Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:7]=1.[Br:22]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[C:11]=2[Br:22])=[CH:6][CH:7]=1
Reactant: COc1cc(COc2ccc(N)nn2)cc(OC)c1OC
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(COc2ccc(N)nn2)c(Br)c(OC)c1OC
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3-Amino-6-(3,4,5-trimethoxybenzyloxy)pyridazine (Intermediate 1, 2.91 g, 10 mMol) in acetic acid (20 ml) was treated dropwise with a solution of bromine (1.59 g, 10 mMol) in acetic acid (2 ml) over 5 minutes. After 0.5 hours, the mixture was filtered to give a cream solid which was suspended in water and basified with sodium hydroxide solution. The mixture was extracted with chloroform and the extracts were washed with water, dried (Na2SO4) and evaporated in vacuo to yield a cream solid which was recrystallised from toluene to give the title compound (2.76 g) as cream needles, m.p. 160°-161° C., NMR δH(CDCl3) 6.93(1H,s,ArH) 6.91(1H,JAB,8.8Hz,5H), 6.80(1H,JAB,8.8Hz,4H), 5.49(2H,s,CH2), 4.95(2H, brs,NH2), 3.91(3H,s,OCH3), 3.90(3H,s,OCH3) and 3.89(3H,s,OCH3).
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18](O)=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18]([Cl:28])=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1
Reactant: C[C@H](C(=O)O)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: O=S(Cl)Cl
Product: C[C@H](C(=O)Cl)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To 2.0 g of (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoic acid was added 20 ml of thionyl chloride and the mixture was stirred at 80° C. for 40 minutes. The reaction solution was concentrated under reduced pressure to give 2.1 g of (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[OH:31]>C(OCCO)C>[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[CH:26][C:25]=1[OH:31]
Reactant: Nc1ccc(Br)c(O)c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(Br)c(O)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 131.7 mg (1.1 mmol) of pyridine hydrochloride and 286.7 mg (1.3 mmol) of 4-bromo-3-hydroxy-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 374.1 mg (88.6%) of the product as a pink solid, m.p. 146° C. (dec.), mass spectrum (electrospray, m/e): M+H 369.9.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[C:13]([CH:14]=[O:15])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1.[CH3:20][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[CH:12]=[C:13]([CH:14]([OH:15])[CH3:20])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
1-(Cyclopropylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole-4-carbaldehyde (0.323 g, 1.2 mmol) was dissolved in tetrahydrofuran (6 mL), cooled down to 0° C. and to it was added methylmagnesium bromide (1.0 M in dibutyl ether, 2.2 mL, 2.2 mmol) dropwise. After 1.5 h, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate (3×30 mL). The organic layer was washed with water (20 mL), brine (20 mL) and dried (Na2SO4). The crude product obtained after evaporation of solvent was purified by flash chromatography on silica gel (2% MeOH/CH2Cl2) affording 286 mg (84%) of product as light yellow oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.11 (s, 1 H), 7.62 (s, 1 H), 7.46 (s, 1 H), 5.38-5.49 (m, 1 H), 4.16 (d, J=6.1 Hz, 1 H), 4.06 (d, J=7.0 Hz, 2 H), 1.70 (d, J=6.7 Hz, 3 H), 1.29-1.40 (m, 1 H), 0.69-0.80 (m, 2 H), 0.45 (q, J=5.2 Hz, 2 H). 308.17 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][O:9][CH2:10][CH2:11][Br:12]>>[BrH:12].[CH3:8][O:9][CH2:10][CH2:11][N:4]1[CH:3]=[C:2]([CH3:1])[S:6][C:5]1=[NH:7]
Reactant: COCCBr
Reactant: Cc1cnc(N)s1
Product: Br
Product: COCCn1cc(C)sc1=N
Temperature: 85 °C
Yield: 40.4 %

Procedure:
A mixture of 5-methyl-thiazol-2-ylamine (1.0 g, 8.8 mmol) and 2-bromoethyl methyl ether (1.0 mL, 11 mmol) were heated at 85° C. for 16 hours. The mixture was cooled to ambient temperature, triturated with ethanol and the solid was collected by filtration to afford 0.90 g (40%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 2.25 (d, J=1.4 Hz, 3H), 3.36 (s, 3H), 3.72-3.81 (m, 2H), 4.36-4.43 (m, 2H), 6.61 (d, J=1.7 Hz, 1H), 9.54 (s, 1H); MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][S:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)(=[O:19])=[O:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>CO.C(Cl)Cl.CCOCC>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][S:17]([C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)(=[O:18])=[O:19])=[O:15])[CH2:10][CH2:9]1.[ClH:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCNCC1

Procedure:
2 g of 4-(3,5-bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-piperidine-1-carboxylic acid tert.-butyl ester are dissolved in a mixture of 1 ml MeOH and 9 ml of CH2Cl2. The resulting mixture is treated at RT with 20 ml of 3 N HCl in (C2H5)2O for ca. 16 hours. Solvent is evaporated and N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride is obtained. m.p. 285-291°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(N(CC)C(C)C)(C)C.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:17]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 21 h
Yield: 46.3 %

Procedure:
To a suspension of imidazole-2-carboxaldehyde (1.00 g, 10.4 mmol) in DMF (16 mL) was added N,N-diisopropylethylamine (4.0 mL, 23.0 mmol) followed by a solution of trityl chloride (3.19 g, 11.4 mmol) in DMF (10 mL), and the mixture was stirred at 30° C. for 21 h. The mixture was concentrated in vacuo then dissolved in EtOAc (60 mL). The solution was washed with saturated NaHCO3(aq) (2×30 mL) and brine (15 mL) then dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave a yellow solid (1.63 g, 46%). 1H NMR (CDCl3) δ 7.03 (s, 1H), 7.12 (m, 6H), 7.32 (m, 10H), 9.23 (s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:19][C@H:20]1[CH2:25][N:24]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:15]([F:18])([F:17])[F:16])[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.850 g, 4.24 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (20 mL), extracted with dichloromethane (3×15 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.70 g (99% yield) of tert-butyl (2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 444 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13]([O:15]CC)=O)=[C:8]([O:19][CH3:20])[CH:7]=1>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:15])[NH:3][CH2:2][CH2:1][N:4]=2)=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: NCCN
Reactant: CCOC(=O)C(=O)c1ccc(F)cc1OC
Solvent: CCO
Product: COc1cc(F)ccc1C1=NCCNC1=O
Yield: 79.2 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was added to a solution of ethyl 2-(4-fluoro-2-methoxyphenyl)-2-oxoacetate (2.26 g, 10.0 mmol) in ethanol (30 ml) and refluxed 4 hr. After removal of the solvent under reduced pressure, residue was washed with ethanol-diethyl ether to give 5,6-dihydro-3-(4-fluoro-2-methoxyphenyl)pyrazinone (1.76 g, 79%).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]4)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:31].Cl.[CH3:38][O:39][NH2:40].Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][CH:2]([F:36])[O:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]([NH:40][O:39][CH3:38])=[O:30])[CH2:26][CH2:27]4)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:31]
Reactant: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CONC(=O)C1CCN(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)CC1
Temperature: 50 °C
Yield: 3.5 %

Procedure:
A solution of Example 23 (0.108 g, 0.22 mmol), O-methylhydroxylamine hydrochloride (0.022 g, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.053 g, 0.26 mmol) and DIPEA (0.057 g, 0.44 mmol) in DMF (5 mL) was stirred at r.t. for 18 h. Further O-methylhydroxylamine hydrochloride (0.10 g, 1.2 mmol) and DIPEA (300 μL) were added and the reaction mixture was heated at 50° C. for 2 days. The reaction mixture was cooled to r.t., treated with water (10 mL) and extracted with DCM (3×50 mL). The combined organic layers were concentrated in vacuo, and the resulting orange oil was purified by FCC (eluting with 3-10% MeOH in DCM), to give the title compound (4 mg, 3%) as an orange solid. HPLC-MS (pH 10): MH+ m/z 523.8 [M+H]+, RT 1.82 minutes.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](Cl)=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH3:22].O>C1COCC1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](=[O:19])[NH2:22])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N
Reactant: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC1Cc2ccc(C(N)=O)cc2C1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
In a 50 ml-round bottomed flask, 5.00 g (18.2 mM) of 2-octylindan-5-carboxylic acid was placed and 7.0 ml of thionyl chloride and one drop of N,N'-dimethylformamide (DMF) were added thereto, followed by heat-refluxing for 30 minute. An excessive thionyl chloride was distilled off under reduced pressure from the above mixture to obtain 2-octylindan-5-carbonyl chloride. A solution of the above-obtained 2-octylindan-5-carbonyl chloride in 50 ml of THF was gradually added dropwise to 45 ml of 30%-ammonia water which had been cooled to about 0° C. on an ice-common salt bath under stirring. After the addition, the resultant mixture was stirred for 4.5 hours at room temperature. After the reaction, 300 ml of water was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and successively washed with water and methanol to obtain 4.59 g of 2-octyl-5-carbamoylindan (Yield: 92.1%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[C:18](Br)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:24][C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:24])[CH:30]=3)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(Br)cc2o1
Reactant: Nc1cccc(OB(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(-c3cccc(N)c3)cc2o1
Yield: 40.3 %

Procedure:
The 2-(1-Boc-2-(R)-pyrrolidinyl)-5-chloro-6-bromo furo[3,2-b]pyridine (0.469 g, 1.2 mmol), obtained in Example 50a above, was dissolved in toluene (10 mL). 3-Aminophenyl boric acid (0.445 g, 2.87 mmol), Pd(O) tetrakis(tri-phenylphosphine) (0.04 g) and 2 M aqueous NaHCO3 (1.5 mL) were added to the solution. The mixture was refluxed for two days. The solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 2:1) to afford an oil (0.20 g, 41%). MS (CI/NH3) m/z: 414 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 1.34, 1.46 (s, 9H), 1.95-2.08 (m, 2H), 2.15 (m, 1H), 2.28 (m, 1H), 3.58-3.68 (m, 2H), 4.98, 5.10 (br s, 1H), 6.24 (m, 1H), 6.63 (s, 1H) 6.76 (d, J=9.3 Hz, 2H), 6.82 (d, J=9.3 Hz, 1H) 7.62 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:12][C:10]1[N:9]=[C:8]2[N:13]([C:24]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[N:14]=[CH:15][C:7]2=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2cnn(C(=O)NCc3ccccc3)c2n1
Yield: 23.9 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (210 mg, 1 mmol) in DMF (2 mL) was treated with benzyl isocyanate (123 μL, 1 mmol) and a catalytic amount of DMAP, stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by preparative HPLC (MeOH/H2O gradient) to give the title compound (80 mg, 24%) as a pale yellow solid. Method Q 4-(2-Furyl)-1-(4-indolymethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (Example 65)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C(=O)N([Cl:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:16][CH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cnc(C)cn1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cnc(CCl)cn1
Temperature: 80 °C
Yield: 20.2 %

Procedure:
To a solution of 2,5-dimethylpyrazine (500 mg, 4.62 mmol) in carbon tetrachloride (7 mL) was added NCS (679 mg, 5.09 mmol) followed by BPO (20 mg) and the mixture was heated to 80° C. for 6 hours. The mixture was diluted with DCM and extracted with saturated aqueous sodium sulfite solution and brine. The organic layer was dried and concentrated to give a crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (1:0 to 15:1) to give 2-(chloromethyl)-5-methylpyrazine (133 mg, 20.19% yield) as yellow oil. LCMS retention time 0.557 min; LCMS MH+ 143.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)(=[O:3])[CH3:2].Cl.[N:15](OC(C)(C)C)=[O:16]>C(Cl)Cl.O1CCOCC1>[CH:10]([N:8]1[C:7](=[O:13])[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[N:15]/[OH:16])=[CH:9]1)([CH3:11])[CH3:12]
Reactant: CC(=O)c1ccc(=O)n(C(C)C)c1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)n1cc(C(=O)/C=N/O)ccc1=O
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
5-Acetyl-1-isopropyl-2(1H)-pyridone was dissolved in CH2Cl2 (300 ml). The solution was cooled to −30˜−25° C. To the cooled solution were added 4N hydrogen chloride in dioxane (55.3 ml) and t-butyl nitrite (10.4 g) at −30˜−25° C. The temperature of the reaction mixture was raised to 20-25° C. The mixture was stirred at the same temperature for 3 hours. The precipitated crystal was collected by filtration, and dried in the air at ambient temperature, to give (1E)-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)(oxo)acetaldehyde oxime (14.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([OH:19])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:19])[NH:12]2
Reactant: Clc1ccccc1-c1cccc2[nH]ccc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2ccccc2Cl)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2-chloro-phenyl)-1H-indole (2.4 g, 10.6 mmol) in t-BuOH:ethanol:acetic acid (67 mL:40 mL:21 mL) was added pyridinium tribromide (10.5 g, 32 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (52 mL). Zinc dust (3.5 g, 53 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.96 g (76%) of 4-(2-chloro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: C([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5](F)[CH:4]=1)#N.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C[N:26]([CH3:29])C=O>O>[C:29]([C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[S:18])=[C:7]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:10][CH:9]=2)[CH:17]=1)#[N:26]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: CN(C)C=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(C=S)c(-c2ccccc2)c1
Temperature: 90 °C

Procedure:
A stirred mixture of 4-cyano-2-fluorobenzaldehyde (1.49 g, 10 mmol), thiophenol (1.21 g, 11 mmol) and potassium carbonate (1.21 g, 11 mmol) in dimethylformamide (10 ml) was heated to 90° C. for 30 minutes under nitrogen atmosphere. The mixture was cooled, diluted with water (10 ml) and the precipitate filtered, washed with water and dried (2.45 g). Recrystallisation from isopropylalcohol (20 ml) gave 4-cyano-2-phenylthiobenzaldehyde as yellow needles, m.p. 88° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([NH:23]C(OCC=C)=O)=[C:21]([NH:30][CH2:31][CH:32]3[CH2:40][CH2:39][C:35]4([CH2:38][CH2:37][CH2:36]4)[CH2:34][CH2:33]3)[N:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C1COCC1.CCOC(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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([NH2:23])=[C:21]([NH:30][CH2:31][CH:32]3[CH2:40][CH2:39][C:35]4([CH2:38][CH2:37][CH2:36]4)[CH2:34][CH2:33]3)[N:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)Nc1c(NCC2CCC3(CCC3)CC2)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2N)CC1
Reaction time: 1 h

Procedure:
To a solution of the crude 4-(2-{5-allyloxycarbonylamino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester (230 mg) in THF (10 mL) are added trietylamine (1.25 mmol) and Pd(PPh3)4 (catalytic amount) at room temperature under N2 atmosphere. After stirring at the same temperature for 1 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The resulting residue is purified by silica gel column chromatography to give 4-(2-{5-Amino-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester; 1H-NMR (CDCl3), δ: 0.97-1.07 (2H, m), 1.13-1.28 (4H, m), 1.42-1.88 (25H, m), 2.69 (2H, t), 3.22 (2H, s), 3.31 (2H, t), 4.04-4.16 (2H, m), 4.40 (2H, t), 4.51 (1H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24](OCC)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CCO>[Cl:18][C:6]1[CH:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([OH:29])=[CH:31][CH:32]=3)=[O:25])[O:21][N:20]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2cc(Cl)c(OCc3ccc(OC)cc3)c(Cl)c2)no1
Reactant: NCc1ccc(O)cc1
Solvent: CCO
Product: COc1ccc(COc2c(Cl)cc(-c3noc(C(=O)NCc4ccc(O)cc4)n3)cc2Cl)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
Ethyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (4 g, 9.46 mmol) and 4-hydroxybenzylamine (2.33 g, 18.91 mmol) were heated in EtOH (150 mL) at 80° C. forming a yellow solution. After 1 h a colourless precipitate formed and the mixture was cooled to room temperature. The solid was filtered off, washed with EtOH and dried in a vacuum oven giving the title compound (4.16 g, 8.32 mmol, 88%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 3.81 (2H, s), 4.41 (2H, d, J=6.08 Hz), 5.12 (2H, s), 6.76 (2H, d, J=8.08 Hz), 7.00 (2H, d, J=8.20 Hz), 7.20 (2H, d, J=8.06 Hz), 7.49 (2H, d, J=8.18 Hz), 8.13 (2H, s), 9.38 (1H, s), 9.95 (1H, t, J=6.15 Hz). LCMS (10 cm_esci_AmmBicarb_MeCN) tR 4.18 min; m/z 498 [M]−.