Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.O>C1COCC1>[Cl:12][C:10]1[CH:9]=[C:8]([C:13]#[N:14])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:22][C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[N:11]=1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Yield: 33.3 %

Procedure:
A solution of methyl 2,6-dichloro-4-cyanonicotinate (455 mg, 1.97 mmol), triethylamine (0.549 mL, 3.94 mmol) and m-toluidine (0.32 mL, 2.95 mmol) in THF (10 mL) was stirred at RT for 3 days. Water was added to the resulting mixture, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a yellow solid (198 mg, 33.3%). 1H NMR (500 MHz, CDCl3) δ ppm 2.40 (s, 3H), 3.99 (s, 3H), 6.92 (s, 1H), 7.05-7.14 (m, 4H), 7.33 (t, J=7.81 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17]C(=O)OC(C)(C)C)[N:16]=2)[N:13]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)=[N:13][N:12]2[CH:14]=1
Reactant: COc1cc(COc2ccc3nc(NC(=O)OC(C)(C)C)cn3n2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(COc2ccc3nc(N)cn3n2)cc(OC)c1OC

Procedure:
t-Butyl N-[6-(3,4,5-trimethoxybenzyloxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (Example 13, 0.43 g, 1 mmol) was dissolved in dichloromethane (2 ml) and treated with trifluoroacetic acid (1 ml). After 2 h at ambient temperature the mixture was evaporated in vacuo to give a brown oil which was triturated with diethyl ether to give the title compound (0.25 g) as a cream solid, m.p. 150°-157°, NMR δH (DMSO) 8.0 (1 H, JAB 8.8 Hz, 8 H), 7.48 (1 H, s, 3 H), 7.16 (1 H, JAB 8.8 Hz, 7 H), 6.44 (2 H, s, CH2), 4.5 (brs, NH3), 3.89 (6 H, s, OMe) and 3.75 (3 H, s, OMe).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([CH2:15][CH2:16][OH:17])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[Si:28]([O:17][CH2:16][CH2:15][C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C:12]([OH:14])=[O:13])([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@H](CCO)C(=O)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O)ccc(C#N)c1Cl
Temperature: 0 °C

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar and a septum was added (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-4-hydroxybutanoic acid (1.49 g, 5.55 mmol). This was dissolved in dry DMF (68 mL) under an atmosphere of nitrogen. This mixture was cooled to 0° C. followed by addition of imidazole (3.02 g, 44.36 mmol) and TBDMSCl (4.18 g, 27.75 mmol). The reaction was allowed to slowly warm to room temperature overnight quenched by slow addition of aqueous ammonium chloride (sat) (60 mL). The solution was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with (5%) aqueous citric acid (100 mL) (×2), water (80 mL) then dried over Na2SO4, filtered, and concentrated under reduced pressure to reveal a yellow oil (4.2 g). This material was used directly in the next step.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][C:32]#[CH:33]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.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>[C:34]1([CH2:30][CH2:31][C:32]#[C:33][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Clc1nc2ccccc2o1
Reactant: C#CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1nc2ccccc2o1)CCc1ccccc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 40.5 %

Procedure:
To a solution of CuI (15 mg, 81 μmol) in triethylamine (3 mL) were added 2-chlorobenzo[d]oxazole (250 mg, 1.63 mmol), (PPh3)2PdCl2 (57 mg, 81 mmol), triphenylphosphine polymer bound 3 mmol/g (98 mg, 293 μmol) and a solution of 1-(but-3-ynyl)benzene (250 mg, 1.92 mmol) in DMF (0.5 mL). The reaction mixture was stirred for 25 min at 120° C. in the microwave cavity. The reaction was quenched as described in Example 1. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 163 mg (0.66 mmol, 40%) of 2-(4-phenylbut-1-ynyl)benzo[d]oxazole as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](C(OCC)=O)=[CH:10][NH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(CN)O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][NH:11][C:12]=2[S:13][C:14]([F:16])([F:15])[F:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]c(SC(F)(F)F)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCO
Solvent: ClCCl
Product: FC(F)(F)Sc1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A solution of ethyl 4-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole-3-carboxylate (8.0 g, 0.023 mol) in 10% aqeuous sodium hydroxide solution is refluxed for several hours, stirred at room temperature overnight, poured into ice-water, treated with concentrated hydrochloric acid and extracted with ether. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown semi-solid. A solution of the semi-solid (6.9 g) in ethanolamine is heated at 110° C. for several hours, poured into ice-water and extracted with chloroform. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown oil. The oil is dissolved in methylene chloride, filtered through a bed of silica gel and the filtrate is concentrated in vacuo to obtain the title product as a grey semi-solid (4.8 g, mp 44°-46° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[N:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[N:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ncc2ccc([N+](=O)[O-])cc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncc2ccc(N)cc2n1
Reaction time: 6 h
Yield: 92.2 %

Procedure:
Compound 25A (0.400 g, 2.12 mmol) was dissolved in EtOAc (20 mL) and Pd/C (10% Pd, 0.045 g) was added. Hydrogen was then introduced to the flask with a balloon. After 6 h, the reaction was filtered through celite rinsing with EtOAc. Concentration in vacuo gave compound 25B as a yellow solid (0.311 g). This was taken on without purification to subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:26])[F:25])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.CCOCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:25])[F:26])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(Br)ccc1OC(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (3.60 g, 0.025 mol) in anhydrous 1,2-dimethoxyethane (8 ml) is added sodium methoxide (1.51 g, 0.028 mol) in one portion. After stirring at this temperature for 5 minutes a solution of 5-bromo-2-difluoromethoxy-benzaldehyde (5.66 g, 0.023 mol) in 1,2-dimethoxyethane (8 ml) is added dropwise over 10 mins, followed by stirring at 0° C. for a further 1 hour. After warming to room temperature the reaction mixture is diluted with ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulfate and evaporated in vacuo to afford 4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (8.89 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1
Reactant: Nc1cccc2cccnc12
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Product: COc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 56.5 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (220 mg, 2 mmol) and 4-methoxy-2-nitrobenzene-1-sulfonyl chloride (420 mg, 2 mmol) gave the title compound (406 mg, 74%) after purification by column chromatography with heptane/EtOAc (50:50-0:100) gradient elution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccccc2)ccc1Cl
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Two portions of 4-Chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) were dissolved in CH2Cl2 (7.0 mL) in reaction flasks. Aniline (757 mg, 8.13 mmol) was added drop-wise at room temperature, followed by slow additions of pyridine (2.0 mL). After 16 h of continued stirring, the reaction mixtures were diluted with ethyl acetate (50 mL) and washed with 1 M HCl (3×50 mL). The organic phases were dried (MgSO4) and evaporated to brown solids, which upon re-crystallization from ethanol/water gave off-white solid of the product 2.04 g (96%): 1H NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H), 7.80 (dd, 1H), 7.61 (d, 1H), 7.30 (t, 2H), 7.20 (t, 1H), 7.09 (d, 2H), 6.79 (bs, 1H); MS (CI) 310.8 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:56]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:49])=[CH:44][C:43]=5[CH3:56])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N2CCOCC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCOCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-morpholin-4-yl-methanone (159 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-137) as a brown powder (58 mg, 62%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C@@H:7]1([NH2:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C@@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×10 mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([Sn](CCCC)(CCCC)[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[S:22]1[C:18]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:19][N:20]=[CH:21]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2cncs2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available ethyl 3-iodobenzoate (1.000 g; 3.62 mmol), 5-(tributylstannyl)thiazole (1.355 g; 3.62 mmol), and PdCl2(PPh3)2 (254 mg; 0.36 mmol) in anh. THF (20 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded ethyl 3-(thiazol-5-yl)benzoate as a pale yellow solid. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 233.94 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]>>[F:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([C@H:17]3[CH2:18][CH2:19][C@H:14]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]3)=[CH:25][CH:24]=2)[N:3]=1
Reactant: Fc1cncc(Cl)n1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3cncc(F)n3)cc2)CC1

Procedure:
In an analogous reaction to Example 1b, 2.17 g (16.41 mmol) of 2-chloro-6-fluoropyrazine (prepared as described in Example 1a) and 4.50 g (16.41 mmol) of 4-(trans-4-pentylcyclohexyl)phenylboronic acid gives 3.36 g of 2-fluoro-6-[4-(trans-4-pentylcyclohexyl)-phenyl]pyrazine. ##STR19## 3b
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:5]([CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[O:21][CH3:22].[F-].[K+].[F:25][C:26](I)([F:28])[F:27].O>CN(C=O)C.[Cu]I>[CH:18]([C:5]1[CH:4]=[C:3]([O:21][CH3:22])[C:2]([C:26]([F:28])([F:27])[F:25])=[CH:7][C:6]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:20])[CH3:19]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Reactant: FC(F)(F)I
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(F)(F)F
Yield: 107.9 %

Procedure:
To a hot mixture of 1-Iodo-4-isopropyl-2-methoxy-5-(toluene-4-sulfonyl)-benzene (0.5 g, 1.12 mmol), CuI, KF in anhydrous DMF (10 ml) at 120° C. oil bath temperature, was added trifluoromethyl iodide (0.64 g, 4.48 mmol) in portions over 30 min. The reaction mixture was heated for 4 hrs and poured into H2O (100 ml). The insoluble solid, which was collected by filtration was triturated with methylene chloride, filtered and concentrated to give 1-Isopropyl-5-methoxy-2-(toluene-4-sulfonyl)-4-trifluoromethyl-benzene (0.45 g, 100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11]O)[C:6]=2[CH:13]=1.N1C=CC=CC=1.S(Cl)([Cl:22])=O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11][Cl:22])[C:6]=2[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1=CCOc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: ClCC1=CCOc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2.86 g of 6-chloro-4-hydroxymethyl-2H-1-benzopyrane in 50 ml of ether is reacted with 2 ml of pyridine. To the resulting mixture are then slowly added dropwise, with cooling by ice/water, 1.71 g of thionylchloride in 10 ml of diethylether. Reaction is continued for 5 hours at room temperature, the mixture poured onto ice/water and the ether phase separated. This is then washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and concentrated by evaporation. The product is used directly for further reaction.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]2[O:9][C:10]([CH3:25])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>O1CCCC1>[C:3]([C:5]1[CH:27]=[CH:26][C:8]2[O:9][C:10]([CH3:25])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2oc(C)c(Cc3ccc(-c4ccccc4)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc2ccc(C(=O)O)cc2c1Cc1ccc(-c2ccccc2)cc1
Yield: 54 %

Procedure:
5-(Methoxycarbonyl)-2-methyl-3-(4-phenylbenzyl)benzo[b]furan (1.31 g) was refluxed for 1 hr in a mixed solution of a 10% aqueous solution (10 ml) of sodium hydroxide, methanol (10 ml) and tetrahydrofuran (10 ml). The reaction mixture was concentrated and concentrated hydrochloric acid was added to acidify the solution. The precipitated solid was collected by filtration, washed with water and diisopropyl ether and dried to give the objective compound (0.68 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][O:20][C:15]3=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][O:20][C:15]3=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCO3
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCO3
Yield: 87.9 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.52 mL, 4.8 mmol) was added to a stirred solution of chloride 222 (359 mg, 1.6 mmol) in DME (40 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 223 (390 mg, 88%) as a yellow solid: mp (MeOH/DCM) 192-194° C.; 1H NMR δ 7.45 (s, 1H, H-9), 7.35 (br s, 1H, NH), 6.96 (s, 1H, H-5), 6.23 (s, 2H, H-7), 3.35-3.39 (m, 2H, CH2N), 2.42 (t, J=6.7 Hz, 2H, CH2N), 2.18 [s, 6H, N(CH3)2]; 13C NMR δ 158.9, 155.2, 148.7, 146.9, 125.3, 103.2, 101.6, 95.9, 57.8, 45.2 (2), 38.6. Anal. calcd for C12H15N5O3: C, 52.0; H, 5.5; N, 25.3. Found: C, 52.1; H, 5.5; N, 25.3%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]([F:15])[F:14])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)Oc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 3-bromophenol (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (2.82 g, 18.49 mmol) and Cs2CO3 (4.82 g, 14.79 mmol). The reaction mixture was heated at 100° C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re-extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T18.1 as an oil that was used without further purification (yield 61%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]1=[O:20])[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:20])[CH3:2]
Reactant: [H][H]
Reactant: CCn1c(=O)ccc2cnc(Nc3ccccc3)cc21
Agent: [Ni]
Solvent: CCO
Product: CCN1C(=O)CCc2cnc(Nc3ccccc3)cc21
Yield: 12.9 %

Procedure:
A suspension of 1-ethyl-7-phenylamino-1H-[1,6]naphthyridin-2-one from Example W (75 mg, 0.29 mmol), 0.6 g of Raney nickel, and 50 mL of ethanol was stirred under 50 psi of hydrogen at room temperature for 23 hours. The suspension was filtered and the filtrate was concentrated to a solid residue that was purified by preparative thin layer chromatography to give 1-ethyl-7-phenylamino-3,4-dihydro-1H-[1,6]naphthyridin-2-one (10 mg, 13% yield): mp 137-138° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:35]([NH2:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(Cl)Cl>[CH2:35]([NH:42][C:9](=[O:11])[C:8](=[O:12])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCNC(=O)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A suspension of phenylpyruvic acid (2.1 g; 12.8 mmol) in DCM (50 ml) was cooled to 0° C. Then EDCl (3 g, 15.6 mmol) and HOBt (0.2 g, 1.5 mmol) were added successively. The resulted solution was cooled to −5° C. and then heptylamine (1.5 g, 13 mmol) was added dropwise at temperature below 0° C. Upon the addition the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into 1% aqueous hydrochloric acid solution (30 ml). The DCM phase was washed with water and concentrated in vacuum. The crude product was chromatographed on a silica gel column using ethylacetate/hexane (1:2) as eluent to provide the title compound (0.8 g, 24% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.[CH2:8]=[O:9]>CO>[OH:9][CH2:8][N:4]1[CH:5]=[C:6]([CH3:7])[C:2]([CH3:1])=[N:3]1
Reactant: Cc1c[nH]nc1C
Reactant: C=O
Solvent: CO
Product: Cc1cn(CO)nc1C
Yield: 95 %

Procedure:
96 g (1.0 mol) of 3,4-dimethylpyrazole in 50 ml of methanol were dissolved in 100 g (1.0 mol) of formalin solution (30%) at room temperature. Water and methanol were then evaporated. The title compound remained as a white solid (yield 95%).