Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].Cl[C:5]1[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]2=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[N:10]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]1[N:10]=[C:5]([C:2]#[N:3])[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]=12
Reactant: N#C[Cu]
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(Cl)cc2c1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C#N)cc2c1C
Temperature: 25 °C
Yield: 24.1 %

Procedure:
Copper(I) cyanide (9.3 g, 102.6 mmol) was added to a solution of 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (3.2 g, 10.3 mmol) prepared in Example 656 in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble materials. The reaction mixture was washed with water. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 750 mg of the titled compound as a white solid. (Yield: 26%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=O.[H-].[Na+].[C:14]([O:21][CH2:22][CH3:23])(=[O:20])[C:15](OCC)=O.Cl.[NH:25]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1)[NH2:26]>CN(C)C=O>[CH2:22]([O:21][C:14]([C:15]1[CH:1]=[C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[N:25]([C:27]2[CH:32]=[N:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:26]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(NN)cn1
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)n(-c2ccc(OC)nc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methoxyacetophenone (300 mg) was dissolved in N,N-dimethylformamide (4 mL). 60% Sodium hydride (160 mg) was added to the resultant mixture at 0° C., followed by stirring at room temperature for 0.5 hours. Under cooling with ice, diethyl oxalate (542 μL) was added to the reaction mixture, followed by stirring at room temperature for 14 hours. 5-Hydrazino-2-methoxypyridine hydrochloride (406 mg) obtained from Referential Example 1 was added to the reaction mixture, followed by stirring at 80° C. for 3 hours. The mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine. Subsequently, the organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily substance (517 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][F:77])([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[F:77][CH2:76][C:73]1([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]2[CH:79]=[C:66]([CH2:65][NH:64][C:23]([C:20]3[C:19]4[N:15]([CH:16]=[CH:17][CH:18]=4)[C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=5)([C:26]([F:29])([F:27])[F:28])[O:13][N:12]=4)=[CH:22][CH:21]=3)=[O:25])[CH:67]=[CH:68][C:69]1=2
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (124 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (183 mg, 0.48 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (126 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the final title product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][N:12]([CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:11]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[CH2:10]2)[CH:2]=[CH2:3].[C:41](=O)([O-])[O-:42].[K+].[K+].C(Br)C=C.C(OCC)(=O)C>CN(C=O)C>[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([F:37])[CH:34]=1)[CH2:30][C@H:29]1[C@@H:28]([C@H:11]2[CH2:10][C:9]3[C:14](=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=[CH:7][CH:8]=3)[CH2:13][N:12]2[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:40][C:41](=[O:42])[NH:39]1
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Solvent: CCOC(C)=O
Product: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-benzhydryl-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step F (14), 40 mg, 0.076 mmol) in DMF (2 mL) were added potassium carbonate (52 mg, 0.38 mmol) and allyl bromide (73 mg, 0.61 mmol). The mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with H2O (70 mL) twice, and dried over Na2SO4, and concentrated under vacuum to give the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.50 (1H, m), 2.76 (1H, d, J=15 Hz), 2.90 (1H, d, J=35 Hz), 3.19 (1H, m), 3.26 (1H, dd, J=5, 10 Hz), 3.75 (1H, d, J=20 Hz), 3.80 (1H, m), 4.00 (1H, m), 4.13 (1H, d, J=20 Hz), 4.40 (2H, m), 4.72 (1H, dd, J=5, 10 Hz), 4.83 (1H, s), 4.87 (1H, s), 5.12-5.17 (2H, m), 5.84 (1H, m), 6.65 (1H, d, J=10 Hz), 6.75-6.80 (4H, m), 7.13-7.16 (1H, m), 7.19-7.32 (6H, m), 7.36 (2H, d, J=5 Hz), 7.42 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 567.19.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C(=O)C)=[CH:8][N:7]=1)(=O)C.[ClH:16]>CC(CC)=O>[ClH:16].[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[N:7][CH:8]=1
Reactant: CC(=O)OCc1ccc(OC(C)=O)cn1
Agent: Cl
Solvent: CCC(C)=O
Product: OCc1ccc(O)cn1

Procedure:
220.0 g of the above ester is added to 2,200 ml of 6 N-hydrochloric acid and the resulting solution is refluxed for 18 hours. Then, the solution is evaporated to leave an oily viscous residue. This residue is digested with ethyl methyl ketone to yield 5-hydroxy-2-pyridinemethanol hydrochloride melting at 122°-123°. (The corresponding free base is prepared by adding a saturated solution of potassium carbonate to the hydrochloride, extracting the resulting suspension with chloroform, drying the chloroform extract over sodium sulfate, filtering and evaporating the filtrate to yield the free base.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]=[CH2:16])=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][C:21]=1[F:27])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:27])[CH3:2]
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(C(=O)NCc2ccc(Br)cc2F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc(OCC(=O)OCC)c(C(=O)NCc2ccccc2F)c1
Reaction time: 8 h

Procedure:
A solution of [4-allyloxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (0.998 g, 2.35 mmol) in ethanol (150 mL) and ethyl acetate (5 mL) was degassed and put under a nitrogen atmosphere. Palladium catalyst (10% Pd-c, Degussa) was added and the flask was evacuated and treated with hydrogen (balloon). After stirring overnight, the solution was filtered through a pad of silica gel and washed with methanol. After concentrating the solution, the crude product was purified by flash collumn chromatography (30% hepatane in ethyl acetate) to give [4-propyloxy-2-(2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].C1COCC1.[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C(C)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a mixture of methyl 5-acetylpyridine-2-carboxylate (1.00 g), THF (24 mL), and methanol (12 mL) was added sodium borohydride (110 mg), followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and then to the obtained residue was added a saturated aqueous sodium chloride solution. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and then dried under reduced pressure to obtain methyl 5-(1-hydroxyethyl)pyridine-2-carboxylate (897 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH3:21][CH:20]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH3:22]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (5.0 g, 30.1 mmol) and imidazole (2.4 g, 35.4 mmol) in dry DMF (20 mL) was added chlorotriisopropylsilane (6.8 mL, 31 mmol) dropwise at 0° C. The mixture was stirred at rt for 16 h. Then water was added (100 mL), and the product was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the remaining crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 10:1→1:1) to afford the title compound (9.66 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 2H), 6.89 (d, 2H), 4.33 (quart, 2H), 1.38 (t, 3H), 1.27 (m, 1H), 1.10 (d, 18H); DCI(NH3)-MS m/z 323 (MH)+; HPLC RT (Method G) 6.19 min.
Reaction SMILES: CN[C:3]([C:5]1[CH:25]=[CH:24][C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[C:6]=1[CH3:26])=[O:4].[OH-:27].[Na+]>C(O)CO>[CH3:26][C:6]1[C:7]2[O:11][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH:24]=[CH:25][C:5]=1[C:3]([OH:27])=[O:4]
Reactant: CNC(=O)c1ccc2c(c1C)OC(c1ccccc1)(c1ccccc1)O2
Reactant: [OH-]
Agent: [Na+]
Solvent: OCCO
Product: Cc1c(C(=O)O)ccc2c1OC(c1ccccc1)(c1ccccc1)O2
Yield: 34.4 %

Procedure:
A solution of 1.60 g of N,4-dimethyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide and 1.00 g of sodium hydroxide in 10 ml of ethylene glycol was heated to 190° C. for 2.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate, adjusted to pH 2 by the addition of 3N hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the solid residue was crystallized from ethanol to give 0.53 g of 4-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylic acid, m.p. 263°-265° C.
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[CH:31]1(N)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:16]2[C:15]([NH:5][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:29][CH:28]=1
Reactant: NC1CCCCC1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with cyclohexylamine ([108-91-8]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as brown oil. MS: m/e=327.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc([N+](=O)[O-])c1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-chloro-3-nitrophenol (1.5 g, 8.64 mmol) in acetone was added potassium carbonate (1.194 g, 8.64 mmol). After 5 minutes, allyl bromide (0.823 ml, 9.51 mmol) was added and the solution was heated to reflux overnight. The reaction mixture was cooled, filtered, and concentrated. Chromatography was performed with an Analogix 280 with an SF 40-80 column, 0% to 10% ethyl acetate/hexane gradient over 30 minutes to provide the title compound. MS (DCI+) m/z 231.1 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClCC#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC#Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (3-chloro-l-propynyl)benzene (0.754 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4: 1) and the resulting solids were crystallized from diethyl ether-hexane to give 0.8 g of alpha-oxo-4-[(3-phenyl-2-propynyl)oxy]benzeneacetic acid methyl ester mp 57°-59° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@@H:26]([OH:29])[CH2:27][NH2:28]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][CH2:27][C@H:26]([OH:29])[CH3:25])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@@H](O)CN
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NC[C@@H](C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 116 μL of R-(−)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide. MS (Q1) 397.4 (M)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][CH:2]=1.[S:15]([Cl:19])(=[O:18])(=[O:17])[NH2:16].Cl>C(#N)C.C(O)(C)C>[ClH:19].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][O:14][S:15](=[O:18])(=[O:17])[NH2:16])[CH:4]=[CH:3][CH:2]=1
Reactant: OCCOc1cccc2cccnc12
Reactant: NS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CC(C)O
Product: NS(=O)(=O)OCCOc1cccc2cccnc12

Procedure:
Using the procedure of Example 4, 5.4 g (0.029 mole) of 2-(8-quinolinyloxy)ethanol was reacted with sulfamoyl chloride. During work-up of the reaction, a light-yellow material deposited out from the organic-aqueous system. 1H NMR of this material suggested that it might be a quaternary salt. The oily product obtained at the end of the work-up procedure weighed 2.7 g. This oil was dissolved in acetonitrile-isopropyl alcohol and acidified with 37% hydrochloric acid. The mixture was evaporated to almost dryness and then redissolved in methanol. To the solution was added ethyl acetate and most of the methanol was evaporated carefully. The light-yellow solid was collected and dried at 40° C. in vacuum overnight to give 2.4 g solid, mp 138°-140° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:36]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:17](=[O:35])[N:18]([CH2:27][CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[C:11]([F:54])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(NCC)C>C(OCC)(=O)C>[NH2:36][C@@H:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[F:54])[C:17]([N:18]([CH2:27][CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:35]
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1F)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1F)OCC
Yield: 93 %

Procedure:
To a mixed solution of 9H-fluoren-9-ylmethyl N-((1S)-2-(4-(benzyloxy)-2-fluorophenyl)-1-((2,2-diethoxyethyl)((6-fluoropyridin-2-yl)methyl)carbamoyl)ethyl)carbamate described in Production Example 1-1-2 (14.4 g) and THF (30 mL) was added diethylamine (5.27 mL, 50.4 mmol) at room temperature. The resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under a reduced pressure, methanol, water and heptane were added to the residue, and the resultant mixture was partitioned. An aqueous layer was washed with heptane, and was then concentrated under a reduced pressure. Water was added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1, and then ethyl acetate) to give the title compound (6.87 g, yield: 93%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClCCl.[CH2:20]([C@@:27]1([OH:50])[C@@:31]2([CH2:41][O:42][C@H:28]1[C@H:29]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[OH:49])[O:30]2)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:1]([O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C@@H:29]1[O:30][C@:31]2([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([OH:50])[C@H:28]1[O:42][CH2:41]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@]2(O)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Oc1ccccc1[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@]2(O)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Benzoyl chloride (0.06 ml, 0.52 mmol) and anhydrous triethylamine (0.073 ml, 0.52 mmol) were added to an anhydrous dichloromethane (3 ml) solution of the compound (24) (168 mg, 0.40 mmol), and the mixture was stirred for 3 hours at room temperature. After water was added to the reaction solution, the system was extracted with ethyl acetate 3 times. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to obtain a colorless oily substance (25) (209 mg, 93%).
Reaction SMILES: [CH3:1]C(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][CH:16]([F:39])[CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH:35]=[O:36])[CH2:31][CH2:30]1)[C:24](=[O:37])[NH:23][C:22]2=[O:38].[CH:40]1([O:45][C:46]2[CH:51]=[CH:50][C:49](CO)=[CH:48][C:47]=2[O:54][CH3:55])[CH2:44][CH2:43][CH2:42][CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:40]1([O:45][C:46]2[CH:51]=[C:50]([CH:49]=[CH:48][C:47]=2[O:54][CH3:55])[CH2:1][N:23]2[C:22](=[O:38])[C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:17][CH:16]([F:15])[F:39])[CH:20]=3)[N:25]([CH:29]3[CH2:34][CH2:33][N:32]([CH:35]=[O:36])[CH2:31][CH2:30]3)[C:24]2=[O:37])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1cc(CO)ccc1OC1CCCC1
Reactant: O=CN1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(OCC(F)F)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC1CCCC1
Reaction time: 12 h
Yield: 35.1 %

Procedure:
0.172 g of DIAD is added to a solution of 0.15 g of 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 3.7, 0.142 g of [4-(cyclopentyloxy)-3-methoxyphenyl]methanol and 0.223 g of PPh3 in 3 ml of anhydrous THF. The mixture is stirred at AT for 12 h 00 and then at 60° C. for 1 h 00. It is evaporated under reduced pressure and the residue is purified on silica gel, elution being carried out with AcOEt, to give 0.083 g of the expected product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])OC.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13]2.Cl>C1COCC1>[CH3:3][O:4][C:5]([CH:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([F:9])[CH:11]=2)[CH2:15]1)=[O:8]
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1Cc2ccc(F)cc2C1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a mixture of NaH (2.64 g, 66 mmol) in dimethylcarbonate (4.2 mL, 50 mmol) in THF (30 mL) was added a solution of 5-fluoroindanone (commercially available from Aldrich) (5 g, 33 mmol). After 30 m at 65° C. the mixture was cooled to rt, acidified with HCl (aq) and extracted with Et2O or EtOAc. The organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residue was used in the next step without further purification. The keto-ester was dissolved in AcOH (100 mL) and 70% perchloric acid (2 mL). 10% Pd/C (2 g) was added and the mixture was hydrogenated at 50 psi for 18 h. The mixture was diluted with Et2O or CHCl3 and water and filtered through a pad of celite. The organic layer was separated and the aqueous layer was extracted with Et2O. The organic fractions were pooled, washed with water, dried over MgSO4, filtered and evaporated to leave a residue. The residue was purified by chromatography on silica gel with 15% EtOAc: hexane to give 5-fluoro-indan-2-carboxylic acid methyl ester (Intermediate EIGHTEEN-3), 2.25 g. Use of 5-fluoro-indan-2-carboxylic acid methyl ester (Intermediate EIGHTEEN-3) in Method SEVENTEEN produced 4-(5-fluoro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 145).