Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[CH3:10][Li]>C(OCC)C>[CH3:10][C:5]1([OH:8])[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH:3]=[CH:4]1
Reactant: [Li]C
Reactant: CC1(C)C=CC(=O)CC1
Solvent: CCOCC
Product: CC1(C)C=CC(C)(O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4,4-dimethylcyclohex-2-enone (40.0 g, 322 mmol) in anhydrous diethyl ether (400 mL) at −78° C. was added an ethereal solution of methyllithium (220 mL of a 1.6 M). The resulting solution was allowed to warm to room temperature, stirred for 18 hours. The reaction was quenched by the addition of water (200 mL). The phases were separated and the aqueous layer extracted with diethyl ether (2×200 mL). The combined organic phase was washed with water (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as clear, light yellow oil (41 g, Yield: 90%). Rf 0.5 (5:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 5.46 (d, J=10.0 Hz, 1H), 5.43 (d, J=10.0 Hz, 1H), 1.73-1.70 (m, 2H), 1.59-1.56 (m, 1H), 1.50-1.45 (m, 1H), 1.27 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H) ppm; Mass spectrum (ESI +ve) m/z 123 (M−H2O+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][NH:11][CH3:12])=[CH:4][CH:3]=1.B.C1COCC1.ClO.CN.CC1(C)CCCC(C)(C)N1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Cl>C(O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][N:11]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[F:34])[CH3:12])=[CH:6][CH:7]=1
Reactant: CNCCC(O)c1ccc(Cl)cc1
Reactant: Fc1ccccc1CCl
Agent: B
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCC(O)c1ccc(Cl)cc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(4-chlorophenyl)-3-hydroxy-N-methylpropylamine (prepared by borane-THF reduction of β-p-dichloropropiophenone followed by reaction of the resulting chloro-alcohol with methylamine in ethanol) (10 g, 50 mmM), 2,2,6,6-tetramethylpiperidine (8.4 ml, 50 mM), o-fluorobenzyl chloride (7.25 g, 50 mM) and acetonitrile (100 ml) was stirred for 24 hours at ambient temperature. The mixture was filtered, the filtrate evaporated and the residue partitioned between 2 N hydrochloric acid and ether. The aqueous layer was basified and extracted with dichloromethane. The organic phase was dried, evaporated and the residue recrystallised from 60°-80° petrol to give the title compound (8.8 g) m.p. 52°-4° C. Found: C, 66.0; H, 6.2; N, 4.4%; C17H19ClFNO requires: C, 66.3; H, 6.2; N, 4.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[C:16](O)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:29](C(C)C)C(C)C.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:16]([C:13]1[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:24])[CH3:25])[N:11]=[C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][C:14]=12)(=[O:17])[NH2:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2nn(COCC[Si](C)(C)C)c(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2nn(COCC[Si](C)(C)C)c(C(N)=O)c2C1
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product obtained in Step C (600 mg, 1.564 mmol) in DMF (15 mL) was added DIPEA (1.366 mL, 7.82 mmol) and ammonium chloride (2.5 g, 46.9 mmol). After stirring for 30 min, HATU (1190 mg, 3.13 mmol) was added. The resulting mixture was stirred at room temperature under nitrogen for 22 h, diluted with ethyl acetate (200 mL), washed with 1N hydrochloric acid (2×100 mL), dried over Na2SO4, filtered and concentrated to give the crude title compound. LC-MS: 383.2 (M+H).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1>C(#N)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC#N
Product: O=C([O-])/C=C/c1ccc(O)cc1

Procedure:
Sitagliptin free base (2.0 gms) and coumaric acid (0.80 gms) were dissolved in acetonitrile (15 ml) at 60° C. to 65° C. and cooled the solution to −10° C. to −5° C. over a period of 6 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 6 hours to obtain the title compound. Yield: 1.62 gms.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1>O1CCOCC1>[O:18]=[C:15]1[CH2:16][CH2:17][N:11]([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:12][CH2:13][NH:14]1
Reactant: O=C1CCNCCN1
Reactant: OB(O)c1cnc(Cl)nc1
Solvent: C1COCCO1
Product: O=C1CCN(c2ncc(B(O)O)cn2)CCN1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 1,4-diazepan-5-one (288.34 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixture was heated at 100° C. under microwave irradiation for 45 minutes. The resulting slurry was concentrated under vacuum and triturated with MeOH to afford the title compound (145 mg, 30%) as a cream precipitate, which was used without further purification. Method C HPLC-MS: MH+ m/z 237, RT 0.40 minutes.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[C:6]([F:15])=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][C:10]=1[F:11].Cl.[OH-].[Na+]>O.C(OCC)C>[Cl:4][C:5]1[C:6]([F:15])=[C:7]([CH:8]=[CH:9][C:10]=1[F:11])[NH2:12]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(F)c(Cl)c1F
Temperature: 40 °C
Yield: 89.5 %

Procedure:
135 g of tin(II) chloride (dihydrate) was added in small fractions to a stirred suspension of 23 g of 3-chloro-2,4-difluoronitrobenzene in 110 cm3 of a 37% aqueous hydrochloric acid solution and 25 cm'of diethyl ether. After the addition, the mixture was heated for 30 minutes at a temperature in the region of 40° C. After cooling the reaction mass, the mixture was poured over 300 cm3 of water supplemented with 150 g of ice. The mixture was made highly alkaline by addition of caustic soda, and then extracted twice with 250 cm3 of chloroform. The extracts were combined, dried over magnesium sulphate, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 17.4 g of 3-chloro-2,4-difluoroaniline was obtained in the form of a beige solid, which melted at 58° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>>[CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Clc1ccccn1
Reactant: CNCCNC
Product: CNCCN(C)c1ccccn1
Reaction time: 18 h

Procedure:
A mixture of N,N'-dimethylethylene-diamine (25 g) and 2-chloropyridine (1.3 g) is warmed at 85° with stirring for 18 h. The excess dimethylethylenediamine is removed by distillation at reduced pressure. The distillation residue is distributed between ethyl acetate (150 ml) and water (100 ml). The organic phase is separated, dried over sodium sulfate and the organic solvent removed under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]=[CH:27][N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1>CC#N>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]([CH2:7][C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH:27]=[N:28][CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1
Temperature: 25 °C

Procedure:
4-Cyanobenzyl bromide (0.159 g, 0.813 mmol) and the imidazole from step 5 (0.430 g, 0.813 mmol) in CH3CN (4 mL) were heated at 60° C. for 18 hrs. The reaction was cooled to room temperature and the solvent evaporated in vacuo The residue was suspended in methanol (10 mL) and heated at reflux for 1 hr, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat. NaHCO3 and CH2Cl2 and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 3:97 to 4:96 gradient elution) to afford the free base which was converted to the hydrochloride salt to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].CO>C1COCC1>[Cl:13][CH2:14][CH2:15][NH:16][C:17]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)=[O:18]
Reactant: O=C=NCCCl
Reactant: Cc1cc(N)c2ccccc2n1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 4-amino-2-methylquinoline (12.6 g, 80 mmol) in THF (480 mL) is added 2-chloroethylisocyanate (10.2 mL, 120 mmol) at rt. The reaction mixture is stirred for 40 h at rt. MeOH (100 mL) is added, and stirring is continued an additional hour. The reaction mixture is evaporated and the residue is taken up in CH2Cl2. The organic layer is shaken with 1 N HCl (250 mL), and the resulting precipitate is collected by filtration. The solid is washed with CH2Cl2 (100 mL), saturated NaHCO3 (2×100 mL), and with water (4×100 mL). The resulting solid is dried under HV at rt for 14 h to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([F:25])[CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:27]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([F:25])[CH:24]=[C:19]3[CH:18]=2)[CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:6][C:5]=1[F:27]
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1F
Temperature: 50 °C
Yield: 92.7 %

Procedure:
A mixture of 4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (1.50 g, 3.93 mmol) and 10% palladium on activated carbon (300 mg) in methanol (300 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-2-fluoro-benzoic acid methyl ester (1.40 g, 92%): LC/MS m/e calcd for C22H22F2N2O2 [M+H]+ 385.43, observed 384.9.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:3][C:9]1[C:8]2[C:13](=[CH:14][C:15]([F:17])=[CH:16][C:7]=2[F:6])[N:12]=[CH:11][N:10]=1
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
Phosphoryl chloride (3.32 ml) was added to a stirred mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (5 g), diisopropylethylamine (7.16 ml) and acetonitrile (120 ml) that was cooled in an ice bath. The resultant reaction mixture was heated to 80° C. for 2 hours. A second portion of phosphoryl chloride (1.52 ml) was added and the reaction mixture was heated to reflux for a further 2.75 hours to provide a solution of 4-chloro-5,7-difluoroquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (International Application WO 01/94341, Example 17, Note [30]; 4.95 g) in acetonitrile (15 ml) was added and the reaction mixture was heated to 80° C. for 4 hours. The resultant reaction mixture was stirred at ambient temperature for 16 hours. A solution of a second portion of 6-chloro-2,3-methylenedioxyaniline (1.18 g) in acetonitrile (5 ml) was added and the reaction mixture was reheated to 80° C. for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was stirred for one hour. The resultant slurry was filtered and the isolated solid was washed with acetonitrile (20 ml) and dried. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline as a mono-hydrochloride salt (7.88 g, 99.3% HPLC purity using Method A, retention time 4.46 minutes); NMR Spectrum: (DMSOd6) 5.5-6.0 (br s, 1H), 6.15 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.7 (s, 1H), 1.9-2.0 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.P(OCC)(OCC)OCC.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.[H-].[Na+]>O1CCCC1.C1OCCOCCOCCOCCOC1>[C:20]1(=[CH:2][C:3]2[S:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(CBr)s1
Agent: C1COCCOCCOCCOCCO1
Agent: CCOP(OCC)OCC
Agent: [H-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C=C2CCCC2)s1
Reaction time: 2 h

Procedure:
In a second process, 20 g of 5-bromomethyl-thiophene-2-carbonitrile is heated with 200 ml of triethyl phosphite for 4 hours to 150°. Then triethyl phosphite is removed at 40°-60°/0.06 mbar, and the residue is distilled on a bulb tube at 130°-150°/0.004 mbar, resulting in 24 g of (5-cyano-2-thienyl)methylphosphonic acid diethyl ester. Of this product, 5 g is added dropwise, with 1.5 ml of cyclopentanone in 5 ml of tetrahydrofuran, to a suspension of 581 mg of sodium hydride/oil (80% strength) and 116 mg of 15-crown-5 in 5 ml of tetrahydrofuran. After 2 hours of agitation at room temperature, the mixture is poured on water and extracted with ethyl acetate. The ethyl acetate phase is dried and evaporated, and the residue is recrystallized from isopropanol, thus obtaining 3.0 g of 5-cyclopentylidenemethylthiophene-2-carbonitrile, identical to the product described above.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29](=[O:32])[CH2:30][N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)OC(C)(C)C)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and t-butylbromoacetate in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (1% MeOH/CH2Cl2 as eluant). Ethyl 1-(2-tert-butoxy-2-oxoethyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (72%), m.p. (EtOAc/hexanes) 149-151° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.34 (s, 1H), 8.57 (s, 1H), 7.78 (dd, J=10.0, 1.9 Hz, 1H), 7.61 (dd, J=8.4, 1.0 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.43 (d, J=1.2 Hz, 1H), 4.62 (s, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.42 (s, 9H), 1.33 (t, J=7.1 Hz, 3H). Anal Calcd for C20H22FIN2O5: C, 46.5; H, 4.3; N, 5.4. Found: C, 46.7; H, 4.2; N, 5.5.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18](O)[C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=2)=[N:6]1.P(Cl)(Cl)([Cl:31])=O.CCN(C1C=CC=CC=1)CC>>[Cl:31][C:18]1[C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl

Procedure:
6.54 g (17.2 mmol) of methyl 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxypyrimidine-5-carboxylate (example 105A) were taken up in 26.5 ml (284 mmol) of phosphoryl chloride. Then 5.95 g (34.5 mmol) of diethylaniline were added and the mixture was reacted at 90° C. for 60 min. After cooling, the precipitate formed was filtered off and washed with water. Then it was dried under high vacuum. Thus, 6.11 g (78% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[C:11]2=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[C].[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:11]2=[O:22])=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: CCCCCOc1ccc2c(c1OCCCCC)CN(CCc1ccc([N+](=O)[O-])cc1)C2=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1ccc2c(c1OCCCCC)CN(CCc1ccc(N)cc1)C2=O
Yield: 93.5 %

Procedure:
4,5-Dipentyloxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (19.69 g, 43.3 mmol, 1.0 eq) obtained in Example 7-30 was dissolved in ethanol (200 ml), and 5% palladium-carbon catalyst (3.8 g, water content 50%) was added. The reaction mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours under the pressure of 3 kgf/cm2, and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1/2) to give 2-[2-(4-aminophenyl)ethyl]-4,5-bispentyloxy-2,3-dihydroisoindol-1-one (17.19 g, 93.5%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(OCCCC)c1cc(C)ccc1[N+](=O)[O-]
Yield: 199.5 %

Procedure:
Dissolve 5-methyl-2-nitrobenzaldehyde (7.84 g, 47.52 mmol), 1-butanol (10.55 g, 142.6 mmol) and toluene-4-sulfonic acid (0.5 g) in toluene (200 mL). Heat to reflux, and remove the water using a Dean-Stark apparatus. Heat for 3 hours. Add water, and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter, concentrate under reduced pressure, and purify by flash chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to give 14 g (99%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.CC1C=CC(S(O[CH2:43][C@@H:44]2[O:46][CH2:45]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:43][C@H:44]1[CH2:45][O:46]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[C:2]([Cl:1])[CH:7]=1)#[N:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Temperature: 50 °C
Yield: 94 %

Procedure:
N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-methylurea (600 mg) was added to dimethylformamide (4 ml), and then (2R)-(−)-glycidyl p-toluenesulfonate (484 mg) and potassium carbonate (450 mg) were added thereto and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain the title compound (650 mg) as light yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[ClH:13].Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C(O)C>[ClH:13].[NH:15]1[CH2:16][CH:17]=[C:18]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:19][CH2:20]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 7.7 g of 5-nitro-1H-indole and 225 ml of ethanol saturated with hydrogen chloride and 22.5 g of the hydrate of 4-piperidone hydrochloride was refluxed for 3 hours under a nitrogen atmosphere and the mixture was then stirred at room temperature for one hour and at 0° C. for another hour. The mixture was filtered and the recovered product was rinsed with iced ethanol, with ethyl acetate and ether to obtain 14 g of raw product. The latter was crystallized from 600 ml of 1-1 methanol-water mixture and after standing overnight at 0° to 5° C., the mixture was filtered. The product was rinsed with methanol and dried to obtain 9.8 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole hydrochloride melting at 275° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:14])[CH3:13]>C(O)CCC>[CH2:12]([NH:14][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2)[CH3:13]
Reactant: CCN
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: CCNc1nc(Cl)nc2nc[nH]c12
Temperature: 84 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2,6-dichloropurine (2 g, 10.6 mmol) in n-butanol (3 ml), is added ethylamine (2M in THF)(15 ml). The solution is stirred at 84° C. for 2.5 hours and then cooled to ambient and stirred for a further 2 hours. The resulting precipitate is isolated by filtration, washed with n-butanol, methanol and ethyl acetate. The solid is dried at 70° C., under vacuum, for 16 hours to give 6-ethylamino-2-chloropurine; ES+ (M+1)197.5,198.2; mp 237-239° C.