Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:30][CH2:29][C:15]3([CH2:19][C@H:18]([NH:20]C(=O)OC(C)(C)C)[C@H:17]([OH:28])[CH2:16]3)[CH2:14][CH2:13]1)=[N:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2.Cl.O1CCOCC1>CO>[NH2:20][C@H:18]1[CH2:19][C:15]2([CH2:29][CH2:30][N:12]([C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:31][CH3:32])[N:9]=4)[N:4]=[CH:3][C:2]=3[F:1])[CH2:13][CH2:14]2)[CH2:16][C@H:17]1[OH:28]
Reactant: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C4)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl {(2S,3R)-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-8-azaspiro[4.5]dec-2-yl}carbamate (0.92 mg, 0.206 mmol) in MeOH (2 mL) at 25° C. was added dropwise a 4M solution of HCl in dioxane (360 μL, 1.40 mmol). After 12 h, the solution was concentrated the residue neutralized using excess MP carbonate resin in DCM affording the free amine (26 mg, 36%) which was used without further purification: LCMS (ES) m/e 347 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[CH3:11]COCC.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH3:11][N:6]1[C:2]([Cl:1])=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5]1
Reactant: COC(=O)c1c[nH]c(Cl)c1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)n(C)c1
Reaction time: 1 h

Procedure:
Methyl 5-chloropyrrole-3-carboxylate (800 mg., 5 mmoles) was dissolved in 75 ml. of ether. Sodium hydride (57% dispersion in oil, 430 mg., 10 mmoles) was added and the mixture stirred under nitrogen for 1 hour. Dimethyl sulfate (1 ml., 10.7 mmoles) was added and stirring continued for 2 hours. Excess sodium hydride was decomposed by cautious addition of 20 ml. of water. The ether phase was washed with 20 ml. of water and evaporated to yield methyl 1-methyl-5-chloropyrrole-3-carboxylate (oil); the entire batch being used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=375.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)(C)CN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)CNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
A mixture of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), neopentylamine (530 mg, 6.0 mmol) and triethylamine (1 mL) in acetonitrile (20 mL) was stirred at room temp for 4 h. After the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to afford the product (1.11 g, 87%). C11H13ClFN3 MS m/e=242 (M+H).
Reaction SMILES: [CH2:1]=[CH:2][S:3]([O-:6])(=[O:5])=[O:4].[Na+:7].[CH3:8][NH:9][CH3:10]>>[CH3:8][N:9]([CH3:10])[CH2:1][CH2:2][S:3]([O-:6])(=[O:5])=[O:4].[Na+:7]
Reactant: C=CS(=O)(=O)[O-]
Reactant: CNC
Agent: [Na+]
Product: CN(C)CCS(=O)(=O)[O-]

Procedure:
Sodium ethylenesulfonate (18.2 ml, 25% aqueous solution w/w) and dimethylamine (4.43 ml, 40% aqueous solution w/w) were heated in a sealed finger tube at 105° C. for 48 h before concentrating in vacuo to yield the subtitle compound as a white solid. Yield: 9.80 g.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[F:35][C:34]([F:36])([F:37])[C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([CH:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:7][C:6]([OH:38])=[O:5])=[CH:15][CH:16]=3)[CH:23]=2)=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Ester 50.4 (48 mg, 0.09 mmol) was dissolved in dichloromethane/TFA solution (3:1, 2 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent removed under reduced pressure, and the product was purified on reserve phase HPLC to yield acid 50 (30 mg). MS ESI (pos.) m/e: 472 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17](OC)=[O:18])(=O)[CH3:14]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:13]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:17](=[O:18])[C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)[nH]c2cc(-c3ccccc3)nn2c1=O
Yield: 85.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine (4 g, 25.1 mmol) and dimethyl 2-acetylsuccinate (12 mL, 74.0 mmol) in xylene (120 mL) was added p-toluenesulfonic acid monohydrate (50 mg, 0.263 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 20 h. The solid was filtered and washed with hexanes to afford the title compound (6.4 g, 86%). 1H-NMR (400 MHz, MeOD) δ 2.37 (3 H, s), 3.66 (2 H, s), 3.72 (3 H, s), 6.46 (1 H, s), 7.34-7.53 (3 H, m), 7.87-8.06 (2 H, m).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH:4]([S:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][N:9](N)[C:10](=[O:12])[CH3:11].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=C(C(O)=O)[CH:29]=1>>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:14]([CH:4]([C:3](=[O:27])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:11]2[CH:29]=[N:28][C:37]3[C:32]([CH:31]=2)=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:12])=[O:15])=[CH:17][CH:18]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)C(CCCCN(N)C(C)=O)C(=O)NO)cc1
Reactant: O=C(O)c1cnc2ccccc2c1
Product: CC#CCOc1ccc(S(=O)C(CCCCNC(=O)c2cnc3ccccc3c2)C(=O)NO)cc1

Procedure:
6-(Amino-acetylamino)-2-(4but-2-ynoxy-benzenesulfinyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with 3-quinolinecarboxylic acid (1.2 g, 4.0 eq) according to the procedure in Example 13, Step E to give quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide resin.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: Clc1nccc2cc[nH]c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Temperature: 200 °C
Yield: 44.2 %

Procedure:
A mixture of 259 (420mg, 2.76 mmol), 2-fluoro-4-nitrophenol (651 mg, 4.14 mmol) and K2CO3(1.14 g, 8.28 mmol) in Ph2O (15 mL) was heated at 200° C. for 6 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried and concentrated. The residue was purified by flash column chromatography with gradient elution from hexane to hexane/EtOAc (3:1), to afford the title compound 260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH:20]=[CH:19]1.O>O1CCCC1>[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:20]=[CH:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC1(C)C=CC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C=CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.2 g, 55 mmol) in tetrahydrofuran (100 ml) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (11.2 g, 50 mmol) over 30 min, and the mixture was stirred at room temperature for 1 h. To this was added 4,4-dimethyl-2-cyclohexene-1-one over 20 min and the reaction mixture was stirred for a further 1 h. Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (9.7 g, 100%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Brc1ccccn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromopyridine
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1.S(Cl)([Cl:13])=O>>[Cl:13][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1cc(CO)nn1
Product: CCCn1cc(CCl)nn1
Temperature: 25 °C

Procedure:
To a solution of aluminum lithium hydride (0.58 g) in THF (51.4 ml) was added dropwise a solution of methyl 1-propyl-1,2,3-triazole-4-carboxylate (2.6 g) in THF (26 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-hydroxymethyl-1-propyl-1,2,3-triazole (1.9 g). To 4-hydroxymethyl-1-propyl-1,2,3-triazole (1.9 g) was added thionyl chloride (32 ml) at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, to give 4-chloromethyl-1-propyl-1,2,3-triazole (1.75 g).
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:17][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(F)c(=O)[nH]c2c1
Solvent: CN(C)C=O
Product: COc1ccc2cc(F)c(Cl)nc2c1
Yield: 97 %

Procedure:
3-Fluoro-7-methoxyquinol-2(1H)-one (300 mg, 1.55 mmol), (prepared as in Tetrahedron, Vol. 52, No. 9, pp. 3223–3228, 1996), was dissolved in thionyl chloride (3 ml), treated with DMF (1 drop) and heated at reflux for 1 hour. The excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene (3×). The residue was basified to pH8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (3×20 ml). The organic solution was washed with water and brine then dried (MgSO4) and evaporated to dryness to give 2-chloro-3-fluoro-7-methoxyquinoline (320 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:24].[C:25]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[Cl:41])(=[O:27])[CH3:26]>C(O)(C)C>[ClH:41].[ClH:24].[C:25]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[NH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:27])[CH3:26]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)c2cc1OC(C)=O
Temperature: 85 °C
Yield: 79.8 %

Procedure:
A mixture of N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (178 mg), 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride (150 mg) and isopropanol (5 ml) was stirred and heated to 85° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and the solid was isolated and washed in turn with isopropanol (5 ml) and isohexane (2×5 ml). There was thus obtained the title compound (249 mg, 80%); NMR: 2.17 (s, 3H), 2.38 (s, 3H), 3.56 (m, 4H), 3.72 (m, 4H), 4.0 (s, 3H), 7.16 (m, 1H), 7.37 (m, 2H), 7.52 (s, 1H), 7.68 (m, 1H), 7.87 (m, 1H), 8.24 (m, 1H), 8.67 (s, 1H), 8.8 (s, 1H), 10.6 (s, 1H), 11.50 (s, 1H); m/s: M+H+ 529.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[O:45][C:46]1[N:51]=[C:50]2[S:52][C:53]([NH:55][C:56]([CH:58]3[CH2:60][CH2:59]3)=[O:57])=[N:54][C:49]2=[CH:48][CH:47]=1.O>N1C=CC=CC=1>[CH:58]1([C:56]([NH:55][C:53]2[S:52][C:50]3[C:49]([N:54]=2)=[CH:48][CH:47]=[C:46]([O:45][C:44]2[CH:61]=[C:40]([NH:39][C:7](=[O:9])[C:6]4[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=4)[CH:41]=[CH:42][C:43]=2[CH3:62])[N:51]=3)=[O:57])[CH2:59][CH2:60]1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(OC(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzoic acid (37.5 mg, 0.185 mmol) in pyridine (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.185 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (60 mg, 0.176 mmol) produced in Example C47(i) was added to the obtained solution, and the mixture was stirred at 70° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (2 mL) was added, and the obtained yellow precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (48.5 mg, 52%) as a yellow powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].ON1C2C=CC=CC=2N=N1.[C:30]([C:33]1[N:34]=[CH:35][C:36]2[NH:37][C:38]3[C:43]([C:44]=2[CH:45]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3)(O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH:35]1[C:36]2[NH:37][C:38]3[C:43]([C:44]=2[CH:45]=[C:33]([C:30]([C:2]2([NH2:1])[CH2:8][CH2:7][C:6]4[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=4[N:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:3]2=[O:19])=[O:31])[N:34]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3
Reactant: NC1CCc2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1(C(=O)c2cc3c(cn2)[nH]c2ccccc23)CCc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
In 15 ml of dimethylformamide were dissolved 0.252 g of 3-amino-1-phenyl-2,3,4,5-tetrahydro-1-benzoazepin-2(1H)-one, 0.127 g of 1-hydroxybenzotriazole, 0.223 g of 3-carboxy-β-carboline and 0.2 g of 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride and 0.5 ml of triethylamine was added to the solution, and the mixture was stirred at room temperature for one day. After the solvent was removed under reduced pressure, a 10% aqueous citric acid and chloroform were added to the residue and the mixture was stirred. Thereafter, the chloroform layer was separated, washed with a 10% sodium hydroxide aqueous solution and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The precipitates were collected by filtration to obtain 0.312 g of the title compound as crystals. Melting point: 302° to 304° C., IR (Nujol) (cm-1): 3360, 3290, 1730, 1670, 1650, 1625, MS (m/z): 446 (M+), 264 (base)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cccc1Sc1ccccc1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1c(CCl)cccc1Sc1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-methoxy-3-(2-chlorophenylthio)benzyl alcohol (9 g), thionyl chloride (4.6 ml) and pyridine (3 drops) in dried benzene (60 ml) was refluxed under heating for 30 minutes. The reaction mixture was cooled to the ambient temperature and evaporated under reduced pressure. The residue was dissolved in diethyl ether, and the solution was washed with water, saturated aqueous sodium bicarbonate and water in turn, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-chlorophenyl 2-methoxy-3-chloromethylphenyl thioether (9.2 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:29])[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:29])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2N)cc1
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
To a solution of 0.340 g (0.88 mmol) of the product of Step 1 in 15 mL of absolute ethanol was added 35 mg of 10% palladium on carbon catalyst and the mixture was hydrogenated at 40 psi of hydrogen on a Parr apparatus. Reduction was complete after 1.5 hours and the reaction mixture was filtered and evaporated in vacuo to afford a tan solid (0.300 g, 95%) which was used in the subsequent step without further purification: NMR (CDCl3) δ 1.33 (t, J=10 Hz, 3H), 2.59 (s, 3H), 2.64 (s, 3H), 2.84 (q, J=10 Hz, 2H), 3.70 (br s, 2H), 5.48 (s, 2H), 6.70-6.82 (m, 2H), 6.90 (s, 1H), 7.03-7.22 (m, 4H), 7.36 (d, J=10 Hz, 2H); MS (FAB) m/e 357 (MH+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 91 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (117 mg), 120 mg 6-(3-methoxyphenyl)-2-oxindole and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 190 mg (91%) of the title compound as a brown solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][SH:9].[CH3:10][O:11][C:12](=[O:44])[C:13](=[N:32]OS(C1C=CC(C)=CC=1)(=O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:28][N:29]=[CH:30][CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12](=[O:44])[C:13](=[N:32][S:9][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:28][N:29]=[CH:30][CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1
Reactant: CS
Reactant: CC=NOC(c1ccc(Cl)cc1)c1ccccc1C(=NOS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC=NOC(c1ccc(Cl)cc1)c1ccccc1C(=NSC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2 ml triethylamine in 15 ml chloroform saturated with methanethiol are added 5.15 g (10 mmol) 2-{2-[1-(4-chloro-phenyl)-ethylideneaminooxymethyl]-phenyl}-tosyloxyimino-acetic acid methyl ester. The mixture was stirred at room temperature for 48 hours. After evaporation the residue is purified by silicagel chromatography (ethyl acetate 1, hexanes 5) to give—after elution of 2-[1-(4-chloro-phenyl)-ethylideneaminooxymethyl]-benzonitrile as by-product—1.0 g (28%) of the 2-{2-[1-(4-chloro-phenyl)-ethylideneamino-oxymethyl]-phenyl}-methylthioimino-acetic acid methyl ester. Melting point of 112-113° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(C)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cccc(-c2cc(=O)c3c(O)cc(O)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1Cl
Temperature: 180 °C

Procedure:
A mixture of compound of example 44 (1.0 g, 2.25 mmol) and pyridine hydrochloride (3.0 g, 25.95 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.