Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]=[C:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][C:64](=[CH2:63])[CH2:65][CH2:66]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C=C1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CC1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-methylene-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][NH2:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>>[CH:26]1([C:23]2[NH:24][N:25]=[C:21]([NH:20][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:12][CH2:11][C:3]4[C:2]([CH3:1])=[CH:10][CH:9]=[C:8]5[C:4]=4[CH:5]=[CH:6][NH:7]5)[N:19]=3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1ccc2[nH]ccc2c1CN
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2[nH]ccc2c1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A mixture of 304 (53 mg, 0.331 mmol) 53 (94 mg, 0.397 mmol), and DIPEA (128 mg, 0.993 mmol) in WA (2 mL) under nitrogen atmosphere was heated in a sealed tube at 120° C. for 18 h. The crude was purified by preparative HPLC to afford 38 mg (32%) of I-122.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH:4]=[CH2:5].F[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1>O1CCCC1>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(ccn2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60%, 254 mg, 6.35 mmol) in 15 mL tetrahydrofuran (THF) was added 5-allyloxyindole (Step A; 1.0 g, 5.77 mmol) in 5 mL THF and the mixture was stirred for 1 hour at ambient temperature. 4-fluorochlorobenzene (0.69 mL, 6.35 mmol) was added and the reaction heated to reflux for 21 hours. After cooling, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue purified by flash chromatography on silica gel (15% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[C:9]=2[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.O[Li].O.[Br:26]Br.[Li+].[OH-].[OH-].[Na+]>CO.O>[Br:26][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:10](=[O:14])[NH:11][N:12]=1
Reactant: BrBr
Reactant: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cn[nH]c2=O)cc1
Agent: [Li+]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)c(Br)n[nH]c2=O)cc1
Temperature: 70 °C
Reaction time: 0.05 h
Yield: 192.5 %

Procedure:
To a stirred solution of 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (10 g, 32.5 mmol) and LiOH.H2O (1.37 g, 32.65 mmol) in MeOH (200 mL) at 70° C. was added bromine (2.6 g, 16.26 mmol). The reaction mixture was stirred at 70° C. for 3 min. After this time, bromine (5.2 g, 32.5 mmol) and LiOH. H2O (2.74 g, 65.3 mmol) were added and the reaction mixture was stirred at 70° C. for an additional 3 min. After this time, another portion of bromine (2.6 g, 16.26 mmol) and LiOH.H2O (1.37 g, 32.65 mmol) was added and the reaction mixture was stirred for 3 min at 70° C. A final portion of bromine (2.6 g, 16.26 mmol) followed by LiOH. H2O (1.37 g, 32.65 mmol) was added and the reaction mixture was stirred at 70° C. for another 3 min. HPLC (Method A) showed disappearance of the starting material. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a light yellow solid. This solid was diluted with water (100 mL) and the pH was adjusted to 7 with aq 1.0 N NaOH. The product was extracted with EtOAc (2×100 mL). The combined organic layer was washed with saturated NaCl, dried (MgSO4), filtered and the filtrate was concentrated to obtain 4-(6-bromo-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile as a pale yellow solid (12.1 g, 96%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18].C([O-])(=O)C.[Na+]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:18][C:17]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc(Nc2nc(C)nc3ccccc23)cc(OC)c1OC

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (179 mg, 1.0 mmol), 3,4,5-trimethoxy-aniline (183 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 239 mg (73.5%) of white solids. 1H NMR (CDCl3): 7.88 (t, J=7.2 Hz, 2H), 7.77 (t, J=7.2 Hz, 1H), 7.51 (t, J=8.1 Hz, 2H), 7.22 (s, 2H), 3.92-3.87 (m, 9H), 2.72 (s, 3H).
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4]C.[CH3:20]C(C)CCS>>[CH3:20][CH:3]([CH3:4])[CH2:2][CH2:1][S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1
Reactant: CC(C)CCS
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Product: CC(C)CCSc1c[nH]nc1C1CN2CCC1CC2
Yield: 20 %

Procedure:
Compound 49H was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using 3-methyl-1-butanethiol as reagent. Subsequent purification by flash chromatography (EtOH) afforded compound 49G.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[OH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3 mL) was added hydroxyl amine HCl (0.427 g, 6.19 mmol) and potassium carbonate (1.14 g, 8.26 mmol). The reaction mass was stirred at RT for 15-17 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water, acidified with dilute HCl and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m, 2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:26]=[CH:25][N:24]=[CH:23][C:14]3=[N:15][C:16]=2[NH:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:7][CH2:6]1.[CH3:32][C:33](C)=[O:34].CC(OC(C)=O)=O>O1CCOCC1.[Pd]>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:26][CH2:25][N:24]([C:33](=[O:34])[CH3:32])[CH2:23][C:14]3=[N:15][C:16]=2[NH:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(N[C@H]3CCOC3)nc2C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine (2.0 g, 4.68 mmol) in dioxane:acetone (50 ml; 1.5:1) was added Ac2O (4.8 mL, 50.9 mmol) and Pd/C (400 mg, 3.76 mmol); then, the reaction was stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. The mixture was filtered through a pad of Celite™ and washed with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into sat. aqueous NaHCO3 (50 ml), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by flash column chromatography to yield the title compound (193.4 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.89 (m, 4H), 2.05-2.09 (m, 4H), 2.60-2.90 (m, 4H), 3.30-3.40 (m, 4H), 3.55-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.85-3.95 (m, 2H), 4.38-4.51 (m, 4H), 5.91 (dd, J=6.0, 4.4 Hz, 1H), 7.01 (m, 1H), 7.25-7.31 (m, 2H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1.[O-:24][C:25]#[N:26].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:19]=[N:18][N:17]([C:25]([NH2:26])=[O:24])[CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1
Reactant: N#C[O-]
Reactant: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)n1cc(Nc2ncc3cnn(Cc4ccccc4F)c3n2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 88), (111 mg, 0.36 mmol) in ACN/H2O (9:1, 4 mL) was added potassium cyanate (35 mg, 1.2 eq). After 30 min at rt, the reaction mixture was neutralized with saturated sodium carbonate and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title product. 1H NMR (d6-DMSO) δ 10.12 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.41-7.28 (m, 2H), 7.26-7.14 (m, 2H), 5.58 (s, 2H); LC-MS method B, (ES+) 353.0, RT=7.75 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[C:26]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=2)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:24][C:25]1[C:26]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:36](=[O:40])[CH:35]=2)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: O=c1cc(OCc2ncc(Cl)cc2Cl)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 66.5 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.396 mmol) and 4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one (107 mg, 0.396 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (150 mg, 66%) as a green oil: ESI MS m/z 569 [M+H]+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13](O)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13]([Cl:23])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1OC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC(=O)c1ccccc1

Procedure:
A solution of 3-benzoyloxy-4-methoxybenzoic acid (29.3 g; that is prepared as described in Reference Example 9) in toluene (300 mL) is treated with thionyl chloride (30 mL) and heated on the steam bath for 6 hours. It is then cooled, filtered and concentrated, to give 3-benzoyloxy-4-methoxybenzoyl chloride (28.7 g), m.p. 120-122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CN(C)C=O.O.[Cu]I.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([C@@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)=[CH:18][CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc[nH]n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-n3cnc(-c4ccc(F)cc4)n3)cc2)C1
Temperature: 150 °C
Reaction time: 48 h

Procedure:
3-(4-Fluorophenyl)-1H-1,2,4-triazole (CAS [95728-10-2], 200 mg, 0.9 mmol) was dissolved in a mixture of dimethylformamide and water (5.5 ml; v/v=10:1) and (S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (368 mg, 1.08 mmol), cesium carbonate (1.46 g, 4.48 mmol), copper(I)-iodide (5.1 mg, 0.027 mmol) and 8-hydroxyquinoline (4 mg, 0.027 mmol) were added successively. The glass was closed and the reaction mixture was allowed to stir at 150° C. for 48 h. According to TLC, the reaction was finished. After cooling, water and ethyl acetate were added. The organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, gradient heptane/ethyl acetate), off-white solid (205 mg, 54%), MS (ISP): 425.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25].S(Cl)(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([S:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)(=[O:26])=[O:25])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ncccc2Cl)CC1
Yield: 17 %

Procedure:
Sulfonylation of 1-(3-chloropyridin-2-yl)piperazine (632 mg, 3.2 mmol) with naphthalene-2-sulfonyl chloride (725 mg, 3.2 mmol) was carried out according to a similar procedure described for example 2A (except that the sulfonyl chloride was added before the diisopropylethylamine) using anhydrous dichloromethane (10 mL) as solvent and diisopropylethylamine (1.4 mL, 8.0 mmol) as base. 1-(3-chloropyridin-2-yl)-4-(2-naphthylsulfonyl)piperazine was obtained in 17.0% yield (210.2 mg) as white solid.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[N:10]=[N:11][C:6]2=[N:5][CH:4]=1)=C.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:32].[Na+]>O.O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:19]1[C:20]2[C:15](=[CH:14][C:13]([CH2:12][N:9]3[C:7]4=[N:8][C:3]([CH:1]=[O:32])=[CH:4][N:5]=[C:6]4[N:11]=[N:10]3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.7 %

Procedure:
To a mixture of 6-((6-vinyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (100 mg, 0.347 mmol) and 2,6-dimethylpyridine (74.3 mg, 0.694 mmol) was added a solution of osmium(VIII) oxide (297 mg, 1.387 mmol) in water (1.333 mL), followed by addition of a solution of sodium periodate (88 mg, 6.94 mmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred at rt for 10 h. The solvent was removed in vacuo and DCM was added to dilute the residue. The resulting solution was washed with saturated NaHCO3 solution, NH4Cl and brine. The organic layer was separated, dried over Na2SO4, and concentrated to give the crude product which was purified with Analogix system on silica gel (hexanes:EtOAc) to afford 45 mg (43%) of the title compound. LCMS (method B): [MH]+=291, tR=1.00 min.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1.[H-].[Na+].O>CN(C=O)C>[CH:10]1[C:11]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:16]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(-n2c3ccccc3c3ccccc32)nc(-n2c3ccccc3c3ccccc32)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of carbazole (97.0 g, 0.58 mol) and 2,6-dichloropyridine (41.0 g, 0.28 mol) in dry DMF (200.0 ml) was slowly added NaH (20.0 g, 0.83 mol) at room temperature under nitrogen atmosphere and stirring. The addition of NaH was taken over 60 minutes. After the addition of NaH, the mixture was heated to 160° C. and kept at this temperature for 12 hours. After cooling, water (300.0 ml) was added into the reaction mixture. The product as a brown solid was collected by filtration. The crude product was purified with recrystallization from acetone/water to give 92.2 g (81.3 g) of product.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C1CCNC1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCCC2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and pyrrolidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:20][C:21]1[C:28]([F:29])=[C:27]([CH3:30])[C:26]([F:31])=[C:25]([F:32])[C:22]=1[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>>[F:20][C:21]1[C:28]([F:29])=[C:27]([CH3:30])[C:26]([F:31])=[C:25]([F:32])[C:22]=1[CH2:23][N:8]([CH2:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: Cc1c(F)c(F)c(CBr)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2c(F)c(F)c(C)c(F)c2F)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 2,3,5,6-tetrafluoro-4-methylbenzylbromide (283 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.051 g (11.9%); MS m/z: 428.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.11 (t, 3H, 3J=7.6 Hz); 2.18 (s, 3H); 2.50-2.54 (m, 2H); 4.47 (s, 2H); 4.70 (s, 2H); 6.87-6.91 (m, 2H); 7.07 (d, 2H, 3J=7.9 Hz); 7.14 (d, 2H, 3J=7.9 Hz); 7.37 (d, 1H, 3J=8.9 Hz), 7.96 (s, 1H); 12.05 (br s, 1H); HPLC (METHOD [A]): rt 19.03 min (93.3%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:22])[CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:12]=[CH:13][CH:14]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzene sulfonylchloride (1.10 g, 4.32 mmol) in pyridine (5 mL) was added 8-quinolinamine (1, 623 mg, 4.32 mmol) and the reaction mixture was stirred overnight at 25° C. Ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated sodium carbonate (X 3), dried over magnesium sulfate, filtered and concentration under reduced pressure to afford a light brown solid (2, 1.57 g, 3.80 mmol). MS(ESI) [M+H+]+=363.1; 365.1 (1:1)
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[N:31]1([CH2:36][CH2:37][O:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[CH3:27][N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]3[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=[C:11]([NH:43][C:42]4[CH:44]=[CH:45][C:39]([O:38][CH2:37][CH2:36][N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:40][CH:41]=4)[N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1ccc2c(Nc3nc(Nc4ccc(OCCN5CCCC5)cc4)ncc3C(N)=O)cccc21
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (62 mg, 0.15 mmol) in NMP (1 ml) was added 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (31 mg, 0.15 mmol) and p-toluenesulfonic acid hydrate (28 mg, 0.15 mmol). It was heated at 100° C. for 4 h, and was purified by preparative HPLC to give 4-(1-methyl-1H-indol-4-ylamino)-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidine-5-carboxamide (32 mg). MS found for C26H29N7O2 as (M+H)+ 472.4. UV: λ=216.9, 257.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: C1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: Cc1cc(N2CCCCC2)c2cccc(O)c2n1

Procedure:
The mixture of 4-chloro-8-hydroxy-2-methylquinoline 600 mg), piperidine (6.13 ml) and tetrabutylammonium iodide (10 mg) was refluxed for 18 hours. The cooled reaction mixture was concentrated in vacuo and to the residue was added chloroform and aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from n-hexane to give 8-hydroxy-2-methyl-4-piperidinoquinoline (712 mg) as pale brown crystals.