Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:18][C@H:19]([C:25]([C@@:27]1([N:36]2[C:46]3[N:45]=[C:43]([NH2:44])[NH:42][C:40](=[O:41])[C:39]=3[N:38]=[CH:37]2)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]1[OH:29])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>N1C=CC=CC=1>[NH2:18][C@H:19]([C:25]([C@@:27]1([N:36]2[C:46]3[N:45]=[C:43]([NH2:44])[NH:42][C:40](=[O:41])[C:39]=3[N:38]=[CH:37]2)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]1[OH:29])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: NCCCC[C@H](N)C(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 800 mg of (Nα-FMOC-lysyl)guanosine in anhydrous pyridine was added anhydrous piperidine (4 mol eq.). The mixture was allowed to stir for 5 hr at 0° C. and then was evaporated to dryness. The residue was dissolved in DMF and purified by slow addition of the DMF solution to a rapidly stirred solution of EtOH—Et2O, yielding a precipitate.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH:15]([C:16]([O:18]CC)=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+]>CO.O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH:15]([C:16]([OH:18])=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc2c(c1)C(=O)CSC2C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCc1ccc2c(c1)C(=O)CSC2C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
In methanol (150 ml) was suspended ethyl 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (41 g) followed by addition of 2N-KOH (150 ml). The mixture was stirred at room temperature for one hour. The reaction mixture was poured in water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (27.5 g, yield 74%). Recrystallization from ether-hexane gave colorless plates.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=N)[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=O)C.Cl.[OH2:39]>COCCO>[OH:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:39])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=1)([CH3:19])[CH2:9][CH2:8]2
Reactant: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2
Reactant: O
Agent: Cl
Solvent: COCCO
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CCOc1ccc(CC3SC(=O)NC3=O)cc1)CC2

Procedure:
560 mg of 5-{4-[2-(6-acetoxy-7,8-dimethoxy-2,5-dimethylchroman-2-yl)ethoxy]benzyl}-2-iminothiazolidin-4-one (prepared as described in Example 7) were added to a mixture of 7 ml of concentrated hydrochloric acid, 2.5 ml of water and 10 ml of ethylene glycol monomethyl ether, and the mixture was heated under reflux for 13 hours. The reaction mixture was then processed and purified as described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel eluted with a 9:1 by volume mixture of chloroform and ethyl acetate, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O:11][CH2:12][CH3:13])=[O:10]>>[CH2:12]([O:11][C:9](=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:19]=1)[CH3:13]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichloropyrimidine was coupled to 3-carboethoxyphenylboronic acid following procedure A. LC-MS showed the product to be >95% pure and to have the expected M+H+ of 195.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:14][SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: CC(=O)CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, 4-phenyl-2-butanone (148 mg, 1.0 mol) and 1,1,1,3,3-pentamethyldisiloxane (371 mg, 2.5 mmol) were added through a syringe, and iron complex A (5.0 mg, 0.01 mmol) was added as catalyst. The solution was stirred at room temperature for 24 hours. At 0° C., THF (1 mL) and tetrabutylammonium fluoride in THF (1 M, 1 mL) were then added to the solution, which was stirred at 0° C. for 1 hour. The solvent was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (3/1) as developing solvent, obtaining 4-phenyl-1-butanol (139 mg, 0.92 mmol, 92%). The results are shown as Entry 2 in Table 7. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]=O)[CH2:14][O:13][C:12]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:22]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[OH:30])[CH2:23]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][N:27]2[CH2:28][CH2:29][C:24]3([CH2:22][CH2:23]3)[C@H:25]([OH:30])[CH2:26]2)[CH2:14][O:13][C:12]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: CC1(C)OC[C@H](CC=O)N1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@H](CCN2CCC3(CC3)[C@H](O)C2)N1C(=O)OCc1ccccc1
Yield: 97.3 %

Procedure:
To a solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid benzyl ester (8.51 g, 30.7 mmol) in dichloromethane (140 mL) were added (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 5.03 g, 30.7 mmol), triethylamine (3.11 g, 30.7 mmol) and sodium triacetoxyborohydride (9.11 g, 43.0 mmol) at room temperature. After 1 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The aqueous layer was extracted twice with dichloromethane, the combined organic phases were dried (MgSO4), filtered, and evaporated to afford the title compound (11.6 g, 97%). Light yellow gum, MS (ISP)=389.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 6 h
Yield: 7.4 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[methyl(propyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.75 g) in DMF (4 mL) was added potassium tert-butoxide (0.29 g) at 0° C., and the mixture was stirred for 6 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (50 mg, 8%) as a pale-yellow oil.
Reaction SMILES: [CH:1]([C@@H:4]([NH2:7])[CH2:5]O)([CH3:3])[CH3:2].O=S(Cl)Cl.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[NH:7][C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][S:24]1
Reactant: CC(C)[C@@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](C(C)C)CS1

Procedure:
(1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23].CN(C)C=O>CN(P(N(C)C)(N(C)C)=O)C>[CH2:22]([N:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2](=[O:1])[N:7]2[N:8]=[CH:9][N:10]=[C:6]12)[CH3:23]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2ncnn2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2ncnn2c1=O
Yield: 37.9 %

Procedure:
Ethyl 7-hydroxy-1,2,4-triazolo [1,5-a]pyrimidine-6-carboxylate (10.4g, 50mM), potassium carbonate (7.0g, 50mM), ethyl iodide (8.0ml, 15mM), dry dimethylformamide (80ml) and hexamethylphosphorotriamide (80ml) was heated at 80° C for 4 hours. The resulting mixture was evaporated in vacuo and water added (100ml). The solution was washed with ether (5 × 100ml) then extracted with ethyl acetate (10 × 100ml). The ethyl acetate extracts were dried over magnesium sulphate, filtered and evaporated in vacuo. The crystals were filtered off and recrystallised from ethyl acetate. 37.9% yield (4.47g); mpt 129° - 131° C. δ (CDCl3) 8.62 (1H,s) and 8.12 (1H,s), ##STR55## 4.47 (2H,q) and 4.38 (2H,q), (OCH2CH3 and NCH2CH3), 1.62 (3H,t) and 1.50 (3H,t), (OCH2CH3 and NCH2CH3); ν max (KBr) 3400 (broad) 1715, 1690, 1610, 1570, 1480, 1370, 1325, 1210, 1175, 790cm-1 ; λmax (EtOH) 209 (εm 12,400), 252 (εm 8,260) and 290 (εm 11,800)nm.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:17])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([C:31]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH:4]=2.[N+](=[CH:48][CH3:49])=[N-].CCOCC>CO>[CH2:23]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][CH2:19][O:18][C:16]([C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[C:3](=[CH:4][C:5]([C:31]([O:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])=[CH:6][CH:7]=3)[C:2]([O:1][CH2:48][CH3:49])=[CH:15][C:14]=2[CH:13]=1)=[O:17])[CH2:24][CH2:25][CH3:26]
Reactant: CC=[N+]=[N-]
Reactant: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)cc(O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Solvent: CO
Solvent: CCOCC
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)cc(OCC)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Reaction time: 8 h

Procedure:
The corresponding 9-ethoxy derivative is prepared by reacting a solution of bis[3-(dibutylamino)propyl] 9-hydroxyphenanthrene-2,7-dicarboxylate in methanol with diazoethane by co-distillation with ether into the reaction mixture at -10° to 30°C. After standing overnight, the crude bis[3-(dibutylamino)propyl]9-ethoxyphenanthrene-2,7-dicarboxylate so obtained is converted to its dihydrochloride salt by the addition of ethereal hydrogen chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:7][C:8]1[C:13]([NH2:14])=[C:12]([C:15]2[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:11]=[CH:10][N:9]=1)[CH2:5][CH3:6].[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([N:7]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:13]=2[N:14]=[C:25]([CH3:27])[C:24]1=[O:28])[CH2:5][CH3:6]
Reactant: CCOC(=O)C(C)=O
Reactant: CC[C@H](COC)Nc1ncnc(-c2ccc(OC)nc2C)c1N
Solvent: CCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(-c3ccc(OC)nc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(1-Methoxymethyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.2 g, 0.63 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.70 ml, 6.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.0 mg of (R)-8-(1-methoxymethyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 651a). 1H NMR (300 MHz, CDCl3) δ ppm 8.93 (s, 1 H), 7.62 (d, J=8.42 Hz, 1 H), 6.64 (d, J=8.42 Hz, 1 H), 4.23 (m, 1H), 3.94 (s, 3 H), 3.68 (m, 2 H), 3.25 (s, 3 H), 2.45 (s, 3H), 2.34 (s, 3 H), 1.22 (m, 2H), 0.82 (t, J=7.51 Hz, 3 H). MS (EI) 370.3 [(M+H)+, 100].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH:20]=3)[CH:16]([CH2:15][CH2:14]2)[CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C2C3CCC2CN(C(=O)OCc2ccccc2)C3)c1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C2C3CCC2CN(C(=O)OCc2ccccc2)C3)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
8-(3-Amino-phenyl)-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (185 mg, 0.55 mmol) was dissolved in pyridine (3 mL), cooled to 0° C. then charged with methanesulfonylchloride (0.064 mL, 0.825 mmol) dropwise, causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by APCI MS after 1 h. Following a 1N HCl quench (10 mL), the product was extracted with EtOAc (2×30 mL), washed with saturated aqueous NaHCO3 solution (1×30 mL), saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4, filtered and concentrated to give an orange liquid (153 mg, 67%). (TLC 30% EtOAc/hexanes Rf 0.15); 1H NMR (400 MHz, CDCl3) δ 7.33–7.19 (m, 5H), 7.21 (t, J=7.9 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J=7.9 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 5.24 (s, 2H), 4.03 (d, J=12.5 Hz, 1H), 3.94 (d, J=12.6 Hz, 1H), 3.07 (d, J=12.5 Hz, 1H), 3.03 (d, J=12.5 Hz, 1H), 2.90 (s, 3H), 2.86 (s, 1H), 2.50 (br s, 1H), 2.44 (br s, 1H), 1.60 (m, 2H), 1.47 (m, 2H); APCI MS m/z 415.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](/[CH:9]=[CH:10]/OCC)=[CH:4][N:3]=1.Cl>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:9]=[CH:10][NH:8][C:6]=2[CH:7]=1
Reactant: CCO/C=C/c1cnc(Cl)cc1N
Agent: Cl
Solvent: CO
Product: Clc1cc2[nH]ccc2cn1
Temperature: 75 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
To a solution of 2-chloro-5-[(E)-2-ethoxyvinyl]pyridin-4-amine (preparation 36b, 1.00 g, 5.30 mmol) in methanol (20 mL) was added concentrated hydrochloric acid (1.00 mL, 32.64 mmol) and the mixture was stirred at 75° C. for 21 h. The mixture was concentrated under reduced pressure, treated with a saturated aqueous solution of potassium carbonate and extracted with ethyl acetate. The organic layer was dried and evaporated to yield the title compound (0.76 g, 99%) as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:25])=[O:23])[CH3:20]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12](/[CH:13]=[C:24](\[CH3:25])/[C:22]([O:21][CH2:19][CH3:20])=[O:23])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1cc(F)c(OCc2ccccc2)c(F)c1

Procedure:
A solution of 4-(benzyloxy)-3,5-difluorobenzaldehyde (7) (1.32 g, 5.34 mmol) and (1-ethoxycarbonylethylidene)triphenyl phosphorane (2.32 g, 6.41 mmol) in tetrahydrofuran (53 mL) was refluxed for 2 hours. The reaction was concentrated in vacuo and was purified by flash column chromatography (0-100% EtOAc in hexanes) to give (E)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylacrylate (8).
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:25]1([B-](F)(F)F)[CH2:27][CH2:26]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([CH:25]2[CH2:27][CH2:26]2)[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=1
Reactant: F[B-](F)(F)C1CC1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CC1
Temperature: 110 °C
Yield: 8 %

Procedure:
To a microwave vial was added 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.037 mmol, from peak 1 from Example 167, step 4), potassium cyclopropyltrifluoroborate (8 mg, 0.06 mmol, from Frontier Scientific, item # C10298), potassium phosphate (23 mg, 0.11 mmol), and tetrakis(triphenylphosphine)palladium (4.2 mg, 0.0036 mmol) and then toluene (0.3 mL)/water (0.1 mL). The vial was sealed and degassed with N2 three times. The reaction was heat at 110° C. for 20 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 8%). The product was isolated as a single enantiomer. LCMS calculated for C19H23ClN5O (M+H)+: m/z=372.2; Found: 372.2.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:14][S:13][CH2:12][C:9]=3[N:10]([CH3:11])[C:4]=2[CH:3]=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[C:9](=[CH:12][S:13][CH:14]=3)[N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)c(Cl)cc21
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1c2cc(Cl)c(Cl)cc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.40 g. of 6,7-dichloro-1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one in 2.7 ml. of dry pyridine is added, in portions, a total of 0.18 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid which separates is collected and recrystallized from methanol-water to give off-white crystals, m.p. 270°-272°C. (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CCNCC1
Product: CC(C)(C)c1ccc(-n2c(N3CCCCC3)c(C=O)c3ccccc32)cc1
Yield: 87 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperidine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-piperidin-1-yl-1H-indole-3-carboxaldehyde (87% yield) as an off-white solid. TLC (silica gel, heptane-30% ethyl acetate); Rf=0.23; ESI/MS 361 (M+H); RT=4.48 min; NMR 10.14 (1H, s); 8.11 (1H, d, J=6 Hz); 7.66 (2H, d); 7.46 (2H, d); 7.16 (2H, m); 6.91 (1H, d, J=9 Hz); 3.27 (4H, m); 1.46 (6H, m); 1.36 (9H, s).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[CH:30]=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=481.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCCOCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 99.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (154 mg, 0.223 mmol) prepared in Example 158c, triethylsilane (0.20 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL), to yield the title compound (120 mg, 99%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (214 mg, 0.75 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (268 mg, 71%).