Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: OB(O)c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ccc([N+](=O)[O-])cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
[Ref. Mederski, W. W. K. R., et al. Tetrahedron, 1999, 55, 12757-12770.] To a solution of 2-hydroxy-5-nitropyridine (1.07 g, 7.64 mmol) in dry methylene chloride (50 mL) were added phenylboronic acid (1.86 g, 15.3 mmol), cupric acetate (1.71 g, 9.41 mmol), pyridine (1.2 mL, 15.3 mmol), triethylamine (2.1 mL, 15.3 mmol) and activated 4 Å molecular sieves (2 g). The resulting mixture was stirred in air at rt for 2 d. The mixture was then filtered through celite and washed with methylene chloride. The crude material was purified by silica gel chromatography, eluting with CH2Cl2:EtOAc (85:15) to give the title compound as a white solid. LC-MS (ES, Pos.): 217 [MH+], and 1H NMR (CDCl3, 400 MHz): δ=6.67 (d, J=10.1 Hz, 1H), 7.39-7.42 (m, 2H), 7.53-7.58 (m, 3H), 8.17 (dd, J=10.1, 3.1 Hz, 1H), 8.67 (d, J=3.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:15][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]([F:55])([CH2:53][NH2:54])[CH2:51][NH2:52].CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1.C(Cl)Cl>[NH2:52][CH2:51][C:50]([F:55])([F:49])[CH2:53][NH:54][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][CH2:12][C:13]2[S:17][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:15][CH:14]=2)[CH:4]=1
Reactant: NCC(F)(F)CN
Reactant: O=C(O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCC(F)(F)CNC(=O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
To a mixture of 4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzoic acid (compound 52A, 21 mg, 0.06 mmol) and HATU (38 mg, 0.1 mmol) in DMF (0.2 ml) and THF (0.4 ml), were added 2,2-difluoro-1,3-propanediamine (ref. Tetrahedron, 8617, 1994) (60 mg, 0.54 mmol) and DIPEA (26 mg, 0.2 mmol). The resulting mixture was stirred at RT for 18 h, then diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography [silica gel, 5% (NH3/MeOH(2M) in EtOAc] to afford the title compound (17 mg, 65%) as a white solid. LC/MS; (M+H)+=437.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[N:28][C:29]=3[CH3:30])=[O:23])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=O)C.Cl>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:29]([CH3:30])=[N:28][CH:27]=[N:26][C:25]=3[CH3:31])=[O:23])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a solution of COMPOUND 111 (880 mg, 1.59 mmol) in MeOH (10 mL) was added 6N HCl (20 mL) and the solution was stirred at room temperature for 18 hours and heated at 40° C. for 3 hours to give 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide as a white solid (813 mg, 100%) following a basic work-up.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Clc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (28.5 mg, 0.0529 mM), then 4-chloro-benzaldehyde (7.4 mg, 0.053 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered, the resulting solid was diluted with a saturated aqueous sodium bicarbonate solution and then the solution was extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (13.0 mg, yield: 57%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[NH:10][CH:11]([CH2:31]OS(C1C(C)=CC=CC=1)(=O)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][S-:45].[Na+]>C(O)C.CO>[CH2:1]([O:8][C:9](=[O:43])[NH:10][CH:11]([CH2:31][S:45][CH3:44])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: Cc1ccccc1S(=O)(=O)OCC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CSCC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-toluenesulfonyloxymethylethylcarbamic acid benzyl ester 2.4 g, 3.99 mmol) in ethanol (40 ml), a solution of sodium methanethiolate (560 mg, 7.99 mmol) in methanol (4 ml) was added and stirred at 40° C. for 3 hours. The mixture was evaporated under reduced pressure to remove the solvent, mixed with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=5:1), giving the titled compound (1.63 g, 86%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](B(O)O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].Br[C:19]1[N:20]=[CH:21][NH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Brc1c[nH]cn1
Reactant: CCCCNc1ccc2ncc(B(O)O)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCNc1ccc2ncc(-c3c[nH]cn3)n2n1
Temperature: 140 °C
Yield: 74.1 %

Procedure:
A mixture of (6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)boronic acid (120 mg, 0.5 mmol), 4-bromo-1H-imidazole (75 mg, 0.5 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (40 mg, 0.050 mmol), potassium phosphate (210 mg, 1.0 mmol), DME (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 140° C. for 600 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford butyl-[3-(1H-imidazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine (95 mg, 72%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.99 (br. s., 1H), 7.82 (d, J=1.0 Hz, 2H), 7.60 (d, J=9.6 Hz, 1H), 6.68 (d, J=9.6 Hz, 1H), 3.44 (t, J=7.1 Hz, 2H), 1.69-1.82 (m, 2H), 1.46-1.60 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); LCMS (ESI) m/e 257.2 [(M+H)+, calcd for C13H17N6 257.1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2cccc(F)c2)nc2nccnc12
Reactant: Nc1ccncc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1cccc(-c2nc(Nc3ccncc3)c3nccnc3n2)c1

Procedure:
The title product was synthesized by reaction of the 2-(3-fluorophenyl)pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)-amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [N+:1](/[CH:4]=[C:5]1\[NH:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][CH2:11]\1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][CH2:11][CH:5]1[CH2:4][NH2:1]
Reactant: O=[N+]([O-])/C=C1/CCCc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCCc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 182D (0.643 g, 3.15 mmol) in tetrahydrofuran (31.5 mL) under argon was added dropwise lithium aluminum hydride in tetrahydrofuran (9.45 mL, 18.89 mmol), and the mixture was stirred at room temperature for 30 minutes. Water was added carefully and the mixture was extracted once with dichloromethane. The organic extract was dried over Na2SO4, and the solvent was evaporated to obtain the crude title compound which was used was used without purification for the next reaction. MS (ESI+) m/z 177.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=[O:27])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9].[OH-].[Li+]>C1COCC1.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][C@@H:25]([CH3:30])[C:26]([OH:28])=[O:27])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9]
Reactant: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(C(=O)N2CCCC2(C)C)c(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cc1-c1ccc(C(=O)N2CCCC2(C)C)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a vigorously stirred slution of the product from step e) (307 g) in THF (3 L) was added a solution of lithium hydroxide (148 g) in water (0.6 L) and the reaction stirred at RT for 45 min. Aqueous 20% brine solution (2.5L) was added and the layers separated. The organic fraction was concentrated in vacuo, the residue re-dissolved in water (6 L) and the stirred mixture acidified to pH 1 with conc HCl. The resulting precipitate was filtered and washed with portions of water until the filtrate was pH 6. Iso-hexane was eluted through the filter cake to remove excess water and the solid was dried in a vacuum oven for 48 h at 40° C. to give the title product in crude form (259 g).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=[O:28])[O:26]1>C(Cl)(Cl)Cl>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27](=[O:28])[O:26]2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6.3 g of 4-biphenylylacetic acid in 30 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, gives the phthalidyl 4-biphenylylacetate.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C1(C)C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([C:32](=O)[CH2:33][CH3:34])[CH:28]=[C:29]([F:31])[CH:30]=1>C(OCC)(=O)C>[F:24][C:25]1[CH:26]=[C:27]([C:32]2([CH2:33][CH3:34])[O:4][CH2:1][CH2:2][O:3]2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CCC(=O)c1cc(F)cc(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC1(c2cc(F)cc(F)c2)OCCO1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Ethylene glycol (773 mg) and a catalytic amount of tosylic acid monohydrate were added to a toluene (20 ml) solution of 1-(3,5-difluorophenyl)propan-1-one (1.06 g). A Dean-Stark tube was attached to the reactor, the reaction liquid was stirred overnight with heating under reflux, then diluted with ethyl acetate, and washed with aqueous saturated sodium hydrogencarbonate solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain the entitled compound (1.31 g) as a colorless oil.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([Cl:30])[CH:18]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:30][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:16][NH2:15]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CN)cc1Cl
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add 4N hydrogen chloride in dioxane (0.9 mL, 3.6 mmol) to a solution of N-(tert-butoxycarbonyl)-3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine (100 mg, 0.3 mmol) in dichloromethane (6 mL) and stir overnight. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid into saturated aqueous NaHCO3 and stir for 30 min. Extract twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (66 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:23][NH:24][C@H:25]1[C@H:29]([S:30][CH3:31])[CH2:28][NH:27][CH2:26]1>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:27]3[CH2:28][C@@H:29]([S:30][CH3:31])[C@H:25]([NH:24][CH3:23])[CH2:26]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Reactant: CN[C@@H]1CNC[C@H]1SC
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NC)[C@H](SC)C3)ccc2c1=O

Procedure:
With use of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester obtained in Example A-1 (4) and trans-3-methylamino-4-methylthiopyrrolidine, there was obtained 1,4-dihydro-7-(trans-3-methylamino-4-methylthio-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester in the same manner as in Example C-1 (1).
Reaction SMILES: [O:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[CH2:19]=[O:20].C([O-])([O-])=O.[K+].[K+].Cl.[Na+].[Cl-]>CCO>[OH:20][CH2:19][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])[C:2](=[O:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=O
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(CO)C(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
tert-butyl 1-oxo-1-phenylpropan-2-ylcarbamate (40) (1.3 g, 5.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (39 mL). Next, a 37% solution of formaldehyde (8.1 mL, 100 mmol, 20.0 equiv.) was added to the reaction mixture and the solution heated to 35° C. Finally, a 0.5 M solution of K2CO3 (350 mg, 2.5 mmol, 5.0 mL dH2O, 0.5 equiv.) was added to the reaction flask and the solution stirred vigorously for 24 h. The solution was neutralized with 1% HCl, transferred to a separatory funnel with a 1.7 M solution of NaCl (5.0 g, 85.0 mmol, 50 mL H2O), and extracted with CH2Cl2 (5×50 mL). The organic layers were combined and dried over Na2SO4. The resulting solution was concentrated on a rotary evaporator and dried under vacuum to give a crude oil. The residue was purified by flash column chromatography (30% EtOAc/Hexanes) to give 1.1 g (79%) of 41 as a colorless oil. Rf=0.29 (50% EtOAc/Hexanes); IR (film) 3352, 2977, 1684, 1367, 1166 cm−1; 1H NMR (500 MHz, CDCl3) δ Major Rotamer: 8.00 (br s, 2H, Ph-H), 7.42 (br s, 3H, Ph-H), 5.87 (br s, 1H, carbamate-NH), 5.49 (br s, 1H, Boc-NH—CH), 4.12 (m, 2H, C—CH2), 3.76 (m, 2H, C—CH2), 3.32 (br s, 2H, CH2—OH), 1.63 (s, 3H, C—CH3), 1.26 (s, 9H, t-butyl-CH3). Minor Rotamer: 8.15 (br s, 2H, Ph-H), 7.51 (br s, 3H, Ph-H), 5.82 (br s, 1H, carbamate-NH), 3.09 (br s, 2H, CH2—OH), 1.09 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) Major Rotamer: δ 202.8, 155.1, 132.9, 128.5, 128.3, 80.5, 67.9, 64.4, 28.2, 21.6; LRMS (ESI-MS m/z): Mass calcd for C15H21NNaO4 [M+Na]+, 302.32. Found 302.
Reaction SMILES: Cl[CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].C[O-].[Na+].C[CH2:17][O:18]C(C)=O>CO>[CH3:17][O:18][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(Cl)c1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)c1nc2ccccc2[nH]1

Procedure:
2-(1-chloroethyl)-1H-benzo[d]imidazole (0.39 g) and 25 wt % solution of Sodium Methoxide in Methanol (0.96 mL) in 10 mL of Methanol was heated for 20 minutes at 150° C. in a microwave synthesizer. The reaction mixture was extrated with EtOAc and sat NH4 chloride. The organic layer was dried, filtered and concentrated to afford crude 2-(1-methoxyethyl)-1H-benzo[d]imidazole in quantitative yield.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (277 mg, 0.156 mmol) was reacted with the product from Example 4c (361 mg, 0.156 mmol) for 5 h by the procedure in Example 1g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (231 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3H) 2.77 (s, 3H) 6.29 (d, J=6.99 Hz, 1H) 6.73 (d, J=8.82 Hz, 2H) 7.01 (d, J=7.72 Hz, 1H) 7.19 (d, J=8.46 Hz, 2H) 7.24 (s, 1H) 7.27 (s, 1H) 7.81 (d, J=8.82 Hz, 1H) 8.44 (d, J=6.99 Hz, 1H) 9.01 (d, J=8.82 Hz, 1H) 9.91 (s, 1H) 11.03 (s, 1H) 14.38 (br. s, 1H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:25][C:26](=[O:35])[CH:27](Br)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:24]>CN(C)C=O>[CH2:23]([O:25][C:26](=[O:35])[CH:27]([N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:24]
Reactant: CCOC(=O)C(Br)C1CCCCC1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Temperature: 100 °C
Reaction time: 22 h
Yield: 58 %

Procedure:
To the solution of 1.0 g (4.4 mmol) 2-(4-chlorophenyl)benzimidazole (commercially available) in 10 mL N,N-dimethylformamide, 4.6 g (14.0 mmol) cesium carbonate and 3.3 g (13.1 mmol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added and the brown suspension was stirred for 22 h at 100° C. After cooling to room temperature the reaction was poured on water and extracted three times with ethyl acetate. The organic phases were washed with water and brine, dried over magnesium sulfate and filtered. To the filtrate silica gel was added and the solvent evaporated. The adsorbed crude product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate 100:0 to 50:50) to give the desired compound as a colorless solid (58%). MS (Turbo Spray): m/z=397.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:33])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 200.0 mg (0.418 mmol) of ethyl 4-[(5,6-dihydro-5,5- dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 199.4 mg (1.463 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 4.0 ml of THF, and 2-methylphenyl lithium (prepared by adding 133.9 mg (1.23 ml, 2.09 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (−78° C.) of 178.7 mg (1.045 mmol) of 2-methylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ 7.97 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.49-7.19 (6H, m), 6.81 (1H, d, J=1.6 Hz), 5.89 (1H, t, J=4.5 Hz), 4.36 (2H, q, J=7.1 Hz), 2.43-2.14 (2H, dq, J=3.7, 5.4 Hz), 2.15 (3H, s), 1.39-1.34 (9H, m).