Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH3:32])=[CH:26][CH:25]=1.[OH-].[Na+]>CN1C(=O)CCC1.O.Cl>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:32])[C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=[O:20])[CH2:16]4)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: O=C(O)C1CCc2ccc(Oc3ccnc(Cl)c3)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CN(C)c2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)ccn2)cc1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A solution of 7-[(2-chloropyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.50 g, 4.94 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (2.24 g, 14.8 mmol) in NMP (9 mL) was heated in a sealed tube at 150° C. for 40 hr. The reaction mixture was allowed to cool to rt and diluted with water and 1N HCl solution. The pH was adjusted to 4 by the addition of 1N NaOH solution. The mixture was extracted with EtOAc (3×) and the organic solutions were combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give 7-({2-[(4-methoxybenzyl)(methyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid as an off-white solid (581 mg, 28.1%). LCMS: (FA) ES+ 419.2, ES− 417.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:7]12.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH:25]=[O:26])=[C:13]([CH3:15])[N:12]=[C:7]12
Reactant: CN(C)C=O
Reactant: Cc1cn2ccc3c(Cl)cccc3c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 7-chloro-2-methylimidazo[2,1-a]isoquinoline (4 g) in N,N-dimethylformamide (40 ml) was added dropwise to a mixture of N,N-dimethylformamide (5.7 ml) and phosphoryl chloride (1.86 ml) under ice cooling. After being stirred at 85°-90° C. for 6 hours, the mixture was poured into ice-water, basified with aqueous sodium hydroxide, heated at 80° C. for 20 minutes and cooled. The resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give 7-chloro-3-formyl-2methylimidazo[2,1-a]isoquinoline (0.356 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[CH3:30]>O1CCCC1>[F:22][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ncnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(OC)c34)c2F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 58 %

Procedure:
To (3-amino-2,6-difluoro-phenyl)-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (36, 30.0 mg, 0.0986 mmol) 1.0 mL of tetrahydrofuran and pyridine (23.9 μL, 0.296 mmol) are added, followed by 4-ethyl-benzenesulfonyl chloride (59, 40.4 mg, 0.197 mmol). The reaction vial is stirred at room temperature for 5 days, then extracted by adding aqueous saturated sodium chloride and ethyl acetate. The organic layer is washed with water, then sodium bicarbonate, then brine, and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1008, 27 mg). MS (ESI) [M+H+]+=473.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nn1ccc2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of pyrrolo[3,2-b]pyridine (1.64 mmol) and potassium tert-butoxide (3.29 mmol) in DMF (7.3 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl. in ether (16.3 mL) is added drop-wise at rt and the reaction mixture is stirred at rt for 3 h. The reaction mixture is quenched with 5% Na2S2O3 aqueous solution (10 mL), and extracted with ether. The combined organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc to afford pyrrolo[3,2-b]pyridin-1-ylamine (136 mg, 62%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.89 (br, 2N—H), 6.61 (d, H), 7.16 (m, H), 7.38 (d, H), 7.76 (d, H), 8.47 (d, H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][CH2:29][CH2:30][Cl:31].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:31][CH2:30][CH2:29][CH2:28][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCCl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (278 mg, 0.783 mmol) in DMSO (4.0 mL) was added 3-bromo-1-chloropropane (1.23 g, 7.83 mmol) and Cs2CO3 (765 mg, 2.35 mmol), and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (silica gel, CH2Cl2/MeOH, 100:1) yielded 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. To a solution of 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (84 mg, 0.19 mmol) in DMF (1.0 mL) was added K2CO3 (0.13 g, 0.97 mmol), dimethylamine (1.94 mL, 3.88 mmol, 2.0 M in THF) and KI (32 mg, 0.19 mmol), and the reaction was heated to 45° C. for 18 h. The reaction mixture was cooled, diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography (Biotage 25+M column, CH2Cl2/MeOH/NH4OH, 50:1:0 to 20:1:0.1) provided the title compound (54 mg, 63%): 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.75-7.70 (m, 5H), 7.60-7.43 (m, 3H), 6.92-6.91 (m, 1H), 6.53-6.51 (m, 1H), 4.49 (t, J=6.8 Hz, 2H), 2.29 (t, J=6.8 Hz, 2H), 2.23 (s, 6H), 2.13-2.08 (m, 2H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH:5]1[C:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[N:6]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([C:9]5[N:8]=[N:7][N:6]([CH:2]([CH3:4])[CH3:3])[N:5]=5)[CH:11]=4)=[CH:35][C:20]=3[C:21]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:25][CH:26]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(C(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 31 %

Procedure:
2-iodopropane (29 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.57 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.32 Hz), 7.99-8.05 (2H, m), 7.87-7.94 (2H, m), 7.79-7.83 (1H, m), 7.72-7.78 (1H, m), 7.70 (1H, t, J=7.78 Hz), 7.41 (2H, t, J=8.70 Hz), 5.17-5.27 (1H, m), 2.87 (3H, d, J=4.58 Hz), 1.66 (6H, d, J=6.71 Hz). LC-MS retention time: 2.02 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.39 min, purity=97%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:32]([O:39][C:40]([NH:42][CH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:41])[NH:42][CH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](=[O:51])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:46][CH2:45]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt (0.100 g, 0.533 mmol) in DCM (1.35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol), (0.075 g, 0.56 mmol) and trans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid (0.21 g, 0.70 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with sat. NaHCO3 (aq) and brine, then dried over Na2SO4 and the solvent removed in vacuo. The residue thus isolated was chromatographed over silica gel eluting with EtOAc/hexane (1:1) to afford 0.173 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m, 2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br, 1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21](C)[NH:22]C(=O)CC1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=O)[CH:38]=[C:39]([F:41])[CH:40]=1>>[F:41][C:39]1[CH:38]=[C:37]([CH2:42][C:43]([NH:22][CH2:21][C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])=[O:45])[CH:36]=[C:35]([F:34])[CH:40]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: O=C(Cc1cc(F)cc(F)c1)NCC(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that N1-[(2,3-cis)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]glycinamide (106a) was used as the amine component and 3,5-difluorophenylacetic acid was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (80 mg), white solid, m.p. 125-130° C. 1H NMR (300 MHz, d6-DMSO) δ 4.76 (t, 1H, J=7 Hz), 5.12 (d, 1H, J=7 Hz), 6.91-7.49 (m, 12H), 7.67 (d, 1H, J=7 Hz), 8.25 (s, 1H), 10.49 (s, 1H). MS APCI, m/z=482(M+1). LC/MS: 2.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1OCCN1CCOCC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(OCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 85.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.65 g) and 5-amino-2-(2-morpholinoethoxy)benzonitrile (0.95 g), the title compound (1.02 g) was obtained, melting point: 187–189° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:21][C:11]2=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:4].Br[CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:26][N:25]=1>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:21]([CH2:23][C:24]2[CH:28]=[C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[O:26][N:25]=2)[C:11]2=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
105 mg (4.16 mmol) NaH (96%) were added to a solution of 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 50 mL absolute DMF and the mixture was stirred for 30 min. at room temperature. 1.05 g (3.78 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the the mixture and stirring was continued for 3 h. After addition of 21 mg (0.832 mmol) NaH (96%) and 210 mg (0.756 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and standing overnight the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 and the solution washed with saturated NaHCO3 solution. The solvent was removed in vacuo and the residue purified by flash chromatography over silica gel using n-heptane/ethyl acetate=3/2 as solvent. The fractions containing the product were concentrated.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([O:14]C)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Oc2ccccc2)c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc(Oc2ccccc2)c1

Procedure:
3-Phenoxyanisole (8.3 g) was added to a mixture of 50 mL of 40% HBr and 100 mL of glacial acetic acid. The resultant mixture was heated under reflux for 48 hours, then cooled and concentrated under reduced pressure. The residue was taken up in EtOAc, washed with water, saturated NaHCO3, and brine. After drying with MgSO4, and concentration under reduced pressure, 3-phenoxyphenol was obtained and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[Br:9]Br.O>C(O)(=O)C>[Br:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: Oc1ccc(Cl)cn1
Solvent: CC(=O)O
Solvent: O
Product: Oc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-hydroxypyridine (100 g) and bromine (40.1 mL) in acetic acid (400 mL) was stirred at r.t. for 1 h. The mixture was poured into 3 L of water and stirred for 30 min then filtered. The residual solid was washed with 2 L of cold water, air dried and then coevaporated with toluene three times and with benzene two times. The white solid (81 g) so obtained was used in the subsequent reaction.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][C:35]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:36]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)CCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 4-bromobutyric acid (2.5 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through preparative thin-layer chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.6 g (yield: 58%) of 4-bromo-N-(2,4-difluorophenyl)butanamide as colorless needle-like crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:11]2=[N:10][CH:9]=[CH:8][CH:7]=[C:6]2[CH:5]=[CH:4]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) was added in portions over 25 min to a solution of 7-azaindole (39.8 g, 0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was then added slowly over 15 min, keeping the temperature of the reaction mixture below 10° C. After 1 h, the reaction was quenched with water (500 mL) and the mixture was extracted with CH2Cl2 (5×300 mL) The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>[OH-].C[N+](C)(C)C.C(Cl)Cl>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)=[O:16]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: ClCCl
Product: C=Cc1ccc(OC(=O)C(Cl)(Cl)Cl)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
About 10.0 gs (6.17×10-2 moles of 4-acetoxystyrene was dissolved in 42.5 mL of 25 wt % tetramethylammonium hydroxide with stirring. The solution was cooled to 5° C. and to it was added 12.63 gs (6.95×10-2 moles) of trichloracetyl chloride dissolved in 150 mL of methylene chloride. The addition was done slowly with stirring while cooling with an ice bath so as to avoid heating the reaction mixture above 15° C. After 15 mins. of reaction, workup was done by separating the methylene chloride layer, washing it with 3×40 mL of 6 wt % tetramethylammonium hydroxide and several 40 mL aliquots of distilled water. The washed organic layer was dried over magnesium sulphate, filtered over silica gel, and the solvent removed under vacuum. The residue was recrystallized from pet ether to give 10.2 gs (62% yield) of 4-trichloroacetoxystyrene.
Reaction SMILES: C(=S)(OC1C=CC=CC=1)O[CH:3]([C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[C:4]([F:7])([F:6])[F:5].[SnH](CC1C=CC=CC=1)(CC1C=CC=CC=1)[CH2:29]C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH2:13]([N:11]1[CH:12]=[C:8]([CH2:3][C:4]([F:5])([F:6])[F:7])[C:9]([CH3:29])=[N:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)C(OC(=S)Oc1ccccc1)c1cnn(Cc2ccccc2)c1
Reactant: c1ccc(C[SnH](Cc2ccccc2)Cc2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: Cc1nn(Cc2ccccc2)cc1CC(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of O-(1-(1-benzyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl) O-phenyl carbonothioate (compound 314.4, 1.34 g, 3.30 mmol) in toluene (20 mL) was added Bn3SnH (3.84 mL, 13.2 mmol), AIBN (320 mg, 1.95 mmol). The reaction mixture was stirred for 1 h at 80° C. under nitrogen, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:20) as the eluent to furnish 650 mg (78%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:21][CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: c1ccc(NCC2CCN(c3ccc(CN4CCCC4)cc3)CC2)cc1

Procedure:
Prepared from the product of Example 16 and aniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:18][CH:19]([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][C:63](O)=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:63](=[O:64])[CH2:62][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][N:56]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Nc1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: O=C(O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(-c2ccc3nc(NC(=O)Cc4ccccn4)sc3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (121.8 mg, 0.382 mmol) and HATU (215.9 mg, 0.568 mmol) were suspended in DCM (2.9 ml) and diisopropylethylamine (0.21 ml, 1.2 mmol) and 2-pyridylacetic acid hydrochloride (94.3 mg, 0.543 mmol) were added. The reaction was stirred under nitrogen at room temperature overnight, concentrated and purified on a silica gel column (20:1 DCM/MeOH). Fractions with product were collected, concentrated, and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes). Fractions with product were collected, concentrated, and dried under high vacuum in a water bath (˜50° C.), then at room temperature overnight to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)-2-(pyridin-2-yl)acetamide (57.5 mg, 34% yield). MS (ESI pos. ion) m/z: 438. Calculated exact mass for C22H20ClN5OS 437.