Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][CH:10]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].[I:18]I>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][C:10]=2[I:18])[CH:7]=1
Reactant: II
Reactant: OCc1ncc2ccc(F)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1nc(I)c2ccc(F)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a round-bottomed flask, (6-fluoro-imidazo[1,5-a]pyridin-3-yl)-methanol (225 mg, 1.15 mmol) was dissolved in ethanol (2 ml) and water (1 ml). Sodium bicarbonate (341 mg, 4.06 mmol) was added followed by iodine (383 mg, 1.51 mmol). The dark brown suspension was stirred at room temperature for 3 h then quenched with 10% Na2S2O3-solution and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-40% EtOAc) to provide 157 mg (50%, 2 steps) of (6-fluoro-1-iodo-imidazo[1,5-a]pyridin-3-yl)-methanol as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>COC(C)(C)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 78.2 %

Procedure:
Prepared by a method analogous to that of Example 1(b) from 6.75 g (11.5 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(8-phthalimidooctyloxy)carbonyl-pyridine and 1.7 ml (34.5 mmol) of hydrazine hydrate. 4.13 g (78%) of yellow crystals melting at 129°-131° C. obtained with tert.-butyl methyl ether.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1.[C:16](Cl)(Cl)=[S:17]>C(Cl)Cl>[Cl:7][C:8]1[C:13]([N:14]=[C:16]=[S:17])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1ccc(Cl)nc1Cl
Reaction time: 48 h

Procedure:
A slurry of sodium carbonate (15.2 g, 144 mmol), 2,6-dichloropyridin-3-amine (9.00 g, 55.2 mmol), and thiophosgene (5.50 mL, 71.8 mmol) in 100 mL anhydrous DCM was allowed to stir in a sealed vessel for 2 days. The reaction mixture was filtered through a glass frit, rinsing with DCM. The filtrate was concentrated in vacuo to give 2,6-dichloro-3-isothiocyanatopyridine as a peach-colored solid.
Reaction SMILES: [CH2:1]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15](Cl)[N:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([NH:35][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(Cc3ccccc3)nn12
Reactant: NC1CCCC1
Product: c1ccc(Cc2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 31.8 %

Procedure:
A solution of 4-(2-benzyl-7-chloropyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (65 mg, 0.16 mmol) in cyclopentylamine (2 mL, 20 mmol) was heated at 116° C. for 16 hours. The reaction mixture was cooled and the excess cyclopentylamine was removed in vacuo. The crude material was chromatographed (19:1 dichloromethane:acetone) to provide N-{4-[2-benzyl-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (23 mg 32%) as a pale yellow solid. Rf 0.12 (5:1 hexanes:ethyl acetate); 1H NMR δ 8.18 (d, 1H), 7.59 (d, 1H), 7.30–7.10 (m, 6H), 6.65 (d, 1H), 5.99 (d, 1H), 4.59 (s, 2H), 4.30 (m, 1H), 3.98 (m, 1H), 2.21–2.00 (m, 4H), 1.90–1.50 (m, 12H); MS m/z 453 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)C.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[C:20]1([CH2:19][CH2:18][CH:17]=[N:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CCCc1ccccc1
Reactant: CCc1ccc(C(=O)NN)cc1
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(C(=O)NN=CCCc2ccccc2)cc1

Procedure:
4-ethyl-benzoic acid hydrazide (10 g, 60.9 mmoles) was dissolved in 32 mL of methanol. Acetic acid (1 mL) was added, the mixture was brought to reflux, and hydrocinnamaldehyde (5.77 g, 67 mmoles) was then slowly added. The reaction mixture was refluxed for 10 h and monitored by TLC. The precipitates were collected via filtration and washed with hexanes. 4-Ethyl-benzoic acid (3-phenyl-propylidene)-hydrazide was obtained as a white solid (9.34 g, 54.7% yield). Rf=0.36 (1:1 EtOAc:n-hexane); 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.72-7.24 (m, 10H), 2.87 (t, J=15.2 Hz, 2H), 2.79-2.57 (m, 4H), 1.24 (t, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([CH2:42][NH2:43])[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:28][C@@H:29]([CH2:42][NH:43][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:12][C:11]3=[O:13])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(=O)CC4)cc3)S2)CC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(NC[C@H](O)COc5cccc6[nH]c(=O)[nH]c56)CC4)cc3)S2)CC1

Procedure:
The title compound was prepared from 1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 29) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a yellowish solid; mp>150° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.85-2.00 (m, 2 H), 2.24 (s, 3 H), 2.40-3.00 (m, 11H), 3.50-4.10 (m, 7 H), 6.56 (d, J=8.1Hz, 1 H), 6.62 (d, J=8.1Hz, 1 H), 6.84 (dd, J=8.1, 8.1Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.48 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H), 10.3-11.0 (brs, 2 H); MS (ES) m/z: 296.5 ((M+2H)2+, 100%); 592.1 (MH+, 20%); HRMS Calcd. for C30H38N7O4S (MH+): 592.2760. Found: 592.2685.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[CH2:8]1[O:9][C:10]2[CH:11]=[CH:12][C:4]([CH2:3][O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]=2[O:7]1
Reactant: ClCCCCCBr
Reactant: OCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCOCc1ccc2c(c1)OCO2
Yield: 24.1 %

Procedure:
60% Sodium hydride (0.6 g) was suspended in dimethylformamide (10 ml), and piperonyl alcohol (1.5 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane(1.8 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 0.6 g of 5-((3,4-methylenedioxyphenyl)methoxy)pentyl chloride.
Reaction SMILES: C1(CC2CCCC[N:9]2[CH2:14][CH:15]([C:17]2C=CC=C(Br)C=2)[CH3:16])CCCCC1.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27]>C(OCC)C>[CH3:27][C:26]1[CH:16]=[C:15]([CH:17]=[CH:24][CH:25]=1)[C:14]#[N:9]
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc(C#N)c1
Yield: 212 %

Procedure:
Following a procedure similar to that described in Example 7, 18.9 g. (0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.095 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 12.4 g. (0.106 mole) of 3-methylbenzonitrile to give 10.7 g. of 2-cyclohexylmethyl-1-{2-[3-(3-methylbenzoyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:15]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].CS(C)=O>O>[Cl:8][C:7]1[C:2]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)[C:15]2=[O:33])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3ncc(C(F)(F)F)cc3Cl)C2=O)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A flask was charged with 2,3-dichloro-5-(trifluoromethyl)pyridine (0.2919 mL, 2.093 mmol), (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.415 g, 1.395 mmol), Na2CO3 (0.2958 g, 2.791 mmol), and DMSO (5 mL). The reaction mixture was stirred at 130° C. overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, filtered, concentrated. The residue was purified using silica gel column chromatography with 30% ethyl acetate in hexanes to provide (S)-tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.51 g, 76.63% yield). Mass spectrum (apci) m/z=377.2 (M+H-Boc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[CH:33]=[CH:34][O:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccon1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccon2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and isoxazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[CH:5][CH:4]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2C=O)cn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2n(-c2ccc(OC)nc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
6.4 g (28 mmol) of 2-(6-methoxy-3-pyridinylamino)nicotinaldehyde was dissolved in ethanol (50 mL), and 6.7 g (42 mmol) of diethyl malonate and 0.95 g (11 mmol) of piperidine were added thereto. The resulting mixture was stirred for 4 hours at 100° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was washed with a mixed solution of ethyl acetate and diisopropyl ether. Thus, 4.1 g of the title compound was obtained as a pale yellow solid (yield: 45%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:10]#[N:11].[OH-:17].[NH4+]>>[Br:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:10]([NH2:11])=[O:17]
Reactant: [OH-]
Reactant: N#Cc1c(Cl)ccc(Br)c1F
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1c(Cl)ccc(Br)c1F
Temperature: 55 °C

Procedure:
Concentrated sulfuric acid (15 mL) was placed in a 100 mL 3-neck flask equipped with an internal thermometer and then heated to 55° C. 3-Bromo-2-fluoro-6-chlorobenzonitrile (11.0 g, 47 mmol) was added portion-wise to the acid with stirring maintaining the temperature above 50° C. The dark solution was heated at 65° C. for 24 hours then cooled to room temperature and poured over ice and cautiously neutralized with concentrated ammonium hydroxide. The mixture was extracted with two portions of ethyl acetate and the combined organic layers dried over Na2SO4 (with charcoal). Filtration and concentration gave 3-bromo-2-fluoro-6-chlorobenzamide (11.5 g, 45.5 mmol) as a light orange solid: mp 157-158° C., 1H NMR (CDCl3): δ 7.54 (t, 1H), 7.14 (dd, 1H), 6.03 (bs, 1H) 5.81 (bs, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-].[Na+].CO.Cl>O>[C:3]1([CH:8]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 1.02 g (7.49 mmol) of 2'-hydroxyacetophenone, 0.49 g (3.65 mmol) of 1,4-benzodicarboxaldehyde, 1.5 g NaOH (in 5 mL of water) and 30 mL MeOH was stirred for 21 hours before the solution was poured into 200 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystalization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 20 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 22% overall yield. MP: 385°-387° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 1.2. Extinction coefficient εmax (M-1 cm-1) 36,000. λmax (abs)=380 nm and λmax (em)=560 nm.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH3:8])=[O:4].C[O:10][P:11]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1>>[CH2:6]([O:5][C:3]([CH2:2][P:11]1(=[O:10])[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1)=[O:4])[CH2:7][CH3:8]
Reactant: CCCOC(=O)CBr
Reactant: COP1OC(C)C(C)O1
Product: CCCOC(=O)CP1(=O)OC(C)C(C)O1
Yield: 95.1 %

Procedure:
Using the procedure of Step A of Example 1, 3.8 g of n-propyl bromoacetate and 2.42 g of 2-methoxy-4,5-dimethyl -1,3,2-dioxaphospholane were reacted to obtain 3.62 g of raw 2-propoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane which was used as is for the next step.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].CCCCCC>CN(C)C=O>[F:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:2]([O:1][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]#[CH:4])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(O)COc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamide and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. The organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:20]/[NH:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:25]=[CH:24][N:23]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCCOc1ccnc(N/N=C/c2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of (E)-8-(tert-butyldimethylsilyloxy)-2-((2-(4-(2-methoxyethoxy)pyridin-2-yl)hydrazono)methyl)quinoline (0.101 g, 0.223 mmol) in DCM (1.0 mL) was added iodosobenzene diacetate (0.0719 g, 0.223 mmol). After stirring at ambient temperature for 5 hours the reaction mixture was partitioned between DCM and aqueous saturated Na2S2O3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 DCM/MeOH) to provide 70 mg (70%) of desired product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2/[CH:26]=[CH:27]\[CH3:28])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40].C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O:23][C:35]3[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=3[F:29])=[O:22])=[CH:19][C:18]=2/[CH:26]=[CH:27]\[CH3:28])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C/C=C\c1cc(C(=O)O)ccc1N1CCN(CCOCc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C\c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
(Z)-4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-(prop-1-en-1-yl)benzoic acid (13 mg, 0.0331 mmol) was dissolved in ethyl acetate (3.3 mL). At room temperature, pentafluorophenol (7.3 mg, 0.0397 mmol) and N,N′-dicyclohexylcarbodiimide (8.2 mg, 0.0397 mmol) were added sequentially, and the mixture was stirred at room temperature for 14 hours. The reaction solution was added water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (16 mg (yield 86%)) was obtained as a pale yellow crystal.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nn(C)c(Oc2ccnc(Cl)n2)c1Sc1ccccc1Cl
Yield: 76.2 %

Procedure:
A mixture of 2.4 g (10 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole, 1.5 g (10 mmol) of 2,4-dichloropyrimidine and 1.5 g (11 mmol) of potassium carbonate was refluxed for 1 hour in 10 ml of acetonitrile. After completing the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and dried. Then the organic layer was concentrated. The residue was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (3:1 v/v)) to give 2.8 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(2-chloropyrimidine-4-yloxy)pyrazole
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].Cl[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].C(N(CC)CC)C>O1CCCC1>[C:10](=[O:11])([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])[O:12][CH2:13][CH:14]=[CH2:15]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of N-hydroxysuccinimide (4.78 g, 0.042 mol) and allyl chloroformate (5.0 g, 4.40 ml, 0.042 mmol) in dry tetrahydrofuran (60 ml) was cooled to 0° C. under nitrogen. A solution of triethylamine (4.2 g, 5.78 ml, 0.042 mol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. After completion of the addition, the mixture was stirred at room temperature for 4 hours, and then filtered and concentrated. Ethyl acetate (200 ml) was added and the resulting solution was washed sequentially with water (3×), saturated sodium bicarbonate solution and water (3×). Drying (MgSO4) and removal of the solvent in vacuo gave the title compound as a clear, colourless oil. (D23).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+]>COCCOCCOC.C(Cl)Cl>[F:18][C:14]1([F:19])[C:2]2([CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:1]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: C=C1CCC(C(=O)OCC)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: CCOC(=O)C1CCC2(CC1)CC2(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diglyme (3 mL) was added a solution of sodium 2-chloro-2,2-difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diglyme via syringe pump at 0.5 ml/h at 150° C. The reaction was cooled to rt, then diluted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) ppm 4.09-4.19 (2H, m), 2.29-2.45 (1H, m), 1.89-2.03 (2H, m), 1.55-1.72 (5H, m), 1.45-1.54 (1H, m), 1.31-1.39 (1H, m), 1.21-1.30 (3H, m), 0.84-0.94 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.BrC1C=CC=CC=1>CCCCCC>[N:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:18]=1[NH:17][C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[OH:16])=[O:13]
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Reactant: Nc1nc2ccccc2[nH]1
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nc3ccccc3[nH]2)c(=O)n1C
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 82.5 %

Procedure:
199 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 98 mg of 2-amino-benzimidazole were added to 2 ml of bromobenzene, then, the mixture was stirred for 9.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 202 mg of N-(2-benzimidazolyl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 28) represented by the formula: