Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[C:6]([C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[OH:29])[O:12][CH2:13][CH:14]([OH:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[CH3:30][CH2:31][O:32]CC>CS(C)=O.C(OCC)(=O)C(OCC)=O.C(O)C.Cl>[C:2]([C:3]1[O:29][C:28]2[C:9]([C:6](=[O:8])[CH:7]=1)=[CH:10][C:11]([O:12][CH2:13][CH:14]([OH:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[CH:26][CH:27]=2)([O:32][CH2:31][CH3:30])=[O:1]
Reactant: CC(=O)c1cc(OCC(O)COc2ccc(C#N)cc2)ccc1O
Reactant: CCOCC
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(=O)C(=O)OCC
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(OCC(O)COc3ccc(C#N)cc3)ccc2o1

Procedure:
To a suspensioin of sodium ethoxide, prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml) and dimethyl sulphoxide (50 ml), was added a suspension of 1-(3-acetyl-4 -hydroxyphenoxy- 2-hydroxy-3-(p-cyanophenoxy) propane (26.2 g) in diethyl oxalate (30 ml). The resulting suspension was heated under reflux for 2 hours, cooled, and poured onto ice (200 g). After acidification with a solution of acetic acid (24 ml) in water (160 ml), the ether layer was separated, and the aqueous layer extracted with ether (3 × 50 ml). The combined organic extracts were evaporated under reduced pressure to give a yellow solid. This was dissolved in ethanol (200 ml) containing hydrochloric acid (20 drops) and the solution heated under reflux for 1 hour. After cooling, the beige solid (20.0 g) was filtered off. Recrystallization from aqueous dioxane gave 1-(2-carbethoxychromon-6-yloxy)-2-hydroxy-3-(p-cyanophenoxy) propane (17.3 g) as pale yellow crystals, m.p. 150°-152° C.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.S(=O)(=O)(O)O.O.C(#[N:19])C>>[NH2:19][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -16 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
Into a 300 ml flask, 30 ml of acetonitrile was introduced. It was then cooled to -16° C. At this temperature, a solution in which 10.0 g (75.8 mmol) of cis-(+)-1,2-epoxyindan (VI: optical purity: 95.1% e.e.) had been dissolved in 10 ml of acetonitrile as well as 11.5 g (113.6 mmol) of 97% sulfuric acid were dropwise added thereto independently at the same time in a period of 2 hours 10 minutes. The cooling was stopped so that the reaction liquid gradually returned to room temperature. When 72 ml of water was added thereto, a white crystal deposited. The reaction mixture was heated and 74 ml of a water/acetonitrile azeotrope was distilled off. The remaining mixture was stirred for 1 hour under a reflux. The white crystal of the oxazoline derivative disappeared to form a transparent solution. This reaction liquid was cooled to room temperature and washed twice with 50 ml of dichloromethane. The pH of the water phase was adjusted to 10.5 by an addition of an aqueous solution of 25% sodium hydroxide. The grayish white scaly crystal deposited thereby was filtered off under reduced pressure, washed with a small quantity of water, and then dried in vacuo to yield 6.69 g (yield: 59.3%) of cis-(-)-1-aminoindan-2-ol (V). The chemical purity and optical purity of this crystal were 96.9% and 99.6% e.e., respectively.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:53])[N:30]([C@H:41]3[CH2:46][CH2:45][C@H:44]([O:47][CH:48]([CH3:52])[C:49]([NH2:51])=O)[CH2:43][CH2:42]3)[C:31]3[N:32]([N:37]=[C:38]([CH3:40])[N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[C:23]([F:54])[CH:22]=1)#[N:14]>C(OCC)(=O)C>[F:54][C:23]1[CH:22]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]2[NH:14][C:4](=[O:7])[O:5][N:3]=2)[CH:26]=[CH:25][C:24]=1[CH2:27][C:28]1[C:29](=[O:53])[N:30]([C@H:41]2[CH2:46][CH2:45][C@H:44]([O:47][CH:48]([CH3:52])[C:49]#[N:51])[CH2:43][CH2:42]2)[C:31]2[N:32]([N:37]=[C:38]([CH3:40])[N:39]=2)[C:33]=1[CH2:34][CH2:35][CH3:36]
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(N)=O)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C#N)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanamide (0.37 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL), pyridine (0.21 mL) and trifluoroacetic acid anhydride (0.18 mL) were added at 0° C., and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.11 g, 28%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[C:18]([C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)=[O:25])[CH:17]=3)=[CH:12][CH:11]=2)=[N:7][N:6]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[C:18]([C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)=[O:25])[CH:17]=3)=[CH:14][CH:15]=2)=[N:7][N:6]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1

Procedure:
4′-[5-(Azidomethyl)-1,3,4oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 35) (208 mg) and palladium on carbon (10% w/w, 21 mg) in ethanol (10 ml) were hydrogenated under 1 Atm. of hydrogen for 24 hours at room temperature. The reaction was filtered through celite and the filtrate reduced to dryness under vacuum. The residue was applied to a bond-elut (silica, 10 g) and eluted with an ethyl acetate/cyclohexane gradient (50-100% ethyl acetate) and then with methanol in ethyl acetate (0-50%). The solvent was evaporated from the product fractions under vacuum to give 4′-[5-(aminomethyl)-1,3,4oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18](Cl)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:33][CH:34]([CH3:36])[O-:35].[Li+]>CC(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:35][CH:34]([CH3:36])[CH3:33])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:27])([F:28])[F:26])=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC(C)[O-]
Agent: [Li+]
Solvent: CC(C)O
Product: Cc1nc(OC(C)C)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (161 mg, 0.324 mmol) and lithium isopropoxide (64.3 mg, 0.973 mmol) in 2-propanol (2.2 mL) was stirred at 70° C. for 17 hr. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (71.0 mg, 0.137 mmol, 42%).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)([O-:10])=[O:9].N1CCCCC1.Cl.[NH2:26]/[C:27](/[CH3:32])=[CH:28]\[C:29]([O-:31])=[O:30]>C1C=CC=CC=1>[CH3:5][C:3]1[NH:26][C:27]([CH3:32])=[C:28]([C:29]([OH:31])=[O:30])[CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N+:8]([O-:10])=[O:9])[C:2]=1[C:1]([OH:7])=[O:6]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C/C(N)=C/C(=O)[O-]
Reactant: CC(=O)CC(=O)[O-]
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC1=C(C(=O)O)C(c2ccccc2[N+](=O)[O-])C(C(=O)O)=C(C)N1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
In 100 ml of benzene were dissolved 10 g of 2-nitratoethy acetoacetate, 7.91 g of 2-nitrobenzaldehyde and 0.7 ml of piperidine. The solution was reacted under azeotropic dehydration for 1.5 hours, and poured into ice water. Dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with 15% aqueous sodium hydrogen sulfite solution, 15% aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. Evaporation of the solvent gave a residue, to which 10.68 g of 3-nitratopropyl 3-aminocrotonate was then added. The mixture was heated at 75°-85° C. for 4 hours with stirring, and ice water was poured into this mixture. The mixture was extracted with dichloromethane, and the dichloromethane layer was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave a residue which was then subjected to column chromatography on silica gel (eluted with dichloromethane) and recrystallized from ether to obtain 12.1 g of 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nitratoethyl) ester-5-(3-nitratopropyl) ester.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[N:3]=[CH:2]1.C1N=CN([C:16]([N:18]2[CH:22]=[N:21][CH:20]=[CH:19]2)=O)C=1.CCN(CCC[CH:31]([NH:33][C:34]1[CH:35]=[C:36](/C=C/C2C=CC=CC=2Cl)[N:37]=[C:38]2[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=12)C)CC>C1COCC1>[Cl:44][C:42]1[CH:43]=[C:38]2[C:39]([C:34]([NH:33][CH2:31][CH2:22][N:18]([CH3:16])[CH2:19][CH2:20][NH:21][C:8](=[O:10])[CH2:7][CH2:6][C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[CH:35][CH:36]=[N:37]2)=[CH:40][CH:41]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1c[nH]cn1
Solvent: C1CCOC1
Product: CN(CCNC(=O)CCc1c[nH]cn1)CCNc1ccnc2cc(Cl)ccc12
Reaction time: 2 h
Yield: 23 %

Procedure:
3-(1H-Imidazol-4-yl)propionic acid (140 mg, 1 mmol) was dissolved in dist THF, and a condensing agent CDI (200 mg, 1.3 mmol) was added to this solution. The solution was stirred. After two hours, 2Q (278 mg, 1 mmol) dissolved in dist THF was added and continued to be stirred. After reaction overnight, the reaction solution was filtered through a Kiriyama funnel. The filtrate was concentrated under a reduced pressure to give a yellow oil and this oil was purified by HPLC. Yield: 23%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:13][S:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:30][N:29]([CH2:26][CH2:27][CH3:28])[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:13][S:12][CH2:11][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)CSCC1=Cc1ccc(Cl)c(Cl)c1
Reactant: CCCNN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN1NC(c2ccc(Cl)c(Cl)c2)C2=C1C(=Cc1ccc(Cl)c(Cl)c1)CSC2
Yield: 68.5 %

Procedure:
A suspension of tetrahydro-3,5-bis-(3,4-dichlorophenylmethylene)-4H-thiopyran-4-one (6.5 g, 15 mmole) and n-propylhydrazine (1.1 g, 15 mmole) in methanol/chloroform (1:1, 250 ml) is heated at reflux temperature overnight. When the reaction mixture is slightly cooled, unreacted starting material precipitates out and is removed (about 2.2 g) by filtration. The filtrate is concentrated in vacuo and dissolved in CHCl3 and washed with dilute HCl and water. The organic layer is dried (anhydrous MgSO4) and concentrated in vacuo to give 5 g of a semi-solid material. This is applied to a wet-packed (hexane) Al2O3 column (neutral, activity I), and eluted with 0-100% ether/hexane. The major product is obtained eluting with 10-40% ether/hexane. The later fractions, eluted with 50-80% ether/hexane, are combined, concentrated and the residue crystallized from MeOH/CHCl3 to give 0.4 g of the product in crystalline form (99% pure), m.p. 161°-162.5° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH:29][OH:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]([OH:30])[C:16]([C:14]1[CH:15]=[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[C:11]2=[CH:12][N:13]=1)=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Reactant: ONCc1ccccc1
Agent: Cl
Product: O=C(c1cc2ccn(Cc3ccc(F)cc3)c2cn1)N(O)Cc1ccccc1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-benzyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 8.92 (s, 1H), 8.11 (s, 1H), 7.91 (d, 1H, J=2.8 Hz), 7.26-7.38 (m, 7H), 7.16 (d, 2H, J=8.5 Hz), 6.72 (d, 1H, J=2.8 Hz), 5.58 (s, 2H), 4.97 (s, 2H). LCMS (API-ES, M+H+): 376.1, HRMS calcd for C22H19FN3O2 (M+H) 376.1461, found 376.1448. Anal. (C22H18FN3O2) C, H, N. HPLC: 100% purity.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[O:10]2)=[CH:5][CH:4]=1.N1C(C)=CC=C[C:22]=1[CH3:28].ICC.[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH2:22][CH3:28])[O:10]2)=[CH:5][CH:4]=1)(=[O:34])[CH3:33]
Reactant: Cc1cccc(C)n1
Reactant: Cc1c([C@H]2CCCN2)oc2c(C)c(O)ccc2c1=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H]1c1oc2c(C)c(OC(C)=O)ccc2c(=O)c1C
Reaction time: 6.5 h
Yield: 58.7 %

Procedure:
To a solution (suspension) of 7-hydroxy-3,8-dimethyl-2-[(2R)-pyrrolidin-2-yl]-4H-chromen-4-one hydrochloride (78 mg, 0.30 mmol) obtained in Example 2-3 and 2,6-lutidine (52 μL, 0.45 mmol) in dimethylformamide (1.5 mL), iodoethane (31 μL, 0.39 mmol) was added dropwise under cooling with ice, and then the mixture was brought back to room temperature and stirred for 6.5 hours. 2,6-Lutidine (105 μL, 0.90 mmol) was added to the reaction solution, and the mixture was cooled with ice again. Then, acetyl chloride (43 μL, 0.60 mmol) was added dropwise thereto, and the mixture was brought back to room temperature and stirred overnight. The reaction solution was concentrated, and then a saturated aqueous solution of sodium bicarbonate was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→90/10) to obtain 58 mg of the title compound (yield: 59%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(OCC)n1ccnc1
Temperature: 130 °C
Yield: 72.4 %

Procedure:
Imidazole (6.81 g, 0.10 mol, 1.0 eq), triethyl orthoformate (66.5 mL, 0.40 mol, 4.0 eq) and para-toluenesulfonic acid (0.5 g) were combined and heated at 130° C. Ethanol was slowly distilled off. After the distillation of the ethanol ceased, the reaction was distilled using a floor pump (0.1 mm). Excess triethyl orthoformate distilled at 50° C. and then the product was distilled at 78°-84° C. to give the title compound (12.316 g, 72%). B. 2-Butyl-1H-imidazole
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)=[CH:11][C:5]2[N:6]([CH2:29][C:28]#[CH:27])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
0.3 g (0.87 mmol) of 3-(7-fluoro-2,3-dihydro-1,4-benzoxazin-3-on-6-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 1 ml of DMF, and 0.04 g (1 mmol) of 60% sodium hydride was added under cooling with ice, followed by stirring at room temperature for 15 minutes. Then, 0.12 g (1 mmol) of propargyl bromide was added thereto. The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.24 g (yield: 72%) of the desired product. Melting point: 166-168° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:15]3[N:14]([CH:18]=[CH:17][N:16]=3)[CH2:2][CH2:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Reactant: c1c[nH]cn1
Product: Cc1ccc(C2=CCCn3ccnc32)cc1

Procedure:
Combine 100 g (0.51 mole) of 4-chloro-4'-methylbutyrophenone with 300 g (4.4 mole) of imidazole and heat to 175° C. under nitrogen for 24 hr. Purification from 1 kg of silica gel using methylene chloride as solvent, followed by crystallization from ether provides the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@H:14]2[C@@H:5]([C@@H:6]3[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@@:9]2([CH3:20])[CH2:16][C:17](=[O:19])[CH2:18][C@@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:20][C@:9]12[C@@:16]3([CH2:17][O:19]3)[CH2:22][CH2:18][C@@H:8]1[CH2:7][C@H:6]1[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[C@]12CC(=O)C[C@@H]1C[C@H]1[C@@H](CC[C@H]3C[C@H](O)CC[C@@H]31)C2
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of compound 45 (45 mg, 0.16 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (202 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water was added (20 mL) and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 46 (35 mg, 75%) as a white solid: mp 165-167° C.; [α]D25 +20.0 (c 0.12, CHCl3); 1H NMR (CDCl3) δ 4.08 (s, 1H), 2.90 (d, J=15.2 Hz, 1H), 2.60 (d, J=15.2 Hz, 1H), 0.87 (s, 3H); 13C NMR (CDCl3) δ 70.5, 66.5, 53.6, 48.3, 47.2, 47.0, 42.1, 40.4, 40.2, 37.9, 36.2, 34.2, 34.0, 32.8, 29.0, 28.8, 25.8, 23.3, 14.3; IR νmax 3418, 1443, 1378, 851 cm−1. MS (FAB) for [C19H30O2]+: 290.2246. Found: 290.2243.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]1[O:21][C:20]([C:22]2[CH:30]=[C:29]([C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3S(C2C=CC=CC=2)(=O)=O)=[N:19][N:18]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[OH-].[Na+]>C(#N)C.C(O)(C)C>[NH:35]1[C:36]2[C:32](=[C:31]([C:29]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[C:22]([C:20]4[O:21][C:17]([CH2:16][N:4]5[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]6[CH2:10][CH2:11][O:12][CH2:13][CH2:14]6)[CH2:6][CH2:5]5)=[N:18][N:19]=4)[CH:30]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: C1CN(CCN2CCOCC2)CCN1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1cc(-c2cc(-c3nnc(CN4CCN(CCN5CCOCC5)CC4)o3)c3cn[nH]c3c2)c2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
4-[2-(1-piperazinyl)ethyl]morpholine (14.1 mg, 0.11 mmol) and 4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.102 mmol) were dissolved in acetonitrile (0.5 ml) and N,N-diisopropylethylamine (0.026 ml, 0.15 mmol) was added, followed by sodium iodide (15.3 mg, 0.102 mmol). The solution was stirred at 70° C. for 18 h and blown to dryness under a stream of nitrogen. Isopropanol (0.3 ml) was added followed by 2M sodium hydroxide (0.3 ml) and stirred for 5 h when the mixture was neutralised and the solvent removed under a stream of nitrogen. The crude product was dissolved in dimethylsulphoxide (0.3 ml) and methanol (0.15 ml) with formic acid (0.05 ml) then purified by Mass Directed Automated Preparative HPLC (Method F) to give the title compound (26.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.COC(=O)C1C=CC(O)=CC=1.CC1(C)CCCC(C)C1CCC(Cl)C>>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: ClCC1CCCCC1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Agent: CC(Cl)CCC1C(C)CCCC1(C)C
Agent: COC(=O)c1ccc(O)cc1
Product: COC(=O)C=Cc1ccc(OCC2CCCCC2)cc1

Procedure:
(melting point: 104° C.) was prepared by the method described in 1.1 by substituting, on an equimolar basis, 4-hydroxy-cinnamic acid methyl ester and chloromethyl cyclohexane for the 4-hydroxybenzoic acid methyl ester and 4-(1,1,3-trimethyl-2-cyclohexyl)-2-butyl chloride used in Example 1.1.