Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(F)cc1

Procedure:
The title compound, light yellow solid (92 mg, 82%), MS (ISP) m/z=449.3 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-fluoro-benzoic acid.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].N1C=CC=CC=1>ClCCl>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:25][CH2:21][CH2:22][C:23]#[CH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Triphenylmethyl chloride (122 g, 0.44 mol) is added to a solution of but-3-yne-1-ol (25 g, 0.36 mol) in dichloromethane (400 ml) containing pyridine (50 ml) and stirred overnight at room temperature. The reaction mixture is filtered and washed with cold dilute hydrochloric acid, aqueous sodium bicarbonate and water. The dried solution is concentrated to a solid which is crystallized from ether-petroleum ether to give 4-triphenylmethyloxybut-1-yne (60 g), m.p. 97°-99° (ether-petroleum ether).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([CH3:33])[CH:35]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)c1
Yield: 38.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-methylbenzylamine (available from Aldrich Chemical Company, Inc.; 75 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-methyl-benzylcarbamoyl)-biphenyl-2-carboxylic acid (46 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.07 (t, J=5.9 Hz, 1H), 8.46 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.19-7.26 (m, 1H), 7.11-7.18 (m, 2H), 7.07 (d, J=7.3 Hz, 1H), 4.48 (d, J=5.8 Hz, 2H), 2.30 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:12]2([CH3:11])[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:13]2)=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccc(C#N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a solution of p-cyanobenzaldehyde (1.6 g, 11.8 mM) and 2,5-dimethyl-2-(4-fluorphenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (75 mL), was added 1N aqueous sodium hydroxide (1.0 mL, 1 mM). After the reaction solution was stirred at room temperature for two days, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give an orange liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give a yellow crystalline solid (1.2 g, 38% yield), m.p. 140°-142° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:29][C@@H:30]([CH2:43][NH2:44])[CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:29][C@H:30]([CH2:31][O:32][C:33]1[C:41]2[NH:40][C:39](=[O:42])[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cccc(OC[C@@H](O)CNC3CCN(c4ccc(NS(=O)(=O)c5ccc(-c6ccccn6)s5)cc4)CC3)c2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 227) (0.21 g, 0.5 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) (0.11 g, 0.5 mmol) were mixed in dimethylformamide (10 mL) and then treated with sodium triacetoxyborohydride, (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The precipitate which formed was collected and purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the titled compound as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.40 (m, 2 H), 1.80–1.90 (m, 2 H), 2.50–2.90 (m, 5 H), 3.53 (brd, J=9.0 Hz, 2 H), 3.85–4.00 (m, 2 H), 4.00–4.10 (m, 1 H), 4.91 (brs, 1 H), 6.56 (d, J=5.7 Hz, 1 H), 6.61 (d, J=5.7 Hz, 1 H), 6.80–6.90 (m, 3 H), 6.96 (d, J=6.6 Hz, 2 H), 7.36 (dd, J=3.3, 1.2 Hz, 1 H), 7.41 (d, J=3.0 Hz, 1 H), 7.75 (d, J=3.0 Hz, 1 H), 7.88 (dd, J=6.0, 1.2 Hz, 1 H), 7.98 (d, J=6.0 Hz, 1 H), 8.54(d, J=3.3 Hz, 1 H), 10.60 (s, 1 H), 10.70 (s, 1 H); MS (ES) m/z: 621.0 (MH+); HRMS Calcd. for C30H33N6O5S2 (MH+): 621.1954. Found: 621.1952.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:32]=[C:31]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:30]=3)=[O:27])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:41]([C:31]1[CH:30]=[C:29]([NH:28][C:26](=[O:27])[NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:13]=3)=[CH:16][CH:17]=2)[N:33]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:32]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methoxyacetyl chloride (64.2 μl, 0.703 mmol) was added slowly to a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl) urea (8) (89 mg, 0.176 mmol) and DIPEA (153 μl, 0.878 mmol) in THF (5 mL). The reaction mixture was stirred at 0° C. for a further 20 min and then warmed to RT. After 2.5 hr, the reaction was quenched by the addition of a solution of 1% NH3 in MeOH (3 mL), and the resulting mixture stirred for a further 45 min. The volatiles were removed in vacuo and the residue was dissolved in a mixture of MeOH (5 mL) and AcOH (2 mL) and subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The crude material was purified by flash column chromatography (SiO2; 12 g) eluting with 0 to 60% [5% MeOH in EtOAc] in iso-hexane to give N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1) (62 mg, 61%) as a white solid: m/z 579 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.31 (3H, s), 3.99 (2H, s), 6.41 (1H, s), 6.70 (1H, dd), 7.32-7.40 (3H, m), 7.44-7.48 (2H, m), 7.55-7.61 (1H, m), 7.63-7.67 (2H, m), 7.84 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.79 (1H, s), 9.13 (1H, s), 10.02 (1H, s).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH3:1][N:2]([CH2:3][C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CNCC1(N2CCCCC2)CCCCC1
Product: CC(=O)N(C)CC1(N2CCCCC2)CCCCC1

Procedure:
A mixture of 1-[1-[(methylamino)methyl]cyclohexyl]-piperidine (1.0 g., 0.005 mole) and acetic anhydride (10 ml) was heated on a steam-bath for 30 mins. The solution was evaporated to dryness and water (5 ml) was added to the residue. A saturated solution of sodium carbonate (10 ml) was added and the alkaline solution was extracted with chloroform (50 ml × 3) and dried (anhyd. Na2SO4). The chloroform solution was evaporated to dryness and the oily residue re-evaporated with ether. This was dissolved in petroleum ether (60°-80°C), treated with decol. charcoal, and filtered (hyflo). The combined filtrates were evaporated to dryness to give N-methyl-N-[(piperidino cyclohexyl)methyl]acetamide (1.3 g.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][C@@H:36]4[C@@H:38]([CH:37]4[C:40]([N:46]4[CH2:49][CH:48]([OH:50])[CH2:47]4)=[O:41])[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Reactant: OC1CNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CC(O)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with azetidin-3-ol (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H44Cl2N5O4 [(M+H)+] 704.2765, observed 704.2764.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: NCCCO
Reactant: O=Cc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: OCCCNCc1ccccc1Br

Procedure:
To a stirring solution of 2-bromobenzaldehyde in dichloroethane (0.4 M) at RT under nitrogen was added 3-aminopropanol (1.5 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (4 eq). After 5 hr the reaction was carefully quenched with 2M sodium carbonate and extracted with methylene chloride. The organic phase was extracted with 1N hydrochloric acid. The aqueous phase was neutralized with 1N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. EI-MS m/z 245 (M+H)+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)C)#[C-:15]>>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][C:4]([C:5]2[O:6][CH:16]=[N:14][CH:15]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Product: FC(F)(F)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1B, substituting 4-(trifluoromethyl)benzaldehyde for 3-fluoro-4-(trifluoromethyl)benzaldehyde and substituting p-toluenesulfonylmethyl isocyanide for 1-(1-isocyanoethylsulfonyl)-4-methylbenzene.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(OCCO)C>>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2c1sc1ncccc12
Reactant: Nc1cccc(Br)c1
Solvent: CCOCCO
Product: Brc1cccc(Nc2ncnc3c2sc2ncccc23)c1
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 4-chloropyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine (72 mg, 0.32 mmol) (see previous experimental), 3-bromoaniline (0.04 mL, 0.37 mmol) and 2-ethoxyethanol (5 mL) is heated under N2 with stirring at 135 C. for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at ~80 C. to give 4-(3-bromoanilino)pyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine (45 mg, 39.4%). 1H NMR (DMSO) δ9.96 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz), 8.85 (1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.20 (1H, t, J=2.0 Hz), 7.84 (1H, ddd, J=8.0, 2.0, 1.3 Hz), 7.69 (1H, dd, J=8.0, 4.7 Hz), 7.39-7.31 (2H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][O:23][C:22]2[CH:26]=[C:27]([NH2:30])[CH:28]=[CH:29][C:21]1=2.[I-].[Na+]>CC#N>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:30][C:27]4[CH:28]=[CH:29][C:21]5[N:20]([CH3:19])[CH2:25][CH2:24][O:23][C:22]=5[CH:26]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: CN1CCOc2cc(N)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCOc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 180 °C
Yield: 16.3 %

Procedure:
4-Chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (112 mg, 0.36 mmol) and 3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazin-7-amine (130 mg, 0.72 mmol) were dissolved in CH3CN (3 mL), Sodium iodide (10 mg, 0.06 mmol) was added and the reaction was heated via microwave at 180° C. for 40 minutes. Solvent was removed and the residue was purified by preparative TLC to obtain the product as a beige foam (24 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:16]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]2[CH:36]=1)[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[O:42]1[C:44]([CH3:46])([CH3:45])[CH2:43]1>O1CCCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:16]2[C:7]3[N:8]([C:36]([CH2:43][C:44]([CH3:46])([OH:42])[CH3:45])=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=3)[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3n3cc(CC(C)C)nc23)cc1
Reactant: CC1(C)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3n3c(CC(C)(C)O)c(CC(C)C)nc23)cc1
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a solution of the 2-isobutyl-N,N-bis(4-methoxybenzyl)imidazo[1,2-a]quinoxalin-4-amine (134 mg, 0.28 mmol) (Example 1, D) in 2 mL of tetrahydrofuran was added n-butyl lithium (2.5M, 0.2 mL, 0.50 mmol) at −78° C. After being stirred at that temperature for 1 hour, 1,2-epoxy-2-methylpropane (72 mg, 1.0 mmol) was added. The reaction mixture was stirred at −78° C. for 2 hours, and then at room temperature for 4 hours. The reaction was quenched with 10 mL of saturated aqueous ammonium chloride. The resulting mixture was extracted with 100 mL of ethyl acetate. The organic layer was separated and washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (35 mg, 19%) and recovered starting material (100 mg, 63%). MS: MH+=553. 1H NMR (300 MHz, CDCl3): δ 8.41 (dd, 1H), 7.67 (dd, 1H), 7.20-7.37 (m, 6H), 6.84 (m, 4H), 5.31 (brs, 4H), 3.79 (s, 6H), 3.51 (s, 2H), 2.58 (d, 2H), 2.14 (m, 1H), 1.37 (s, 6H), 0.88 (d, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C1COCC1>[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH:26][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCC(OC)OC
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 2-chloro-3-nitrobenzoate (1.1 g, 4.9 mmol) from Step A above in THF (33 mL) was added triethylamine (0.8 mL, 6.0 mmol) followed by 2,2-dimethoxyethanamine (0.7 mL, 6.0 mmol) at room temperature. The reaction mixture was stirred overnight at reflux. The suspension was concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to afford methyl 2-(2,2-dimethoxyethylamino)-3-nitrobenzoate (1.4 g, 98%): 1H NMR (500 MHz, DMSO-d6) δ 8.39 (t, J=4.5 Hz, 8.08-8.05 (m, 2H), 6.83 (t, J=8.0 Hz, 1H), 4.54 (t, J=5.0 Hz, 1H), 3.87 (s, 3H), 3.31 (s, 6H), 2.93 (t, J=5.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:32](=[O:34])[CH3:33])=[C:3]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.050 g (0.106 mmol) of the product from Example 17 in CH2Cl2 (1 mL) at 0° C. was treated with acetyl chloride (8 μL; 0.106 mmol) followed by triethylamine (15 μL; 0.106 mmol). After the addition, the reaction mixture was warmed to RT and stirred for 1 hour. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 515.0 (M+1), 517.0 (M+3); Rt=4.94 min.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([NH2:19])[S:18][C:14]=2[CH:13]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([NH:19][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[S:18][C:14]=2[CH:13]=1
Reactant: Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2s1
Reactant: O=C(O)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2s1)C1CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
add 23 mg of cyclopropanecarboxylic acid to a solution of 70 mg of 6-[(2,6-dichlorobenzyl)oxy]-1,3-benzothiazol-2-amine in 1.5 cm3 of anhydrous pyridine. After stirring for one hour at around 20° C., the reaction mixture is concentrated to dryness under reduced pressure (0.2 kPa). The residue is taken up in 25 cm3 of water, then the mixture obtained is extracted three times with 20 cm3 of dichloromethane. The combined organic phases are washed twice with 20 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (92/8 by volume)], we obtain 51 mg of N-{6-[(2,6-dichlorobenzyl)oxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide in the form of a cream-coloured powder, which has the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]([CH3:24])[CH3:23])[CH:8]=2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:1]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:22]([CH3:24])[CH3:23])[CH:8]=3)[N:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(NCc3ccccc3)c2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3ccccc3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-benzylamino-6-dimethylaminoquinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.53 g of the title compound is obtained, m.p.: 156° C.