Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:30][CH2:31][O:32][CH3:33]>C(OCC)(=O)C>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:3]1[C:2]([O:1][CH2:30][CH2:31][O:32][CH3:33])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCOc1c(O)cc([N+](=O)[O-])cc1C(=O)OC
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOc1cc([N+](=O)[O-])cc(C(=O)OC)c1OCCOC
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a mixture of methyl 3-hydroxy-2-{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate (4.4 g, 16.2 mmol), potassium carbonate (4.5 g, 33 mmol) and acetonitrile (100 mL) was added 1-bromo-2-(methyloxy)ethane (2.5 mL, 24 mmol). The resulting mixture was heated at reflux 18 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (100 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed (silica gel, 30-50% ethyl acetate-hexane) to provide to give methyl 2,3-bis{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate, (4.9 g, 14.8 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): 8.27-8.26 (d, 1H), 7.92-7.91 (d, 1H), 4.37-4.35 (m, 2H), 4.27-4.25 (m, 2H), 3.94 (s, 3H), 3.83-3.81 (m, 2H), 3.77-3.74 (m, 2H), 3.45 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:30][CH3:31])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 23 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103 mg, 0.75 mmol) and ethyl iodide (156 mg, 1.0 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 23%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][OH:20])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:21]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH:19]=[O:20])[CH3:22]
Reactant: CCN(CC)CC#CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC#CCCC=O
Temperature: 25 °C

Procedure:
To a solution of oxalyl chloride (32 mL, 352 mmol) in methylene chloride (800 mL) under argon atmosphere at -78° C. was added dimethylsulfoxide (54.4 mL, 704 mmol) in methylene chloride (40 mL) over 15 minutes. After stirring for 5 minutes 6-diethylaminohex-4-yn-1-ol (50 g, 296 mmol) dissolved in methylene chloride (60 mL) was added dropwise over 35 minutes. After stirring 20 minutes triethylamine (224 mL, 1600 mmol) was added at -78° C. over 30 minutes and the reaction mixture was allowed to warm to room temperature. Water (400 mL) was added, the layers were separated, and the organic layer was washed with water (2×200 mL). The aqueous layer was back-extracted with methylene chloride (2×150 mL) and the combined organic extracts were washed with brine and dried (MgSO4). Removal of solvent under reduced pressure gave a quantitative yield of the product as an oil. 1H NMR (CDCl3) δ: 1.13 (t, 6H), 2.48-2.58 (m, 6H), 2.65 (q, 2H), 3.39 (d, 2H), 9.80 (s, 1H) ppm.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH2:10])[C:4]([N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[N+:14]([O-:16])=[O:15].C(O[NH2:25])C1C=CC=CC=1.C[O-].[Na+].Cl>CS(C)=O>[CH:1]1[C:2]([N+:14]([O-:16])=[O:15])=[C:3]([NH2:25])[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([NH2:10])[C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: NOCc1ccccc1
Reactant: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
DMSO (15 ml) is added with rapid stirring to a mixture of picramide (0.477 g, 2.09 mmol), O-benzylhydroxylamine (1.64 g, 10.3 mmol) and sodium methoxide (1.91 g, 35.4 mmol). The brown suspension is stirred at ambient temperature for 15 hr. The reaction mixture is poured into cold 0.12N aqueous HCl (200 ml). The resulting precipitate is collected, washed with water and dried to yield 0.444 g (87%) of DATB.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH:9]=[CH:8][C:7]([C:10]([NH2:12])=[O:11])=[CH:6]1.Cl.[Cl-].[Na+].[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([C:9]1[S:5][CH:6]=[C:7]([C:10]([NH2:12])=[O:11])[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1ccsc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C(N)=O)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of aluminium chloride (66.5 g) in acetyl chloride (200 ml) was stirred at room temperature for 1 h. Thiophene-3-carboxamide (12.7 g) was added in one aliquot and the resulting pale yellow solution stirred at room temperature for 4 h before being added cautiously to ice (1 kg) and dilute hydrochloric acid (400 ml). The resulting solution was saturated with sodium chloride and extracted with butanone (6×500 ml) and then ethyl acetate (6×500 ml). The combined organic extracts were evaporated to small volume, diluted with ethyl acetate (1000 ml) and washed thoroughly with sodium carbonate solution (6×100 ml) and water (100 ml) and then dried and evaporated to small volume to deposit the title compound as a white crystalline solid (14.0 g) m.p. 156°-157° which recrystallised from ethyl acetate, m.p. 156°-158°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:29])[NH:13][C@@H:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH3:15])[C@H:9]([OH:11])[CH3:10])(C)(C)C.[ClH:31].O1CCOCC1>C(Cl)Cl>[ClH:31].[ClH:31].[ClH:31].[NH2:7][C@@H:8]([C@H:9]([OH:11])[CH3:10])[C:12]([NH:13][C@@H:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH3:15])=[O:29]
Reactant: Cc1ccc(-c2ccc([C@@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)nc2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc([C@@H](C)NC(=O)[C@@H](N)[C@@H](C)O)nc2)cn1
Reaction time: 1.5 h

Procedure:
{(1S,2R)-2-hydroxy-1-[(R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylcarbamoyl]-propyl}-carbamic acid tert-butyl ester (0.23 g, 0.45 mmol) was dissolved in CH2Cl2 (2 mL) and 4M HCl in dioxane (2 mL, 4 mmol) was added. After 1.5 hours, the volatiles were removed under a stream of N2 to give 300 mg of (2S,3R)-2-amino-3-hydroxy-N-[(R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethyl]-butyramide trihydrochloride salt as a tan powder, m/z 315.7 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([S:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][CH:6]=1)(=O)C.N>C(O)C>[OH:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([S:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CSc1cccc(OC(C)=O)c1CC(=O)OCC
Agent: N
Solvent: CCO
Product: CCOC(=O)CSc1cccc(O)c1CC(=O)OCC
Reaction time: 2 h

Procedure:
Ethyl 6-acetoxy-2-(ethoxycarbonylmethylthio)-phenylacetate (132 g) is added at room temperature to a solution of ammonia (34 g) in anhydrous ethanol (1.0 L). After standing for 2 hours the solvent is evaporated in vacuo and the residue is mixed with methylene chloride and 1 N hydrochloric acid. The layers are separated and the organic layer is washed with water to neutrality, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to obtain (as shown by NMR) ethyl 6-hydroxy-2-(ethoxycarbonylmethylthio)-phenylacetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH2:13][C:14]([CH2:16][N:17]3[C:21](=[O:22])[C:20]4=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]4[C:18]3=[O:27])=O)[CH2:9][N:8]=[C:7]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])[C:6]=2[CH:36]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:14]([CH2:16][N:17]4[C:21](=[O:22])[C:20]5=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]5[C:18]4=[O:27])=[CH:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])[C:6]=2[CH:36]=1
Reactant: O=C(CNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1)CN1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in example 20, 7-chloro-5-(2,6-difluorophenyl)-2-[(3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal is treated with concentrated sulfuric acid, then quenched to give after neutralization, 8-chloro-1-(phthalimidomethyl)-6-(2,6-difluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=O.[CH3:10][C:11]([CH3:13])=[O:12].CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH2:10][C:11](=[O:12])[CH3:13]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccco1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)c1ccco1
Reaction time: 8 h

Procedure:
A mixture of methyl 2-furoate (23 g, 0.18 mole) and acetone (10.6 g, 0.18 mole) was slowly added to a stirred suspension of potassium tert-butoxide (41 g, 0.36 mole) in anhydrous toluene (300 ml) at 0° C. Upon standing overnight at room temperature, glacial acetic acid (22 ml, 0.36 mole) and then water (100 ml) were added. The organic layer was separated, combined with an ether extract of the aqueous phase, washed with water, dried, and distilled to give 1-(2-furyl)-1,3-dioxobutane: b.p. 66°-70° C./0.1 mm (18.5 g).
Reaction SMILES: [OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:10]1([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:30]([CH:32]1[O:34][CH2:33]1)Cl>[O-]S([O-])(=O)=O.[Na+].[Na+]>[O:34]1[CH2:33][CH:32]1[CH2:30][N:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:23][CH:24]=1
Reactant: CCN(CC)c1ccc(C=NNc2ccccc2)cc1
Reactant: ClCC1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCN(CC)c1ccc(C=NN(CC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of potassium hydroxide powder (KOH, 85%, 198 g, 3 mol,) and anhydrous sodium sulfate (Na2SO4, 51 g, 0.369 mol) was added in three stages to a mixture of 4-(diethylamino)benzaldehyde N-phenylhydrazone (267.4 g, 1 mol) and epichlorohydrin (1.5 mol), while keeping the reaction mixture at 20–25° C.: stage quantities added were 33 g of Na2SO4 and 66 g of KOH initially; 9.9 g of Na2SO4 and 66 g of KOH after 1 hour of reaction; and 9.9 g of Na2SO4 and 66 g of KOH after 2 hours of reaction. The reaction mixture was stirred vigorously at 35–40° C. until the starting hydrazone disappeared (approx. 4–5 hours). Subsequently, the mixture was cooled to room temperature, and the solids were removed by filtration. The liquid organic phase was treated with diethyl ether and washed with distilled water until the washed water was neutral. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The solvent and excess epichlorohydrin were removed by evaporation in a rotory evaporator. The residue was recrystallized from diethyl ether and the crystals that formed upon standing were filtered off and washed with 2-propanol to give 260 g of the product (80.4% yield). The melting point was found to be 79–80.5° C. (recrystallized from diethyl ether). The 1H NMR spectrum (250 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.7–6.7 (m, 8H, Ar, CH═N); 6.6 (d, 2H, 2-H, 6-H of p-Ph); 4.4–3.6 (m, 2H, NCH2CH); 3.6–3.0 (m, 5H, CH2CH3, CH2CHCH2); 2.75 (m, 1H, ABX, cis-HA of CH2O); 2.55 (m, ABX, trans-HB of CH2O); and 1.1 (t, J=7.0 Hz, 6H, CH3).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Clc1ccccc1-c1ccncc1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ccccc2-c2ccncc2)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 4-(2-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 4-(4′-vinyl-biphenyl-2-yl)pyridine was isolated. The yield was 42%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21].O>C(O)(=O)C>[F:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccc(F)cc3s2)cc1
Yield: 42.7 %

Procedure:
The mixture of 4,4,4-trifluoro-1-(6-fluorobenzothiazol-2-yl)butane-1,3-dione (800 mg, 2.7 mmol) and 4-sulfamoylphenyl-hydrazine (720 mg, 3.8 mmol) was heated under reflux in acetic acid (10 ml) for 16 hours. After cooling, the reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate, and then evaporated. The residue was subjected to purification using chromatography on silica gel to afford 4-[5-(6-fluorobenzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (510 mg, 42%) as a colorless needle. NMR(CDCl3 -DMSO-d6) δ: 6.70 (2H, bs), 7.22-7.39 (2H, m), 7.57-7.67 (3H, m), 7.91-7.96 (1H, m), 8.05 (2H, d, J=8.6 Hz); mp 260-261° C. (toluene)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.FC1C=C2C(C(C3CCNCC3)=NN2C2C=CC=CC=2)=CC=1.Cl[CH2:47][CH2:48][CH2:49][CH:50]([C:58]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(C)CC(=O)C>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH:50]([C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:49][CH2:48][CH2:47][N:20]2[CH2:21][CH2:22][CH:17]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]=3)[CH2:18][CH2:19]2)=[CH:56][CH:55]=1
Reactant: Fc1ccc2c(C3CCNCC3)nn(-c3ccccc3)c2c1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(C(CCCN2CCC(c3nn(-c4ccccc4)c4cc(F)ccc34)CC2)c2ccc(F)cc2)cc1
Yield: 23.7 %

Procedure:
A stirred mixture, under nitrogen, of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole (1.5 g, 0.005 mol), the free base of Example 98, 4-chloro-1,1-bis-(4-fluorophenyl)butane (1.6 g, 0.0056 mol), Na2CO3 (0.6 g), a few crystals of KI and 4-methyl-2-pentanone (70 ml) was refluxed for 16 hours. The reaction was poured into H2O, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and the solvent was concentrated to a liquid. The liquid was dissolved in anhydrous ether and HCl (g) was added to precipitate a gum. The supernatant ether was decanted, H2O was added to the gum, and the mixture was made basic with NH4OH. The basic suspension was extracted with ether, the extract washed (H2O), dried (MgSO4), and the solvent was concentrated to yield 0.64 g (24%) of a solid. This material was combined with 2.9 g of a compound from another run and recrystallized from isopropyl ether to yield 2.1 g of 3-[1-[4,4-bis(4-fluorophenyl)butyl-4-piperidinyl]-6-fluoro-1-phenyl-1H-indazole, mp 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[C:11]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[CH3:16][C:14]([CH3:17])([O:13][C:11]([NH:18][CH:19]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:30]([O:32][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])=[O:31])=[O:12])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1ccccc1CCl
Product: COc1ccccc1COC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
Following the method of Example 1, 2-methoxybenzyl chloride (3.9) and N α BOC-L-tryptophan (7.6 g) gave the title compound which was recrystallised from ethyl acetate/petroleum ether (3.4 g), m.p. 132°-133° C. 1H NMR (360 MHz, CDCl3) δ7.99 (1H, s), 7.56 (1H, d, J=Hz), 7.33-7.07 (5H, m), 6.93-6.66 (3H, m), 5.21-5.07 (3H, m), 4.70-4.67 (1H, m), 3.01 (3H, s), 3.30 (1H, m), 1.41 (9H, s). Found: C, 67.91; H, 6.65; N, 6.60; C24H28N2O5 requires C, 68.00; H, 6.70; N, 6.66%.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9].[OH-].[Na+]>CC(C)=O>[CH3:7][C:8]1([CH3:10])[O:13][C@@H:12]([C@H:14]2[O:15][C@@H:7]3[O:6][C:14]([CH3:16])([CH3:12])[O:9][C@@H:8]3[C@H:16]2[OH:17])[CH2:10][O:11]1
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Reaction time: 24 h
Yield: 112.5 %

Procedure:
Sulfuric acid (40 ml) is added dropwise to a solution of α-D-glucose (41) (50 g, 0,28 mol) in acetone (1 l) at 0° C. The reaction mixture is stirred for 24 h and then it is neutralized using sodium hydroxide (6 M). The acetone is evaporated and the aqueous layer is extracted with chloroform (X2). The chloroform is dried (MgSO4) filtered and evaporated. Crystallization from cyclohexane yielded the di-isopropylidene glucose (42) (41 g, 57%).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: COc1ccccc1OCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1OCCNc1nc(Nc2cc(C)[nH]n2)cc(C)c1C#N
Temperature: 100 °C
Reaction time: 27 h
Yield: 14.4 %

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(2-methoxyphenoxy)ethylamine hydrochloride (1.10 g) and sodium hydrogencarbonate (1.37 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(2-methoxyphenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (89 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([O:25]CC)=[O:24].[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
5.07 g (12.87 mmol) of ethyl 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate Example 265A were dissolved in 275 ml of THF/methanol (5/1), 64.4 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at 40° C. for 3.5 h. At 0° C., the mixture was acidified to about pH 4 with 6 N aqueous hydrochloric acid and concentrated. The solid formed was filtered off, washed with water and dried under reduced pressure. This gave 4.77 g (98% of theory; purity about 93%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:26]=[CH:25][C:24]2[N:23]=[CH:22][C:21]3[N:27]([CH3:42])[C:28](=[O:41])[N:29]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([CH3:40])([CH3:39])[C:37]#[N:38])=[CH:32][CH:31]=4)[C:20]=3[C:19]=2[CH:18]=1>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:36]([C:33]1[CH:32]=[CH:31][C:30]([N:29]2[C:20]3[C:19]4[CH:18]=[C:17]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH:26]=[CH:25][C:24]=4[N:23]=[CH:22][C:21]=3[N:27]([CH3:42])[C:28]2=[O:41])=[CH:35][CH:34]=1)([CH3:40])[C:37]#[N:38]
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4ccncc4)ccc3ncc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
37 mg (0.3 mmol) of 4-pyridineboronic acid (Aldrich, Buchs, Switzerland), 8 mg of bis(triphenylphosphine)palladium (II) dichloride (Fluka, Buchs, Switzerland) and 0.5 ml of a 1 M solution of Na2CO3 are added to a solution of 84 mg (0.2 mmol) of 2-[4 (8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1i) in 2 ml of DMF. The mixture is stirred for 1 h at 100° C. After this time, the mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is loaded on silica gel and purified by flash chromatography (CH2Cl2-MeOH 97:3 to 18:1) to give the title compound as an off-white solid. ES-MS: 420 (M+H)+; analytical HPLC: tret=2.40 min (Grad 1).