Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH:20]4[O:22][CH2:21]4)[C:10]=3[C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38]>C(O)C>[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH:20]([OH:22])[CH2:19][O:18][C:14]3[C:10]4[C:11](=[O:13])[CH:12]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[CH:17]=[CH:16][CH:15]=3)[CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: O=c1cc(-c2ccccc2)oc2cccc(OCC3CO3)c12
Solvent: CCO
Product: Cn1c(N2CCN(CC(O)COc3cccc4oc(-c5ccccc5)cc(=O)c34)CC2)cc(=O)n(C)c1=O
Yield: 78.1 %

Procedure:
In 30 ml of ethanol, there were heated under reflux for 3 hours 0.88 g of 2-phenyl-5-(2,3-epoxypropoxy)-4-oxo-4H-1-benzopyran (Compound 36) and 0.67 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (Compound 3), and the reaction solution was then concentrated under reduced pressure. The resultant residue was purified through a silica gel column chromatograph (chloroform:methanol=100:1 to 100:5 in volume ratio), and then crystallized from ethyl acetate, thereby obtaining 1.21 g of 1,3-dimethyl-6-(4-[3-(2-phenyl-4-oxo-4H-1-benzopyran-5-yl)oxy-2-hydroxypropyl]piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (the non-hydrochloride of Compound 37).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCCCCCc1ccccc1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCCCCc2ccccc2)n1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of 6-bromopyridine-2-carboxaldehyde (30.0 g), 7-phenyl-1-heptyne (26.8 g), triethylamine (48.9 g), bis(triphenylphosphine)palladium(II)chloride (2.3 g, 2%), and copper(I)iodide (0.31 g, 1%) in dry tetrahydrofuran (100 ml) was heated under nitrogen at 55° C. for 70 hrs. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate was washed with ethyl acetate. The filtrate was evaporated. The residue was dissolved in ethyl acetate, the solution washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The residue was flash chromatographed on silica gel, eluting with 0.5% to 2%-ethyl acetate:hexane. The appropriate fractions were collected and concentrated to yield 29.5 g of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.ClCCl.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.N1CCCC1>>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3ccc4nc(NC(C)=O)sc4c3)c2)cc1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a mixture of N-(6-(3-aminophenyl)benzo[d]thiazol-2-yl)acetamide (0.030 g, 0.1 mmol), pyridine (0.03 g, 0.3 mmol) in dichloromethane (2 g, 24 mmol) was added 4-methoxybenzene-1-sulfonyl chloride (0.05 g, 0.2 mmol) at RT. The resultant was stirred for 4 h, and then pyrrolidine (0.02 g, 0.3 mmol) was added. The resulting mixture was concentrated and diluted with DMSO (2 ml) and purified by HPLC (5-95% acetonitrile in water). Collected pure solutions were concentrated and diluted with DCM, washed with aq. Na2CO3 solution. The organic layer was dried over sodium sulfate and concentrated to give a white solid (0.035 g, 73%). MS (ESI pos. ion) Found m/z: 454, (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].O>C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:11]=[O:12])[CH:18]=2)=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
4-Bromo-3,5-dimethylphenol (10.3 g, 51.0 mmol) and (3-formylphenyl)boronic acid (7.67 g, 51.2 mmol) were dissolved in a mixture of 1 M aqueous sodium carbonate solution (150 mL), ethanol (50 mL) and toluene (150 mL). After argon substitution, tetrakis(triphenylphosphine)palladium(0) (2.95 g, 2.55 mmol) was added, and the reaction mixture was stirred at 80° C. for 24 hr under argon atmosphere. The reaction mixture was allowed to cool, and water was added. The mixture was diluted with ethyl acetate, and the insoluble substance was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (9.53 g, yield 83%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 57.6 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), tributyl-(3-trifluoromethyl-phenyl)-stannane (134 mg, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 55 mg of the title compound. MS: (+) m/z 455.28 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16](OCC)=[O:17])[CH:4]=1.[NH3:22]>CO>[CH3:1][N:2]([CH3:21])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16]([NH2:22])=[O:17])[CH:4]=1
Reactant: N
Reactant: CCOC(=O)c1cc(N(C)C)n(Cc2ccccc2F)n1
Solvent: CO
Product: CN(C)c1cc(C(N)=O)nn1Cc1ccccc1F
Temperature: 50 °C
Reaction time: 72 h

Procedure:
1.34 g of ethyl 5-(dimethylamino)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate 1-9-1 (4.60 mmol, 1.0 eq.) were dissolved in 120 mL of methanol. 60 mL of a 7 N solution of ammonia in methanol were added and the solution was stirred for three day at 50° C. bath temperature. 60 mL of a 7 N solution of ammonia in methanol were added again and stirred for further 24 hours at 50° C. bath temperature. 60 mL of a 7 N solution of ammonia in methanol were added again stirred for 24 hour at 65° C. bath temperature. The solution was concentrated in vacuo to provide 1.33 g (5.07 mmol, quantitative) of analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.C1C(=O)N([I:16])C(=O)C1>ClCCCl>[I:16][C:5]1[NH:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]#[N:8]
Reactant: Cc1n[nH]cc1C#N
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCCl
Product: Cc1n[nH]c(I)c1C#N
Yield: 20.7 %

Procedure:
Into a 10-mL sealed tube, was placed a solution of 3-methyl-1H-pyrazole-4-carbonitrile (compound 257.3, 2.0 g, 18.7 mmol) in DCE (6 mL). NIS (4.20 g, 18.7 mmol) was added to the reaction and the mixture was irradiated with microwave radiation for 1 h at 150° C. The reaction was cooled, then carefully quenched with aqueous Na2S2O3 (sat., 20 mL). The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (5×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a yellow solid (900 mg, 21%).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([Br:58])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([Br:58])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Yield: 86 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (25 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 8.20 (dd, J=7.9 and 1.5 Hz, 1H), 7.91 (dd, J=7.6 and 1.5 Hz, 1H), 7.50-7.45 (m, 2H), 7.38-7.16 (m, 8H), 2.59-2.49 (m, 2H), 2.23-1.97 (m, 3H), 1.80-1.68 (m, 1H). LCMS (Method E): RT=3.91 min, [M+H]+=446/448.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=[N:35][O:36][CH3:37])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:37][O:36][N:35]=[CH:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]3)[CH:24]=[CH:23][C:22]=2[Cl:25])=[CH:32][CH:31]=1
Reactant: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-(methoxyimino)ethyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (80 mg, 0.132 mmol) in THF (0.5 mL), methanol (0.7 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (11 mg, 0.26 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 0.5:9.5 MeOH:DCM) to provide the title compound (44 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:59])(=[N:54][CH:55]2[CH2:58][CH2:57][CH2:56]2)=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:59])(=[N:54][CH:55]7[CH2:58][CH2:57][CH2:56]7)=[O:53])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CS(=O)(=NC1CCC1)Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(NS(C)(=O)=NC5CCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-(4-bromophenyl)-N′-cyclobutyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.14 min; Mass spectrum (ESI+): m/z=726 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[F:22][CH:2]([F:1])[C:3]1[N:4]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:6]=2[N:7]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of methyl 2-(difluoromethyl)-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 68 (500 mg, 1.6 mmol), K2CO3 (442 mg, 3.2 mmol) and 1-(bromomethyl)naphthalene (426 mg, 1.9 mmol) in DMF (15 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The liquid was poured into water (100 mL) and filtered, the filter cake was collected and purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (710 mg, 98%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6,): δ ppm 3.08 (t, 4H, J=4.5 Hz), 3.68 (t, 4H, J=4.5 Hz), 3.94 (s 3H), 6.21 (s, 2H), 6.27 (d, 1H, J=6.9 Hz), 7.21-7.38 (m, 3H), 7.56-7.69 (m, 3H), 7.84 (d, 1H, J=8.4 Hz), 8.00 (d, 1H, J=8.4 Hz), 8.24 (d, 1H, J=8.7 Hz); LC-MS: m/e=452 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1.CC(O)=O>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH:14]=1)[NH2:20]
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Cl)n2n1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Cl)n2n1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
To a stirred solution of 3-chloro-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.25 g, 0.784 mmol) in ethanol (50 mL) and water (10 mL) containing AcOH (4.70 mmol) is added iron (0.218 g, 3.92 mmol). The reaction mixture is heated at 80° C. for 2 hours, cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (100 mL) is added. The mixture is extracted with EtOAc (3×50 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.201 g, 89%) as a yellow solid: Rf 0.32 (EtOAc); LCMS (m/z)=289.4, 291.2 [M+H]+, tR=2.21 min.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:46]1[C:54]2[C:49](=[CH:50][C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)[CH:48]=[C:47]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:47]1[NH:46][C:54]2[C:49]([CH:48]=1)=[CH:50][C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)(=[O:21])=[O:20])(=[O:29])=[O:30]
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(-c3n[nH]c4ccc(NS(=O)(=O)c5ccccc5S(C)(=O)=O)cc34)cc2c1
Yield: 19.3 %

Procedure:
2-Methylsulfonyl-N-[3-(5-methoxy-1H-indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained as described in Example 47 from 1.77 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)-indazole-1-carboxylate, 1.52 g 1-(tert-butoxycarbonyl)-5-methoxy-indole-2-boronic acid, 70 ml of dimethyl-formamide, 5.65 ml of a saturated aqueous sodium hydrogencarbonate solution and 151 mg of tetrakis(triphenylphosphine)palladium[0]. 250 mg of 2-methylsulfonyl-N-[3-(5-methoxy-1H-indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide are thus obtained in the form of an amorphous cream solid (LC/MS analysis: Tr 3.52 minutes MH+=497).
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH2:36][OH:37])[CH:30]=1>CN1CCCC1=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:2]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)=[O:5])=[C:31]([CH2:36][OH:37])[CH:30]=1
Reactant: OCc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1CO
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 1.2 %

Procedure:
2-Fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (625.3 mg, 2.08 mmol), potassium carbonate (287.9 mg, 2.08 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (296 mg, 2.08 mmol) were added to 1-methylpyrrolidin-2-one (3.0 mL) and the reaction was stirred at 80° C. for 10 minutes. The reaction was filtered and the compound was purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 2-[4-fluoro-2-(hydroxymethyl)phenoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (157) (10.3 mg, 1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.66 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.41-7.27 (m, 2H), 7.24-7.12 (m, 1H), 7.12-7.07 (m, 1H), 7.04 (s, 1H), 6.80 (d, J=2.1 Hz, 1H), 6.43 (dd, J=7.3, 2.2 Hz, 1H), 4.47 (s, 2H) ppm. ESI-MS m/z calc. 422.09. found 423.2 (M+1)+; Retention time: 1.32 minutes (3 minutes run).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH:7]([C:19]([OH:21])=[O:20])[O:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:10][CH:11]=[CH2:12])[C:4]=2[CH:3]=1.[Cl-].[Na+].[CH3:26]O>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH:7]([C:19]([O:21][CH3:26])=[O:20])[O:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:10][CH:11]=[CH2:12])[C:4]=2[CH:3]=1
Reactant: CO
Reactant: C=CCC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Product: C=CCC1(c2ccccc2)OC(C(=O)OC)Oc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 20 g of the product A of Example 19, 200 ml of methanol and 6 ml of an ether-boron trifluoride complex was stirred at 20° C. for 16 hours and was then poured into a liter of aqueous saturated sodium chloride solution. The mixture was extracted with ether and the ether phase was washed with water until the wash water was neutral, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with petroleum ether (b.p.=60°-80° C.) containing 5% of ethyl acetate. The product was crystallized from methanol to obtain 3 g of isomer A of methyl 6-chloro-4-phenyl-4-(2-propenyl)-[4H]-1,3-benzodioxin-2-carboxylate melting at 70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OCC)(OCC)(OCC)[CH2:21][CH3:22].O>CN(C=O)C.CO>[CH2:21]([C:22]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1)[CH3:20]
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: CCOC(CC)(OCC)OCC
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nc2cccc(C)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 22.9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.5 g, 1.9 mmol) and triethyl orthopropionate (0.42 mL, 2.1 mmol) in DMF (5 mL) was heated at 150° C. in a microwave oven for 1.5 hours. To the mixture, was added water (30 mL). The mixture was cooled in an ice-water bath. The suspension was filtered to give a solid, which was stirred in methanol (15 mL) overnight. The suspension was filtered and washed with methanol (10 mL) and ethyl acetate (10 mL) to give 3-(2-ethyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (0.13 g, 22% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH3CN/0.1% H3PO4, 5.74 min (98.9%); mp: 228-230° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7 Hz, 3H, CH3), 2.07-2.13 (m, 1H, CHH), 2.50 (s, 3H, CH3), 2.51-2.65 (m, 2H, 2CHH), 2.82-2.92 (m, 3H, CH2, CHH), 5.21 (dd, J=6, 11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.46 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.18, 21.05, 22.48, 28.02, 35.51, 55.26, 118.64, 125.00, 128.86, 133.70, 139.82, 148.27, 157.69, 161.14, 169.75, 172.63; LCMS: MH=300; Anal Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C, 61.30; H, 5.34; N, 13.28.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH:25](C(OCC)=O)[C:26]([O:28][C:29](C)(C)[CH3:30])=[O:27])=[O:24])=[CH:21][CH:20]=1.FC(F)(F)C(O)=O.[OH-].[K+]>>[F:1][C:2]([F:40])([F:41])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g. of tert-butyl ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoylmalonate and 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization from chloroform affords the product as a white solid.