Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][N:20]=[C:21]=[O:22]>C1COCC1>[O:22]1[CH2:18][CH2:19][N:20]=[C:21]1[NH:16][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: NC(Cc1ccc(F)cc1)c1ccccc1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: Fc1ccc(CC(NC2=NCCO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A solution of 2-(4-fluoro-phenyl)-1-phenyl-ethylamine (1.50 g) in THF was treated dropwise with 2-chloroethyl isocyanate (0.89 g) at 0° C. After stirring overnight at room temperature the solvent was evaporated and the residue dissolved in dimethoxy ethane (25 ml). DBU (1,8-diazabicyclo[5.4.0]undec-7-en) was added (1.78 g) and the reaction mixture heated under reflux for 1 hour. Column chromatography on silica yielded 1.3 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([CH:28]([OH:43])[CH:29]([NH2:42])[CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH2:38][CH2:39][CH3:40])[CH:34]=[C:33]([F:41])[CH:32]=2)[CH2:26][O:25][CH:24]([O:44][CH2:45][C:46]([CH2:50][F:51])([CH3:49])[CH2:47][F:48])[CH:23]1[CH3:52])=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH:27]([CH:28]([OH:43])[CH:29]([NH:42][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH2:38][CH2:39][CH3:40])[CH:34]=[C:33]([F:41])[CH:32]=2)[CH2:26][O:25][CH:24]([O:44][CH2:45][C:46]([CH2:50][F:51])([CH3:49])[CH2:47][F:48])[CH:23]1[CH3:52])=[O:21])([CH3:16])([CH3:18])[CH3:17]
Reactant: CCCOc1cc(F)cc(CC(N)C(O)C2COC(OCC(C)(CF)CF)C(C)N2C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1cc(F)cc(CC(NC(C)=O)C(O)C2COC(OCC(C)(CF)CF)C(C)N2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Add triethyl amine (0.025 mL) and acetic anhydride (0.013 mL) to a solution of 5-[2-amino-3-(3-fluoro-5-propoxy-phenyl)-1-hydroxy-propyl]-2-(3-fluoro-2-fluoromethyl-2-methyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (67 mg) in dichloromethane (2 mL). Stir at room temperature for 2 hours. Concentrate under reduced pressure and subject to silica gel chromatography, eluting with a linear gradient from hexanes to ethyl acetate to afford 5-[2-acetylamino-3-(3-fluoro-5-propoxy-phenyl)-1-hydroxy-propyl]-2-(3-fluoro-2-fluoromethyl-2-methyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (49 mg, 68%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:21][CH:22]=4)[CH2:27]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(cc1N1CCOCC1)CNCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(N3CCOCC3)cc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9](=[O:10])[N:8]=[C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[NH:6][C:5]=2[N:21]=1.N(OCCC(C)C)=O>O1CCCC1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][S:11][C:7]1[NH:6][C:5]2[N:21]=[CH:2][S:3][C:4]=2[C:9](=[O:10])[N:8]=1
Reactant: Nc1nc2[nH]c(SCc3cccc(F)c3F)nc(=O)c2s1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: O=c1nc(SCc2cccc(F)c2F)[nH]c2ncsc12
Temperature: 70 °C
Yield: 63.9 %

Procedure:
To a solution of the product from Example 3 (1.0 g) in tetrahydrofuran (50 ml) was added isoamyl nitrite (3 ml) and the mixture heated at 70° C. for 2 hours. The mixture was evaporated to dryness and purified (SiO2, ethyl acetate:chloroform 1:9 as eluant) to give the title compound (0.61 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[F:15])[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO>[CH:26]1([O:25][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:15])[CH2:7]2)=[O:30])[CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2cccc(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3cccc(F)c3C2)c1OC1CCC1
Temperature: 25 °C

Procedure:
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-4-fluoro-indan-2-carboxylic acid ethyl ester (7) (210 mg, 0.51 mmol) is dissolved in EtOH (50 mL) and set to stir at RT. To this solution is added 5M KOH (3 ml). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with concentrated HCl to pH 2. The resultant mixture is washed with EtOAc (3×100 ml). Organics are combined and washed with brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The desired product (267) is obtained as white solid (168 mg, 86%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].O=C1CCC(=O)N1O[C:16](=[O:34])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:19][CH:18]=1>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:22]=1)=[O:34]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from N,N,N′-trimethylethylendiamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, preparative HPLC (method C) (2%, colourless oil). HPLC-MS m/z=356.2 (M+1), Rt: 2.17 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(OC([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH2:22])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1O
Reactant: OCC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccccc1OCC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 236.4 %

Procedure:
To a solution of 1-(4-pyridyl)piperidin-4-ylmethanol (357 mg) and 2-tert-butyloxycarbonylaminophenol (328 mg) in tetrahydrofuran (15 ml) was added triphenylphosphine (447 mg) followed by diethyl azodicarboxylate (0.27 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to a gum which was purified by column chromatography on silica eluting with methanol/dichloromethane (10:90) to give the tert-butyloxycarbonyl protected derivative of 2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline (1.05 g);
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl.CCOC(C)=O>O.C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:24])=[O:4]
Reactant: COC(=O)CCCCCN(c1ccccn1)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCN(c1ccccn1)c1ccccn1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
LiOH (12 mg, 0.50 mmol) in water (0.3 mL) was added to II (33 mg, 0.11 mmol) in THF (0.8 mL) at rt. After 2 h, the reaction mixture was neutralized with 2N HCl, and was then poured onto brine (5 mL), and EtOAc (5 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (2×2 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:1 to 100:4) as eluant to furnish III as a colourless oil (18.1 mg, 58%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=2)[C:3]1=[O:15].[Br-].[Li+].[OH-].[Na+]>C(#N)C.CCCCCC>[OH:14][C:10]1[CH:9]=[C:8]([CH:4]2[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:15])[CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCCC(C2=CC(=O)CCC2)C1=O
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Product: CN1CCCC(c2cccc(O)c2)C1=O

Procedure:
1-Methyl-3-(3-oxocyclohexen-1-yl)-2-piperidone (3.5 g) was refluxed in acetonitrile (100 ml) in the presence of lithium bromide (1.4 g) and cupric bromide (7.6 g) for 0.5 hours. The acetonitrile was evaporated to give a gum, to which 2 N sodium hydroxide (100 ml) was added, the solution filtered, conc. HCl (30 ml) added to the filtrate, the aqueous extracted with chloroform, dried (MgSO4) and evaporated to give an oil, which on standing overnight, at 0° C., in hexane gave a yellow solid. This was collected, washed with ether then acetone to give the title compound as the quarter hydrate, a colourless solid (0.50 g) m.p. 111°-114° C.
Reaction SMILES: N1C=CC=CC=1.C1COCC1.[OH:12][CH2:13][C:14](=[O:16])[CH3:15].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:17]([O:12][CH2:13][C:14](=[O:16])[CH3:15])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 43 h
Yield: 87.8 %

Procedure:
To a pyridine (25 ml) and THF (10 ml) solution of hydroxyacetone (5 g, 67.5 mmol), benzoyl chloride (12 ml, 103 mmol) was added dropwise at 0° C. in a nitrogen atmosphere and the mixture was stirred for 43 hours at room temperature. Ice was added to the reaction mixture, which was then diluted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-1/1 gradient). Desired fractions were concentrated to obtain the title compound (10.56 g, 87.8% yield) as a light yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=6)=[CH:25][CH:26]=5)[NH:21][CH:20]=4)=[O:18])=[C:12]3[CH2:11][S:10]2)[CH:4]=1.[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.[Cl-].[Na+].O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=6)=[CH:25][CH:26]=5)[N:21]([CH2:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])[CH:20]=4)=[O:18])=[C:12]3[CH2:11][S:10]2)[CH:4]=1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
Sodium hydride (95%, 37.4 mg, 1.48 mmol) was added to a solution of 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (0.50 g, 1.14 mmol), prepared according to the method of Example 28, in DMF (30 mL). The reaction mixture was stirred for 30 min. at ambient temperature, and then methyl acrylate (0.40 mL, 4.56 mmol) was added. The reaction mixture was poured into brine and extracted three times with ethyl acetate. The combined organic layers where dried over MgSO4, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[1-(2-carbomethoxyethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (190 mg, 32%) was obtained by flash chromatography on silica gel (5 g, 40%, then 60%, then 80% ethyl acetate, hexanes). 1H NMR (CDCl3, 300 MHz) δ2.93 (t, 2 H, J=6, 8 Hz), 3.68 (s, 3H), 4.53 (dd, 3H, J=6, 11 Hz), 4.7 (dd, 1H, J=2, 15 Hz), 6.38 (d, 1H, J=3 Hz), 6.43 (s, 1H), 6.78 (d, 1H, J=3 Hz), 7.15 (t, 2H, J=9, 10 Hz), 7.35 (dd, 1H, J=5, 8 Hz), 7.5 (dd, 2H, J=3, 10 Hz), 7.6-7.1 (m, 3H), 7.95 (s, 1H), 8.45 (dd, 1H, J=1, 9 Hz), 8.6-8.68 (m, 2H). MS (DCI/MH3) m/e 526 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:36][CH2:37][CH2:38][CH2:39][OH:40]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:36]([CH2:37][CH2:38][CH2:39][OH:40])[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCCNCc1ccccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCCO)Cc2ccccn2)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C(NCC)C.C(Cl)CCl.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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CN1Cc2c(C#C[Si](C)(C)C)ncn2-c2ccc(F)cc2C1=O

Procedure:
67.8 g (190 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 8 hours with 23.4 g (238 mmol) of ethynyltrimethylsilane, 300 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 70 mg of copper(I) iodide in 280 ml of diethylamine and 25 ml of ethylene chloride. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with chloroform/ethyl acetate (3:1). By recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 184°-185°.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])C.Cl.C[C@@H]1CCCN1>CS(C)=O>[CH3:25][C@@H:23]1[CH2:24][CH2:22][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: C[C@@H]1CCCN1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (250 mg, 1.05 mmol) in DMSO (2 mL) was added DIEA (850 mg, 4.2 mmol), and (R)-2-methylpyrrolidine hydrochloride (300 mg, 2.35 mmol), and the resulting mixture was stirred for 3 h at 70° C. Then the reaction was quenched by the addition of water (10 mL). The solids were collected by filtration to afford (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (216 mg, 72%).
Reaction SMILES: N1CCCCC1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=O)[S:11][CH:12]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>C(Cl)Cl.C(OC(C)C)(C)C>[Br:7][C:8]1[CH:9]=[C:10](/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])[S:11][CH:12]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(O)/C=C/c1cc(Br)cs1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Piperidine (1.036 mL, 10.47 mmol) was added to a mixture of 4-bromothiophene-2-carbaldehyde (20 g, 105 mmol) and malonic acid (13.07 g, 126 mmol) at 80° C. under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 100° C. The reaction mixture was cooled to room temperature and extracted with EA/water. The organic phase was washed with 2N NaOH. The aqueous phase was acidified and a precipitate was formed. The solid was stirred in a mixture of DCM and diisopropyl ether (1:1). The solid was sucked off and dried under reduced pressure to give a bright beige solid (12.3 g, 50.4%).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([OH:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[P:26](=[O:44])(Cl)([S:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:26](=[O:44])([S:38][CH2:39][CH2:40][CH2:41][CH3:42])([O:18][C:7]1[C:8]2[C:17](=[CH:16][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1
Reactant: CCCCSP(=O)(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(O)c2cc3ccccc3cc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCSP(=O)(Oc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Nitro-1-anthrol (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-trifluoromethylphenyl) S-butyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-trifluoromethylphenyl) O-(4-nitro-1-anthryl) S-butyl phosphorothioate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17](=O)[C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1>>[CH3:22][O:21][C:20]1[CH:19]=[C:18]([C:17]2[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=2)[CH:27]=[CH:26][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Product: COc1ccc(-c2nc3cnc4ccccc4c3n2CC(C)C)cc1OC

Procedure:
Following the general method of Example 195, Step B, 3-amino-4-(isobutylamino)quinoline was reacted with veratraldehyde to provide 2-(3,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinoline, melting point 192°-199° C. Analysis: Calculated for C20H23N3O2 : % C, 73.1; % H, 6.4; % N, 11.6. Found: % C, 72.7; % H, 6.3; % N, 11.4.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12]O)[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]C(Cl)(Cl)C(Cl)(Cl)Br>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12][Br:39])[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(CO)cc2c(Br)ccc(OC(C)C)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)cc2c(Br)ccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
To a solution of 4.00 g (12.3 mmol) 1-bromo-7-hydroxymethyl-4-isopropoxy-5-methoxy-naphthalene in 40 mL dry dichloromethane, 3.24 g (12.3 mmol) triphenylphosphane and 4.00 g (12.3 mmol) 1,2-dibromotetrachloroethane were added under Ar. After stirring for 30 min at room temperature, the solvent was removed and subsequently the residue was filtered over a short silica gel column (petroleum/ethyl acetate, 4:1) to give 5.00 g (95%) 1-bromo-7-bromomethyl-4-isopropoxy-5-methoxy-naphthalene as a colorless solid (m.p. 126° C.).
Reaction SMILES: NCCOCCN.C([O-])(=O)C.C(=O)(O)[O-].[Na+].[CH2:17]([O:24][C:25]([NH:27][CH2:28][C:29]([O:31]C1C(F)=C(F)C(F)=C(F)C=1F)=[O:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1c(F)c(F)c(F)c(F)c1F
Agent: CC(=O)[O-]
Agent: NCCOCCN
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 56 %

Procedure:
The aminoethyl ether of Example 1 as the acetate (210 mg, 0.180 mmol) was dissolved in N,N-dimethylformamide (2 mL). To this solution 1M sodium bicarbonate (200 μL, 0.200 mmol) and pentafluorophenyl N-benzyloxycarbonylglycinate (106 mg, 0.270 mmol) were added. After 1 h, the reaction mixture was diluted with water (2×). Isolation by reverse-phase (C18) flash column chromatography eluting with 50-80% acetonitrile/water gave, after lyophilization of the product-containing fractions, the N-CBZ glycine conjugate of the above formula was obtained (130 mg):
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[C:36]([NH:35][C:33]1[N:34]=[C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]3[CH:23]=[C:22]([NH:21][C:7]([C:6]4[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=4)=[O:9])[CH:41]=[CH:40][CH:39]=3)=[N:31][N:30]2[CH:32]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: Cn1cncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cncn4C)c3)ccc2n1
Yield: 47.2 %

Procedure:
Using 1-methyl-1H-imidazole-5-carboxylic acid (80 mg, 0.64 mol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (111 μL, 1.27=mol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (150 mg, 0.53 mmol) and N,N-dimethylacetamide (3.0 mL) as starting materials and in the same manner as in Example 119, the title compound (98 mg, 47%) was obtained as a white powder.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[OH:20][CH2:21][CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCO)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-ethylamine and DIEA to give 2-(2-hydroxy-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 300 (MH+).