Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:11][C:12]=1[C:13](=O)[NH:14][NH:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[O:17]>ClCCl>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:11][C:12]=1[C:13]1[O:17][C:16]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[O:23][CH3:24])=[N:15][N:14]=1
Reactant: COc1ccsc1C(=O)NNC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 100 °C
Yield: 23 %

Procedure:
TBTU (160.4 mg, 0.4995 mmol) and Et3N (33.70 mg, 46.42 μL, 0.3330 mmol) were added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) and 3-methoxythiophene-2-carboxylic acid (52.67 mg, 0.3330 mmol) in CH2Cl2 (2.000 mL) and the resulting solution stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (3×5 mL), and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo to leave 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide as a yellow oil. POCl3 (1.788 g, 1.087 mL, 11.66 mmol) was added to 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide and the resulting mixture heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and ice/water added carefully with vigourous stirring between additions. The mixture was left to stir at room temperature for 20 min and then diluted with dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and combined organics dried over MgSO4 and concentrated in vacuo. Solid obtained is re-dissolved in CH2Cl2 and purified by column chromatography on the ISCO column companion system (12 g column, 0-5% MeOH/ CH2Cl2). Product fractions were combined and concentrated in vacuo. This was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (33.0 mg, 23% yield) 1H NMR (400 MHz, DMSO) d 2.98 (s, 3H), 3.01 (s, 3H), 4.07 (s, 3H), 7.30 (d, 1H), 7.56 (d, 2H), 7.70 (br s, 2H), 7.96 (d, 1H), 8.14 (d, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 423.19
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C(C)=O)c3ccc(=O)[nH]c23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
5-Acetyl-8-hydroxy-1H-quinolin-2-one (29.5 g, 0.15 mol) was suspended in N,N-dimethylformamide (145 mL), potassium carbonate (22.2 g, 0.16 mol) and successively 4-methoxybenzyl chloride (22.7 g, 0.15 mol) were added thereto, and the mixture was stirred at 90° C. overnight. To the reaction mixture was added purified water (0.5 L) and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with purified water, dried under reduced pressure to obtain 5-acetyl-8-[(4-methoxyphenyl)methoxy]-1,2-dihydroquinolin-2-one (26.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1.Cl.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[C:18](O)=[O:19].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]2[NH:9][C:18](=[O:19])[CH:13]3[CH2:14][O:15][CH2:16][CH2:17][N:12]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: Cc1nc(Cl)nc(Cl)c1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)nc2c1NC(=O)C1COCCN21
Temperature: 100 °C
Yield: 4.1 %

Procedure:
A round-bottom flask was charged with crude 2,4-dichloro-6-methylpyrimidin-5-amine (6.644 g, 37.3 mmol), morpholine-3-carboxylic acid hydrochloride (7.51 g, 44.8 mmol), DIPEA (26.1 mL, 149 mmol) and DMSO (49.0 mL). The flask was heated overnight at 100° C. The mixture was subsequently cooled to room temperature and then poured into ice. The solution was stirred while slowly warmed to room temperature. The mixture was subsequently filtered, and the filtrate was purified by preparatory HPLC using a gradient of 15-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a white solid (387 mg, 4.1%). 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3 H), 2.54 (s, 1 H), 2.87-2.99 (m, 1 H), 3.43-3.52 (m, 1 H), 3.91 (dd, J=11.72, 3.42 Hz, 1 H), 4.10-4.22 (m, 2 H), 4.29 (dd, J=10.74, 3.91 Hz, 1 H), 10.51 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C10H11ClN4O2, 255.06; found 255.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])N.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(O)cc1Cl
Yield: 30 %

Procedure:
To a 0° C. solution of 3-chloro-4-methoxy aniline (1.0 g; 6.4 mmol) in 1:1 H2O:conc. H2SO4 (100 mL) was added very slowly a solution of NaNO2 (0.5 g; 7.6 mmol) in H2O (10 mL). Thick yellow fumes were emitted, and the black solution was then heated to reflux for 30 min. The mixture was extracted with EtOAc (4×50 mL) and the combined extracts were concentrated in vacuo. The residue was chromatographed (SiO2; 4:1 hex:EtOAc) to obtain 3-chloro-4-methoxy phenol (300 mg; 30%) as a yellow oil.
Reaction SMILES: C[Si](I)(C)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=1)[NH:12][N:11]=[C:10]2[NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34]>CO>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[NH:12][N:11]=[C:10]2[NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)c(Br)cc12
Yield: 32.3 %

Procedure:
10 cm3 of trimethylsilyl iodide are added to 500 mg of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, prepared previously, and the mixture is refluxed for 4 hours. 25 cm3 of methanol are added and the reaction medium is refluxed for 15 minutes and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 50 cm3 of ethyl acetate and is washed with 2×50 cm3 of 10% sodium thiosulphate solution and then with 50 cm3 of water and 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure to give 1 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 10 cm3 of ethyl acetate, filtered off, washed with 2×5 cm3 of ethyl acetate and dried (90 Pa; 45° C.) to give 130 mg of N-[5-bromo-6-(4-hydroxyphenyl)-1H-indazol-3-yl]butanamide melting above 260° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([O:33]CC)=[O:32])=[N:22]2)=[N:18][CH:19]=1)=[O:12].O.[OH-].[Li+]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([OH:33])=[O:32])=[N:22]2)=[N:18][CH:19]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2cnc(NC(=O)c3ccc4ccccc4c3)cn2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2cnc(NC(=O)c3ccc4ccccc4c3)cn2)c2ccccc12
Yield: 29.7 %

Procedure:
Ethyl 2-[1-[[5-(2-naphthamido)pyrazin-2-yl]methyl]-1H-indazol-3-yl]acetate (0.466 g, 1.0 mmol) was dissolved in 20 mL tetrahydrofuran, and in an ice bath, was added 10 mL aqueous solution dissolving lithium hydroxide monohydrate (0.18 g, 4.3 mmol). It was reacted at room temperature for 3 h, rotate evaporated to dryness to remove the solvent, purified by preparative liquid phase (methanol:water=50%) to obtain a white solid 130 mg, at a yield of 29.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[O:4][N:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[O:30][CH3:31]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][O:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1cc(C)no1
Temperature: 105 °C
Yield: 46.6 %

Procedure:
Step H (1): 3-Methyl-5-(tributylstannyl)isoxazole (2.4 g, 6.4 mmol, H. Yamanaka et. al Tetrahedron, 1991, 47, 5111) and dichlorobis(triphenylphosphine)palladium (II) (45 mg, 0.0643 mmol) were added to a degassed solution of 1-bromo-2-methoxy-4-nitrobenzene (1.26 g, 5.5 mmol) in dioxane (25 mL). The resulting mixture was heated to reflux (105° C. oil bath temperature) for 24 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography to afford 5-(2-methoxy-4-nitrophenyl)-3-methylisoxazole (600 mg, 40% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [CH3:1][C:2]1([CH2:12][CH:13]=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1([CH2:12][CH2:13][OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(CC=O)CCOc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CCO)CCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a chilled (0° C.) solution of 3 g (16 mmol) of (4-methylchroman-4-yl)acetaldehyde in 30 mL of anhydrous tetrahydrofuran was added 0.3 g (8 mmol) LiAlH4 in one portion. The mixture was then warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0° C. and carefully quenched with a few drops of water. The reaction was warmed to room temperature, dried over magnesium sulfate, filtered through diamataceous earth and concentrated in vacuo to afford 2.8 g (93%) of 2-(4-methylchroman-4-yl)ethanol as an oil.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCl)(C)(C)C.CCN(C(C)C)C(C)C.[C:34]1([OH:44])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:34]1([O:44][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[O:18])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCCCCOc1ccc(C=O)c2ccccc12
Agent: CC(C)(C)OCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)Oc2cccc3ccccc23)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A solution of 4-pentyloxy-naphthalene-1-carbaldehyde (121 mg,.0.5 mmol) in CCl4 (2 mL) is treated with t-BuOCl (8.82 M, 170 μL, 1.5 mmol) and stirred at 50° C. for 1 h. After addition of DIEA (0.3 mL, 1.7 mmol) and 1-naphthol (216 mg, 1.5 mmol) the mixture is refluxed for 2 h and distributed between 1M KHCO3 (5 mL) and DCM (2×5 mL). The combined organic phases are dried over Na2SO4 and concentrated. Flash chromatography (cyclohexane/acetone) yields 82 mg (43%) of colourless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=1
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2[nH]c(Cl)nc2c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 5-methyl-1,3-dihydrobenzimidazol-2-one (2) (24.4 g) and phosphoryl chloride (245 mL) was stirred at 90° C. for 5 hr. After cooling to room temperature, chloroform (250 mL) was added to the reaction mixture. After stirring at room temperature, the resulting precipitate was collected by filtration, and washed 5 times with chloroform (100 mL). To the precipitate was added a mixture of ethyl acetate and saturated sodium hydrogen carbonate solution. After stirring at room temperature, the organic phase was successively washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was powdered with hexane and diisopropyl ether to give 2-chloro-5-methyl-1H-benzimidazole (3) (20.4 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][O:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[CH3:38])=[O:21])C)(C)(C)C.O.C(=O)(O)[O-].[Na+]>ClCCl.CCOCC>[F:29][C:24]1[C:23]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=2[CH3:38])=[C:22]([CH:27]=[CH:26][C:25]=1[F:28])[C:20]([NH:19][O:18][CH2:17][CH2:16][NH:14][CH3:13])=[O:21]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCCN(C)C(=O)OC(C)(C)C)ccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
Trifluoroacetic acid (3.0 mL, 39 mmol) was added to a 0° C. solution of [2-({1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (0.75 g, 1.3 mmol) in dichlormethane (12 mL). The resultant solution was stirred 2.5 h at 0° C. and diluted with ether (50 mL). Water (20 mL) was added and, with vigorous stirring, the pH of the aqueous layer was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The heterogeneous mixture was stirred 30 min and the precipitate was removed by filtration and washed with water-ethanol (2:1) and acetone. The solid (471 mg) was dried overnight in vacuo and was further triturated with hot methanol and dried at 70° C. under reduced pressure to afford 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methylamino-ethoxy)-benzamide (272 mg) as a white powder: m.p. 183-185 (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.69 (t, J=7.0 Hz, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.33 (dd, J=8.6, 2.0 Hz, 1H), 6.95 (app q, J=9.0 Hz, 1H), 6.40 (t, J=7.8 Hz, 1H),3.87(br t, J=4.4 Hz, 2H), 2.82 (br s, 2H), 2.47 (s, 3H), 2.24 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −137.7 (d, J=7.6 Hz), −143.3 (d, J=20.2 Hz). Anal Calcd./Found for C17H18F2IN3O2+0.07 C4H10O: C, 44.50/44.61; H, 4.01/3.97; N, 9.01/8.72.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)N
Reactant: Clc1ccnc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccnc(Cl)n1

Procedure:
In analogy to compound 1.1, a solution of 0.347 g (2.33 mmol) of 2,4-dichloro-pyrimidine in 15 ml of acetonitrile is reacted with 0.22 ml (2.52 mmol) of isopropylamine in the presence of 0.39 ml (2.83 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.26 g (65% of theory) of the product.
Reaction SMILES: C(O[C:4]([NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=O)C.C(=O)(O)N.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CCOCC>[CH3:4][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1
Reactant: CCOC(=O)NC1Cc2ccccc2C1
Agent: NC(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CNC1Cc2ccccc2C1
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a solution of the carbamate 2-(ethoxycarbonyl-amino)indane (6.07 g, 29.6 mmol) in Et2O (100 mL) is added slowly to a mixture of LiAlH4 (1.70 g, 44.7 mmol) in Et2O (100 ml) chilled at 0°. The resulting mixture is stirred for 18 h and allowed to warm to 20°. The reaction mixture is re-chilled to 0° and treated cautiously with H2O (1.7 mL), 15% NaOH (1.7 mL) and again H2O (5.1 mL). The mixture is stirred for 20 minutes, warming slowly to 20°. The precipitate is vacuum filtered and the filtrate extracted into 1N HCl. The acid solution is washed with fresh Et2O, then basified with cold 1N NaOH. The cloudy mixture is extracted with Et2O, washed with saturated brine, dried over Na2SO4, is filtered and concentrated to an oil.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:22][C:3]1[C:2]([NH:31][CH:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH3:30])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(N)c1ccccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1ccccn1
Temperature: 150 °C
Yield: 44.6 %

Procedure:
This compound (16 mg, 44% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (27 mg, 0.09 mmol), 1-(2-pyridyl)ethylamine (16.7 mg, 0.14 mmol) [Matrix Scientific, cat# 012223] and DIEA (24 μL, 0.13 mmol) in 2 mL of NMP (heated in a microwave at 150° C. for 30 min)1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (1H, br.), 8.51 (1H, d, J=4.5 Hz), 7.89 (1H, d, J=7.4 Hz), 7.77 (1H, m), 7.62 (2H, m), 7.55 (1H, d, J=7.8 Hz), 7.33 (1H, m), 7.21 (1H, m), 7.00 (1H, br.), 6.90 (1H, d, J=2.0 Hz), 5.31 (1H, t, J=7.1 Hz), 3.47 (2H, m), 3.11 (2H, m), 2.70 (3H, s), 1.69 (3H, d, J=7.0 Hz). m/z (EST, +ve) 399.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.C[CH2:21][N:22](C(C)C)C(C)C.N#CBr.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(#N)C.O>[NH2:22][C:21]1[N:11]2[CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:18]=[CH:19][C:10]2=[CH:9][N:8]=1
Reactant: COC(=O)c1ccc(CN)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cnc(N)n2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-aminomethylnicotinate trifluoroacetate (390 mg) was dissolved in toluene (35 ml) and treated with Hünig's base (230 μl). Cyanogen bromide (0.35 ml of a 5 M solution in acetonitrile) was then slowly added dropwise. After stirring at RT for 3 h, the solvent was stripped off and the residue was taken up with water and saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed from the acetonitrile and freeze-dried. The residue was then taken up with a little water, treated with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 110 mg of the desired compound were obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C([O-])(=O)C.[Na+]>[Pd].CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])#[N:5]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccccc1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
0.67 ml of the stock solution from Example 52, 3.05 g (16.8 mmols) of 2-bromobenzonitrile, 1.99 ml (18.4 mmols) of ethyl acrylate and 1.50 g (18.4 mmols) of anhydrous sodium acetate are added, under argon, to 16.3 ml of DMF, and the reaction mixture is stirred at 130° C. for 3 hours. After working up as described in Example 1, the crude product is recrystallised from a mixture of pentane and carbon tetrachloride. 1.5 g (7.5 mmols) of ethyl o-cyanocinnamate are obtained in the form of white crystals of melting point 56° C., corresponding to a yield of 44% of theory (conversion figure 4400; Pd content 0.01 mol %). Analysis for C12H11NO2 (molecular weight 201.23): calculated C 71.63; H 5.51; N 6.96; O 15.90, found C 71.17; H 5.64; N 6.88; O 16.56.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([Br:28])=[CH:21][N:20]=1>O1CCCC1>[Br:28][C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
A solution of 2-(2-cyanoethyl)malonic acid diethyl ester (24.2 g) in tetrahydrofuran (15 ml) was added to a suspension of sodium hydride (2.45 g) in tetrahydrofuran (30 ml) at 20° C under nitrogen. To this was added 2-chloro-3-nitro-5-bromopyridine (22 g) and the mixture so obtained was heated to 93°-95° C. A small amount of tetrahydrofuran was allowed to distil off. The mixture was heated under Reflux for 2.5 hr. The reaction mixture was poured into water and neutralised to pH 7 with concentrated hydrochloric acid. The aqueous phase was extracted with chloroform, dried (MgSO4) decolourised with charcoal and filtered through a silica column. The chloroform eluant was evaporated to yield an oil which slowly crystallised The crystals were washed in petroleum ether (40°-60° C.) and dried to yield 4-(5-bromo-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (28 g) m.p. 58°-62° C.