Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].[C:10]([N:18]=[C:19]=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:7]([C:6]1[CH:5]=[C:4]([CH3:9])[S:3][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:20])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1cc(C#N)c(N)s1
Product: Cc1cc(C#N)c(NC(=O)NC(=O)c2ccccc2)s1

Procedure:
Prepared as in Example 1a from 2-amino-5-methylthiophene-3-carbonitrile and benzoyl isocyanate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.36 (d, J=1.2 Hz, 3H), 6.89 (d, J=1.2 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.66 (d, J=7.2 Hz, 1H), 8.03-8.01 (m, 2H), 11.60 (brs, 1H), 12.08 (bs, 1H). MS 286 (MH+).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7](OS(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[CH:20]1([O:24][C:25]2[C:34]([C:35]3[CH:36]=[N:37][NH:38][CH:39]=3)=[CH:33][CH:32]=[C:31]3[C:26]=2[CH2:27][CH2:28][C@H:29]([CH3:44])[N:30]3[C:40]([O:42][CH3:43])=[O:41])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][C@@H:7]([N:37]2[CH:36]=[C:35]([C:34]3[C:25]([O:24][CH:20]4[CH2:21][CH2:22][CH2:23]4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:40]([O:42][CH3:43])=[O:41])[C@@H:29]([CH3:44])[CH2:28][CH2:27]4)[CH:39]=[N:38]2)[C@@H:2]([F:1])[CH2:3]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@@H](F)C1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4F)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 56 %

Procedure:
(3S,4S)-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (96 mg, 0.322 mmol) was added to a solution of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (100 mg, 0.293 mmol) and cesium carbonate (153 mg, 0.469 mmol) in DMF (1.0 mL), and the reaction mixture was heated at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford methyl (S)-6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (89 mg, 56%) as a colorless oil. MS (ESI, pos. ion) m/z 543 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11]C=O)=[N:8][C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2]1>CO.C1COCC1.Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH2:11])=[N:8][C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2]1
Reactant: O=CNc1nc(-c2ccccc2)c(-c2ccoc2)s1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccc2)c(-c2ccoc2)s1

Procedure:
N-(5-Furan-3-yl-4-phenyl-thiazol-2-yl)-formamide (5.7 g, 21 mmol) was dissolved in a mixture of methanol (210 mL) and THF (90 mL), and conc. squeous hydrochloric acid (8.7 mL) was added dropwise at room temperature. The reaction mixture was stirred over night and the solvent was removed by evaporation. The residue was extracted with ethyl acetate, and washed with NaHCO3 (aq.; sat.) and water and dried over sodium sulfate. The solvent was removed and the crude product was purified on neutral Al2O3 using 30-35% ethyl acetate in hexane as eluent. Yield: 2.5 g, 49%.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:13]([F:24])[C:12]=1[O:25][CH3:26]>>[F:24][C:13]1[C:12]([O:25][CH3:26])=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Product: COc1c(-c2ccccc2)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared by a method analogous to Example 461 using phenylboronic acid and 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): mass calcd. for C17H14FN3O, 295.11; m/z found, 296.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.58-8.55 (m, 1H), 8.12 (d, J=1.5, 1H), 7.65 (dd, J=8.1, 7.5, 1H), 7.61-7.54 (m, 2H), 7.48-7.42 (m, 2H), 7.41-7.34 (m, 1H), 7.23 (dd, J=8.2, 1.4, 1H), 4.69 (s, 2H), 3.74 (d, J=0.9, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)=[CH:18][CH:19]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1ccc(B(O)O)cn1
Reactant: Clc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(-c2cnc(Cl)nc2)cn1
Yield: 37.6 %

Procedure:
A reaction of 109 mmol of 5-bromo-2-chloropyrimidine, 109 mmol of 2-butoxypyridine-5-boronic acid, 218 mmol of sodium carbonate and 1.1 mmol of tetrakis(triphenylphosphine)palladium(0) in 200 ml of toluene, 100 ml of ethanol and 100 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 10.8 g (38%) of a colorless solid, m.p. 117° C., cl.p. 130° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)#N.[OH-:26].[Na+].C[OH:29]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:29])=[O:26]
Reactant: [OH-]
Reactant: N#Cc1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Reactant: CO
Agent: [Na+]
Product: O=C(O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1

Procedure:
2-(3-Cyanophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (1.15 g, 3.5 mmol) obtained in Example 41 is dissolved in methanol (50 ml), and thereto is added a 30% aqueous sodium hydroxide solution (30 ml), and the mixture is heated under reflux for 20 hours. The reaction solution is concentrated under reduced pressure, and the pH value of the mixture is adjusted to pH 3 with a 15% aqueous hydrochloric acid solution, and the mixture is extracted with chloroform/THF (2:1) (50 ml×3). The organic layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol), and crystallized from diethyl ether to give the title compound (0.86 g) as colorless crystals, m.p. 208-209° C.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O1CCN([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)CC1.O(C)[Na]>C1COCC1>[C:20]1([CH:21]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:23]=[CH:24][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 83.5 %

Procedure:
2.5 g (15.8 mmol) of 2-hydroxyacetophenone, 2.8 g of 4-morpholinobenzaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 2.52 g (56%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.99 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.93-7.84 (m, 3H), 7.52-7.48 (m, 2H), 7.03 (d, d, J=0.9, 8.4 Hz, 1H), 6.97-6.92 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 3.86-3.83 (m, 4H), 3.69-3.66 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(hydroxymethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (223 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=2:3→ethyl acetate) to give the title compound as a free base (basic TLC:Rf=0.03 (hexane:ethyl acetate=1:1)) (yield 142 mg). A solution of the obtained free base (141 mg) in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (43 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 107 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:33])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[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].Br[CH2:35][CH2:36][OH:37].C(N(CC)CC)C.CN([CH:48]=[O:49])C>O>[CH3:1][C:2]1[NH:3][C:4]([CH3:33])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:35][CH:36]([OH:37])[CH2:48][OH:49])=[CH:30][CH:31]=2)=[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: CN(C)C=O
Reactant: OCCBr
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCC(O)CO)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
Similarly, a solution of 4.5 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-aminophenyl)ethoxycarbonyl]-1,4-dihydropyridine (11), 1.8 mL 2-bromoethanol, 2 mL triethylamine and 20 mL DMF was stirred at 80° C. for 3 h. The mixture was added to water and extracted with ethyl acetate. The ethyl acetate was washed with water, dried over Na2SO4, evaporated to a residue, and purified by silica gel chromatography with 75% ethyl acetate-hexane to afford 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethylamino)phenyl]ethoxycarbonyl)-1,4-dihydropyridine (1) as a free base. This was dissolved in methanolic HCl and evaporated under reduced pressure to yield 2.6 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethylamino)phenyl]ethoxycarbonyl)-1,4-dihydropyridine hydrochloride as an amorphous solid, m.p. 102°-104° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Dimethyl sulfoxide (20.80 ml, 22.90 g, 29.3 mmol) in dichloromethane (75 ml) was added dropwise to a cooled (−70° C.) solution of oxalyl chloride (13.95 ml, 20.30 g, 160 mmol) in dichloromethane (350 ml). The mixture was stirred at −70° C. for 15 minutes, then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 36.91 g, 133 mmol) in dichloromethane (150 ml) was added dropwise. The mixture was stirred at −70° C. for 20 minutes, then allowed to warm to −30° C. The mixture was cooled to −50° C. and triethylamine (55.95 ml, 40.45 g, 400 mmol) was added slowly. The mixture was allowed to warm to 0° C. and diluted with ice-cooled dichloromethane (250 ml). The mixture was washed with ice cold aqueous citric acid solution (5%, 2×300 ml) and water (300 ml), dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (42.3 g), which was used immediately without further purification. 1H NMR (250 MHz, CDCl3) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])C=O.[NH:14]1[CH2:19][CH2:18][C:17](=[C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][N:22]3[CH:31]=[CH:32][N:33]=[C:21]23)[CH2:16][CH2:15]1.[H][H]>CO.S1C=CC=C1.[Pd]>[N:33]1[CH:32]=[CH:31][N:22]2[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:20](=[C:17]3[CH2:18][CH2:19][N:14]([C:5]4[CH:8]=[C:9]([O:12][CH3:13])[C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:15][CH2:16]3)[C:21]=12
Reactant: [H][H]
Reactant: c1ccc2c(c1)CCn1ccnc1C2=C1CCNCC1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: COc1cc(N2CCC(=C3c4ccccc4CCn4ccnc43)CC2)cc(OC)c1O
Yield: 67.1 %

Procedure:
A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (8 g) and 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (9 g) in methanol (250 ml) and thiophene (4%, 3 ml) was hydrogenated at room temperature with palladium on activated carbon (10%, 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and evaporated, yielding 9.5 g (65%) of 4-[4-(5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)- 1-piperidinyl]-2,6-dimethoxyphenol (intermediate 8).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](C2OC3(C)C(C)(C3)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)=[CH:15][N:14]=1
Reactant: CC12CC1(C)OC(c1cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c1)O2
Reactant: Brc1cnc2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2cnc3ncccc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
(Some starting materials may be obtained from Princeton Biomolecular Research, Inc., Monmouth Junction, N.J.) To a 50 mL round-bottomed flask was added 3-bromo-1,8-naphthyridine (73 mg, 351 μmol), N-(2-chloro-5-(1,5-dimethyl-2,4-dioxa-bicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (140 mg, 351 μmol), tetrakis(triphenylphosphine)palladium (41 mg, 35 μmol), sodium carbonate (351 μl, 702 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (1 mL) and extracted with CH2Cl2 (5×20 mL). The organic extract was washed with saturated NaCl (2 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2 to give N-(2-chloro-5-(1,8-naphthyridin-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (98 mg, 67% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H12ClFN4O2S: 414.0; found 415.0. 1H NMR (300 MHz, MeOD) δ ppm 7.30 (t, J=8.77 Hz, 2 H) 7.76 (dd, J=8.18, 4.38 Hz, 1 H) 7.89 (dd, J=8.99, 5.04 Hz, 2 H) 8.44 (d, J=2.34 Hz, 1 H) 8.62 (dd, J=8.18, 1.90 Hz, 1 H) 8.70 (d, J=2.34 Hz, 1 H) 8.79 (d, J=2.48 Hz, 1 H) 9.15 (dd, J=4.38, 1.90 Hz, 1 H) 9.39 (d, J=2.48 Hz, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[O:9])=[CH:4][CH:3]=1.[OH2:30].CC(O)=[O:33]>>[N+:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:27])[F:28])=[O:9])=[CH:4][CH:3]=1)([O-:33])=[O:30]
Reactant: Nc1ccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Reactant: CC(=O)O
Reactant: O
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 1 h

Procedure:
(4-Aminophenyl)[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.050 g, 0.127 mmol) in AcOH (2 mL) is added slowly to a stirred solution of NaBO3 4H2O (0.098 g, 0.637 mmol) in AcOH (3 mL) at 55° C. over 40 min. After 1 h, the reaction is cooled, poured into water and extracted with methylene chloride. The extracts are washed with saturated aq sodium bicarbonate, dried over MgSO4 and concentrated. The residue is purified by chromatography eluting with 10:90 ethyl acetate:hexane to afford the title compound (0.0157 g). MS (ESI) m/z 423; HRMS: calcd for C23H13F3N2O3+H, 423.09565; found (ESI, [M+H]+), 423.0943.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C[C]1[C](C)[C](C)[C](C)[C]1C.C1CC=CCCC=C1.Cl[Ru]>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:3](/[CH:4]=[CH:5]/[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:2][O:1][CH:21]=2)=[CH:16][CH:15]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: ON=C(Cl)/C=C\c1ccccc1
Agent: Cl[Ru]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Solvent: CCN(CC)CC
Solvent: C1=CCCC=CCC1
Product: Clc1ccc(-c2conc2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A screw-top Schlenk flask (250 mL) purged with dry nitrogen was charged with compound 25B (7.31 g, 40 mmol) and 4-chlorophenylacetylene (5.0 g, 36.6 mmol). At room temperature, degassed 1,2-dichloroethane (100 mL) was added followed by [Cp*RuCl(cod)] (450 mg, 1.18 mmol) and triethylamine (6.38 mL, 45.8 mmol). The flask was purged with N2 and capped. After being stirred at room temperature for 7 h, the reaction mixture was passed through a plug of silica gel, and washed with DCM. The resulting solution was concentrated and the residue was purified by column chromatography on silica gel (pure hexanes to 10:1 hexanes/EtOAc) to provide the desired compound. MS (m/z) 282.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O>>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Cc1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 99 %

Procedure:
This product was prepared using the same procedure as for intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 4-methylbenzaldehyde (0.74 g, 1 equiv.) and TFA (1 mL, 2 equiv.) to give the title compound (1.6 g, 100%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH3:15][CH:16](O)[CH:17]=[CH2:18]>COC(OC)(C)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: C=CC(C)O
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2cc(OC)c(OC)cc2C1=O
Yield: 26.5 %

Procedure:
A solution of 20 g of 5,6-dimethoxy-1-indanone, 21.5 ml (0.25 mol) of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 21.5 ml of 2,2-dimethoxypropane and 200 ml of anhydrous toluene was boiled under reflux for 24 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 3:2). 6.8 g (27%) of (RS)-2-(2-buten-1-yl)-5,6-dimethoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Br:43][C:44]1C=[CH:48][CH:47]=[CH:46][C:45]=1CBr>>[Br:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:15]=1[CH2:14][N:11]1[C:9]2[N:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([N:16]3[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]3)[C:8]=2[N:13]=[N:12]1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: BrCc1ccccc1Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3Br)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-(bromomethyl)benzene and isolated as colorless gum (6.6 mg, 35%). MS (m/e): 451.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].[F:36][C:37]1[CH:59]=[CH:58][C:40]([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[NH:51][CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:55]2[CH2:54][CH2:53][CH:52]([NH:51][C:43]3[N:42]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:59][CH:58]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:57][CH2:56]2)([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Product: COc1cc(CN2CCC(CCCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 23.4 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.