Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)=[CH2:14].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][OH:22])[CH2:19][CH2:20]1)[CH3:14]
Reactant: C=C(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(CO)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of (1-{1-[2,4-bis(trifluoromethyl)phenyl]ethenyl}piperidin-4-yl)methanol (12.6 g) in methanol (178 mL) was added sodium borohydride (2.02 g). The reaction mixture was stirred at room temperature for 20 min, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.9 g).
Reaction SMILES: [C:1](=O)([O:6][C:7]1[C:15]2[O:14][C:13]([CH3:17])([CH3:16])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[O:2]C(Cl)C.[CH3:19][N:20](C)C1C=CC=CC=1>N1C=CC=CC=1>[CH3:19][NH:20][C:1](=[O:2])[O:6][C:7]1[C:15]2[O:14][C:13]([CH3:17])([CH3:16])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)c1ccccc1
Reactant: CC(Cl)OC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: c1ccncc1
Product: CNC(=O)Oc1cccc2c1OC(C)(C)C2

Procedure:
The procedure is as in (a) followed by (b), but pyridine is replaced by N,N-dimethylaniline and the intermediate carbonate is not distilled. Starting with 16.4 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 16.8 g (76%) of CARBOFURAN are then obtained, M.p. 147° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:39])[CH2:8][CH2:7][N:6]([C:9]2[C:14]([CH2:15][N:16]([CH3:27])[C@@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[C:13]([CH3:28])[N:12]=[C:11]([C:29]3[C:34]([CH2:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:37][CH3:38])[N:10]=2)[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[C:46](OC(=O)C)(=[O:48])[CH3:47].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.CCOC(C)=O>[CH2:35]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:37][CH3:38])[C:29]=1[C:11]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][C:3]([CH2:2][NH:1][C:46](=[O:48])[CH3:47])([OH:39])[CH2:4][CH2:5]2)[C:14]([CH2:15][N:16]([CH3:27])[C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[C:13]([CH3:28])[N:12]=1)[CH3:36]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC(O)(CN)CC2)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC(O)(CNC(C)=O)CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing 4-(aminomethyl)-1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}methyl)pyrimidin-4-yl]piperidin-4-ol (25 mg, 0.047 mmol) in DMA (1.0 mL) is added K2CO3 (33 mg, 5.0 eq., 0.24 mmol) and acetic anhydride (0.023 mL, 5.0 eq., 0.24 mmol) and allowed to stir at room temperature for 16 h. EtOAc (2.0 mL) and sat NaHCO3 (2.0 mL) are then added and the organic layer is transferred directly onto a SiO2 plate and the product is eluted with 20:1 CHCl3:MeOH affording the title compound as a white foam. [mass expected (569.78); mass found (569.30)].
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[N:35](CCCCC=C)[N:34]=NN=3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[CH2:11][CH:12]4[CH2:7][CH2:8][CH2:9][CH2:10][N:34]4[N:35]=3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCCCn1nnnc1-c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c(=O)c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCCc1nc2ccc(C3=NN4CCCCC4C3)cc2c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A mixture of 5.43 g of 4'-[[2-butyl-6-[1-(5-hexenyl)-1H-tetrazol-5-yl]-4-oxo-3(4H)-quinazolinyl]methyl][1,1'-biphenyl]-2-carbonitrile in 100 ml of diphenylether is heated for 3 hours. The reaction mixture is cooled to room temperature and diluted with 1L of hexanes. The oily compound is separated from the hexanes-diphenylether mixture and purified by column chromatography on silica gel by eution with 75% ethyl acetate-hexanes to give 2.1 g of the desired product as solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=2[N:15]=[N:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:19]=[CH:18][C:17]4[S:13][N:14]=[N:15][C:16]=4[CH:21]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2snnc2c1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2snnc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzo[d][1,2,3]thiadiazole-5-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H), 9.19 (s, 1H). MS (DCI/NH3) m/z 315. Anal. Calculated for C16H18N4OS.HCl: C, 54.77; H, 5.46; N, 15.97. Found: C, 53.27; H, 4.94; N, 15.47.
Reaction SMILES: [NH:1]1[C:6](=O)[CH2:5][CH2:4][C:3]2([CH2:12][CH:11]3[CH2:13][CH2:14][CH:8]2[CH2:9][CH2:10]3)[C:2]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[OH-].[Na+]>O>[NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:12][CH:11]3[CH2:13][CH2:14][CH:8]2[CH2:9][CH2:10]3)[CH2:2]1
Reactant: O=C1CCC2(CC3CCC2CC3)C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C1CNCC2(C1)CC1CCC2CC1
Reaction time: 1 h

Procedure:
An amount of 50 g (0.24 mole) of spiro[bicyclo[2.2.2]octane-2,3'-piperidine]-2',6'-dione is introduced portionwise by means of a connecting tube in the course of 15-20 minutes, with stirring, into a mixture of 14 g (0.37 mole) of lithium aluminum hydride in 3 liters of abs. ether. The temperature during the addition is not to exceed 25°. The mixture is refluxed under nitrogen for 32 hours. After subsequent cooling, successive additions are made dropwise of 14 ml of water, 28 ml of 2N sodium hydroxide solution and a further 28 ml of water. The mixture is then stirred for 1 hour; it is afterwards filtered under reduced pressure and the residue subsequently well washed with ether. The filtrate is dried over sodium sulphate and concentrated by evaporation. The residue is fractionated in high vacuum to obtain spiro[bicyclo[2.2.2]octane-2,3'-piperidine], B.P. 95°-130°/0.2 Torr. From this base there is obtained, with excess ethereal hydrogen chloride solution, spiro[bicyclo[2.2.2]octane-2,3'-piperidine]-hydrochloride, M.P. 207°-208.5° (from acetone/ether).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:26](=[O:28])[NH2:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][N:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18](=[O:25])[CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.C1(C)C=CC=CC=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:20][N:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:18](=[O:25])[CH:17]=2)=[CH:14][CH:15]=1)[C:26]([NH2:27])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(=O)n(C(C)(C)C)s2)cc1)C(N)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)n1sc(-c2ccc(C[C@H](N)C(N)=O)cc2)cc1=O

Procedure:
A solution of 1-G (0.76 g, 1.8 mmol) in 30% TFA in CH2Cl2 (15 mL) was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to give a solid. The salt was co-evaporated with toluene (2×20 mL) to yield 1-H as a tan solid (quantitative) which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:5]2[C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17].[C:28]([OH:34])([C:30](F)(F)F)=[O:29]>ClCCl>[C:28]([CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:5]2[C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17])([OH:34])=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(O)ccc21
Solvent: ClCCl
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7 (3.0 g, 6 4 mmol) in dichloromethane (50 ml) was added TFA (25 ml) and the mixture was stirred at room temperature for 3 h. The mixture was evaporated to dryness and the crude obtained was purified by chromatography on silica-gel using 5% methanol in chloroform to give Hapten-B (2.1 g, 79%).
Reaction SMILES: [CH2:1](OCC)C.C[Mg]Br.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH:28]=[O:29])[C:23]=2[O:24][CH2:25][O:26][CH3:27])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>C1COCC1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH:28]([OH:29])[CH3:1])[C:23]=2[O:24][CH2:25][O:26][CH3:27])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CCOCC
Reactant: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1c(C(C)O)csc1-c1ccc(C(C)(C)C)cc1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
3.0 M Ethyl ether solution (2.0 mL, 6.0 mmol) of methylmagnesium bromide was added dropwise to 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-formylthiophene (0.77 g, 2.5 mmol) in THF (2.5 mL) under cooling with ice, and the reaction solution was stirred for 1 hour under cooling with ice. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1) to give the desired product as a pale yellow oil (0.64 g, yield 80%).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.C(N(CC)CC)C.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=1>C(O)(C)C>[O:1]1[CH2:4][CH:3]([NH:5][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:2]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: NC1COC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC2COC2)nc1
Yield: 24.7 %

Procedure:
In a microwave vial, oxetan-3-amine (125 mg, 1.736 mmol), triethylamine (526 mg, 5.21 mmol) were added to a solution of 2-bromo-5-cyanopyridine (317 mg, 1.736 mmol) in isopropanol (3 mL). The vial was capped and irradiated in a microwave oven at 120° C. for 5 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (chloroform/MeOH, 0-5% EtOAc) to afford 75 mg (25%) of 6-(oxetan-3-ylamino)nicotinonitrile (I-25) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.58-7.61 (dd, J=1.9, 6.9 Hz, 1H), 6.39 (d, J=8.7 Hz, 2H), 5.37 (br. s, 1H), 4.91-5.06 (m, 3H), 4.54-4.57 (m, 2H); ESI-LC/MS (m/z): [M+H]+ 176.2, RT 1.65 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.Cl[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.17 g, 6.61 mmol) was suspended in 30 mL dimethylformamide. The mixture was stirred for 15 min and was cooled at 0° C. with an ice bath. 6-Chloro-4-nitro-1H-indole (1 g, 5.09 mmol) dissolved in 5 mL dimethylformamide was added dropwise and the mixture was stirred 30 min. At the same temperature [2-(chloromethoxy)ethyl](trimethyl)silane (1.1 g, 6.61 mmol) dissolved in 5 mL dimethylformamide was added dropwise and stirred for 30 min at 0° C. The mixture was poured into water and extracted twice with ethyl acetate. The organic were dried over sodium sulphate and concentrated under reduced pressure to give 1.82 g (100% yield) of the title compound as a yellow oil. Purity 96%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2cc1OC
Yield: 90.4 %

Procedure:
Following the procedure of Example 11, a mixture of 149.4 mg (0.50 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 100–110° C. for 1.0 hour to yield 184.4 mg (83.0%) of the product as a yellow solid, mp>280° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=[C:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:12]2[N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:5]=[C:4]2[CH:3]=1
Reactant: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(Cl)cc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Into 8.5 mL of THF, 2.7 g (10 mmol) of Compound B was dissolved, and 1.5 mL (10 mmol) of DBU was added thereto under ice cooling, followed by stirring at room temperature for about 1 hour. During the period, crystals were precipitated from the reaction solution. After completion of the reaction, the precipitated solid was washed with THF to obtain 2.1 g of Compound C as a white solid (yield: 81%).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([CH2:13]Br)[CH:4]=1.[OH-].[NH4+]>CO>[Br:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][CH:12]=1)[C:7](=[O:8])[NH:1][CH2:13]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Ammonia gas was purged to a stirring solution of methyl 4-bromo-2-(bromomethyl)benzoate (200 mg, 0.649 mmol) in methanol at 0° C. for 10 min. To the resulting reaction mixture ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at RT for 16 h. The obtained solid was separated by filtration and dried to afford 5-Bromoisoindolin-1-one as a solid (100 mg, 72%).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[CH:28][CH:27]=3)=[O:25])=[CH:17][C:16]=2[O:43][CH3:44])[CH2:10][C@H:9]1[CH3:45])C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[CH3:45][C@H:9]1[NH:8][C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[CH:28][CH:27]=3)=[O:25])=[CH:17][C:16]=2[O:43][CH3:44])[CH2:10]1
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C1)N(C(=O)c1ccc(-c3cccc(C)n3)c3ccccc13)CC2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(=O)c1ccc(-c3cccc(C)n3)c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 70 h
Yield: 98.7 %

Procedure:
A solution of D6 (380 mg, 0.64 mmole) in EtOH (50 ml) and THF (50 ml) was treated with 10% Pd-C (300 mg) and stirred under a hydrogen atmosphere at ambient temperature and pressure for 70 h. The mixture was filtered through Kieselguhr and concentrated under vacuum. The residue was purified by chromatography on basic alumina eluting with EtOAc followed by crystallisation from Et2O to afford the title compound as a yellow solid (320 mg, 98%). MH+507.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:24]=[C:18]2[C:19](=O)[NH:20][CH2:21][CH2:22][N:17]2[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.CCOC(C)=O>[CH2:7]([O:14][C:15]1[CH:24]=[C:18]2[CH2:19][NH:20][CH2:21][CH2:22][N:17]2[N:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COc2cc3n(n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
A 1 M solution of lithium aluminum hydride in THF (0.77 mL, 0.77 mmol) was added dropwise to a stirred solution of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.16 g, 0.65 mmol) in THF (4 mL) under nitrogen at 0° C. The mixture was stirred at room temperature for 4 hours and diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture was stirred for 20 minutes at this temperature, filtered through a pad of diatomaceous earth and then washed with additional AcOEt. The filtrate was evaporated in vacuo to yield 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.14 g, 97% yield) as a yellow oil, that was used in the next step without further purification.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:17]([NH2:19])=[O:18])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.[NH2:41][C@H:42]([CH2:46][CH3:47])[C:43]([NH2:45])=[O:44].C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.O>[NH2:45][C:43](=[O:44])[C@H:42]([NH:41][C:3]1[N:4]=[N:5][C:6]([C:17]([NH2:19])=[O:18])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:8]=1)[CH2:46][CH3:47]
Reactant: CC[C@@H](N)C(N)=O
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C)cc2)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC[C@@H](Nc1nnc(C(N)=O)c(Nc2ccc(C)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.5 %

Procedure:
3-(Methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide (31 mg, 0.11 mmol) was dissolved in 5 mL NMP. To it was added mCPBA (77%) (100 mg, 0.44 mmol). The mixture was stirred at RT for 1 h. To it was added DIEA (0.20 mL, 1.1 mmol) and (R)-2-aminobutanamide hydrochloride (77 mg, 0.55 mmol). The mixture was stirred at 80° C. for 2.5 h. The mixture was cooled to RT, acidified with TFA (0.3 mL), diluted with water, filtered and subjected to reverse phase preparative HPLC to isolate the title compound (48 mg) as HCl salt. MS found for C15H19N7O2 as (M+H)+ 330.4. UV: λ=235, 278 nm. Proton NMR: (CD3OD) δ 7.60 (2H, d, J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz), 4.40 (1H, dd, J=8.0; 5.2 Hz), 2.36 (3H, s), 2.00 (1H, m), 1.90 (1H, m), 1.05 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[CH:13][O:12]2.C1C(=O)N([I:24])C(=O)C1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[I:24])[CH:14]=[CH:13][O:12]2
Reactant: Fc1ccc(-c2cn3ccoc3n2)c(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a round bottom flask charged with 6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazole (5.0 g, 23 mmol; prepared using A from 6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazole [prepared according to WO2004110990A2, Example 1, Steps 1-3 using 2-bromo-1-(2,4-difluorophenyl)-ethanone in place of 2-bromo-1-(4-fluorophenyl)-ethanone]) and DMF (100 mL) was added a solution of NIS (5.4 g, 24 mmol) in DMF (20 mL) at ambient temperature. The reaction was allowed to stir at ambient temperature for about 1 h upon which time it was poured into water (800 mL). The resulting precipitate was filtered, washed with water (2×20 mL), and dried in a vacuum oven for about 16 h to provide the title compound (7.5 g, 95%) as a light yellow solid: LC/MS (Table 1, Method a) Rt=2.04 min; MS m/z/z: 347.0 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>>[ClH:3].[NH2:7][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[Cl:3])[NH:13][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:8]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: N=C(N)c1c(N)cccc1Cl
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(Cl)cccc1N2

Procedure:
This was prepared by the method of Example 173 using 2-chloro-6-anino benzamidine dihydrochloride (Example B) and ethyl 4-oxopiperidine-1-carboxylate giving the title compound, m.p. 181°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[I:16]([O-])(=O)=O.[K+].[OH-].[Na+]>[Cl-].[Na+].O>[I:16][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:15]
Reactant: [O-][I+2]([O-])[O-]
Reactant: COc1cnc(-c2ccccc2)cc1N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cnc(-c2ccccc2)c(I)c1N
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 80.8 %

Procedure:
To an ice-cooled stirred suspension of 2.70 g (6.20 mmol) 5-methoxy-2-phenyl-pyridin-4-ylamine in 3 ml distilled water was added dropwise 3 ml concentrated sulfuric acid and the mixture was then warmed to 100° C. 1.30 g (6.07 mmol) potassium iodate was added after 3 h, a further 1.30 g (6.07 mmol) potassium iodate was added after an additional 3 h, and finally a further 0.75 g (3.50 mmol) potassium iodate was added after an additional 3 h. Stirred was continued for a further 2.5 h at 100° C., and then the mixture was allowed to cool to room temperature on standing overnight. The mixture was then diluted with saturated brine, made basic by addition of 30% aq. sodium hydroxide solution, and extracted three times with tetrahydrofuran. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 1.60 g (79%) 3-iodo-5-methoxy-2-phenyl-pyridin-4-ylamine as an orange oil which crystallized on standing. ES-MS m/e (%): 327 (M+H+, 100).