Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:30][C:31]1([CH3:48])[CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([CH3:47])([CH3:46])[NH:32]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:35]4[CH2:34][C:33]([CH3:47])([CH3:46])[NH:32][C:31]([CH3:48])([CH3:30])[CH:36]=4)[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:5]=3[CH:10]=[N:9]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCCCC2)c(=O)[nH]1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of 6-bromo-1-cyclohexyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (7% yield). LCMS: 517.35 (M+1)+; HPLC: 99.68% (@ 254 nm), (Rt; 5.761); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.86 (t, 1H), 8.25 (s, 1H), 7.78 (s, 1H), 6.78 (s, 1H), 5.89 (s, 1H), 4.82-4.76 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 2.22 (s, 3H), 2.12 (s, 3H), 2.01-1.85 (m, 8H), 1.53-1.44 (m, 2H), 1.27 (bs, 6H), 1.23 (bs, 2H), 1.17 (bs, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[C:7]2[N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[NH:25][C:26]([CH3:31])=[C:27]([Cl:30])[C:28]=2[Cl:29])=[O:23])[CH2:17][CH2:16]1.Cl.[CH3:33][O:34][NH2:35]>>[CH3:33][O:34][NH:35][C:12]([C:9]1[CH:8]=[C:7]([N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22]([C:24]3[NH:25][C:26]([CH3:31])=[C:27]([Cl:30])[C:28]=3[Cl:29])=[O:23])[CH2:19][CH2:20]2)[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc4c(F)cccc34)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2cccc(F)c2n1

Procedure:
The title compound was prepared from 8-fluoro-4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)quinoline-2-carboxylic acid (Example 280) and O-methylhydroxylamine hydrochloride via the procedure described for Example 8.
Reaction SMILES: ClC(N(C)C)=C.[CH3:7][O:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O.[NH2:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([NH:33][C:34]([NH:36][C:37]3[N:41]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)[N:40]=[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:38]=3)=[O:35])=[CH:25][CH:24]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N.CO>[C:49]([C:39]1[CH:38]=[C:37]([NH:36][C:34](=[O:35])[NH:33][C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:22][CH2:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:10](=[O:12])[C@@H:9]([O:8][CH3:7])[CH3:13])[CH:20]=3)=[CH:24][CH:25]=2)[N:41]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:40]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: CO[C@@H](C)C(=O)O
Agent: C=C(Cl)N(C)C
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
1-Chloro-N,N-dimethylethenamine (50 μL, 0.48 mmol) was added to a stirring solution of (S)-2-methoxypropionic acid (50 mg, 0.48 mmol) in DCM (1.0 mL) and the resulting yellow solution was stirred at RT for 1 hr. The solution was added dropwise to a stirring mixture of 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (50 mg, 0.10 mmol) and DIPEA (167 μl, 0.96 mmol) in DCM (1.0 mL). Stirring was continued overnight. The reaction mixture was stirred in 1% NH3 in MeOH (20 mL), evaporated in vacuo, pre-adsorbed on silica and purified by column chromatography (12 g, 10-50% EtOAc in iso-hexane, gradient elution) to give (S)—N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxypropanamide (Example 4) as a colourless solid (18 mg, 30%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.31 (3H, s), 2.38 (3H, s), 3.30 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.37 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.37 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.06 (1H, s).
Reaction SMILES: C(=O)([O-])[O-].[CH2:5]([P+:9]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH3:10])[CH2:6][CH2:7][CH3:8].[CH2:19]([P+:23]([CH3:32])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].C(=O)=O>O>[CH2:15]([P:9]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[C:33]([O-:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([O-:38])=[O:37].[CH2:28]([P+:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[CH3:32])[CH2:29][CH2:30][CH3:31].[CH2:5]([P+:9]([CH3:10])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CCCC[P+](C)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: CCCCP(CCCC)CCCC
Product: O=C([O-])/C=C\C(=O)[O-]
Reaction time: 2 h

Procedure:
In 10.0 g of water was dissolved 10.0 g of tri-n-butylmethylphosphonium carbonate obtained as in Example 12 (1st step) and a solution of 4.2 g of maleic acid dissolved in 5.0 g of water was gradually added to the solution, whereby carbon dioxide simultaneously generated vigorously. For more completely removing carbon dioxide, degassing was performed for 2 hours at 40° C. and 20 mmHg and after confirming carbonate ions being less than 2 ppm, water was distilled off. The residue formed was recrystallized from methyl ethyl ketone to produce 1-1.2 g (94.1% of the theoretical yield, yield of 59.8% to tri-n-butylphosphine) of tri-n-butylmethylphosphonium monomaleate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[CH:17][C:12]3=[C:11]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[C:23]#[N:24])=[CH:5][CH:4]=1)#N.[OH-:25].[K+].C[OH:28].Cl>O1CCOCC1.O>[C:23]([C:10]1[C:11]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[C:12]2[CH:17]=[N:16][NH:15][C:13]2=[N:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:1]([OH:28])=[O:25])=[CH:8][CH:7]=1)#[N:24]
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2nc3[nH]ncc3c(-c3ccco3)c2C#N)cc1
Reactant: CO
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(-c2ccc(C(=O)O)cc2)nc2[nH]ncc2c1-c1ccco1
Yield: 17 %

Procedure:
A solution of 0.10 g (0.32 mmol) of 6-(4-cyanophenyl)-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 0.22 g (4.0 mmol) of potassium hydroxide in a mixture of 2 ml of dioxane, 2 ml of MeOH, and 0.75 ml of water is refluxed for 24 h. Next, the mixture is cooled, acidified with 1N HCl, then extracted with ethyl acetate and dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated to give 0.018 g (17%) of 4-(5-cyano-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-yl)benzoic acid in the form of brown crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17][Zn+]>C1COCC1.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>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1cc(F)cc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cc(F)cc(F)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen, then (3,5-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 3 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried and concentrated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column, eluent isocratic heptane/EtOAc 8:2 for 2 CV, then a gradient from 20% to 50% of EtOAc in heptane over 6 CV was used as mobile phase. Methyl 2-(3,5-difluorobenzyl)isonicotinate (7.42 g, 86%) was isolated as an oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.18 (s, 2H), 6.66 (tt, 1H), 6.74-6.82 (m, 2H), 7.67-7.75 (m, 2H), 8.67-8.75 (m, 1H). MS m/z 264 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[OH:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1O
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1O
Yield: 33 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and methyl 2-hydroxy-4-aminobenzoate (113 mg, 0.676 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-hydroxy-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (45 mg, 33%) as colorless prisms.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[N:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C.[Pd]>[NH2:7][C:5]1[N:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]([CH3:1])[CH:6]=1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(N)cn1C
Reaction time: 12 h

Procedure:
0.50 g (2.5 mmol) of ethyl 1-methyl-4-nitro-1H-imidazole-2-carboxylate are dissolved in 7.5 ml of ethanol, 0.13 g (0.13 mmol) of palladium-on-carbon (10%) are added and the mixture is hydrogenated at 3 bar for 12 h. The reaction solution is then filtered through kieselguhr and the filtrate is concentrated. The residue is dried in vacuo and reacted further without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminothiazole (117 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (214 mg, 88%) as a yellow solid: mp 106-107° C.; EI-HRMS m/e calcd for C18H21BrN2O3S2 (M+) 456.0177, found 456.0175.
Reaction SMILES: CSC.B.[F:5][C:6]1([F:25])[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][NH:8][C:7]1=O.CN(C)CCN.O1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:33]([N:8]1[CH2:7][C:6]([F:25])([F:5])[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)[C:34]#[C:35][CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)O2
Reactant: C1CCOC1
Agent: B
Agent: CN(C)CCN
Solvent: CSC
Product: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 55 °C

Procedure:
Borane dimethylsulfide (36.3 μL, 0.408 mmol) was added dropwise to a solution of tert-butyl 10,10-difluoro-9-oxo-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (125 mg, 0.408 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated at 55° C. for 2 h then cooled to room temperature. The mixture was quenched with the careful dropwise addition of methanol (˜2 mL). N,N-dimethylethane-1,2-diamine (33.3 μL, 0.313 mmol) was then added and the mixture heated at 70° C. for 40 min. The reaction was concentrated, and silica gel chromatography (4 g silica, 1% triethylamine/4% methanol/dichloromethane)) provided tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate which was taken directly to the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.[Na]>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH:14][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(N)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Agent: [Na]
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 1-[5-fluoro-8-(3-fluorophenyl)quinolin-7-yl]ethanamine (0.39 g, 1.4 mmol, 6-chloropurine (0.27 g, 1.8 mmol) and sodium hydrogenecarbonate (0.17 g, 2.0 mmol) in 1-butanol (4 mL) was heated at 110° C. overnight. The mixture was filtered and purified on a preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H17F2N6 (M+H)+: m/z=403.1; Found: 403.1. The racemic N-{1-[5-fluoro-8-(3-fluorophenyl)quinolin-7-yl]ethyl}-9H-purin-6-amine (70 mg, 0.2 mmol) was submitted for chiral resolution (column: ChiralPak IA, 20×250 mm, 5 μm; mobile phase: 15% ethanol/85% hexanes; flow rate: 15 mL/min) to give two enantiomers. retention times: 8.7 and 13.5 minutes, respectively.
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.P(Cl)(Cl)(Cl)=O.[C:27]([O:36]C)(=[O:35])[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH2:30]>N1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([NH:30][C:29]1[C:28](=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([OH:36])=[O:35])=[O:16]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: COC(=O)c1ccccc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.6 %

Procedure:
To a mixture of 20 ml of dry dioxane and 0.7 g of dry pyridine were added 2 g of 3,4-dimethoxycinnamic acid, 1.6 g of phosphorus oxychloride and 1.6 g of methyl anthranilate. The mixture was heated under reflux for 2 hours to effect reaction. After completion of the reaction, the reaction mixture was concentrated and the residue was dissolved with heating in ethanol and then cooled whereby crystals were precipitated. The crystals were separated by filtration and treated in a manner similar to that described in Example 5 to effect hydrolysis of the ester group. The product was recrystallized from chloroform to obtain 2 g of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid having a melting point of 211°-213°C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11](Br)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([N:25]([CH:43]([CH:45]([CH3:47])[CH3:46])[CH3:44])[C:26]1[CH:31]=[C:30](B2OCC(C)(C)CO2)[CH:29]=[CH:28][C:27]=1[N+:40]([O-:42])=[O:41])#[N:24]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11]([C:30]2[CH:29]=[CH:28][C:27]([N+:40]([O-:42])=[O:41])=[C:26]([N:25]([CH:43]([CH:45]([CH3:47])[CH3:46])[CH3:44])[C:23]#[N:24])[CH:31]=2)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(C)N(C#N)c1cc(B2OCC(C)(C)CO2)ccc1[N+](=O)[O-]
Reactant: Cc1nc(Br)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Product: Cc1nc(-c2ccc([N+](=O)[O-])c(N(C#N)C(C)C(C)C)c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1

Procedure:
Beginning with 1-benzyl-2-methyl-4-bromo-5-(2,4-difluorophenyl)-1H-imidazole and N-[cyano]N-[3-methylbut-2-yl]2-nitro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)aniline, the title compound is prepared essentially as described in Preparation 35.
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[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:19][CH2:20][CH2:21][Cl:22]
Reactant: ClCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc2ccccc2c1

Procedure:
A mixture of β-naphthol (1 gm, 0.006 mole), anhydrous K2CO3 (10 gm, in excess) and 1-bromo-3-chloropropane (0.7 ml, 0.006 mole) was refluxed in dry acetone (50 ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound, m.p. 98° C., (yield 1.5 gm, 97%).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]([O:16][C:17](=[O:30])[CH2:18][CH2:19][N:20]([CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:21]([NH2:23])=[S:22])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:30])[CH2:18][CH2:19][N:20]([C:21]1[S:22][C:2]2[CH2:10][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[N:23]=1)[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)CCN(Cc1cccs1)C(N)=S
Reactant: O=C1c2ccccc2CC1Br
Product: CC(C)(C)OC(=O)CCN(Cc1cccs1)c1nc2c(s1)Cc1ccccc1-2

Procedure:
3-[(8H-Indeno[1,2-d]thiazol-2-yl)-thiophen-2-ylmethyl-amino]-propionic acid tert-butyl ester was prepared (35 mg) following general procedure B using 2-bromo-indan-1-one (22 mg, 0.1 mmol), and 3-(1-thiophen-2-ylmethyl-thioureido)-propionic acid tert-butyl ester (30 mg, 0.1 mmol). LCMS m/z: 414 (M+1)+.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.O1CCCC1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:8][CH2:7][CH:6]1[O:1][C:2]2=[CH:11][S:10][CH:9]=[C:3]2[O:4][CH2:5]1)[CH3:25]
Reactant: OCC1COc2cscc2O1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)COCC1COc2cscc2O1
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL), blanketed by nitrogen. Sodium hydride (1.9 g) was added in portions after which the reaction mixture was stirred for another 30 min. Then ethyl bromoacetate (5.3 mL) was added dropwise and stirring was continued for another hour at 25° C. The reaction mixture was then poured into ethyl acetate, washed with 1M hydrochloric acid, washed with a 1M aqueous solution of sodium hydrogen carbonate and concentrated. This resulted in quantitative formation of pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid ethyl ester as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[Li+].CC([N-]C(C)C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:41])(=O)=O)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1([F:41])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C1(F)CCCN(CC2COc3ccccc3O2)C1
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acid ethyl ester (300 mg, 0.98 mmol) was added 2 M LDA (0.59 ml, 1.08 mmol). The mixture was stirred for 15 minutes. N-fluorobenzenesulfonimide (341 mg, 1.08 mmol) was added and the mixture was stirred for 20 min. The reaction was quenched with sat. NH4Cl solution. The solvent was evaporated and the remaining aqueous mixture was extracted two times with EtOAc. The organic layers were pooled, dried, concentrated and absorbed on silica. Flash chromatography (heptane/EtOAc) gave 160 of the title compound as a mixture of diastereomers.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[NH2:5][N:6]1[C:11](=[O:12])[CH:10]([F:13])[N:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=[C:7]1[SH:18]>[OH-].[Na+].C(Cl)(Cl)Cl>[CH2:1]([S:18][C:7]1[N:6]([NH2:5])[C:11](=[O:12])[CH:10]([F:13])[N:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CC(C)(C)N1N=C(S)N(N)C(=O)C1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCSC1=NN(C(C)(C)C)C(F)C(=O)N1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.9 %

Procedure:
26.6 g (0.22 mol) of allyl bromide were added to a solution of 43.6 g (0.2 mol) of 4-amino-6-fluoro-tert.-butyl-3-mercapto-1,2,4-triazin-5-one in 200 ml of 1 N sodium hydroxide solution at room temperature. The reaction mixture was stirred for approximately 20 hours at room temperature, the organic phase was then taken up in chloroform, and the solution was washed with three times 150 ml of 0.1 N sodium hydroxide solution, dried over sodium sulphate, filtered and concentrated. The oily residue was degassed at 50° C./0.05 mbar, and recrystallized from ethyl acetate/petroleum ether. 20.8 g (40% of theory) of 3-allylthio-4-amino-6-fluoro-tert.-butyl-1,2,4-triazin-5-one of melting point 75° to 74° C. were obtained.