Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:4]Cl)=[CH2:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.CN(C=O)C>[CH2:13]([O:12][C:10](=[O:11])[C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([O:6][CH:1]=[C:2]([CH3:4])[CH3:3])[CH:8]=1)[CH3:14]
Reactant: C=C(C)CCl
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(OC=C(C)C)c1

Procedure:
A mixture of 2-methyl-3-chloropropene (64.2 g, 710 mmol), ethyl 3-hydroxybenzoate (48.21 g, 590 mmol), and potassium carbonate (122.3 g, 890 mmol) in THF (600 ml) and DMF (600 ml) was heated to reflux for 6 hr. The mixure was poured into water (3 L) and extracted with ethyl acetate three times. The ethyl acetate extracts were combined and washed with water and dried with brine. The ethyl acetate extracts were concentrated in vacuo to a yellow oil that was vacuum distilled to a clear oil (112.9 g, 87%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CN(C=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[O:15][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cccc1Cc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2c(Br)cccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
A solution of 2-benzyl-6-bromophenol (3.2 g, 12.2 mmol) in DMF (50 ml) was treated with K2CO3 (2.19 g, 15.9 mmol) and methyl 4-bromomethylbenzoate (3.21 g, 14.02 mmol). The reaction was stirred at ambient temperature overnight, filtered and partitioned between ethyl acetate and water. The organic phase was washed with water (4×), dried (MgSO4) and evaporated to give methyl 4-(2-benzyl-6-bromophenoxymethyl)benzoate (5.96 g), which was used without further purification. MS(CI+):411(M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:24][C:25](OC(C)(C)C)=[O:26])[NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:24][CH2:25][OH:26]
Reactant: CC(C)(C)OC(=O)CC1(NS(=O)C(C)(C)C)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(CCO)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-5H-chromeno[2,3-c]pyridin-5-yl)acetate (isomer A) (720 mg, 1.359 mmol) in dry THF (5.5 mL) was brought to −78° C. and diisobutylaluminum hydride (5.44 mL, 5.44 mmol) was added slowly. The mixture was brought to 0° C. after diisobutylaluminum hydride addition, and stirred at this temperature for 0.5 hr. The reaction mixture was quenched with saturated Rochelle's salt (˜40 mL) and stirred at RT for overnight. The organic layer was separated and the aqueous phase was extracted by EtOAc. The combined organics were washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated to afford N-(7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide as off-white solid that was advanced without further purification.
Reaction SMILES: [C:1]1([N:11]2[C:15]([SH:16])=[CH:14][CH:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][C:18]([S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[CH:13][CH:14]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1ccnn1-c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1ccnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(naphthalen-1-yl)-1H-pyrazole-5-thiol (120 mg, 0.53 mmol), ethyl bromoisobutyrate (0.09 mL, 0.58 mmol) and potassium carbonate (81 mg, 0.58 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% acetone) afforded ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-ylthio)propanoate as a solid. (124 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([C:23]#[N:24])=[CH:18][CH:19]=2)[N:14]=1>>[C:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)#[N:24]
Reactant: N#Cc1ccc2ccc(N)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2ccc3ccc(C#N)nc3n2)cc1
Yield: 11.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (8.2 g), N,N'-carbonyldiimidazole (8.7 g) and 2-amino-7-cyano-1,8-naphthyridine (6.9 g), and heating for 4 hours under reflux. The insoluble product is separated by filtration and the filtrate is poured into water (1000 cc). The resulting precipitate is filtered off, washed with water (3×75 cc) and dried in the air. The solid obtained is purified by flash chromatography (under 30 kPa) on a column 40 mm in diameter containing silica (170 g; 0.04-0.06 mm), eluting with pure methylene chloride and collecting 50-cc fractions. After concentration of fractions 5 to 27 to dryness at 40° C. under reduced pressure (4 kPa), the product obtained is purified by recrystallization in dioxane (160 cc). N-(7-Cyano-1,8-naphthyridin-2-yl)-4-methoxybenzamide (1.4 g), m.p. 283° C., is thereby obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]
Reactant: Ic1ccccc1
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1ccccc1
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.095 g, 0.03 eq.), iodobenzene (0.685 g, 1.1 eq.), triethylamine (0.923 g, 3 eq.), and copper (I) iodide (0.035 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.85 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 4/96 methanol/dichloromethane) to provide an oil. The oil was recrystallized from a mixture of ethanol and 1,2-dichloroethane. The resulting solid was dissolved in 1:1 mixture of ethanol and 1,2-dichloroethane, treated with activated charcoal, combined with a few drops of 10% sodium hydroxide, heated, and then filtered while still hot. The filtrate was concentrated under reduced pressure to provide 0.28 g of 2-ethyl-1-(5-phenyl-4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine as white granules, mp 199.0-202.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.18 (dd, J=8.2, 1.0 Hz, 1H), 7.60 (dd, J=8.3, 0.9 Hz, 1H), 7.35-7.48 (m, 6H), 7.09 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 6.46 (s, 2H), 4.61 (t, J=7.8 Hz, 2H), 3.01 (q, J=7.4 Hz, 2H), 2.66 (t, J=6.5 Hz, 2H), 2.09 (m, 2H), 1.38 (t, J=7.4 Hz, 3H); MS (APCI) m/z 355 (M+H)+; Anal. calcd for C23H22N4.0.02C2H4Cl2: C, 77.64; H, 6.24; N, 15.72. Found: C, 77.68; H, 6.19; N, 15.64.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]=[N+:16]=[N-:17])[O:11][C:10]2=[O:18])=[CH:5][CH:4]=1.[C:19]12CC(CC1)=C[CH:20]=2>O1CCOCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:20]=[CH:19][N:17]=[N:16]3)[O:11][C:10]2=[O:18])=[CH:5][CH:4]=1
Reactant: C1=C2CCC(=C1)C2
Reactant: CSc1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1
Solvent: C1COCCO1
Product: CSc1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1

Procedure:
(5R)-3-(4-Methylthiophenyl)-5-azidomethyloxazolidin-2-one (1.62 g, 6.14 mM) was dissolved in dioxane (30 ml), treated with norbornadiene (2.98 g, 31.5 mM) and heated under reflux for 6 hours. After removal of the solvent, the residue was dissolved in the minimum of hot ethyl acetate, filtered, cooled, then diluted with isohexane to precipitate the desired product (600 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]#[N:28])=[N:19][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[N:19][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc(-c2ccccc2C#N)nc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Product: CCCc1nc2c(C)cccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Yield: 46 %

Procedure:
A mixture of 4-methyl-2-propyl-1-[[2-(2-cyanophenyl)-5-pyridinyl]methyl]-1H-benzimidazole (0.87 g, 2.39 mmol), NaN3 (0.77 g, 11.94 mmol), and tri-n-butyltin chloride (3.88 g, 11.94 mmol) in xylenes (20 mL) was heated under reflux for 20 h. The reaction mixture was concentrated and 2N HCl was added. The mixture was extracted with ether (discarded) and adjusted to pH 5 with 50% NaOH. The aqueous phase was extracted with CH2Cl2, and the extracts were washed with water, dried, and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) and recrystallization from EtOH/EtOAc/ether gave 0.45 g (45%) of product as a white solid, mp 169°-170° C.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([Br:13])[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12.CC(O)CC>O>[Br:2][C:3]1[N:4]=[C:5]([Br:13])[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:1])[C:7]=12
Reactant: Clc1nccn2c(Br)nc(Br)c12
Reactant: N
Solvent: CCC(C)O
Solvent: O
Product: Nc1nccn2c(Br)nc(Br)c12
Reaction time: 8 h

Procedure:
20 M of NH3 in H2O(10 mL) was added to a suspension of 1,3-Dibromo-8-chloro-imidazo[1,5-a]pyrazine (1.726 g, 0.007425 mol) in 2-Butanol (7.49 mL, 0.0817 mol). The mixture was heated in an oil bath set at 90° C. overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography using 1→6% MeOH in DCM to obtain the title compound as a yellow solid. MS (ES+): m/z 294.83 (85) [MH+]. HPLC: tR=1.58 min (Open Lynx polar—5 min). 1H NMR (400 MHz, CD3OD):δ=7.10 (d, J=5.05 Hz, 1H), 7.43 (d, J=5.05 Hz, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N:35]5[CH:39]=[CH:38][CH:37]=[N:36]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-n2cccn2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-n5cccn5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-pyrazol-1-yl-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:33])[NH:21][C:22]([CH3:32])=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:33])[NH:21][C:22]([CH3:32])=[CH:23][C:24]=2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for the example 4 from 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (100 mg, 0.353 mmol) and 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (129 mg, 0.565 mmol), wherein the reaction stir time was 12 h. The product was collected as a white solid (130 mg, 71%). 1H NMR (400 MHz, DMSO-d6) ppm 11.61 (s, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.17-7.26 (m, 6H), 5.81 (s, 1H), 5.04 (m, 2H), 4.42 (s, 2H), 3.96 (s, 2H), 2.10 (s, 3H), 1.45 (d, 6H); MS(ES) [M+H]+ 495.0.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:8])=[CH:6][CH:7]=1)=O.[CH2:9]([O:16][C:17]1[CH2:21][NH:20][C:19](=[O:22])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[CH2:9]([O:16][C:17]1[C:21](=[CH:1][C:3]2[NH:4][C:5]([CH3:8])=[CH:6][CH:7]=2)[NH:20][C:19](=[O:22])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1C=C(OCc2ccccc2)CN1
Reactant: Cc1ccc(C=O)[nH]1
Solvent: CS(C)=O
Product: Cc1ccc(C=C2NC(=O)C=C2OCc2ccccc2)[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-formyl-5-methylpyrrole (4 g; 36.65 mmols) and 4-benzyloxy-3-pyrrolin-2-one (8.24 g; 43.78 mmols) in DMSO (65 ml) 2N sodium hydroxyde (45 ml) was added under nitrogen atmosphere and the mixture was stirred at 60° C. for 8 hours. After dilution with water (200 ml) the yellow suspension was filtered. The crude material was taken up in ethyl acetate, stirred and filtered to give 4-benzyloxy-5-(5-methyl-1H-pyrrol-2-yl-methylene)-1,5-dihydro-pyrrol-2-one (7.7 g; 27.49 mmols) as a 4:1 Z:E mixture. Yield: 75%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:32])[NH:20][C:21]([CH3:31])=[CH:22][C:23]=2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C(O)C.C(N(CC)CC)C>[Pd].C1COCC1>[CH3:13][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:32])[NH:20][C:21]([CH3:31])=[CH:22][C:23]=3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:12]
Reactant: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2cccc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 6 h

Procedure:
To a dried 50 mL round bottom flask was placed 10% Pd/C (0.020 g, 9.63 mol), followed by degassing with N2. Added about 5 mL EtOH and then added 6-bromo-1-(1-methylethyl)-N-{[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide (0.095 g, 0.193 mmol) and ethanol (5 mL) and THF (1 mL). Next added in triethylamine (0.081 mL, 0.578 mmol) via syringe. The mixture was stirred under atmosphere of hydrogen (balloon) for 6 h. The mixture was purged with nitrogen and then diluted with DCM (10 mL) and a small amount of celite, After stirring for 10 min, the contents were then filtered through analytical grade celite and washed with 10% MeOH/DCM, EtOH, and then DCM. The filtrate was concentrated in vacuo and dried under hi vacuum overnight. The crude product was purified by silica gel chromatography (eluent: 5-50% gradient of 10% methanol in dichloromethane and dichloromethane). The final product was concentrated from MTBE and dried in vacuum oven at 45° C. for 18 h. The title compound was collected as a white solid (0.75 g, 92% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.57 Hz, 6H) 2.10 (s, 3H) 3.98 (s, 2H) 4.43 (d, J=5.05 Hz, 2H) 5.03 (quin, J=6.63 Hz, 1H) 5.81 (s, 1H) 7.15-7.31 (m, 5H) 7.39 (t, J=7.71 Hz, 1H) 7.52 (d, J=6.82 Hz, 1H) 7.85 (d, J=8.34 Hz, 1H) 8.34 (s, 1H) 8.50 (t, J=5.05 Hz, 1H) 11.61 (s, 1H); MS (ES) [M+H]+ 415.0.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:22]1[CH2:23][CH2:24][N:19]([C:17]([CH2:16][N:11]2[CH2:10][CH2:9][N:8]([C:6]([CH:5]3[NH:1][C:2](=[O:14])[CH2:3][CH2:4]3)=[O:7])[CH2:13][CH2:12]2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=C1CCC(C(=O)N2CCNCC2)N1
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)N1
Yield: 93.7 %

Procedure:
1-(2-Pyrrolidone-5-carbonyl)piperazine (3.7 g), 3.7 g of 4-chloroacetylmorpholine, 4.4 g of anhydrous potassium carbonate, and 20 ml of N,N-dimethylformamide were stirred at 70°-75° C. for 1 hour. The insoluble matter was removed by filtering the reaction mixture, the solvent was removed by evaporating the filtrate, and the residue was purified by a silica gel column chromatography to give 5.7 g of the product. This was recrystallized from a mixture of ethanol, ethyl acetate and diethyl ether to give 4.2 g of desired product, m.p. 167°-169° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2=[O:22])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:23](OC)(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[SH:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:22]=[C:10]1[N:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]3[S:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[C:23](=[O:31])[N:2]=3)[CH:8]=2)[CH2:13][CH2:12][N:11]1[CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CN1CCN(c2ccnc(C#N)c2)C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Yield: 59.6 %

Procedure:
tert-Butyl [3-(2-cyano-4-pyridyl)-2-oxo-1-imidazolidinyl]acetate (0.80 g, 2.6 mmol) and methyl thiosalicylate (1.33 g, 7.8 mmol) were dissolved in toluene (6 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (3:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.68 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and pyridine-3-sulfonyl chloride (102 mg, 0.63 mmol) were dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford pyridine-3-sulfonic acid [3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (73 mg, yield: 39%) as yellow solid. MS (ESI+APCI) M+1=357.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:3]=1N.[N:15]1C=CC=CC=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([NH2:15])[N:5]=[C:4]([NH:8][CH2:9][C:10]([CH3:11])([CH3:12])[CH3:13])[C:3]=1[C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22]
Reactant: c1ccncc1
Reactant: CC(C)(C)CNc1ncnc(Cl)c1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCOCC
Product: CC(=O)OCC(=O)c1c(Cl)nc(N)nc1NCC(C)(C)C

Procedure:
A solution of 6-chloro-5-amino-4-(neopentylamino)pyrimidine (1 mmol) in diethyl ether was treated with pyridine (3 mmol), and acetoxyacetyl chloride (1.2 mmol) at 25° C. for 12 h. Extraction and chromatography afforded 6-chloro-5-acetoxyacetyl-amino-4-neopentylaminopyrimidine as a yellow solid. TLC: Rf=0.18, 30% EtOAc-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7](=S)[NH:8][CH3:9].[NH2:13][NH2:14]>CS(C)=O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][N:13]=[C:7]2[NH:8][CH3:9]
Reactant: CNC(=S)c1cc(Br)ccc1F
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1n[nH]c2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 5-bromo-2-fluoro-N-methylbenzothioamide (480 mg, 1.9 mmol) and anhydrous hydrazine (0.61 mL, 19 mmol) in dimethylsulfoxide (6 mL) was heated to 80° C. and stirred for 1 hour. The temperature was increased to 100° C. and the reaction was stirred for 40 minutes. The temperature was increased further to 130° C. and the reaction was stirred for another 45 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated and the aqueous was extracted with ethyl acetate (4×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (20-70% ethyl acetate/heptanes) gave the title compound (103 mg, 23%) as a white solid. +ESI (M+H+1) 228.0; 1H NMR (400 MHz, CD3OD, δ): 7.78 (dd, J=1.85, 0.68 Hz, 1H), 7.29-7.40 (m, 1H), 7.17 (dd, J=8.88, 0.68 Hz, 1H), 2.94 (s, 3H).
Reaction SMILES: [O:1]=O.[CH:3]1[CH:8]=[CH:7][NH+:6]=[CH:5][CH:4]=1.[CH:9]1[CH:14]=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[C:24]1([CH3:30])[CH:29]=[CH:28]C=C[CH:25]=1>>[CH3:4][CH2:5][N:6]([C:7]([C:8]1[CH:3]=[CH:28][CH:29]=[C:24]([CH3:30])[CH:25]=1)=[O:1])[CH2:14][CH3:9]
Reactant: O=O
Reactant: c1cc[nH+]cc1
Reactant: Cc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Product: CCN(CC)C(=O)c1cccc(C)c1

Procedure:
Glass coverslips (Thomas Scientific 6661 F52, 22×22 mm No. 1) were cleaned using an O2 plasma cleaner (Harrick PDC-32G) for 20 minutes at 100 mTorr. The DETA (United Chemical Technologies Inc. T2910KG) films were formed by the reaction of the cleaned glass surface with a 0.1% (v/v) mixture of the organosilane in freshly distilled toluene (Fisher T2904). The DETA coated coverslips were then heated to approximately QQ 100° C., rinsed with toluene, reheated to approximately 100° C., and then oven dried [28]. Surfaces were characterized by contact angle measurements using an optical contact angle goniometer (KSV Instruments, Cam 200) and by X-ray photoelectron spectroscopy (XPS) (Kratos Axis 165). XPS survey scans, as well as high-resolution N1s and C1s scans utilizing monochromatic Al Kα excitation were obtained [28].