pentanoate (25.9 g) in DMF (200 ml) was portionwise added sodium hydride (60% oil dispersion, 3.11 g) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. To the reaction mixture was dropwise added a solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (28.8 g) in DMF (50 ml) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 6 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=7:1) to yield the entitled compound (42.6 g) as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9]4)=[CH:4][CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccc(N2CCC(N3CCCCC3)C2)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(N4CCC(N5CCCCC5)C4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[1-(4-iodo-phenyl)-pyrrolidin-3-yl]-piperidine (120 mg, 0.34 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (73 mg, 0.34 mmol).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.O.[CH2:22](O)[CH3:23]>>[CH2:1]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:22][CH3:23])=[O:18])=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
A solution of 2-(n-heptyl)indole-5-carboxylic acid (18.4 g) in ethanol (80 ml) containing a solution of hydrogen chloride gas in ethanol (110 ml, of strength 34% w/v) was refluxed for 6 hours. The solution was poured into water and the solid was collected and was recrystallised from methanol to give ethyl 2-(n-heptyl)indole-5-carboxylate (10.7 g), in the form of buff crystals, m.p. 66°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Na+].[Cl-].[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:14]([OH:17])(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)O)c(Cl)cc1Cl
Temperature: 50 °C

Procedure:
2,4-Dichloronitrobenzene (122 g (0.635 moles)) in 20% fuming sulfuric acid was heated at a temperature of 120° C. to 130° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was added portionwise to 1.5 l of ice water. The resulting aqueous solution was warmed to 50° C. and 400 g of NaCl was added thereto followed by cooling to room temperature. Crystals which separated out were collected by filtration, washed with water and with acetonitrile and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[CH2:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35](Br)[CH:34]=1)[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:35]1[CH:34]=[C:33]([CH2:31][CH3:32])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCc1ccnc(Br)c1
Product: CCc1ccnc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)c1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (˜1 mmol) was used in Procedure A with 4-ethyl-2-bromopyridine (1 mmol). Purified by silica gel chromatography (0-60% ethyl acetate/hexanes) to yield N-(4-chloro-3-(4-ethylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: MS (Q1) 419 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O.Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:12]
Reactant: BrCCCCCBr
Reactant: COc1cccc2c1CCC2=O
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc2c1CC1(CCCCC1)C2=O

Procedure:
A solution of 20 g 4-methoxyindan-1-one and 24 g 1,5-dibromopentane in 150 ml benzene is added quickly dropwise to a solution of potassium tert.-butylate (produced from 9.7 g potassium and excess tert.-butanol) in 200 ml benzene at 80°. The mixture is refluxed for 4 hours, treated with 50 ml water and 200 ml 2 N hydrochloric acid, and extracted with benzene. Chromatography on silicagel of the benzene phase gives 4'-methoxy-spiro(cyclohexane-1,2'-indan)-1'-one. M.Pt. 94°-96°.
Reaction SMILES: [H-].[Na+].[CH2:3]([S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][SH:11])[CH3:4].I[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[C:17]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][S:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][S:5][CH2:3][CH3:4]
Reactant: CCSCCCCCS
Reactant: CCOC(=O)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCSCCCCCSCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
NaH (0.4 g, 8.4 mmol) was washed with hexanes and then suspended in dry THF (55 mL). 5-Ethylthiopentanethiol (8 mmol, 73% pure by GC analysis, contaminated by 1,5-bis(ethylthio)pentane, 1.80 g of mixture) in THF (8 mL) was added and stirred for 1 h at room temperature. Ethyl 5-iodovalerate (2.1 g, 8 mmol) in THF (8 mL) was added and the mixture refluxed for 8 h. The solvent was evaporated in vacuo, the residue was dissolved in EtOAc (150 mL), washed with water (2 ×50 mL), brine (50 mL), dried (Na2SO4), chromatographed (silica gel, EtOAc/hexanes 1:10) and distilled (Kugelrohr) to yield the title compound (1.86 g, 80%) as a colorless oil (bp 147° C.-149° C./0.2 torr). IR (neat): 1740 cm-1. 1H-NMR: 1.25 (t, 6H); 1.50 (quintet, 2H); 1.54- 1.67 (m, 6H); 1.73 quintet, 2H); 2.32 (t, 2H); 2.46-2.57 (m, 8H); and 4.12 (q, 2H). Anal. Calcd for C14H28S2O2 : C, 57.49; H, 9.65%. Found: C, 57.36; H, 9.59%.
Reaction SMILES: F[C:2]1[C:7]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:6]=2[CH:5]=[C:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.[CH3:33][O-:34].[Na+]>CO>[CH3:33][O:34][C:2]1[C:7]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:6]=2[CH:5]=[C:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c2cc(-c2cccnc2)nc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2cccnc2)cc2c1Oc1ccc(-c3cccnc3)cc1[C@@]21COC(N)=N1
Temperature: 25 °C

Procedure:
A solution of (S)-1-fluoro-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (40 mg, 0.094 mmol) and sodium methoxide (52.4 μL, 0.940 mmol) in 15 mL of MeOH was heated to 65° for 5 h. After cooling to rt, the reaction was evaporated to dryness and was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the organics were dried over sodium sulfate, filtered and evaporated to dryness. Flash column (CH2Cl2 to CH2Cl2/MeOH=100:5 to 100:10 to 100:20) gave (S)-1-methoxy-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as an off white solid.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:17])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 23b) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(tert.-butoxycarbonyl)-N-[(4-chlorophenyl)-methyl]-ornithinamide by treating with trifluoroacetic acid in dichloromethane.