Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][CH2:25][CH:26]4[NH:29][C:30]([C:32]4[C:33](=[O:47])[N:34]([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=5)[CH:35]=[CH:36][CH:37]=4)=[O:31])=[CH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(Cl)Cl>C[O-].[Na+].CO>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH:26]3[NH:29][C:30]([C:32]3[C:33](=[O:47])[N:34]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=4)[CH:35]=[CH:36][CH:37]=3)=[O:31])=[CH:21][CH:20]=2)=[CH:11]1
Reactant: O=C(NC1CCCc2ccc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc21)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCc2ccc(-c3c[nH]c4ncccc34)cc21)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [7-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-amide (0.063 g, 0.000097 mol;) was dissolved in 0.5 M of Sodium methoxide in methanol (3 mL) and Methylene chloride (3 g, 0.04 mol;) and heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. Pure fractions were combined and concentrated to give the pure product. ES (+) MS m/e=511.37; (400 MHz, DMSO-d6) δ ppm 1.84 (m, 3H), 2.07 (m, 1H), 2.80 (m, 2H), 5.22 (d, 2H, 5 Hz), 5.25 (m, 1H), 6.62 (t, 1H, J=8 Hz), 6.99 (m, 1H), 7.12 (m, 1H), 7.20 (d, 1H, J=8 Hz), 7.30-7.45 (m, 2H), 7.52 (m, ′H), 7.60 (s, 1H), 7.78 (s, 1H), 8.16 (d, 1H, J=8 Hz), 8.22 (m, 2H), 8.46 (m, 1H), 10.10 (d. 1H, J=8 Hz), 12.55 (s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[CH:10]1>CC#N>[Br:1][C:13]1[N:9]=[CH:10][NH:11][C:12]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1[nH]cnc1Br
Reaction time: 12 h
Yield: 69.1 %

Procedure:
N-bromosuccinimide (0.900 g, 5.0 mmol) was added to a stirred solution of methyl 1H-imidazole-4-carboxylate (0.630 g, 5.0 mmol) in CH3CN (50 mL). The reaction mixture was stirred for 12 h in the dark and then concentrated in the presence of silica gel. The absorbed crude material was purified by column chromatography (20-100% EtOAc/hexanes) to afford the title compound (0.708 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (br. s., 1H), 7.81 (s, 1H), 3.81 (s, 3H). ES-LCMS: m/z 204.9, 206.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>COCCOC.CO.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>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1cccc(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: COCCOC
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2ccccn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-bromopyridine (1.91 ml) and tetrakis(triphenylphosphine)palladium(0) (0.46 g) in 1,2-dimethoxyethane (40 ml) was added 2M aqueous solution of sodium bicarbonate (20 ml) and a solution of dihydroxy(3-nitrophenyl)borane (3.67 g) in methanol (10 ml). The mixture was stirred at 80° C. for 2.5 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:1)) to give 2-(3-nitrophenyl)pyridine (1.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)O[N:10]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[S:24][N:10]=1
Reactant: O=[N+]([O-])c1ccc(C2CC(c3c(Cl)cccc3Cl)=NO2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: O=[N+]([O-])c1ccc(C2CC(c3c(Cl)cccc3Cl)=NS2)cc1

Procedure:
By the method of Asian. J. Chem., 2000, 12, 1358-1360, (±)3-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-2-isoxazoline can be treated with diphosphorus pentasulfide followed by aqueous quench to produce (±)-3-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-2-isothiazoline. The nitrophenyl group can be reduced to the corresponding aniline with tin dichloride or iron powder and ammonium chloride. The aniline, in turn, can be treated with 2,2-dichloroacetyl chloride and triethylamine to yield (±)-2,2-dichloro-N-[4-[3-(2,6-dichlorophenyl)-5-(2-isothiazolinyl)]phenyl acetamide.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.O[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]4[C:35](=[O:47])[N:36]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:37]([CH3:40])[C:38]=4[CH3:39])=[O:33])=[CH:27][C:26]=3[F:48])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[F:48][C:26]1[CH:27]=[C:28]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:37]([CH3:40])[C:38]=2[CH3:39])=[O:33])[CH:29]=[CH:30][C:25]=1[O:24][C:18]1[C:17]2[C:22](=[CH:23][C:14]([O:5][CH2:6][CH2:7][CH2:8][C:9]3([OH:12])[CH2:11][CH2:10]3)=[CH:15][CH:16]=2)[N:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.8 %

Procedure:
To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (240 mg, 1.2 mmol) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (470 mg, 2.4 mmol, Aladdin). After stirring at rt for 12 hrs, the reaction mixture was warmed to 40° C. and stirred for additional 6 hrs. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (40 mL×3). The combined organic phases were dried over Na2SO4, concentrated in vacuo and chromatographed with a silica gel column (5:1 (v/v) EtOAc/n-Hexane) to provide the title compound as a white solid (68 mg, 19%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl>O1CCCC1>[CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)c1ccc(CCCC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCNCc1ccc(CCCC)cc1

Procedure:
A solution of 38.0 g of N-heptyl-4-n-butylbenzamide and 280 ml of borane-tetrahydrofuran complex in 120 ml of anhydrous tetrahydrofuran was refluxed for 18 hours, allowed to cool, and treated with 6N hydrochloric acid. The organic solvent was evaporated and the residue was partitioned between ether and aqueous sodium hydroxide solution. The ether layer was separated, dried, and evaporated. The residue was distilled to yield N-heptyl-4-n-butylbenzenemethanamine as a colorless liquid, bp 115°C. at 80μ.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:19]([O:21]C)=[O:20])=[C:8]2[C:13]=1[O:12][CH2:11][CH:10]([CH2:14][O:15]C(=O)C)[O:9]2)=[O:4].[OH-].[K+].O>C(O)C>[OH:15][CH2:14][CH:10]1[O:9][C:8]2=[C:7]([C:19]([OH:21])=[O:20])[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:13]2[O:12][CH2:11]1
Reactant: COC(=O)c1sc(C(=O)OC)c2c1OCC(COC(C)=O)O2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1sc(C(=O)O)c2c1OCC(CO)O2
Reaction time: 0.5 h

Procedure:
2-Acetoxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid dimethyl ester (60 g, 0.18 mol) was dissolved in ethanol (680 mL). KOH (36 g) was added to this solution after which water (500 mL) was added upon continuous cooling. After addition of the water the reaction mixture was stirred for another 30 minutes after which the solvents were removed by distillation. To the remaining part of the reaction mixture, we dropwise added a mixture of ice (50 g) and concentrated HCl (25 mL), and stirred. The mixture was then filtered and the residue was washed with water. Subsequent drying resulted in quantitative formation of pure 2-hydroxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[K+].O1CCO[CH2:14][CH2:13]1>>[N:9]1[C:2]2[C:3](=[CH:4][CH:13]=[CH:14][N:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Product: c1cnc2ncccc2c1

Procedure:
0.77 g of diacetyltetraphenylmethane obtained by the method described in Example 7 was reacted with 0.51 g of 2-aminonicotinaldehyde and 0.76 g of potassium hydroxide in dioxane and, by treatment in the normal way, TPM-dNTR (0.82 g) shown below was obtained. 1H-NMR (CDCl3, ppm): 9.12 (d·d, 2H), 8.27−8.16 (m, 8H), 8.00 (d, 2H), 7.49−7.44 (m, 6H), 7.34−7.23 (m, 10H)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.0 mmol, Aldrich, Cat. 525057) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (0.40 g, 2.0 mmol) in acetonitrile (7 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL, 2.5 mmol). The mixture was stirred at 70° C. overnight. The mixture was concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-90%) to afford the desired product. LCMS (M+Na)+: m/z=411.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[N:5]=[CH:4][N:3]=1.[NH3:13]>C(O)(C)C>[N:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:13])[CH:7]=2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: N
Reactant: Clc1cc(-n2cncn2)ncn1
Solvent: CC(C)O
Product: Nc1cc(-n2cncn2)ncn1
Yield: 95.7 %

Procedure:
A solution of 4-chloro-6-(1H-1,2,4-triazol-1-yl)pyrimidine (1.24 g, 6.83 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in a sealed vial for 18 h. After cooling the solid precipitate was filtered and dried to give 6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1.06 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (1H, s), 8.35 (1H, s), 8.30 (1H, s), 7.39 (2H, br. s.), 6.83 (1H, d, J=0.76 Hz). LCMS: RT=0.41 min, MH+=163.1
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:13]=2[O:21][CH3:22])[N:8]([CH3:23])[C:7]=1[CH3:24])=[O:5])[CH3:2].C(N)=O>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=2[O:21][CH3:22])[N:8]([CH3:23])[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c(-c2cccc([N+](=O)[O-])c2OC)n(C)c1C
Agent: [Pd]
Solvent: NC=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)c(-c2cccc(N)c2OC)n(C)c1C
Yield: 86 %

Procedure:
5-(3-Nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6f (300 mg, 0.9 mmol) was dissolved in 5 mL of ethyl acetate followed by addition of formamide (227 mg, 1.61 mmol) and 60 mg of palladium on carbon. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound 5-(3-amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6g (234 mg, yield 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:37])[CH2:34][NH:35][CH3:36])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:35]([CH2:34][CH:33]([OH:37])[C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH3:36])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ccc(OC)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(O)CN(C)Cc2cc3c(s2)c(=O)c(C(=O)NCc2ccc(Cl)cc2)cn3C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 48.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.21 mmol), 1-(4-methoxyphenyl)-2-(methylamino)ethanol (Tetrahedron 1999, 55, 4831-4842) (58 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (54 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11](Cl)=[N:10][N:9]2[CH:15]=1)=[O:5])[CH3:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:10][N:9]2[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2nc(N3CCNCC3)ccc2n1

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1.000 g, 4.432 mmol), piperizine (0.458 g, 5.318 mmol) and potassium carbonate (0.620 g, 4.485 mmol) in 50 mL of toluene was refluxed for 48 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The crude product, 6-piperazin-1-ylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, obtained upon removal of solvent was used for next step reaction without further purification. Yield 1.016 g, 83%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)[CH3:2].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:18][CH2:10][C:7]1[CH:6]=[N:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=1
Reactant: CCOc1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cnc(CBr)cn1
Temperature: 80 °C
Yield: 31.8 %

Procedure:
A mixture of 2-ethoxy-5-methylpyrazine (0.86 g, 6.22 mmol), NBS (1.440 g, 8.09 mmol), and diphenylperoxyanhydride (0.151 g, 0.622 mmol) in carbon tetrachloride (20 mL) was heated to 80° C. overnight. Cooled to RT, diluted with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via ISCO (40 g silica, 40 mL/min, 0-30% EtOAc/Hexanes over 25 min) to afford 2-(bromomethyl)-5-ethoxypyrazine (430 mg, 32%). MS (m/z) 217.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[CH:12]/[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=3)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)c2cncc(C(F)(F)F)c2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C/c2cncc(C(F)(F)F)c2)C1
Temperature: 5 °C

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]4([CH2:17][CH2:16]4)[N:8]3[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23])[C:11]=1[F:12].C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]4([CH2:17][CH2:16]4)[N:8]3[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:23])[C:11]=1[F:12]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CC1

Procedure:
To a solution of ethyl 9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carboxylate (1.3 g, 4 mmol) in EtOH/water (50:50 v/v, 55 mL) was added K2CO3 powder (1.65 g, 12 mmol) and the mixture was heated under reflux for 2 h. The solvent was removed to dryness. The remaining solid was acidified to pH6 by using 2N acetic acid. A precipitate formed and was collected by filtration, washed with water and then dried to give the title compound (0.656 g, 2.24 mmol as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (2H, t), 1.8 (2H, t), 4.56 (2H, s), 7.84 (1H, m), 8.51 (1H, s), 14.3 (1H, b). MS (EP) m/z: 294 (M++1). (Calcd for C14H9F2NO4, 293.22)
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:38]([C:39]([OH:41])=[O:40])=[C:37]([CH3:42])[N:36]=[C:35]([CH3:43])[C:34]=1C(O)=O>CCCCCC>[CH3:43][C:35]1[CH:34]=[C:33]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:40][C:39](=[O:41])[C:38]2=[C:37]([CH3:42])[N:36]=1
Reactant: Cc1nc(C)c(C(=O)O)c(-c2ccccc2F)c1C(=O)O
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc2c(c(C)n1)c(=O)oc1ccccc12
Reaction time: 0.83 h
Yield: 28.9 %

Procedure:
To 1400 ml of Dowtherm A heated to 240°-245° C. was added over a 10 minute period 113 g of 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid and the reaction mixture was boiled for 50 minutes, cooled and allowed to stand at room temperature overnight. The crystalline solid, a by-product identified below, was filtered off and the filtrate was extracted with 700 ml of 3N hydrochloric acid followed by a second extraction with 300 ml of 3N hydrochloric acid. The combined acidic extracts were made basic by adding aqueous ammonium hydroxide and the alkaline mixture was extracted with 800 ml of chloroform. Evaporation of the chloroform yielded a brown mixture of solid and liquid, to which was added 300 ml of n-hexane and the mixture chilled. The solid was filtered off and dried. This solid, a by-product, was combined with the above noted solid by-product to yield 25.4 g (29%) of 2,4-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one, m.p. 194°-197° C. The filtrate was concentrated to dryness on a steam bath, the residue taken up with ethanol and the solution concentrated on a rotary evaporator to yield, as a liquid, 55.2 g (70%) of 4-(2-fluorophenyl)-2,6-dimethylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: N#Cc1cccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Yield: 16 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (141 mg, 0.67 mmol) and 3-(bromo methyl)benzonitrile (157 mg, 0.80 mmol) to provide 463 (35 mg, 16% yield) as a white powder. LC-MS (M+H=327, obsd.=327). 1H NMR (400 MHz, DMSO-D6) δ 8.46 (m, 2H), 8.06 (d, J=8.6, 1H), 7.73 (s, 1H), 7.69 (d, J=7.6, 1H), 7.57 (d, J=8.0, 1H), 7.48 (t, J=7.8, 1H), 7.42 (d, J=2.0, 1H), 7.36 (dd, J=4.7, 7.8, 1H), 6.90 (dd, J=2.1, 8.7, 1H), 6.22 (s, 2H), 5.69 (s, 2H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1>CN(C)C=O.C(O)C.C(N)C1C=CC=CC=1>[CH2:12]([NH:13][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:6][CH:7]=1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CN(C)C=O
Solvent: NCc1ccccc1
Solvent: CCO
Product: O[C@H](CNCc1ccccc1)COc1cccc(-c2noc3ncccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and benzylamine in ethanol essentially as described above in Example 102, except that 1.5 equivalents of benzylamine is used.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:29])=[N:10][CH:11]=[C:12]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][C:12]3[CH:13]=[C:8]([NH2:7])[C:9]([CH3:29])=[N:10][CH:11]=3)=[N:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)OC(C)(C)C)c3)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(N)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{5-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-carbamic acid tert-butyl ester 11 (0.33 mmol) is dissolved in DCM (2 mL) and treated with TFA (3 mL). The reaction mix is stirred at rt for 2 h. The solvent is removed to afford an off white solid residue. The residue is taken in water, the pH neutralized with 5% Na2CO3 and extracted with DCM:IPA=3:1 (3×40 mL). The organic layer is washed with brine and dried over Na2SO4. Evaporation of the organic solvent under reduced pressure affords N5-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-2-methyl-pyridine-3,5-diamine 12, which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 10.37 (s, 1H), 8.90 (s, 2H), 8.47 (bs, 1H), 7.79 (bs, 1H), 7.71-7.69 (m, 2H), 7.08-7.06 (m, 2H), 6.36 (bs, 2H), 3.81 (s, 3H), 2.43 (s, 3H). MS (m/z) (M+1)+: 308.2.