Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:47][C:48]3[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=4)[CH:51]=[CH:52][C:53]=3[CH3:54])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (219 mg, 1.019 mmol), HATU (465 mg, 1.223 mmol) and DIPEA (0.337 mL, 2.039 mmol) in DMF (6 mL) was stirred for 15 min at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (300 mg, 1.019 mmol) was added and stirred overnight at rt and overnight at 60° C. The reaction mixture was poured out in 3% citric acid solution and the resulting precipitate was collected and washed with water to give compound 2-chloro-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 68 (389 mg, 78%). (m/z)=491 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]2)[CH2:3][CH2:2]1.O=[C:24]1[CH2:30][CH:29]2[N:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1.C(N(CC)CC)C.[BH4-].[Na+].[OH-].[Na+]>ClCCl.CO.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:35]([O:34][C:32]([N:31]1[CH:26]2[CH2:27][CH2:28][CH:29]1[CH2:30][CH:24]([N:1]1[CH2:2][CH2:3][C:4]3([C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]3)[CH2:5][CH2:6]1)[CH2:25]2)=[O:33])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCNCC2)C1
Reactant: CCOC(=O)N1C2CCC1CC(=O)C2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(C(=O)OC(C)(C)C)Cc1ccccc13)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 123.2 %

Procedure:
tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5a (2.071 g, 6.11 mmol) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.51 g, 7.66 mmol) were dissolved in anhydrous dichloromethane (10 mL) in a 100-mL round-bottom flask and treated with triethylamine (618 mg, 6.11 mmol), followed by titanium tetraisopropoxide (5.21 g, 18.3 mmol). The reaction was stirred under nitrogen at room temperature for 21 h, then cooled in a dry ice/isopropanol bath to −40° C. and quenched with methanol (10 mL). The reaction was stirred for several minutes at the same temperature and treated in one portion with sodium borohydride (462 mg, 12.2 mmol). The reaction was stirred at −40° C. for 30 minutes, then warmed to room temperature. The reaction was then treated with 1 N NaOH (12 mL), diluted with methanol (50 mL) and stirred vigorously at room temperature for 10 minutes. The reaction was filtered through Celite and the solids rinsed with dichloromethane (4×25 mL). The filtrate was washed with H2O, saturated brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 3.641 g tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b as a pale yellow oil. LC/MS m/z [M+H]+ 484.3, retention time 2.32 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[N:17]=[C:16]([CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[C:22]=3[CH:21]=[N:20]2)[CH:15]=[CH:14][CH:13]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48](OCC)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:32][CH2:31]1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48]([NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:22]=4[CH:21]=[N:20][N:19]5[CH2:18][C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([CH3:11])[N:17]=4)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:34][CH2:35]1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: Cc1cccc(Cn2ncc3c(N)cccc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
LHMDS (1.595 mL, 1.595 mmol, 1.0M THF) was added drop-wise to a solution of 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.190 g, 0.7974 mmol) in THF (4 mL) at 0° C., resulting in a dark solution. The mixture was stirred at 0° C. for 10 minutes, then ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.5566 g, 1.674 mmol) was added in one portion and the mixture was stirred overnight. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (5 to 20% MeOH/CH2Cl2 using 5% NH4OH/MeOH) to provide 0.254 g (61%) of the desired product as a pale brown powder. MS (ES+APCI) m/z=525 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1>O1CCOCC1.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>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:25]1[CH:24]=[N:23][C:22]([Cl:21])=[CH:27][CH:26]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccc(Cl)nc1
Temperature: 90 °C
Yield: 123.3 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.6 g, 11.5 mmol), Na2CO3 (1.83 g, 17.3 mmol) and 2-chloropyridin-5-ylboronic acid (1.81 g, 11.5 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) was added and the mixture was heated at 90° C. for 16 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (4.3 g, 70%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: COc1ccc(C#CBr)cc1F
Agent: [Cu+2]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C
Yield: 12.1 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.45 mmol) was dissolved in toluene (5 mL). Copper sulfate (23 mg, 0.090 mmol), 1,10-phenanthroline (33 mg, 0.18 mmol), potassium phosphate (192 mg, 0.90 mmol), and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (113 mg, 0.49 mmol) were added, and the mixture was flushed with nitrogen. The reaction mixture was heated at 80° C. overnight (16 h). Product was detected by LCMS. The reaction mixture was filtered through Celite, and washed with DCM. The combined organic layer was concentrated under reduced pressure to obtain product, which was purified by column chromatography using silica gel and 60-80% EtOAc in hexane as eluent, and repurified by preparative TLC to obtain product as a brown solid (20 mg). 1H NMR (DMSO, oxalate salt) δ (ppm): 7.70 (d, 2H), 7.58 (d, 1H), 7.42 (d, 1H), 7.38 (d, 1H), 7.25 (m, 1H), 4.20 (m, 2H), 3.85 (s, 3H), 3.40 (m, 2H), 3.10 (m, 2H), 2.80 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].CC[N:31]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:31])=[O:25])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(Nc1cccc(C(=O)O)c1)cn2C1CCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C#N)c2c1c(Nc1cccc(C(N)=O)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of 3-((7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)benzoic acid (80 mg) and HOBt ammonium salt (52 mg) in DMF (2 mL) was added EDCI hydrochloride (65 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (65 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[C:29]([F:31])([F:30])[F:32])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1C(=O)NN=C2COc3cc(C(C)C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A mixture of 3-[4-methyl-3-oxo-7-(1-trifluoromethyl-vinyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.25 mmol) and Pd/C (10%, 0.10 g, 0.1 mmol) in EtOAc (60 mL) was stirred under an atmosphere of H2 (40 psi) overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[4-methyl-3-oxo-7-(2,2,2-trifluoro-1-methyl-ethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.020 g, 17%). 1H NMR (CDCl3, 400 MHz): δ 8.62 (brs, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 6.97 (s, 1H), 4.72 (m, 1H), 4.53 (m, 2H), 4.33 (m, 2H), 4.11 (m, 1H), 3.77 (m, 2H), 3.63 (m, 1H), 1.50 (m, 15H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:20][C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.N[C:28]1C=CC=CC=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:20][C:21]4[CH:22]=[CH:28][CH:24]=[CH:25][CH:26]=4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(CNc2ccc3cc(CNc4cccnc4)ccc3n2)o1
Product: Cc1ccc(CNc2ccc3cc(CNc4ccccc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=344.3 (M+H+), was prepared in accordance with the general method of example 49 from (5-methyl-furan-2-ylmethyl)-[6-(pyridin-3-ylaminomethyl)-quinolin-2-yl]-amine and aniline.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:27][C:28]1[C:29]([C:35]([NH2:37])=[O:36])=[N:30][CH:31]=[CH:32][C:33]=1Cl>CS(C)=O.O>[Cl:27][C:28]1[C:29]([C:35]([NH2:37])=[O:36])=[N:30][CH:31]=[CH:32][C:33]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a mixture of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (356 mg, 1.1 mmol) in DMSO (4 mL) in a microwave vial was added NaH (88 mg, 2.2 mmol, 60% dispersed in mineral oil) at rt. The reaction was stirred at rt for 30 minutes, then 3,4-dichloropicolinamide (191 mg, 1.0 mmol) was added. The mixture was microwaved at 160° C. for 2 hours, then cooled to rt, and diluted with water (10 mL). The resulted mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (140 mg, 29%).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+].Cl>ClCCl.CO>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CON=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CONCc1ccc(F)cc1
Reaction time: 96 h
Yield: 40.9 %

Procedure:
A solution of 4-fluorobenzaldehyde-O-methyloxime (93.2 mmol) in dichloromethane (150 ml) was treated with sodium cyanoborohydride (9.18 g, 0.146 mol) followed by 120 ml of 2 N hydrochloric acid in methanol added dropwise over 30 minutes. After 96 h at 22° C., the solvent was evaporated under reduced pressure, the residue was slurried with water and adjusted to pH 9 with 2 N aqueous sodium hydroxide. The aqueous phase was extracted twice with dichloromethane and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual oil was chromatographed on silica gel (elution, toluene-ethyl acetate 0-10%) and gave 5.92 g (41% yield) of the title amine as a clear oil. 1H NMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s), 4.01 (2H, s), 5.69 (1H, broad s), 7.01 (2H, m), 7.31 (2H, m). The hydrochloride salt was obtained as a white solid: mp 170-171° C. Anal. calcd for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.31; H, 5.80; N, 7.26
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1ccccc1Br)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromophenol (8.71 g; 50.3 mmol) and bromoacetophenone (10.1 g; 50.5 mmol) in 50 ml acetone was added K2CO3 (7.02 g; 50.8 mmol). The mixture was heated to reflux for 10 h, cooled to r.t., filtered, diluted with EtOAc (100 ml), washed with HCl (1.0 M, 2×100 ml) and brine, dried over MgSO4 and concentrated. The residual solid was recrystallized from EtOAc:hexane to afford the desired material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[N:2]=1.Cl.O1CCOCC1>C1COCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[N:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccnn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2cccnn2)CC1
Yield: 152.5 %

Procedure:
tert-Butyl (1-pyridazin-3-ylpiperidin-4-yl)carbamate (0.22 g, 0.92 mmol) was dissolved in THF:MeOH 70:30 (15 ml) and HCl in 1,4-dioxane (4M, 1.84 ml, 7.36 mmol) was added and the mixture was refluxed for 1.5 h. The reaction mixture was evaporated to yield the title compound (0.250 g, 100%) as the dihydrochloric salt. (0.250 g, 100%). 1H NMR (CD3OD, 500 MHz): δ 8.72-8.67 (m, 1H), 8.14-8.07 (m, 1H), 8.03-7.97 (m, 1H), 4.55-4.45 (m, 2H), 3.62-3.51 (m, 1H), 3.38-3.27 (m, 2H), 2.27-2.18 (m, 2H), 1.82-1.70 (m, 2H)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]#[N:23].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]([CH2:21][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)#[N:23]
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 0 °C
Yield: 91 %

Procedure:
To an 8 ml dimethylformamide solution of 300 mg of the compound (4) synthesized in Reference Example 4 were added 93 mg of chloroacetonitrile, 355 mg of sodium iodide, and 196 mg of potassium carbonate. This was then heated at reflux for 2 hours. To the reaction was added 10 ml of ice water, then extraction was performed with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol =30:1) to obtain the above-identified compound (26) in an amount of 313 mg (yield of 91%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)(Cl)=O.S(=O)=O.Cl.[CH2:20]([NH:22][CH2:23]C)C.[OH-].[K+]>O.CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:22]([CH3:23])[CH3:20])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CCNCC
Agent: Cl
Agent: O=S=O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cccc(C#N)c1

Procedure:
A mixture of 85.22 g of m-cyanobenzoic acid, 400 ml of toluene, 4.48 ml (4.23 g) of N,N-dimethylformamide and 44.4 ml (72.3 g) of thionyl chloride was gently heated on a steam bath for 2 hours with sulfur dioxide and hydrogen chloride being evolved. The reaction solution was cooled in an ice bath and cautiously added portionwise, over one hour, to stirred and cooled solution of 250 ml of 40% aqueous diethylamine and 100 ml of water. At intervals 2-3 ml of concentrated aqueous potassium hydroxide was added. After the addition was complete, the mixture was stirred for several hours, then the layers were separated and the organic layer washed with water. After permitting the organic layer to evaporate to dryness, the residue was recrystallized from 300 ml of ethanol containing charcoal, giving 68.5 g of the desired compound as white crystals, mp 85°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[I:14]I>CO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[I:14][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (4-methoxyphenyl)acetate (1 mL, 6.3 mmol) in MeOH (40 mL) was added Ag2SO4 (1.96 g, 6.3 mmol) followed by I2 (1.6 g, 6.3 mmol). The reaction was stirred vigorously at room temperature for 1 hour and then the solids were removed by filtration. The filtrate was diluted with EtOAc (200 mL), and washed with aq. NaHSO3 (2×50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford methyl (3-iodo-4-methoxyphenyl)acetate. Rf=0.27 (15% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J=2.0 Hz, 1H), 7.21 (dd, J=8.2, 1.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.52 (s, 2H).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>CN(C=O)C.CC(N(C)C)=O>[F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:31][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH2:21][C:20]3[CH:32]=[CH:33][CH:34]=[C:18]([F:17])[CH:19]=3)[N:23]=[CH:24]4)[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cnc(F)cc45)ccc32)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 80.1 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (30 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 5 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 1-(3-fluorobenzyl)-1H-indazol-5-amine (PCT Int. Appl., 2005058245, 30 Jun. 2005) (2.65 g, 11.0 mmol) in dry DMA (15 mL). The residue of 1-(3-fluorobenzyl)-1H-indazol-5-amine was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 65 h. It was poured into water (200 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (200 mL) was added and stirred at room temperature for 2 h. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (200 mL). The solid was collected by filtration and washed with water (5×25 mL). It was suspended in acetone (80 mL) and stirred at room temperature for 20 min. Water (160 mL) was added and stirred further for 1.5 h. The solid was filtered, dried and finally purified by a silica column (MeOH/dichloromethane: gradient from 0-10%) to give 6-fluoro-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]-pyrimidin-4-amine (202) (3.11 g, 80%) as a pale brown solid, mp 218-221° C.; 1H NMR δ [(CD3)2SO] 10.15 (s, 1H), 8.92 (s, 1H), 8.64 (s, 1H), 8.30 (d, J=1.3 Hz, 1H), 8.28 (br s, 14, 8.19 (poorly resolved d, J=0.7 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 1.8 Hz, 1H), 7.42-7.32 (m, 1H), 7.15-7.01 (m, 3H), 5.71 (s, 2H). Anal, Calcd for C21H14F2N6: C, 64.94; H, 3.63; N, 21.64. Found C, 65.21; H, 3.71; N, 21.63.