Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]([F:16])([F:15])[CH2:9]OCC(O)=O>ClCCl.CN(C)C=O>[F:7][C:8]([F:16])([F:15])[CH2:9][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: O=C(O)COCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCC(F)(F)F

Procedure:
A solution of oxalyl chloride (20 mL, 0.23 mol, 1.15 eq) in dry dichloromethane (50 mL) was added dropwise at room temperature, with stirring, to a solution of (2,2,2-trifluoroethoxy)ethanoic acid (int. Patent Appl., Publication No. WO 87/07270, 31.6 g, 0.2 mol) and N,N-dimethylformamide (5 drops) in dry dichloromethane (400 mL). The mixture was stirred for an additional hour, then heated under reflux for 2 hours, cooled and the bulk of the solvent removed by distillation (bp 40-45° C./760 mm Hg). The residue was transferred to a Claisen distillation flask and the remaining solvent and oxalyl chloride removed by distillation (bp 45-60° C./760 mm Hg). Vacuum distillation of the residue then afforded the product, bp 50-55°/25-32 mm Hg. δH (CDCl3) 4.00 (2H, q, 3JHF 8.3) and 4.57 (2H, s).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:19]([SH:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:31][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: CCCCCCCCCCCCS
Solvent: ClCCl
Product: CCCCCCCCCCCCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (75 mg) was dissolved in dichloromethane (5 ml) and 1-dodecanethiol (0.06 ml) was added. The solution was stirred at room temperature for 7 hours. Removal of the solvent gave a yellow solid which was then recrystallised from absolute ethanol to give 1,8-dihydroxy-10-dodecylthio-9-anthrone (89 mg, 85%) as pale yellow needles, melting point 76° C. (Found: C 73.3, H 8.2, S 7.9; C26H34O3S requires C 73.2, H 8.05, S 7.5%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])=[CH:16][CH:17]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:28][CH:29]=2)[C:18]=1C(OCC)=O)=[O:7])(C)(C)C.CCOC(C)=O>CC#N.O>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[CH2:35][C:15]1[CH:16]=[C:17]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:28][CH:29]=2)[C:18]2[C:6](=[O:7])[N:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)C1=C([C@@H]2CCCN2C(=O)OC(C)(C)C)NC(Cc2ccc(F)cc2F)=CC1c1cnc(C(=O)OCC)cn1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2cc(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Ethyl 5-[2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-6-(2,4-difluorobenzyl)-3-(ethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2-pyrazinecarboxylate (1.3 g, 2.17 mmol) was dissolved in 8 mL of CH3CN and 4 mL of H2O. Ceric ammonium nitrate (2.38 g, 4.34 mmol) was added and the reaction mixture stirred at ambient temperature for 30 min and then EtOAc was added and the organics extracted and washed with H2O, brine, and then dried (Na2SO4), filtered and concentrated to a brown solid. The solid was subjected to TFA (4.5 mL in 1 mL CH2Cl2) for 1 h and then concentrated. The residue was redissolved in CH2Cl2 (5 mL) and treated with Et3N (3 mL). After 16 h the reaction mixture was concentrated to a brown foam. The residue was redissolved in EtOAc and washed 1× pH 4.5 buffer, 1× brine and the organics dried (Na2SO4), filtered and concentrated to yield 0.250 g (26% yield) of the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 9.41 (s, 1H), 9.34 (s, 1H), 7.58 (s, 1H), 7.26–7.21 (m, 1H), 6.80 (dd, J=16.4, 7.4 Hz, 2H), 4.75 (dd, J=10.3, 6.2 Hz, 1H), 4.51 (dd,J=14.2, 7.1 Hz, 2H), 4.27 (s, 2H), 3.78–3.68 (m, 1H), 3.45–3.39 (m, 1H), 2.54–2.43 (m, 1H), 2.37–2.32 (m, 2H), 1.46–1.38 (m, 1H), 1.23 (t, J=7.2 Hz, 3H); ESMS m/z 451 (M+H)+, 449 (M−H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][Si](C(C)(C)C)(C)C)=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:53]=[CH:54][C:55]([OH:58])=[CH:56][CH:57]=3)[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(O)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 68.4 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (42.5 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) affording 25.7 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral anaylsis were consistent with the desired structure).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([O:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:24][CH2:25]2)=[CH:20][C:19]3=[O:40])[CH2:16][CH2:15]1)[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@H:21]([CH2:22][C@@H:23]([O:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:24][CH2:25]2)[CH2:20][C:19]3=[O:40])[CH2:16][CH2:15]1)[CH3:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
Compound 2004 (1.0 g, 1.75 mmol) was dissolved in EtOAc (75 ml) and platinum(IV) oxide (0.012 g, 0.049 mmol) was added. The mixture was placed on a hydrogenation apparatus (atmospheric). The set-up was evacuated to remove the dissolved oxygen and then hydrogen was introduced. The evacuation and introduction of hydrogen process was repeated 2 times. The reaction was stirred under hydrogen at atmospheric pressure for 2.5 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexanes: EtOAc gradient starting with 20:1) giving compound 2005 as a white solid (0.70 g, 71%). 24-t-Butyldimethylsilyloxy-3β-tetrahydropyranyloxy-5α-cholan-7β-ol was obtained as a by-product (21%). (Note: This by-product could be converted to the desired ketone 2005 with Collin's reagent in 64% yield.) Compound 2005: 1H NMR (500 MHz, CDCl3) δ: 4.73-4.66 (m, 1H, THP methine H), 3.95-3.85 (m, 1H, THP CH2O), 3.66-3.52 (m, 3H, THP CH2O & C-24 H), 3.50-3.45 (M, 1H, C-3 H), 1.08 (s, 3H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.64 (s, 3H, C-18 H), 0.04 (s, 6H, TBDMS CH3); IR (CHCl3) 2900, 1685 cm-1 ; MS (CI/isobutane) m/z 575 (M+1, 85%), 491 (M+1-THP, 100%); m.p. 166°-170° C.; Anal. calcd. for C35H62 O4SI: C=73.12, H=10.87; Found: C=72.88, H=10.78.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[C:10]3([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]3=4)[CH2:26][CH2:25][O:24]5)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:29])[C:10]12[CH2:21][O:20][C:19]2[CH:22]=[C:23]3[C:27](=[CH:28][C:18]1=2)[CH2:26][CH2:25][O:24]3
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc2C12COc1cc3c(cc12)CCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccc(F)cc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (91%) as a colorless solid: mp 257-259° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ10.35 (s, 1H), 6.86-6.73 (m, 3H), 6.43 (s, 1H), 6.22 (s, 1H), 4.64 (ABq, 2H), 4.43 (t, J=9.0 Hz, 2H), 2.93-2.90 (m, 2H); MS (ES+) m/z 298.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7]1[N:8]([CH3:17])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH2:5]2.[Li]CCCC.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7]1[N:8]([CH3:17])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH:5]2[Si:27]([CH3:29])([CH3:28])[CH3:26]
Reactant: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A round bottom flask containing 48b (1.11g, 4.17 mmol) in dry ether (27 mL) was immersed in a 25° C. water bath. n-BuLi (1.5 M in THF, 3.33 mL, 5.00 mmol) was added via syringe pump over one hour, generating a brown solution. Following addition of base, the reaction mixture was stirred at 25° C. for an additional 30 minutes and then cooled to −78° C. TMSCl (1.11 mL, 8.76 mmol) was added rapidly via syringe and the solution was subsequently warmed to room temperature. The reaction was diluted with ether, filtered, and concentrated in vacuo. Crude product was purified by flash column chromatography (20:1 hexanes-ethyl acetate followed by a second column 40:1 to 26:1 hexanes-ethyl acetate) to yield 49b as an orange solid in 78% yield (1.09 g, 3.24 mmol). 1H NMR (400 MHz, CDCl3): δ 7.57-7.60 (dd, 1H, J=8.4, 5.2 Hz), 7.19-7.22 (dd, 1H, J=9.6, 2.4 Hz), 7.00-7.04 (m, 2H), 6.78 (s, 1H), 4.01 (s, 3H), 3.97 (s, 1H), 2.61 (s, 3H), 2.49 (s, 3H), −0.15 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 159.7 (d, J=289.5 117.2 (d, J=10.5 Hz), 111.7 (d, J=27.9 Hz), 111.6 (d, J=29.7 Hz), 107.0, 38.2, 31.0, 21.8, 20.1, −2.2; 19F NMR (CD3CD, 376 MHz): δ −118.6 (m) FTIR: cm−1 2952, 1583, 1445, 1357, 1248, 1198, 1037, 838. EI-HRMS: Calcd. for C21H24FNSi+ [M]+: 337.1662, found 337.1664.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[CH:20]=[C:19]([NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[F:30])[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:2]1.C[C:32](N(C)C)=[O:33].C(O)(C(F)(F)F)=O>CN(C=O)C>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[CH2:22][NH:21][C:19]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:4][N:1]([CH:32]=[O:33])[CH2:2]3)=[CH:6][CH:7]=2)[CH:20]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CNC3)cc2)cc1NCc1cc(F)ccc1F
Reactant: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CN(C=O)C3)cc2)cc1NCc1cc(F)ccc1F

Procedure:
Compound 6-(4-(azetidin-3-yl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide (Example 213) (35 mg, 0.08 mmol) was stirred in 4 mL DMF with DMA (300 μL) at 120° C. in a sealed tube for three days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (15 mg). MS found for C23H21F2N5O2 as (M+H)+ 438.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.02 (1H, s), 7.44 (2H, dt, J=8.0; 1.6 Hz), 7.21 (1H, m), 7.15-7.04 (3H, m), 5.85 (1H, s), 4.67 (1H, m), 4.51 (2H, s), 4.46 (1H, m), 4.27 (1H, m), 4.04 (2H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:7]=[C:6]2[C:25]1[N:33]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=1.[F-:44].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][F:44])[CH:7]=[C:6]2[C:25]1[N:33]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=1.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=[C:6]2[C:25]1[N:33]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=1
Reactant: [F-]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCO[Si](C)(C)C(C)(C)C)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCF)c2cc1OC
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCO)c2cc1OC

Procedure:
3-{5,6-Dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}propanol and 2-[5,6-dimethoxy-1-(3-fluoropropyl)indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are prepared by following the procedure described in example 89b, but using 0.605 g of 2-[5,6-dimethoxy-1-(3-tert-butyldimethylsilyloxypropyl)indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1.95 ml of tetrabutylammonium fluoride (TBAF). After purification by flash chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents, argon), 0.243 g of 3-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}propanol is obtained, the characteristics of which are as follows:
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=2[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:15][CH2:16]2)=[O:21])=[C:23]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH:24]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3N3CCOCC3)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCOCC3)CC2)c(C)c1
Yield: 98.2 %

Procedure:
To a mixture of ethyl 2-chloro-4-nitrobenzoate (1.5 g), palladium acetate (73.3 mg), 2-(dicyclohexylphosphino)biphenyl (229 mg), tripotassium phosphate (1.94 g) and morpholine (0.57 mL) was added 1,2-dimethoxyethane (23 mL), and the mixture was stirred with heating under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 2-(morpholin-4-yl)-4-nitrobenzoate (220 mg). The obtained ethyl 2-(morpholin-4-yl)-4-nitrobenzoate (220 mg) and 1-(2,4-dimethylphenyl)piperazine (149 mg) were dissolved in ethanol (3.5 mL), 1N aqueous sodium hydroxide solution (1.1 mL) was added, and the mixture was stirred at 50° C. To the reaction mixture was added 1N hydrochloric acid (1.1 mL), 1-(2,4-dimethylphenyl)piperazine (149 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (218 mg) were added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by silica gel column chromatography to give [4-(2,4-dimethylphenyl)piperazin-1-yl][2-(morpholin-4-yl)-4-nitrophenyl]methanone (206 mg). Then, to a solution of ethanol (3 mL) and water (1 mL) were added ammonium chloride (294 mg) and iron (211 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl][2-(morpholin-4-yl)-4-nitrophenyl]methanone (206 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (188 mg).
Reaction SMILES: C[C:2]1[C:3]([NH2:10])=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.N1C=CC=C[CH:12]=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:10][C:3]2[CH:2]=[CH:6][S:5][C:4]=2[C:7]([O:9][CH3:12])=[O:8])=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: Cc1csc(C(=O)O)c1N
Solvent: ClCCl
Product: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a mixture of methyl 3-aminothiophene-2-carboxylic acid (5.0 g, 35.0 mmol), pyridine(2.82 mL, 35.0 mmol), and dry methylene chloride (160 mL) at 0 C. was added 4-tertbutylbenzoyl chloride(6.21 mL, 31.8 mmol) and stirred for 1 h. The reaction was concentrated, dissolved in ethyl acetate, washed with water (4×) and brine, MgSO4 dried and concentrated. The residue was chromatographed (2% ethyl acetate/hexanes to 5% ethyl acetate/hexanes) to afford the title compound as a solid (9.67 g, 96% yield); NMR(CDCl3) δ1.36(s, 9H), 3.93(s, 3H), 7.54(d, J=8.4 Hz, 2H), 7.54(d, J=5.4 Hz, 1H), 7.95(d, J=8.4 Hz, 2H), 8.30(d, J=5.4 Hz, 1H), 11.16(s, 1H); MS(FD): 317.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:31][O:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])=[CH:37][CH:36]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-methoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (40%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[S:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:23]N1C(=O)CCC1=O.OS([O-])=O.[Na+]>C1COCC1>[I:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[N:14]=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[S:12][N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]ccc3c2)ns1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]cc(I)c3c2)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl (3-(1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.316 mmol) in THF (5 mL) at 0° C. was added N-iodosuccinimide (78 mg; 0.348 mmol) and the reaction was stirred for 1 h at RT. The mixture was treated with saturated aq. NaHSO3 solution (5 mL). The volatile solvent were evaporated and the crude residue was further treated with ice-cold water and petroleum ether to give tert-butyl (3-(3-iodo-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (80 mg, 58.8%) as an off white solid. MS (ESI, pos. ion) m/z: 386.9 (M+1) (carbamic acid mass); 1H NMR (400 MHz, DMSO-d6): δ 12.42 (brs, 1H), 11.76 (brs, 1H), 8.15 (s, 1H), 8.00-7.98 (m, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: O[C:2]([CH:5]([CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14](\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:4][C:2]([CH:5]([CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14](\[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])=[CH2:3]
Reactant: COC(=O)C(CCC/C=C(\c1ccccc1)c1cccnc1)C(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(CCC/C=C(\c1ccccc1)c1cccnc1)C(=O)OC
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
Methyl (E)-2-(1-hydroxy-1-methylethyl)-7-phenyl-7-(3-pyridyl)-6-heptenoate (0.3 g, 0.89 mmole) was dissolved in dichloromethane (10 ml), and the solution was cooled at -10° C. Thionyl chloirde (0.15 ml) was added to the solution, followed by adding pyridine (0.4 ml) and stirring for 10 minutes under the same reaction conditions. After the completion of the reaction, aqueous sodium hydrogencarbonate (5 ml) was added, and the product was extracted with ethyl acetate. The organic layer was worked up in the usual procedure, and the crude product was chromatographed on silica gel, followed by elution with isopropyl ether:ethyl acetate (1:1) to yield methyl (E)-2-(1-methylethenyl)-7-phenyl-7-(3-pyridyl)-6-heptenoate (5-e) (0.25 g, 70%).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[N:15][CH:16]=[C:10]2[CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[N:15][CH:16]=[C:10]2[CH:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCc1ccn2cncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCc1ccn2cncc2c1
Reaction time: 5 h

Procedure:
7-(3-methoxycarbonylpropyl)-imidazo[1,5-a]pyridine (Example 32, 8.0 mg) is dissolved in 0.3 ml of methanol and 0.1 ml of 1 N NaOH is added. The mixture is stirred at 25° for 5 hours, evaporated, and the residue is redissolved in 5 ml of water. The aqueous solution is washed with 2 ml of ethyl acetate, brought to pH=6 with 2 N sulfuric acid and extracted with methylene chloride (3×5 ml). The organic extracts are dried over sodium sulfate/magnesium sulfate and evaporated to yield 7-(3-carboxypropyl)-imidazo[1,5-a]pyridine, IR (CHCl3) 1720 cm-1.