Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:19](NC1C=CC(N)=CN=1)(=[O:21])[CH3:20]>C(O)C>[CH2:19]([O:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1)[CH3:20]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Solvent: CCO
Product: CCOC1=C/C(=C2/C(=O)NN=C2C)Nc2ccccc21
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one (0.033 g, 0.13 mmol) and 2-acetamido-5-aminopyridine (Matrix) (0.058 g, 0.38 mmol) were dissolved in ethanol (1.5 mL). The reaction mixture was heated to 180° C. using a microwave reactor for 6 hrs. The mixture was concentrated and purified by LC-MS to give the title compounds of Example 4 and Example 5.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:6][CH:7]([CH3:9])C)[CH2:4][SH:5].[CH2:12](C(C(OCC)=O)C(OCC)=O)CCC>>[OH:11][CH2:10][C:3]([CH2:2][OH:1])([CH2:6][CH2:7][CH2:9][CH3:12])[CH2:4][SH:5]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Reactant: CC(C)CC(CO)(CO)CS
Product: CCCCC(CO)(CO)CS

Procedure:
2,2-di-hydroxymethyl-hexan-1-thiol was prepared in an analogous manner to 2,2-di-hydroxymethyl-4-methyl-pentan-1-thiol starting from diethyl n-butylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=c1ncc(Br)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Br)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 5-bromopyrimidin-2-one (700 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C. and the precipitate collected. The dried solid was crystallised from ethanol to give the title pyrimidinone (475 mg), m.p. 180°-182° C. (dec), λmax (EtOH) 250.5 nm (ε 14,930), 334.5 nm (ε 3,260).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:33][OH:34])=[C:29]([CH3:32])[CH:30]=3)[N:25]=[C:24]([Cl:35])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:39]=[C:40](O)[CH:41]=[CH:42][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[N:15]1([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:33][O:34][C:42]4[CH:41]=[CH:40][CH:39]=[C:38]([C:37]([F:46])([F:45])[F:36])[CH:43]=4)=[C:29]([CH3:32])[CH:30]=3)[N:25]=[C:24]([Cl:35])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1CO
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1COc1cccc(C(F)(F)F)c1
Yield: 79.7 %

Procedure:
Diisopropylazodicarboxylate (66 mg, 0.33 mmol) was added dropwise at r.t. to a solution of (4-Azepan-1-yl-2-chloro-6-methyl-quinolin-7-yl)-methanol (example 82, 100 mg, 0.33 mmol), 3-trifluoromethylphenol (53 mg, 0.33 mmol), and triphenylphosphine (86 mg, 0.33 mmol) in dichloromethane (2 mL), then after 2 h ethyl acetate was added and the solution was washed with 1 M aq. sodium hydroxide solution and brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) yielded the title compound (118 mg, 80%). White solid, ISP-MS: m/e=449.4 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12].Cl>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCl and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): 1H-NMR (d6-DMSO, 300 MHz) δ12.24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7.12–7.42 (m, 10H), 4.82 (s, 1H); Rf=0.60 (6:1 Hex:EtOAc).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:13].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Cl:13][C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:14]#[N:15])=[CH:3][C:2]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([F:16])[CH:18]=1)=[CH:11]2
Reactant: COc1ccc(B(O)O)cc1F
Reactant: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Product: COc1ccc(-c2cc(C#N)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.20 g, 0.71 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol) according to Method A to yield 0.14 (60%) of a yellow solid: mp 198-200° C.;1H NMR (DMSO-d6): δ 3.91 (3H, s), 7.27-7.33 (1H, m), 7.45 (1H, d, J=8.93 Hz), 7.71-7.74 (1H, m), 7.85 (1H, dd, J=2.23 Hz, J=13.09 Hz), 8.00 (1H, d, J=9.08 Hz), 8.48 (1H, d, J=1.97 Hz), 8.57 (1H, d, J=1.95 Hz), 11.18 (1H, s); MS (ESI) m/z 326/328 (M−H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]([CH3:30])[CH:26]=[CH:27][CH2:28][OH:29])=[CH:22][CH:21]=1>CS(C)=O>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:30])[CH:26]=[CH:27][CH2:28][OH:29])=[CH:31][CH:32]=1)[CH:11]=[N:10]2
Reactant: CC(C=CCO)Oc1ccc(O)cc1
Reactant: Fc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of 1.28 g (7 mmol) of 2-chloro-6-fluoroquinoxaline, 1.16 g (8.4 mmol) of anhydrous, powdered potassium carbonate, 1.55 g (8 mmol) of 4-(4-hydroxyphenoxy)-2-penten-1-ol and 20 ml of DMSO was warmed, under nitrogen, at 110° C. for a period of 2 hours. The mixture was cooled to room temperature, poured into dilute, aqueous HCl and extracted with two portions of ether. The combined organic layers were washed twice with 1 percent aqueous NaOH and with water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with 3:1 hexane:acetone. After removal of solvent the resulting tan crystals were recrystallized from methylcyclohexane to give 1.05 g of crystals which were further purified by recrystallization from toluene to leave nearly colorless crystals, m.p. 109°-111° C. (Compound F)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][CH2:29][C:3]1=2.[ClH:37]>CO>[ClH:37].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][CH2:29][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCCNC5)c(=O)c2)cn1
Temperature: 25 °C
Reaction time: 36 h
Yield: 85 %

Procedure:
tert-Butyl 6-methyl-8-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (50 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and the resulting solution was stirred at ambient temperature for 36 h. The solution was partially concentrated under reduced pressure and diluted with Et2O. The resulting solids were collected by filtration and washed with 99:1 CH2Cl2/MeOH to provide the title compound (37 mg, 85%) as a tan solid: mp 245-250° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 9.10 (br s, 2H), 9.04 (s, 1H), 8.44 (s, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.58 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J=7.0 Hz, 1H), 4.45. (s, 2H), 3.74 (s, 3H), 3.45-3.44 (m, 2H), 3.11-3.09 (m, 2H), 2.66 (s, 3H), 2.08-2.07 (m, 2H); ESI MS m/z 385 [M+H]+; HPLC (Method A) 97.9% (AUC), tR=8.9 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10]3)[CH:2]=1.C(N)CN>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(-c3cccnc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: c1cncc(-c2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
5-Pyridin-3-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (Preparation #17c, 100 mg, 0.31 mmol) and ethylenediamine (133 μL, 2.00 mmol) were dissolved in 1M tetrabutylammonium fluoride in THF (4.0 mL) and the mixture was heated at reflux for about 2 hours. The reactions was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (25 mL), washed with water (2×10 mL) and concentrated under reduced pressure. The crude product was further purified by reverse phase preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) to yield 5-pyridin-3-yl-1H-indazole (61 mg, 64%) as an off-white solid. RP HPLC (Table 1, Method e) Rt=1.65, m/z: (MH)+ 196.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[N:21]1([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1CCCC1=O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:28]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CN1CCCC1=O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCOCC4)c3)nn12
Temperature: 140 °C
Yield: 9.3 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000261 mol) and 3-Morpholin-4-yl-phenylamine (93.0 mg, 0.000522 mol) were dissolved in N-Methylpyrrolidinone (2.0 mL) and the reaction was heated at 140° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 9.70 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as a lyophilated powder. (M+H)=402.20. 1H NMR (400 MHz, DMSO, d6) δ 9.23 (s, 1H), 8.94 (s, 1H), 7.70 (d, 1H, J=7.84 Hz), 7.46 (m, 1H), 7.34 (s, 1H), 7.19 (d, 1H, J=7.83 Hz), 7.08 (m, 3H), 6.90 (m, 2H), 6.87 (m, 1H), 3.75 (s, 3H), 3.63 (m, 4H), 2.83 (m, 4H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:23])[CH:4]([S:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:24](O)(=[O:35])[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([S:10]([CH:4]([C:3](=[O:23])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:24]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[O:35])=[O:11])=[CH:17][CH:16]=1)[C:20]#[C:21][CH3:22]
Reactant: CC#CCOc1ccc(S(=O)C(CCCCN)C(=O)NO)cc1
Reactant: O=C(O)c1ccc2ccccc2n1
Product: CC#CCOc1ccc(S(=O)C(CCCCNC(=O)c2ccc3ccccc3n2)C(=O)NO)cc1

Procedure:
6-Amino-2-(4-but-2-ynoxy-benzenesulfinyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with quinaldic acid (1.2 g, 4.0 eq) according to the procedure in Example 13, Step E to give quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide resin.
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:32][CH:33]([CH3:35])[CH3:34]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC1C(=O)N(NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 3-E) in DMF was treated with Cs2CO3 (0.22 g, 0.678 mmol) and warmed to 60° C. To the reaction mixture was added 1-iodo-2-methylpropane (0.078 mL, 0.678 mmol) and stirring continued for 17 hours. After cooling to 23° C. the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3/MeOH 9:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNC(=O)Nc1ccccc1)CCCC3
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (919 mg, 2.76 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (300 μL, 2.76 mmol) and Et3N (0.77 mL, 5.51 mmol) and allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O (30 mL) and a few drops of MeOH. The solid was isolated by filtration and dried under vacuum to give 460 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea as a white powder. m.p. 180-182° C.;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[S:38]1[CH:42]=[C:41]([CH2:43][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:43]/[C:41]4[N:40]=[CH:39][S:38][CH:42]=4)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2cc(/C=C/c3cscn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (1.00 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.27 g), potassium carbonate (0.44 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-5-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.77 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: [N:1]1([C:7]#[N:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:9][O-:10].[Na+]>CO>[N:1]1([C:7](=[NH:8])[O:10][CH3:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CN1CCOCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCOCC1

Procedure:
In the manner given in Example 2, 4-morpholinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-morpholinecarboximidate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:37])([CH3:36])[C:33](=[O:38])[C:32]=4[C:39]=3[CH3:40])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.O>C1COCC1>[OH:38][C:33]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:32]2[C:39]([CH3:40])=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]=2[O:35][C:34]1([CH3:37])[CH3:36]
Reactant: Cc1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
n-Butyllithium (hexane solution 1.50 M, 3.40 mL, 5.10 mmol) was added dropwise to solution of 4-bromotoluene (1.10 g, 6.43 mmol) in THF (10 ml) under a stream of argon at −70° C. or less and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (1.00 g, 2.5 mmol) obtained in Reference Example 13 in THF (3 ml) at −70° C. or less and the mixture was allowed to warm to 0° C. After stirring under ice cooling for 30 minutes, the resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 1.11 g (yield 90%) of the title compound via recrystallization (ethyl acetate-hexane). mp. 145–147° C.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH:20]=[C:3]([C:2](=[O:1])[CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)OCc1ccccc1
Product: CC(=O)C(=CN(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred benzyl 3-oxobutanoate (1.1 g, 5.7 mmol), dimethylformamide dimethylacetal (1 mL, 7.4 mmol) was added dropwise at room temperature. The mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was azeotroped with toluene (3×10 mL) to provide compound D27-1 as a brown oil (1.4 g, quant.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:5]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CSc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 45 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-methylthiophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (78 mg, 45%) which was obtained as a white solid. MS (ESI): m/e=348.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[F:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:14][CH3:13])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc2ncc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(F)cc2n1
Yield: 93.5 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoxaline (0.1 g, 0.54 mmol) in methanol (15 ml) was added sodium methoxide (0.29 g, 0.54 mmol) at room temperature under nitrogen atmosphere. The reaction mass was heated at reflux for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound 7-fluoro-2-methoxyquinoxaline (0.09 g, 88% yield) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.41 (s, 1H), 8.01-7.98 (d, J=12 Hz, 1H), 7.49-7.46 (d, J=12 Hz, 2H), 7.34-7.3 (m, 1H), 4.09-4 (s, 3H); 19F NMR: δ ppm −108.99 (1F).