Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].O.[OH-].[Na+]>C(O)=O>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Cc1ccnc(N)n1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: Nc1nccc(C=Cc2ccc([N+](=O)[O-])cc2)n1
Yield: 57.5 %

Procedure:
The starting compound is prepared as follows. A solution of 2-amino-4-methylpyrimidine (21.8 g) and p-nitrobenzaldehyde (30.2 g) in formic acid (45 ml) is refluxed (24 hours). After cooling, the reaction mixture is poured into water (1 liter), and the aqueous mixture is neutralized with a 5N sodium hydroxide solution. The crude product is extracted with chloroform, and the extract is dried over sodium sulfate and concentrated to dryness. The crude product is purified on a silica gel column to give 4-[2-(p-nitrophenyl)ethenyl]-2-aminopyrimidine (27.8 g), m.p. 214°-216° C., which is used for the next step without purification.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1.[OH2:12]>C(O)C>[OH:12][CH:5]([C:10]1[CH:9]=[CH:8][C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=1)[CH:6]([CH3:11])[CH3:7]
Reactant: c1ccc2c(c1)CCO2
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(O)c1ccc2c(c1)CCO2
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
Sodium borohydride (1.11 g, 0.029 mol) was added portionwise to a stirred solution of 2,3-dihydrobenzofuran (5.46 g, 0.029 mol) in ethanol (20 cm3) over 0.5 hr. with cooling. The mixture was then stirred at 50°-70° C. for 1.5 hr., cooled, water was added and the mixture was extracted with dichloromethane. The extract was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was subjected to column chromatography on silica using toluene as the eluant. The appropriate fractions were combined and the solvent was removed to give 2,3-dihydro-5-(1-hydroxy-2-methyl-1-propyl)benzofuran (5.26 g, 0.027 mol; 95.2%). (Found: C, 74.59; H, 8.33. C12H16O2 requires C, 74.96; H, 8.39%) RF 0.30.
Reaction SMILES: Cl[C:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])/[C:23](=[N:25]/O)/[NH2:24].Cl>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[N:25]=[C:2]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:17][CH:18]=3)[O:3][N:24]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC(=O)O)cc3)n2)cc1Cl
Temperature: 200 °C
Reaction time: 0.42 h
Yield: 31.5 %

Procedure:
A 25 mL microwave reaction vial was charged with tert-butyl 2-(4-(chlorocarbonyl)phenoxy)acetate (0.815 g, 3.01 mmol) and pyridine (15 mL), (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.459 g, 2.007 mmol) was added. The vessel was capped and the reaction heated at 200° C. for 20 min under microwave irradiation (Biotage Optimizer, 300 W). The mixture was cooled, the reaction mixture was poured into stirring HCl (10%, 100 mL), the resulting suspension was filtered, the solid was washed by HCl (5%, 2×10 mL) and dried to afford grey solid, which was purified by RP-HPLC (A=50 mM ammonium acetate, B=acetonitrile; 30-95% B over 25.0 min (21.0 mL/min flow rate); 21.2×250 mm Thermo Hyperprep C18 column, 8 μm particles) to give 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetic acid (0.246 g, 0.633 mmol, 31.5% yield) as white solid. LC/MS (Table 1, Method f) Rt=2.08 min.; MS m/z: 389.14 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO δ ppm 13.28-13.07 (m, 1H), 8.13 (d, J=9.03 Hz, 2H), 8.05 (d, J=2.13 Hz, 1H), 7.99 (dd, J=8.64, 2.15 Hz, 1H), 7.38 (d, J=9.04 Hz, 1H), 7.18 (d, J=9.06 Hz, 2H), 4.85 (s, 3H), 1.35 (d, J=6.03 Hz, 6H).
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[CH:3]=1.C([Mg]Cl)(C)C.CON(C)[C:29]([C:31]1[CH:35]=[C:34]([CH3:36])[O:33][N:32]=1)=[O:30]>C1COCC1>[CH3:36][C:34]1[O:33][N:32]=[C:31]([C:29]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[CH:3]=2)=[O:30])[CH:35]=1
Reactant: CON(C)C(=O)c1cc(C)on1
Reactant: Cc1cccc(Cn2cc(I)c(=O)c3ccccc32)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3cc(C)on3)c(=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To the solution of 3-Iodo-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one (300 mg, 0.82 mmol, 1.2 eq) in THF (2 ml), was added isopropylmagnesium chloride in THF (0.88 mL, 1.76 mmol, 2.1 eq) slowly at −40° C. The reaction mixture was warmed to room temperature and stirred for 60 min, followed by the addition of 5-Methyl-isoxazole-3-carboxylic acid methoxy-methyl-amide (116 mg, 0.0.68 mmol, 1 eq). The mixture was stirred overnight, quenched with water and purified with HPLC to give the desired product (25 mg). LCMS observed for (M+H)+: 360.1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.C(O[CH:23](N(C)C)[N:24]([CH3:26])[CH3:25])(C)(C)C>>[CH3:23][N:24]([CH3:26])[CH:25]=[C:11]1[C:10](=[O:15])[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1cccc(C(F)(F)F)c1
Product: CN(C)C=C1CCCC(c2cccc(C(F)(F)F)c2)C1=O

Procedure:
2-(3-Trifluoromethyl-phenyl)-cyclohexanone (106 mg, 0.44 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a), to give crude title compound (132 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 298.0 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c1F
Yield: 56.3 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2-fluoro-3-methoxyphenylboronic acid (162 mg, 0.96 mmol) were reacted. After purification the title compound (100 mg, 56% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.04(d, J=4.8 Hz, 1H), 8.59 (m, 1H), 7.26 (m, 2H), 7.02 (m,1H), 3.90 (s, 3H), 2.93 (m, 1H), 0.69 (m, 4H). MS APCI, m/z=371.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH2:23][C:24]#[C:25][CH3:26].O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH2:23][C:24]#[C:25][CH3:26])[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CC#CCBr
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1cnc(C(Cc2ccc(N)nc2)C(=O)OCC)c1
Reaction time: 1 h
Yield: 39 %

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 60 mg (0.23 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT and stirred for 1 h. Then 31 mg (37 μl, 0.23 mmol) of 1-bromo-2-butine were added, and the mixture was stirred at RT for 1 h. 1 ml of water was then added and the mixture was extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatography of the residue on silica gel afforded 28 mg of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:29]#[N:30])C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[C:29]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2)#[N:30]
Reactant: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1O
Temperature: 25 °C
Reaction time: 11 h
Yield: 78.8 %

Procedure:
After dissolving 7-benzyloxy-6-cyano-4-(1H-indol-5-yloxy)quinoline (3 g, 7.6642 mmol) in tetrahydrofuran (250 ml), 10% palladium carbon powder (500 mg, wet) was added and the mixture was stirred for 11 hours at room temperature under a hydrogen atmosphere. After further adding 10% palladium carbon powder (300 mg, wet) and stirring the mixture for 9 hours at room temperature under a hydrogen atmosphere, additional 10% palladium carbon powder (200 mg, wet) was added and the mixture was stirred for 5 hours at room temperature under a hydrogen atmosphere. The solvent was distilled off, washing was performed with ethanol, and then the filtrate was distilled off under reduced pressure. The obtained crystals were suspended in ethanol and diluted with hexane, and the crystals were filtered out, washed with hexane:ethanol=3:1 and dried by aspiration to obtain the title compound (1.82 g, 6.0402 mmol, 79.12%) as light yellow crystals.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([CH2:37][O:38][CH3:39])[CH:34]=[C:33]([F:40])[C:32]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:32]4[C:31]([F:30])=[CH:36][C:35]([CH2:37][O:38][CH3:39])=[CH:34][C:33]=4[F:40])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (256 mg, 0.633 mmol), 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (188 mg, 0.633 mmol), HATU (481 mg, 1.26 mmol) in DMF (1 mL) and DIPEA (0.330 mL, 1.90 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and then extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to yield 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate as an intermediate.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([O:25][CH3:26])[CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][CH:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([O:25][CH3:26])[CH:10]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)cc1OC)C(C)=O
Reaction time: 48 h

Procedure:
A mixture of the product from step (i) (40 g) and 5% Pd—C (3 g) in EtOAc were hydrogenated at 3 Bar for 48 h. The mixture was filtered through celite and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 30% EtOAc/iso-hexane to afford the subtitle compound, 23.35 g.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[N:7]3[N:8]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Reactant: c1c[nH]cn1
Solvent: CS(C)=O
Product: Fc1ccc(-c2nn3c(-n4ccnc4)cccc3c2-c2ccncc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (100 mg) and imidazole (5 eq.) in dimethylsulfoxide (2 mL) in sealed tube was heated at 120° C. overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give 2-(4-fluorophenyl)-7-(1H-imidazol-1-yl)-3-pyridin-4-ylpyrazolo[1,5-α]pyridine. 1H NMR (CDCl3): δ 8.65 (d, 2H, J=5,6 Hz), 7.96 (s, 1H), 7.60 (d, 1H, J=9.5 Hz), 7.44–7.47 (m, 2H), 7.34–7.38 (m, 4H), 7.28 (d, 2H, J=5.7 Hz), 7.02 (m, 2H); MS m/z 356 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc(SCCOC(C)=O)sc2-c2ccc(OC)cc2)cc1

Procedure:
5.0 g of 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are suspended in 50 ml of acetic anhydride and, while stirring, the suspension is heated to the boil and refluxed for 15 minutes. The product is concentrated to dryness by evaporation under reduced pressure, two 30 ml portions of xylene are added, with concentration by evaporation being carried out again after each addition to remove traces of acetic anhydride, and the residue is dried under reduced pressure. 2-(2-Acetoxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of an oil, Rf =0.33 (silica gel toluene/ethyl acetate 10:1), IR-spectrum: νC=O =1730 cm-1 (CCl4).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.[OH-].[K+].Cl>CS(C)=O.O>[CH:11]1([CH2:14][O:15][C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: OCC1CC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCC2CC2)nc1
Temperature: 25 °C
Yield: 88 %

Procedure:
6-Chloropyridine-3-carboxylic acid (1.00 g, 6.347 mmol), cyclopropylmethanol (0.759 mL, 9.520 mmol) and potassium hydroxide (1.424 g, 25.39 mmol) were dissolved in DMSO (25 mL) and heated at 100 C for 18 h. The reaction mixture was cooled to room temperature; water was added and acidified to pH 4-5 with 1M hydrochloric acid. The resultant precipitate was filtered off under vacuum to afford the title compound (1.079 g, 88%). Method B HPLC-MS: MH+ requires m/z=193 Found: m/z=194, Rt=1.95 min (96%).
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18]Cl.CC(C)=O>C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCNC1c1ccccc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NCCN(Cc2ccc(Cl)c(Cl)c2)C1c1ccccc1

Procedure:
140 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 163 g. of 3,4-dichloro benzylchloride in 1,600 cc. of acetone for 6 hours while 330 cc. of triethylamine are added. The hot reaction mixture is filtered to remove precipitated triethyl ammonium chloride and is concentrated by fractional distillation. The resulting crystal fractions are twice recrystallized from 4 l. of 96% ethanol.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])(=[O:24])[CH3:23]
Reactant: Oc1ccccc1Sc1ccccc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1Sc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (1 ml) was added to a solution of 2-(2-fluorophenylthio)phenol (9.4 g) in acetic anhydride (10 ml), and the mixture was stirred at room temperature for 30 minutes. The excess of acetic anhydride was distilled off under reduced pressure, and the resultant oily residue was dissolved in diethyl ether. The ether solution was washed with 10% hydrochloric acid and water in turn, dried and evaporated under reduced pressure to give oily 2-fluorophenyl 2-acetoxyphenyl thioether (11.2 g).
Reaction SMILES: Br[C:2]1[C:3]([CH:16]=[C:17]2[CH:21]([OH:22])[CH2:20][CH2:19][S:18]2)=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.C([O-])=O.[NH4+].C(N(CC)CC)C>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>[OH:22][CH:21]1[CH2:20][CH2:19][S:18][C:17]1=[CH:16][C:3]1[CH:2]=[CH:7][C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:14][CH3:15])[CH:4]=1
Reactant: COC(=O)C(C)c1cc(Br)c(C=C2SCCC2O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C=C2SCCC2O)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
Methyl 2-[5-bromo-4-(3-hydroxythiolan-2-ylidenemethyl)-2-methoxyphenyl]propionate (50 mg) obtained in Example 50 was dissolved in ethylene glycol dimethyl ether (2 ml), and then to the solution was added ammonium formate (25 mg), triethylamine (0.1 ml) and tetrakis(triphenylphosphine)palladium (50 mg). The mixture was stirred overnight at 80° C. in an argon atmosphere. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (30 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=3)[N:12]=[C:11]([C:23](O)=[O:24])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=3)[N:12]=[C:11]([C:23]([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=[O:24])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccc1F
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place starting from the compound of Example 114A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 44 mg (48% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([CH2:13][NH2:14])[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:24]=1>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([CH2:13][NH:14][C:27]2[N:28]=[C:23]([Cl:22])[N:24]=[C:25]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)nc(N3CCOCC3)n2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of the 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester HCl salt (945 mg, 4.24 mmol) and NEt3 (856 mg, 8.48 mmol) in THF (10 mL) at 0° C. was added a suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24 mmol) at 0° C. The reaction mixture was stirred for another 1 hr at 0° C. and allowed to warm to 20° C. and stirred for 1-4 hrs to drive the reaction to completion. Silica gel (20 g) was added to the reaction mixture and the solvent was removed so that product was adsorbed on the silica gel. The silica gel plug was placed on top of a column to purify by flash chromatography using CH2Cl2/MeOH/NH3 (20:1:01) eluent. After unifying the product fraction, and evaporation of solvent, (750 mg, 46% yield) product was obtained as yellow solid; MS (ESI) m/z 385
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:15]([C:20]2[N:24](COCC[Si](C)(C)C)[N:23]=[N:22][CH:21]=2)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]3)[CH2:3][CH2:2]1.[F-].[Cs+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:15]([C:20]2[N:24]=[N:23][NH:22][CH:21]=2)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]3)[CH2:2][CH2:3]1
Reactant: CC(C)C(O)(c1ccc2cc(OC3CC3)ccc2n1)c1cnnn1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C(O)(c1c[nH]nn1)c1ccc2cc(OC3CC3)ccc2n1
Yield: 33.8 %

Procedure:
To a stirred solution of 1-(6-cyclopropoxyquinolin-2-yl)-2-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-yl)propan-1-ol (AR) (0.35 g, 0.77 mmol) in THF (5 mL) was added CsF (0.42 g, 3.08 mmol) followed by TBAF (1 mL, 0.77 mmol, 1M solution in THF) at RT and stirred under reflux for 12 h under inert atmosphere. After consumption of the starting material (by TLC), the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using 30% EtOAc/hexane as eluent to afford 8 (85 mg, 0.26 mmol, 33%) as off-white solid. 1H NMR (500 MHz, CDCl3): δ 11.82-11.60 (br s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.97 (d, J=10.0 Hz, 1H), 7.81 (br s, 2H), 7.38-7.36 (m, 2H), 6.62 (s, 1H), 3.85-3.84 (m, 1H), 2.82-2.80 (m, 1H), 0.98 (d, J=7.0 Hz, 3H), 0.87-0.83 (m, 4H), 0.64 (d, J=7.0 Hz, 3H). HPLC: 98.3%. MS (ESI): m/z 325.9 [M++1].