Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]2[C:23](=[O:24])[N:22]([C:25]([CH:37]([CH3:39])[CH3:38])([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:26](=[O:28])[NH2:27])[C:21]3[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:20]=3[N:19]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:18]2=[O:51])=[O:15])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[F:44][C:42]1[CH:41]=[CH:40][C:21]2[N:22]([C:25]([CH:37]([CH3:38])[CH3:39])([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:26](=[O:28])[NH2:27])[C:23](=[O:24])[CH:17]([NH:16][C:14](=[O:15])[NH:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:52])=[O:5])[C:18](=[O:51])[N:19]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:20]=2[CH:43]=1
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)Nc3cccc(C(=O)OC(C)(C)C)c3)C(=O)N(c3cccnc3)c3cc(F)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)Nc3cccc(C(=O)O)c3)C(=O)N(c3cccnc3)c3cc(F)ccc32)cc1
Reaction time: 1.5 h
Yield: 110 %

Procedure:
A mixture of 84 mg of 3-(3-{7-fluoro-1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-ureido)-benzoic acid tert butyl ester (0.118 mmol) and 4 mL of trifluoroacetic acid was stirred under nitrogen for 1.5 hrs. The trifluoroacetic acid was removed in vacuo and the residue was triturated with diethyl ether. The slurry was filtered, washed with diethyl ether and dried under high vacuum to provide 85 mg the title compound as a white crystalline trifluoroacetic acid salt. 1H NMR (300 MHz, d6-DMSO) d 9.33 (s, 1H), 8.70 (b, 1H), 8.57 (d, 1H, J=4.7), 8.00 (m, 1H), 7.97 (d, 1H, J=8.6), 7.61 (dd, 1H, J=5.5, 9.1), 7.55 (dd, 1H, J=4.88, 8.2), 7.47 (m, 2H), 7.26 (m, 4H), 7.05 (d, 2H, J=9.0), 6.92 (d, 1H, J=7.8) 6.82 (dd, 1H, J=2.8, 9.6), 5.10 (d, 1H, J=7.6), 4.72 (m, 1H), 4.51 (d, 1H, J=16.8), 4.14 (d, 1H, J=16.8), 3.78 (s, 3H), 0.92 (m, 6H); low resolution MS (FAB)m/e 655 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]4[C:34](=[O:35])[C:33](=[O:36])[C:32]=4OC(C)C)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(O)(=O)C>CO>[C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]4[C:34](=[O:35])[C:33](=[O:36])[C:32]=4[N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccc(Nc2nc(-c3ccccc3)cc3ccccc23)cc1)Nc1c(OC(C)C)c(=O)c1=O
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(Nc2nc(-c3ccccc3)cc3ccccc23)cc1)Nc1c(N2CCOCC2)c(=O)c1=O

Procedure:
A solution of methyl (S)-3-[4-(3-phenyl-1-isoquinolinylamino)phenyl]-2-(2-isopropoxy-3,4-dioxocyclobut-1-enylamino)propanoate (20 mg, 0.08 mmol) [prepared in a similar manner to the compound of Example 1]in MeOH (0.2 ml) was treated with morpholine (0.011 ml, 0.12 mmol) and the resulting mixture heated at 60° for 24 h. The mixture was concentrated to dryness then redissolved in anhydrous THF (1.0 ml) and treated with polystyrene methylisocyanate resin (Argonaut Technologies, 120 mg, 2.0 mmol/g, 0.24 mmol) at room temperature for 24 h. The resulting mixture was filtered, and the resin was washed with MeOH(1.0 ml). The combined filtrate was evaporated to dryness then redissolved in THF (0.2 ml) and treated with an aqueous solution of lithium hydroxide monohydrate (0.2 ml of a solution of 100 mg in 4.0 ml water, 0.12 mmol) at room temperature for 24 h. The reaction mixture was quenched with glacial acetic acid (0.007 ml, 0.12 mmol), then evaporated to dryness to give the crude product which was purified by preparative HPLC to afford the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([C:16]2[NH:17][C:18]([CH3:21])=[N:19][N:20]=2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([C:16]3[NH:17][C:18]([CH3:21])=[N:19][N:20]=3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COc1cnc(-c2nnc(C)[nH]2)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-c3nnc(C)[nH]3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of AlCl3 (0.321 g, 2.411 mmol) in CH2Cl2 (0.8 mL) and MeNO2 (0.2 mL) was added 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindole (0.0435 g, 0.190 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.070 mL, 0.756 mmol) was added and the mixture was allowed to stir for 5 h. The mixture was then cooled at 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.0347 g, 60%: LCMS: m/e 316 (M+H)+. This material was dissolved in MeOH (2 mL) and treated with 2.5 M NaOH (0.2 mL, 0.5 mmol). The mixture was allowed to stir for 5 h, at which point the solvent was removed and the residue was diluted with H2O (2 mL). This mixture was acidified to pH 1 with 6 M HCl and the solution was lyophilized to give the title compound (0.062 g), which contained a nominal amount of inorganic salts. This material was used as such in the following step:
Reaction SMILES: [F:1][C@:2]1([C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32]([CH3:40])[CH:31]=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C@:2]1([C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=[C:32]([CH3:40])[CH:31]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl (1R,2R)-1-fluoro-2-{[(4-hydroxyphenyl)sulfonyl]amino}cyclopentanecarboxylate (0.42 g, 1.3 mmol, 1 eq) in DMF (4 mL) was added cesium carbonate (0.86 g, 2 eq) followed by 4-chloromethyl-2-methyl-quinoline. The brown reaction mixture was stirred for 3 days, and then taken up in ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated. Purification using silica chromatography eluting with 40-70% ethyl acetate/hexanes afforded methyl (1R,2R)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate as an off white solid (0.23 g, 41%). MS: 473.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl>>[CH3:7][C:4]1[CH2:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CC1=CCC(C)=C1c1ccccc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC1=CCC(C)=C1c1ccccc1NS(C)(=O)=O
Yield: 67.8 %

Procedure:
2-(2,5-dimethylcyclopenta-1,4-dienyl)phenylamine (0.500 g, 2.699 mmol) was melted in 5 mL of M.C, and then 0.235 g (2.969 mmol) of pyridine and 0.340 g (2.969 mmol) of methanesulfonyl chloride were added thereto. The reactants were reacted at room temperature for 7 hours. Then, 4 mL of 2 N HCl and 10 mL of M.C were added to the reaction product. The organic layer was collected and dried over MgSO4 to remove water contained therein. The solvent contained in the resultant organic layer was removed using a rotary vacuum evaporator. The product was filtered using 10 mL of diethyl ether, thereby obtaining white solid (0.482 g, 68%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: NCC(O)C(F)(F)F
Product: O=C(NCC(O)C(F)(F)F)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 15 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using 3-amino-1,1,1,-trifluoropropan-2-ol instead of rac-2-amino-1-propanol, to the title compound (39 mg, 15%) which was obtained as a white solid MS: m/e=426.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:6]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Reactant: C1CCNCC1
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1C1OCCO1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A mixture of 2-(5-chloro-2-nitrophenyl)-1,3-dioxolane (21.3 g, 0.09 mole) and piperidine (39.6 g, 0.46 mole) was heated at reflux in an oil bath. After 3 hours, excess piperidine was evaporated and the residue partitioned between water and dichloromethane. The organic phase was separated and the aqueous layer extracted with dichloromethane. Combined extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to afford 2-(2-nitro-5-piperdinylphenyl)-1,3-dioxolane (21.6 g, 100%) as a dark colored oil which was used without further purification. An analytical sample was purified by flash chromatography using dichloromethane as eluant to give a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:6]2=[N:7][CH:8]=1.[CH:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][CH:19]=1.C(N(CC)CC)C>O1CCOCC1>[C:17]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:4]=[C:5]4[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:6]4=[N:7][CH:8]=3)[CH2:22][CH2:21]2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1C(=O)Cc2cc(CBr)cnc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1C(=O)Cc2cc(CN3CCN(c4ccccc4)CC3)cnc21
Yield: 65 %

Procedure:
1,3-dihydro-5-bromomethyl-1-methyl-2H-pyrrolo[2,3-b]pyridin-2-one from Preparation 18 (0.14 g, 0.6 mmol) is dissolved in dioxane (20 ml) at room temperature and under argon. Phenylpiperazine (0.1 ml, 0.66 mmol, 1.1 equiv.) and triethylamine (0.1 ml, 0.72 mmol, 1.2 equiv.) are added in succession at the same temperature. After 1 hour 30 minutes' reaction, the reaction mixture is concentrated under reduced pressure and the product is purified on a silica column (dichloromethane/methanol: 97:3). The title compound is obtained in the form of a yellow oil in a yield of 65%. ##STR74##
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH:11]([CH3:28])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:27])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl>[P:4]([CH2:9][CH2:10][CH:11]([CH3:28])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:27])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(CCC(C)CCCC(C)CCCC(C)CCCC(C)C)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of 14.6 g (35 mmol) of 1-(diethylphosphono)-3,7,11,15-tetramethylhexadecane in 40 mL of dichloromethane was added 15.0 g (98 mmol) of bromotrimethylsilane. After 24 h at room temperature, the solution was concentrated to a pale yellowish liquid, and the intermediate silylphosphonate ester was dissolved in 100 mL of methanol. The resultant solution was stirred at room temperature for 30 min and concentrated to a white solid. Dissolution in methanol and concentration were repeated two times, and recrystallization from ethyl acetate afforded 10.5 g (83%) of 1-phosphono-3,7,11,15-tetramethylhexadecane as white crystals, mp 69-72° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([NH:20]C2C=C(C(OC)=S)SC=2C)[CH:17]=[CH:18][CH:19]=1)[CH3:13].C[Al](C)C.[NH4+].[Cl-]>>[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([NH:20][C:4]2[CH:5]=[C:6]([C:8]([NH2:10])=[NH:9])[S:7][C:3]=2[S:2][CH3:1])[CH:17]=[CH:18][CH:19]=1)[CH3:13]
Reactant: COC(=S)c1cc(Nc2cccc(C(C)C)c2)c(C)s1
Reactant: CSc1ccc(C(=N)N)s1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Product: CSc1sc(C(=N)N)cc1Nc1cccc(C(C)C)c1

Procedure:
4-{[3-Methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine: Using a procedure similar to Example 154, step (b), 22.6 mg (0.07 mmol) of methyl 4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate was allowed to react with 8 equiv (0.56 mmol) of the AlMe3/NH4Cl reagent to afford 18.9 mg (78.8%) of) 4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine. 1H NMR (DMSO-d6, 400 MHz) δ 1.18 (d, 6H, J=9.2 Hz), 2.51 (s, 3H), 2.81 (m, 1H), 6.71-6.77 (m, 2H), 6.85 (s, 1H), 7.14 (m, 1H), 7.98 (s, 1H), 8.32 (s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. for C15H19N3S2, 306.11 (M+H), found 306.2.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:11]=[C:10]3[C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH:32]3[CH2:34][CH2:33]3)[N:27]=2)=[N:5][N:6]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1.C(Cl)Cl>[CH:32]1([C:28]2[N:27]=[C:26]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:4]5[O:3][C:2]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:6][N:5]=5)[CH:8]=4)[N:12]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:11]=3)[CH:31]=[N:30][CH:29]=2)[CH2:34][CH2:33]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(Br)o4)ccc32)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(N5CCCC5)o4)ccc32)cc1
Yield: 66.2 %

Procedure:
A brown-orange solution of 2-bromo-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (35.0 mg, 0.065 mmol) and pyrrolidine (16.2 μL, 0.195 mmol) in NMP (1.0 mL) was heated in a sealed microwave process vial under argon at 120° C. for 18 h. The mixture was then diluted with DCM (5 mL), concentrated onto silica gel, and chromatographically purified (silica gel, 0-10% MeOH/DCM) to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(pyrrolidin-1-yl)-1,3,4-oxadiazole (22.7 mg, 0.043 mmol, 66%) as a yellow oil: MS (ESI, pos. ion) m/z: 527.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH3:9])[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccccc5OC)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-2-methoxybenzamide was prepared from o-anisoyl chloride (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 42 mg, 86 μmol, 76%). LC/ESI-MS: m/z=488 [M+H]+; m/z=486 [M−H]−; Rt=3.27 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[C:6](=[O:7])[CH2:8][N:2]([CH3:1])[C:3]2=[O:4])=[CH:13][CH:12]=1
Reactant: CN1CC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN(C)C2=O)cc1
Reaction time: 72 h

Procedure:
To a stirring solution of 1-methylhydantoin (40.0 g, 351 mmol) in DMF (700 mL) at ambient temperature was added 4-methoxybenzyl chloride (49.4 g, 316 mmol) and cesium carbonate (171 g, 526 mmol). The resulting mixture was stirred for 3 days, then partitioned between H2O (2 L) and EtOAc (800 mL). The aqueous layer was extracted further with EtOAc (500 mL) and the combined organic extracts were washed with H2O (2×300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting white precipitate was collected by vacuum filtration and washed with MTBE (200 mL) to provide the title compound. MS: m/z=235.2 (M+1).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:9]=O)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[O:20])=[CH:14][CH:13]=1>O.CO>[F:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:9]/[CH:3]2[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]2)/[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: O=CC1CC=CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C/C(=C\C1CC=CCC1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
5.5 g of sodium hydroxide in 30 ml of water are added to a solution of 40 g of 3-cyclohexenecarbaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C., and 49.7 g of 4-fluorophenylacetaldehyde are rapidly added dropwise, the temperature of the solution not exceeding 30° C. After the mixture has been stirred for 2 hours at room temperature, 200 ml of water are added to the colorless reaction solution and the resulting emulsion is extracted by shaking with methyl tert-butyl ether. The organic phase is separated off, and 34 g (41%) of Z-2-(4-fluorophenyl)-3-(3-cyclohexenyl)-propenal are obtained under 0.5 mbar and at 136°-142° C. by distillation of the remaining residue.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>O.C([O-])([O-])=O.[Na+].[Na+]>[OH:1][CH:2]1[CH2:6][N:5]([S:20]([C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)(=[O:22])=[O:21])[CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
2.62 g of (2S,4R)-4-hydroxyproline are dissolved in 15 ml of water containing 5.9 g of Na2CO3 and 5.21 g of 2-naphthalenesulphonyl chloride are added. After vigorous stirring for 18 hours at RT, the mixture is drained and the filtrate is then acidified to pH=1. The resulting mixture is again drained, washed with water and dried in order to obtain 4.1 g of the expected compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:14])[C:8]=1[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[NH2:5].[C:15](Cl)(Cl)=[S:16].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:15]=[S:16])[CH:6]=[C:7]([Cl:14])[C:8]=1[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: S=C(Cl)Cl
Reactant: CCN(CC)c1c(Cl)cc(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)c1c(Cl)cc(N=C=S)cc1Cl
Yield: 97.5 %

Procedure:
Following procedures similar to those employed in Step A of Example 8, the reaction of 1.9 g (0.0082 mole) of 3,5-dichloro-4-diethylaminoaniline with 1.88 g (0.0163 mole) of thiophosgene and 5.0 g (0.036 mole) of potassium carbonate in 20 ml of water and 100 ml of chloroform yielded 2.2 g of 3,5-dichloro-4-diethylaminophenyl isothiocyanate as an oil. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:10]([C:11]3[CH:12]=[C:13]([CH3:14])[CH:17]=[CH:18][CH:19]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: Cc1cccc(C(=O)O)c1
Product: Cc1cccc(-c2nc3ccc(Br)cc3o2)c1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 3-methyl-benzoic acid.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH:5]1[CH:9]([C:10](O)=[O:11])[CH2:8][CH2:7][C:6]1=[O:13]>C(OCC)C>[NH:5]1[CH:9]([C:10]([Cl:3])=[O:11])[CH2:8][CH2:7][C:6]1=[O:13]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C1CCC(C(=O)Cl)N1
Reaction time: 8 h

Procedure:
To 90 ml of thionyl chloride was added dropwise 23.5 g of 2-pyrrolidone-5-carboxylic acid with stirring under ice-cooling, and the mixture was stirred for 30 minutes at 40°-50° C. After cooling of the reaction mixture, 200 ml of dry diethyl ether was added to the reaction mixture, and the reaction mixture was allowed to stand overnight in a freezing box. Precipitated crystals were collected by filtration, washed with dry diethyl ether, and dried in a desiccator to obtain 27 g of 2-pyrrolidone-5-carbonyl chloride. The obtained acid chloride was dissolved in 500 ml of dry chloroform, and to the solution were added 13.5 g of 2-pyridylmethanol with stirring at room temperature, and then the reaction mixture was heated under refluxing. After completion of the reaction, to the reaction mixture was added an aqueous sodium bicarbonate solution to make the solution basic at pH 9, and the reaction mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from benzene to obtain 16.2 g of 2-pyridylmethyl 2-pyrrolidone-5-carboxylate. (yield 60.0%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29]C)=[O:28])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:33])[C:6]=2[CH:34]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([OH:29])=[O:28])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:33])[C:6]=2[CH:34]=1
Reactant: COC(=O)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a suspension of 7-chloro-5-hydroxy-1-[6-(2-methoxycarbonyl-benzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in methanol (4 ml) is added 5% aqueous sodium hydroxide solution (1.5 ml), and the mixture is stirred at room temperature for one hour. To the reaction solution are added water and diluted aqueous hydrochloric acid solution in order to make the mixture weak acidic. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane-methanol to give 7-chloro-5-hydroxy-1-[6-(2-carboxybenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (150 mg) as white powder.