Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([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:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)cc2c1cnn2C1CCCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-chloro-1-cyclopentyl-1H-indazole-4-carboxylic acid (0.12 g, 0.453 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.128 g, 0.680 mmol), wherein the stir time was 12 h. The crude product was purified by silica gel chromatography (eluent: 5-85% gradient chloroform (containing 10% 2M Ammonia in methanol) and dichloromethane). The isolated product was concentrated from MTBE to afford an off-white solid that was dried in hi-vac oven for 6 h. The final product was collected as 0.165 g (89%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.74 (m, 2H) 1.81-1.91 (m, 2H) 1.91-2.02 (m, 2H) 2.06-2.17 (m, 5H) 2.20 (s, 3H) 4.34 (d, J=4.80 Hz, 2H) 5.16-5.28 (m, 1H) 5.88 (s, 1H) 7.60 (d, J=1.52 Hz, 1H) 8.05 (s, 1H) 8.37 (s, 1H) 8.61 (t, J=4.93 Hz, 1H) 11.54 (s, 1H); LC-MS (ES) m/z=398.8 [M+H]+
Reaction SMILES: [CH3:1][C:2]12[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[CH:6][C:5](=[O:13])[CH2:4][CH2:3]2.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.CCCCCC.O>[CH2:34]([CH:10]1[CH2:9][CH2:8][C:7]2[C:2]([CH3:1])([CH2:3][CH2:4][C:5](=[O:13])[CH:6]=2)[C:11]1=[O:12])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC12CCC(=O)C=C1CCCC2=O
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: CC12CCC(=O)C=C1CCC(Cc1ccccc1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3,4,8,8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione (2.5 g, 0.014 mole) in dry tetrahydrofuran (20 ml) was added to lithium diisopropylamide [made from dry diisopropylamine (1.95 ml 0.014 mole) and n-butyl-lithium (12.0 ml of a 1.15 M solution in hexane, 0.014 mole)] at -65° C. under nitrogen. The solution was allowed to warm to 0° C. and a solution of benzyl bromide (2.39 g, 0.014 mole) in dry tetrahydrofuran (6 ml) was added. This was stirred at room temperature overnight, poured into water and extracted with diethyl ether (100 ml). The organic phase was washed with 1 N hydrochloric acid (50 ml) and water (50 ml), then dried (Na2SO4) and evaported to give a dark oil. This was chromatographed on silica gel using diethyl ether/petroleum ether (1:1) as eluant giving the title compound which was further purified by distillation b.p. 190° C./0.01 mm. The product was isolated as a mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12]3[S:13][C:14]4[CH2:19][NH:18][CH2:17][CH2:16][C:15]=4[C:11]=3[C:10]3=[N:20][CH:21]=[N:22][N:9]3[C:8]2=[O:23])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12]3[S:13][C:14]4[CH2:19][N:18]([CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:17][CH2:16][C:15]=4[C:11]=3[C:10]3=[N:20][CH:21]=[N:22][N:9]3[C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1n(Cc2ccc(Cl)cc2)c2sc3c(c2c2ncnn12)CCNC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(Cl)cc2)c2sc3c(c2c2ncnn12)CCN(Cc1ccccc1)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
6-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (80 mg, 0.22 mmol), sodium tri(acetoxy)borohydride (68 mg, 0.32 mmol), benzaldehyde (27 mg, 0.25 mmol) and THF (2 ml) were combined and stirred at room temperature for 18 hours. The mixture was concentrated, diluted with methanol, filtered and purified via reverse phase HPLC to yield 102 (50 mg, 40%) as the trifluoroacetic acid salt.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>C1COCC1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: Cc1ccncc1N1CCc2ccc(N)cc2C1=O
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCc2ccc(NC(=O)C3CC3)cc2C1=O
Yield: 14.1 %

Procedure:
Using analogous reaction conditions as described in Example 24, 7-amino-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (I-25a: 100 mg, 0.3533 mmol) in THF (5 mL) was reacted with cyclopropanecarbonyl chloride (35.5 mL, 0.3886 mmol) and TEA (74.4 mL, 0.5299 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane), followed by preparative HPLC afforded 16 mg of the product (14% yield).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[C:20]([CH:26]=1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].O>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:16]1[CH:17]=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[C:20]([C:21](=[O:22])[N:23]([CH3:24])[CH3:25])[CH:26]=1)[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Sodium hydride (350 mg) was dissolved in dimethylformamide (10 mL)), and the solution was cooled to 0° C. After addition of tert-butyl methyl malonate (1.52 g), the mixture was stirred for one hour, and the 5-chloro-N,N-dimethyl-2-nitrobenzamide (1.0 g) obtained in Example 2a) was added thereto. The mixture was stirred at 70° C. for 4.5 hours and water was added thereto. The resulting solution was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:1 to give the title compound (1.29 g).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C(Cl)Cl.C1C=CC=CC=1>[Cl:19][CH2:15][C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: ClCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 10 h
Yield: 94.1 %

Procedure:
To a suspension of 9-anthracenemethanol (50 g, 0.24 mole) in methylene chloride (50 ml), a solution of thionyl chloride (32.3 g, 0.27 mole) in benzene (300 ml) was added, and reacted with stirring for 10 hours under reflux. The reaction mixture was poured into ice-water (500 ml). An organic layer separated was washed with H2O (100 ml×3), dried over anhydrous MgSO4 and evaporated to give 51.2 g of 9-chloromethylanthracene as residual crude orange yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C)C=O>[CH2:17]([O:16][CH:15]([O:19][CH2:20][CH3:21])[CH2:14][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1cc([N+](=O)[O-])ccc1OC)OCC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of 7.50 g 2-methoxy-5-nitro-phenol, 9.61 g 2-bromo-1,1-diethoxy-ethane and 15.89 g cesium carbonate in 75 ml N,N-dimethylformamide was stirred at 100° C. for 4 hours. After cooling to room temperature the reaction mixture was treated with an aqueous 1% solution of sodium hydroxide and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration of the solvent under reduced pressure the residue was dissolved in a mixture of ethyl acetate and n-heptane. After removal of the ethyl acetate under reduced pressure the resulting residue was filtered off and the clear solution concentrated under reduced pressure. The residue was directly subjected to the subsequent reaction without further purification. Yield: 9.45 g
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)[CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCOCCOc1cccc(OB(O)O)c1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in methylene chloride (15 ml) were added 3-(2-propoxyethoxy)phenylboric acid (0.67 g) and molecular sieves 4A (0.8 g), and the resulting mixture was stirred for 5 minutes. Thereto were added cupric acetate (0.27 g) and triethylamine (1.04 ml), and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was washed with ethyl acetate. The resulting solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain methyl 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.36 g).
Reaction SMILES: C(N(CC)CC)C.O=C1C2NC=CC=2C2C=C(S(=O)(=O)NC3C=CC=CC=3)C=CC=2N1.C(C([O-])=O)C.[CH3:37][NH:38][CH2:39][C:40]([NH2:42])=[O:41].Cl[S:44]([C:47]1[CH:56]=[CH:55][C:54]2[NH:53][C:52](=[O:57])[C:51]3[NH:58][CH:59]=[C:60]([C:61]([OH:63])=[O:62])[C:50]=3[C:49]=2[CH:48]=1)(=[O:46])=[O:45]>ClCCl.CN(C)C=O>[C:40]([CH2:39][N:38]([CH3:37])[S:44]([C:47]1[CH:56]=[CH:55][C:54]2[NH:53][C:52](=[O:57])[C:51]3[NH:58][CH:59]=[C:60]([C:61]([OH:63])=[O:62])[C:50]=3[C:49]=2[CH:48]=1)(=[O:46])=[O:45])(=[O:41])[NH2:42]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CNCC(N)=O
Agent: CCC(=O)[O-]
Agent: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccccc3)cc2c2cc[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(N)=O)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
584 μL (3 mmol) of triethylamine and 208 mg (1.68 mmol) of 2 methylamino-acetamide are added to 456 mg (1.4 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 4 mL of anhydrous dichloromethane and 1 mL of anhydrous dimethylformamide. The reaction mixture is stirred for 3 days at room temperature. The solvents are evaporated then the residue is taken up in methanol. The solid is filtered, rinsed with methanol then diisopropyl ether and dried under vacuum to give 279 mg (53%) of 8-(carbamoylmethyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[As](=O)(O)(O)O.O[CH2:18][CH:19]([CH2:21]O)O.S(=O)(=O)(O)O>O.C(Cl)(Cl)Cl>[CH3:11][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[C:10]2[C:2]=1[N:1]=[CH:21][CH:19]=[CH:18]2
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(C(=O)O)ccc2cccnc12
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 3-amino-2-methylbenzoic acid (Intermediate M1) (6.06 g, 39.6 mmol) (commercially available from Aldrich) and arsenic acid (H5As3O10) 7.43 g (commercially available from VWR/ALFA) in glycerol (5.8 mL, 79.2 mmol), and sulfuric acid (9 mL) was heated to 160° C. for 5 h. The mixture was cooled to rt, diluted with water and filtered through a bed of diatomaceous earth. The pH was adjusted to pH 6-7 with 2 M NaOH. The aqueous layer was exhaustively extracted with CHCl3:MeOH (3:1). The organic fractions were pooled and evaporated under vacuum to give a solid. This solid was titurated with CHCl3, and collected on a glass frit. The solid material was washed with hexanes and dried under high vacuum to give a pure solid, 8-methylquinoline-7-carboxylic acid (Intermediate M2) 3.86 g (51%).
Reaction SMILES: C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[O:14]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C2C(=O)C3C(=CC=CC=3)OC=2C=CC=1>C(O)C.[Cu].[Na].[Hg]>[CH:18]1[CH:19]=[C:20]2[CH:23]([OH:24])[C:22]3[C:21]([O:14][C:15]2=[CH:16][CH:17]=1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: O=c1c2ccccc2oc2ccccc12
Solvent: Oc1ccccc1
Solvent: CCO
Product: OC1c2ccccc2Oc2ccccc21

Procedure:
The xanthydrols are either known to the art or are prepared by the following procedure. A 2-halobenzoic acid is reacted with a phenol preferably in the presence of a base such as potassium carbonate and in the presence of cuprous iodide and copper bronze. The resulting 2-phenoxybenzoic acid is cyclized by treating with acid for example polyphosphoric acid. The resulting xanthone is reduced, for example using sodium amalgam in ethanol, to give the xanthydrol.
Reaction SMILES: [CH2:1]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]Br)[CH2:2][CH3:3].CC([O-])(C)C.[K+].O>C1C=CC=CC=1.CS(C)=O>[CH2:5]([CH:4]([CH2:9][CH2:10][CH3:11])[CH2:1][CH:2]=[CH2:3])[CH2:6][CH3:7]
Reactant: CCCC(CCC)CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: C=CCC(CCC)CCC
Reaction time: 2 h

Procedure:
To 100 g of 4-propylheptyl bromide in 400 ml of benzene was added 90 g of t-BuOK in 300 ml of DMSO. The temperature was kept below 50° C. during the addition. The mixture was stirred for 2 hrs and 600 ml of water was added. The organic phase was separated and the aqueous phase extracted with petroleumether (b.p. 40°-60°). The combined organic phases were washed with water and brine. After drying with Na2SO4 and evaporation the residue was distilled. Yield: 23.2 g (b.p. 56°-59° C. /75 Torr). 1H-NMR(CDCl3): δ0.9(6H,CH3), 1.2(9H,CH2,CH), 2.0(2H,CH2C=C), 4.8-5.1(2H,CH2 =C), 5.5-6.0(1H,CH=C)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:28][NH:29][O:30][CH3:31].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH3:28][N:29]([O:30][CH3:31])[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (2.50 g, 12.3 mmol) in THF (15.0 mL) was added 1,1′-carbonyldiimidazole (2.39 g, 14.8 mmol) portionwise over about 10 min. After stirring 30 min at RT, a solution of N,O-dimethylhydroxylamine hydrochloride (1.32 g, 13.5 mmol) and DIPEA (2.36 mL, 13.5 mmol) in DMF (4.0 mL) was added. The reaction mixture was stirred for 2 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (2×20 mL), saturated aq. NaHCO3 (2×20 mL), and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (2.60 g, 88%) as a clear, colorless oil. LC-MS m/z 247 (M+H)+, 0.94 min (ret time).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (70.0 mg, 0.311 mmol) using the same procedure employed for Example 2 (2), but with 4-nitrophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a slightly yellow solid (7.1 mg, 6%) having the following characteristics.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH3:16][CH:17]1[O:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:23][CH:21]1[O:22][CH:17]([CH3:16])[CH2:18][N:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:20]1
Reactant: CC1CNCC(C)O1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Product: CC1CN(c2nnc(N)nc2-c2ccc(F)cc2)CC(C)O1
Yield: 19.4 %

Procedure:
6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (110 mg, 20%) was prepared from 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.50 g, 1.87 mmol) and 2,6-dimethylmorpholine (1.06 g, 9.36 mmol) according to the general procedure of Example 2.
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[OH-].[Na+].Cl>O>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:9]3[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=[C:11]([S:14][CH3:15])[N:10]=3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1ncc(C(=O)O)c(Nc2ccc3[nH]ncc3c2)n1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To the solution of methanol (80 ml) was added the 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (5 g) obtained by the preparation example 1, and the solution was hydrolyzed at 40-50° C. for 1 hr, adding H2O (30 ml) and3N aq. NaOH (15 ml). The reaction mixture was cooled, measured pH 5 at 20° C., slowly adding 3 N aq. HCl. And then the reaction mixture was slowly added H2O (100 ml),stirred at 20° C. for 1 hr, filtered, washed with H2O (30 ml), and obtained a solid product. The solid product was dried at 50° C. in vacuo to obtain the desired compound (4.44 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:21]4[CH:26]=[CH:25]C=[C:23](F)[CH:22]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30].ClC1[N:39]=CC(C2C=CC3N(C(I)=C(NC(=O)C)N=3)N=2)=CC=1NS(C)(=O)=O.N1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:21]4[CH:22]=[CH:23][N:39]=[CH:25][CH:26]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1cccc(F)c1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1I
Agent: OB(O)c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1ccncc1
Yield: 28 %

Procedure:
Following the procedure described for N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (TFA salt) (Example 22), N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (0.250 g, 0.493 mmol) (Example 21) was reacted with pyridine-4-boronic acid (0.0606 g, 0.493 mmol, Boron Molecular) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.040 g, 0.049 mmol, Strem Chemical, Inc., Newburyport, Mass.) for 6 h at 90° C. to afford the title compound as a yellow solid (0.080 g, 28%). MS (ESI, positive ion) m/z: 458 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.12 (s, 3H), 3.24 (s, 3H), 8.17 (d, J=9.6 Hz, 1H), 8.27 (d, J=6.1 Hz, 2H), 8.42 (d, J=9.4 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.79 (d, J=6.1 Hz, 2H), 9.01 (d, J=2.0 Hz, 1H), 9.98 (br s, 1H), 10.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=2)[C:21]([N:23]([CH2:25][C:26]([OH:28])=O)[CH3:24])=[O:22])=[CH:12][CH:11]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN1C(=O)CCC1>[CH3:32][S:33]([NH:36][C:26](=[O:28])[CH2:25][N:23]([CH3:24])[C:21](=[O:22])[C:20]1[CH:29]=[CH:30][CH:31]=[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:11][CH:12]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: CS(N)(=O)=O
Reactant: CN(CC(=O)O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Solvent: CN1CCCC1=O
Product: CN(CC(=O)NS(C)(=O)=O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
1,1-Carbonyldiimidazole (671 mg, 4.14 mmol) was added to a stirred solution of {[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid (1.1 g, 3.07 mmol) in 5 mL NMP in an ice bath under argon for 3 hrs. To this mixture was added methanesulfonamide (437 mg, 4.6 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.684 mL, 4.6 mmol). The reaction was stirred at RT overnight. An additional 0.5 equiv. each of 1,1-carbonyldiimidazole (335 mg, 2.07 mmol), methanesulfonamide (197 mg, 2.07 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.34 mL, 2.07 mmol) were added and let stir over the weekend. The reaction mixture was concentrated, dissolved in 250 mL ethyl acetate, washed with H2O and concentrated. The crude product was purified by flash chromatography with a 0-25% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in CH2Cl2 and lyophilized to yield 153 mg (38.6%) of N-(2-methanesulfonylamino-2-oxo-ethyl)-N-methyl-3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzamide as an amorphous solid. LC-MS (ES) calculated for C24H21F2NO5S, 506.50; found m/z 507 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3ccc(-c4ccccc4)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(1,1′-biphenyl-4-yl)ethylamine gave the title compound as an oil.