Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:23]=[O:24])=[C:17]([O:21][CH3:22])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:25])[O:10][C:9]=2[C:8]([CH3:26])=[C:7]([O:27][CH3:28])[CH:6]=1)=[O:4].Cl.O1CC[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:23]([OH:24])[CH2:31][CH3:32])=[C:17]([O:21][CH3:22])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:25])[O:10][C:9]=2[C:8]([CH3:26])=[C:7]([O:27][CH3:28])[CH:6]=1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(OC)cc(C)c1C(=O)O2
Agent: Cl
Product: CCC(O)c1c(OC)cc(C)c2c1Oc1c(C(=O)OC)cc(OC)c(C)c1OC2=O
Reaction time: 1 h

Procedure:
The compound from Example 3 (0.15 mmol) was dissolved in absolute tetrahydrofuran. A solution of 2M Grignard reagent (0.7 ml, 1.4 mmol) in tetrahydrofuran was added under ice bath. The mixture was stirred for 1 h. Upon completion, 2 ml of 1N hydrochloric acid was added, and the mixture was extracted with methylene chloride. The organic layer was subsequently washed with water and saturated brine, dried over anhydrous MgSO4, filtered and evaporated by a rotatory evaporator. After chromatographic purification on silica, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: COc1cc(N)ccc1-c1cnn(C)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Step K (3): Dichloromethane (25 mL) was added to a flask charged with 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (1.5 g, 7.38 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (2.57 g, 11.1 mmol). The resulting mixture was stirred for 16 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (30% EtOAc/dichloromethane). The fractions containing product were combined and concentrated. The resulting solid was recrystallized from hexane to afford 4-(4-isothiocyanato-2-methoxyphenyl)-1-methyl-1H-pyrazole (1.46 g, 5.95 mmol, 81% yield) as a light yellow solid. LC-MS (M+H)+ 272.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.57 (d, J=1.83 Hz, 1 H) 7.07 (d, J=1.53 Hz, 1 H) 6.94-7.04 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:4][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:6][C:7]=1[OH:8].C(O)(=O)C.[N:31]([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:14][N:12]1[CH:13]=[C:9]([C:5]2[N:4]=[C:3]3[N:15]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)[N:31]=[N:1][C:2]3=[C:7]([OH:8])[CH:6]=2)[CH:10]=[N:11]1
Reactant: O=N[O-]
Reactant: Cn1cc(-c2cc(O)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2cc(O)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ol (170 mg, 0.49 mmol) was added to a solution of acetic acid (3 mL) and H2O (3 mL) at 0° C., followed by the addition of NaNO2 (69 mg, 10 mmol) in H2O (0.3 mL). The reaction mixture was stirred at 0° C. for 1 h, then basified with aqueous 30% NaOH to pH=6-7 and purified by chromatography to afford the title compound (120 mg). MS (m/z): 358 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:14][N:15]=[N+]=[N-])[CH2:9][C@@H:10]([CH3:13])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH3:19]O>[Pd]>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:14][NH2:15])[CH2:9][C@@H:10]([CH3:13])[CH2:11][CH2:12][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC[C@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCC[C@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Reaction time: 96 h

Procedure:
A mixture of 125 (2.8 g, 10.4 mmol) and 10% Pd/C (1.0 g) in methanol (50.0 mL) was hydrogenated at 41 PSI for 96 hours. The solution was filtered to give 1.7 g of crude 126 which was used in the next step without further purification. MS, m/z (relative intensity): 244 [M+1H, 100%], 285 [M+1H+CH3CN, 25%].
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:25]2/[C:24](=[O:26])[NH:23][C:22](=[O:27])[S:21]/2)=[CH:7][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccccc1C(O)COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1C(O)COc1ccc(/C=C2\SC(=O)NC2=O)cc1
Yield: 80.2 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.81 g, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C@@H:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1CCN[C@@H](C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (2.7 g, 11.1 mmol) and triethylamine (4.6 ml, 33.3 mmol) in 30 mL of methylene chloride was added 4-methoxy-benzenesulfonyl chloride (2.3 g, 11.1 mmol). The mixture was warmed to ambient temperature and stirred for 4 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and the organic mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the resulting crude product was purified by silica gel chromatography (elution with 3:8 ethyl acetate/hexanes) to provide (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O>CO.[Pd]>[C:9]([C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:13]2)=[CH:12][CH:11]=1)#[N:10]
Reactant: CN(C)C=Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc2cc[nH]c2c1
Yield: 72.5 %

Procedure:
4-(2-Dimethylamino-vinyl)-3-nitro-benzonitrile (28.5 g, 131 mmol) was dissolved in MeOH (850 mL) and hydrogenated over 10% Pd/C (6.0 g) at 60 psi for 1.5 h at room temperature. The reaction was filtered over celite and evaporated in vacuo. The residue was partitioned between 5% aqueous HCl solution and Et2O (2×200 mL) and the combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6-cyano-1H-indole (13.5 g, 72%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) 11.7 (1H, br s), 7.89 (1H, s), 7.72 (1H, d, J=8.2 Hz), 7.65 (1H, m), 7.32 (1H, m), 6.59 (1H, m); MS m/e 141 (M−H)−. Anal calcd. for C9H6N2.0.10 H2O : C, 75.09; H, 4.34; N, 19.46. Found: C, 74.92; H, 4.29; N, 19.34.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[C:15]([C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][N:13]=[CH:12][N:11]=1>>[CH3:6][N:4]([CH:3]=[C:17]([C:18](=[O:21])[CH2:19][CH3:20])[C:16]([C:15]1[C:10]([CH3:9])=[N:11][CH:12]=[N:13][CH:14]=1)=[O:22])[CH3:5]
Reactant: CCC(=O)CC(=O)c1cncnc1C
Reactant: COC(OC)N(C)C
Product: CCC(=O)C(=CN(C)C)C(=O)c1cncnc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To 181 mg of dimethylformamide dimethyl acetal was added 250 mg of 1-(4-methylpyrimidin-5-yl)pentan-1,3-dione. The mixture was stirred for 16 hours at room temperature and the volatiles removed by bulb-to-bulb distillation (80° C.; 0.01 mm Hg) to yield 278 mg of 2-(dimethylaminomethylene)-1-(4-methylpyrimidin-5-yl)pentan-1,3-dione as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:34]([CH3:48])[CH2:35][CH2:36][N:37]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23]([C:14]2([CH:11]3[CH2:10][CH2:9][N:8]([CH:34]([CH3:48])[CH2:35][CH2:36][NH2:37])[CH2:13][CH2:12]3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1
Product: CC(CCN)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1

Procedure:
Using general procedure C with the above carbamate (170 mg, 0.37 mmol), then using general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (70 mg, 0.32 mmol) followed by general procedure D gave 3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (46 mg, 68% over 3 steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)[CH:31]=[CH:30][N:29]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccnc(F)c1
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: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccnc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 68.5 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2-fluoropyridine-4-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.065 g) to obtain the title compound (0.085 g) as a colorless foam. MS (ISN): 483.4 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(N)ccc1F
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a suspension of 2-fluoro-5-nitrobenzonitrile (5.20 g) in ethanol (150 mL) was added 5% Pd/C (1.00 g). The reaction was placed on a hydrogenator (50 psi) for 10 minutes. The reaction mixture was filtered through celite and the filtrate evaporated to give 4.25 g of 5-amino-2-fluorobenzonitrile. 1H NMR (CDCl3) δ3.75 (bs, 2H, NH2), 6.83 (m, 2H, aromatic H), 6.99 (m, 1H, aromatic H). GC mass spectrum z (rel. intensity) 137 (M+H, 100).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27](F)=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].Cl>CN(C)C=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
29.36 g of cyclopropylmethanol are dissolved in 310 ml of N,N-dimethylformamide and cooled to about 10° C. in an ice bath. Then 41.58 g potassium tert-butoxide is added in batches, while the temperature should stay below 15° C. The reaction mixture is then stirred for another 30 minutes at 10° C., then 31.19 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline is added in batches, while again the temperature should not exceed 15° C. The dark red reaction mixture is stirred for another hour at 15° C. For working up, the mixture is poured onto 2.5 1 of water and neutralized with 2N hydrochloric acid. The yellowish precipitate formed is suction filtered, washed with water, and dried at 50° C. in a drying cupboard. Yield: 36.02 g (100% of theory); melting point: 204° C.; mass spectrum (ESI+): m/z=389, 391 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)[C:3](=[O:18])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]([C@@H:19]1[CH2:23][CH2:22][N:21]([CH2:30][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)[CH2:20]1)[C:3](=[O:18])[CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C(=O)CC(c1ccccc1)c1ccccc1)C1CCNC1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)CC(c1ccccc1)c1ccccc1)[C@@H]1CCN(Cc2ccncc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-3,3-diphenyl-N-pyrrolidin-3-yl-propionamide(0.45 g, 1.46 mmol) in CH2Cl2 (10 ml) was added 4-pyridinecarboxaldehyde(0.14 ml, 1.46 mmol), sodium triacetoxyborohydride(0.4 g, 1.89 mmol) and ACOH (0.17 ml, 2.92 mmol). The resulting solution was stirred at room temperature under nitrogen overnight. The reaction mixture was quenched with saturated NaHCO3 (4 ml), and product was extracted with EtOAc (3×30 ml). Drying the EtOAc extract over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using acetone:EtOAc (1:1) gives the desired product in good yield.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[C:34]([CH2:35]Br)=[CH:33][CH2:32][CH2:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[C:34]([CH2:35][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CCCC2CO)c1
Yield: 37.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled compound (83 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11](O)([C:14]#[N:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]=[C:11]([C:14]#[N:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(O)CCN(c2ncccc2F)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CCN(c2ncccc2F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3′-Fluoro-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonitrile 19 (100 g, 450.2 mMol) was dissolved in dry pyridine (1,000 mL) and cooled to 0° C. under nitrogen. Phosphorus oxychloride (85 mL, 940 mMol) was added dropwise ensuring the temperature did not rise above 10° C. during the addition, and the resulting mixture stirred at 0° C. overnight using a lagged cooling bath. The mixture was cautiously poured into ice-water (3,000 mL) with stirring, and the pH adjusted to 6.0 using potassium phosphate buffer. The mixture was extracted with ethyl acetate (3×2,000 mL), dried (MgSO4) and the solvent evaporated to dryness in vacuo to leave orange oil. Flash chromatography of the residue eluting with hexanes:ethyl acetate (10:1) gave the title compound 20 (65 g, 72%) as a white solid m.p.=76-77° C. δH {400 MHz, CDCl3} 8.01 (1H, d, J=5 Hz), 7.27 (1H, dd, J=20, 8 Hz), 6.79 (1H, m), 6.71 (1H, m), 4.16 (2H, dd, J=12, 3 Hz), 3.65 (2H, t, J=6 Hz), 2.50 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[C:10]2[N:11]=[C:19]([C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][C:17]=3[C:23]([F:25])([F:24])[F:26])[NH:12][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cncc(N)c1N
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cncc2[nH]c(-c3ccc(F)cc3C(F)(F)F)nc12
Temperature: 220 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A mixture containing ethyl 4,5-diaminonicotinate (79; 0.9 g, 5 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (82; 1.0 g, 5.2 mmol) in nitrobenzene (50 mL) was stirred at 220° C. for 18 h. Upon cooling to room temperature, the reaction mixture was diluted with ether. The resulting solids were collected by filtration, washed with ether, and dried to provide 2-(4-fluoro-2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester 83 (600 mg, 39%).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15]Cl.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)CCC>[OH:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:3]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[C:5]([CH3:13])[C:4]=3[CH2:14][CH2:15]2)=[C:20]([CH3:25])[CH:19]=1
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Reactant: Cc1cc(O)ccc1N
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(O)ccc1N1CCc2c(C)nc3ccccc3c21
Yield: 12 %

Procedure:
A solution of 4-chloro-3-chloroethyl-2-methylquinoline hydrochloride (1.28 g, 4,6 mmol) and 4-hydroxy-2-methylaniline (1.13 g. 9.2 mmol) in n-butanol(20 ml) was heated at reflux under a nitrogen atmosphere for 20 hours, thenevaporated. Chromatography (silica gel, 5-7% methanolic ammonia in dichloromethane) and recrystallisation from aqueous methanol gave 1-(4-hydroxy2-methylphenyl)-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.16 g), m.p. 315°-318°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][C@H:9]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1Br)C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1c2ccccc2OC[C@H]1C1CCCCC1
Yield: 67.5 %

Procedure:
A mixture of (R)-2-(2-tert-butoxycarbonylamino-2-cyclohexylethoxy)bromobenzene (500 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.126 mmol) and sodium tert-butoxide (181 mg 1.88 mmol) in toluene (4.0 ml) was exposed to microwave irradiation for 10 min at 120° C. The resulting mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloro-methane and combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 0-17% (v/v) ethyl acetate in heptane to afford (R)-4-tert-butoxycarbonyl-3-cyclo-hexyl-3,4-dihydro-2H-1,4-benzoxazine (270 mg, 0.85 mmol). This reaction was repeated 13 times on the same scale to afford the same intermediate (a total of 3.98 g, 12.5 mmol).
Reaction SMILES: [I:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7](O)[C:6]=1[O:14][CH2:15][CH2:16][I:17].[C:18]([O:26]CC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1CCCCC1.C(O)C>[I:17][CH2:16][CH2:15][O:14][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][C:5]=1[O:4][CH2:3][CH2:2][I:1])[O:26][C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(OCCI)c(OCCI)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(OCCI)c(OCCI)cc2oc1=O

Procedure:
To 1.73 g (10.8 mmol) of the bis-iodoethoxy-hydroxybenzaldehyde from Example 33 was added diethyl malonate, 2.1 g (4.6 mmol), and this mixture was heated on a steam bath. When the mixture had become homogeneous, two drops of piperidine were added. After the mixture had cooled, a precipitate formed. The solution was diluted with a few milliliters of ethanol and reheated to boiling on the steam bath. After the solution had cooled, it was filtered and the precipitate product retained. The product was a solid with a m.p. of 162°-165° C. Proton NMR confirmed the structure of the product.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:23]=[N:24][N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([N:35]3[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]3)=[N:27][C:26]=12.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:23]=[N:24][N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([N:35]3[CH2:36][CH2:37][CH:38]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH2:39][CH2:40]3)=[N:27][C:26]=12
Reactant: C1COCCN1
Reactant: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccccc1-c1nnn2c1nc(N1CCC(N3CCOCC3)CC1)c1ccccc12
Reaction time: 48 h
Yield: 71 %

Procedure:
Sodium triacetoxyborohydride (0.53 g, 2.75 mmol) was added portionwise over 10 min to a solution of 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.30 g, 0.83 mmol) and morpholine (0.36 g, 4.1 mmol) in CH2Cl2 (5 ml) and the mixture was allowed to stir for a further 48 h. The mixture was diluted with CH2Cl2 (150 ml), washed with water (50 ml) and brine (50 ml), dried over MgSO4 and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with CH2Cl2:MeOH (98:2) followed by trituration with diethyl ether gave 3-(2-fluorophenyl)-5-[4-(morpholin-4-yl)piperidin-1-yl]-[1,2,3]triazolo[1,5-α]quinazoline (0.255 g, 71%) as a white solid. δH (400 MHz; CDCl3) 1.78-1.88 (2H, m), 2.04-2.08 (2H, m), 2.43-2.53 (1H, m), 2.58-2.68 (4H, m), 3.07-3.14 (2H, m), 3.75-3.78 (4H, m), 4.17-4.22 (2H, m), 7.19-7.30 (2H, m), 7.33-7.39 (1H, m), 7.61 (1H, ddd, J=8, 8 and 1), 7.88 (1H, ddd, J=8, 8 and 1), 8.00 (1H, d, J=8), 8.13 (1H, ddd, J=7, 7 and 2), 8.69 (1H, d, J=8); m/z (ES+) 433 (M+H+).