Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: Cc1ccc(Cl)c2c1NC(=O)C2=O
Product: Cc1ccc(Cl)c2c1[nH]c1nc3nnc(Cc4ccc(O)cc4)n3nc12

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4-chloro-7-methyl-1H-indole-2,3-dione (117.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) was used for the preparation.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[CH:10][S:9][C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=3[CH3:31])=[C:8]([C:20]([F:23])([F:22])[F:21])[S:9][CH:10]=2)=[C:13]([F:19])[CH:14]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2F)csc1C(F)(F)F
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(Cl)cc3F)csc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(2-fluoro-4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(2-fluoro-4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.30 (dd, J=11.5, 5.5 Hz, 2H), 7.14 (dd, J=10.7, 4.5 Hz, 2H), 6.92 (d, J=6.5 Hz, 1H), 6.57 (d, J=6.5 Hz, 1H), 4.92 (s, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.15 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(C)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCc1cc(C)c([N+](=O)[O-])cc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a stirred mixture of 2-ethyl-4-methylbenzoic acid (compound 48.2, 2 g, 12.18 mmol, 1.00 equiv) in sulfuric acid (30 mL) at −10° C. was added dropwise a solution of nitric acid (1.6 g, 16.50 mmol, 2.08 equiv) in sulfuric acid (10 mL). After stirring for 30 min at −10° C., 200 mL of H2O/ice was carefully added and the resulting mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with 2×50 mL of brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by re-crystallization from ethyl acetate/petroleum ether in the ratio 1:10 to yield 1.0 g (37%) of 2-ethyl-4-methyl-5-nitrobenzoic acid as a light-yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CSCCN1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)nc21
Yield: 38.5 %

Procedure:
A suspension of 0.271 g (1.0 mmol) of 7-chloro-1,4-dihydro-1-ethyl-6-fluoro-4-oxo,1,8-naphthyridine-3-carboxylic acid, 0.316 g (3.0 mmol) of thiomorpholine and 30 ml of acetonitrile was heated at reflux for 18 hours. The solvent was removed in vacuo and the residue was recrystallized from aqueous ethanol to give 130 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-1,8-naphthyridine-3-carboxylic acid; mp 241°-243° C.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:39]>CO.ClCCl>[ClH:39].[ClH:39].[OH:38][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1

Procedure:
The free base was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1. The free base was dissolved in methanol/dichloromethane and treated with hydrogen chloride gas. After concentrated the solvents the product was obtained as a yellowish solid; mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.90 (m, 2 H), 2.05-2.25 (m, 2 H), 2.80-3.30 (m, 7 H), 3.60-4.40 (m, 11H), 6.90-7.10(m, 3 H), 7.14(d, J=8.7 Hz, 2 H), 7.51 (d, J=8.7 Hz, 2 H), 7.57 (s, 1 H), 8.92(brs, 1 H), 9.36(brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)2+, 100%); 523.1(MH+, 30%); HRMS Calcd. for C28H35N4O3S (MH+): 523.2379. Found: 523.2394.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].I[CH2:16][CH3:17].C[O-].[Na+].C(OC1C=CC(OC)=CC=1C(N)=O)C>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:16][CH3:17])=[C:9]([CH:13]=1)[C:10]([NH2:12])=[O:11])([O:3][CH3:4])=[O:2]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)c(C(N)=O)c1
Agent: CCOc1ccc(OC)cc1C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(=O)OC)cc1C(N)=O

Procedure:
5-Carbomethoxy-2-ethoxybenzamide (m.p. 159°-161°) was prepared from 5-carbomethoxysalicylamide, iodoethane, and sodium methoxide in methanol in a manner analogous to that described for the preparation of 2-ethoxy-5-methoxybenzamide in Preparation 14A.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CC1CCNCC1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C(=O)N5CCOCC5)cn4)ccc3o2)CC1

Procedure:
The product from Example 44E and 4-methylpiperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.97 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 14H), 3.05 (m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.5 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 434 (M+H)+;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[OH:6].CCN(CC)CC.Cl[C:42]([O:44][CH3:45])=[O:43]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:13][C:9]1[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[C:7]([C@:5]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)([OH:6])[CH2:4][CH2:3][CH2:2][NH:1][C:42]([O:44][CH3:45])=[O:43])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: Cc1cccc(-c2c(Cl)cccc2[C@](O)(CCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-4-amino-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carboxylate (800 mg, 1.69 mmol) in anhydrous CH2Cl2 (15 mL) were added 4-dimethyaminopyridine (1.24 g, 10.17 mmol) and Et3N (2.35 mL, 16.95 mmol). The mixture was cooled with an ice bath and methyl chloroformate (0.65 mL, 8.47 mmol) in CH2Cl2 (5 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The solvent was removed in vacuo and the residue was purified by column chromatography to afford (R)-tert-butyl 3-((S)-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxy-4-(methoxycarbonylamino)butyl)piperidine-1-carboxylate (700 mg, 78%). 1H NMR (400 MHz, CD3OD): 1.00-1.70 (m, 17H), 2.30-2.50 (d, 3H), 2.50-2.70 (s, 1H), 2.90-2.31 (m, 2H), 3.50-3.52 (m, 3H), 3.80-4.20 (m, 2H), 6.0-7.15 (m, 3H), 7.15-7.40 (m, 3H), 7.50-7.70 (m, 1H); MS (E/Z): 531 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][NH:28][CH3:29].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:28]([CH3:29])[CH3:27])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)N(C)C)cc2)=C(C)C1=O
Yield: 17.2 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and dimethylamine hydrochloride (62 mg, 0.75 mmol) and triethylamine (76 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (38 mg, 0.10 mmol, yield 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([CH:8]2OCC[O:9]2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:13]([OH:16])([CH3:14])[CH3:15])[CH:3]=1)[CH:8]=[O:9]
Reactant: CC(C)(O)c1cc(Cl)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(O)c1cc(Cl)cc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
To a solution of 2-(3-chloro-5-(1,3-dioxolan-2-yl)phenyl)propan-2-ol (5.45 g, 22.46 mmol) in acetone (50 mL) was added p-toluenesulfonic acid hydrate (0.85 g, 4.47 mmol) and the reaction mixture was stirred at room temperature for 1 h to give an orange-red solution. The solvent was evaporated in vacuo to give an orange-brown residue. The residue was partitioned between aqueous saturated NaHCO3 solution (25 mL) and ethyl acetate (50 mL), the organic layer was removed, washed with brine (1×25 mL), dried over anhydrous sodium sulfate, filtered and evaporated in-vacuo to give an orange-red viscous liquid (4.75 g). Purification of the crude product by Silica-gel flash chromatography on silica gel column and elution with 5-40% ethyl acetate in n-hexane afforded the desired product as a cream crystalline solid (2.35 g). 1H NMR (400 MHz, CDCl3): δ 1.59 (s, 6H, (CH3)2C—OH), 1.76 (brs, 1H, (CH3)2C—OH), 7.71 (dd, J=1.80 Hz, 1H), 7.75 (appt, J=1.80 Hz, 1H), 7.85 (appt/dd, J=1.40 Hz, 1H), 9.96 (s, 1H, —CHO). 1H NMR spectrum of the solid was consistent with the suggested structure of the product.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[OH:1][CH:3]([CH2:4][NH:29][CH:26]([CH3:28])[CH3:27])[CH2:2][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Reactant: CC(C)N
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)C)cc3)n(C)c(=O)c2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one and isopropylamine.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:23][C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.[OH-].[Na+]>S(=O)(=O)(O)O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[C:17]3=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]3[NH:23][C:15]=2[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=2)=[CH:26][CH:27]=1
Reactant: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccnc(NCc4ccccc4)c3)[nH]c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccnc(N)c3)[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
7.8 g (19 mmoles) of Benzyl-{4-[3-(4-fluoro-phenyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-yl}-amine is suspended at room temperature in 40 mL of concentrated sulfuric acid. After 1 hour, the reaction is poured into ice (250 g) and kept at 0° C. while adding 170 mL of concentrated sodium hydroxide solution to reach pH=10. The resulting precipitate is filtered, suspended again in hot water and stirred at reflux for 1 hour. The reaction mixture is then filtered again and washed with hot water to give 6 g of 4-[3-(4-Fluoro-phenyl)-6-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-ylamine as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:33])=[C:15]([C:17]34[CH2:24][CH:23]3[CH2:22][CH2:21][S:20][C:19]([NH:25]C(=O)OC(C)(C)C)=[N:18]4)[CH:16]=2)=[O:9])=[N:6][CH:7]=1>ClCCl.FC(F)(F)C(O)=O>[NH2:25][C:19]1[S:20][CH2:21][CH2:22][CH:23]2[C:17]([C:15]3[CH:16]=[C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[O:9])[CH:12]=[CH:13][C:14]=3[F:33])([CH2:24]2)[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2CCS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2CCS1
Temperature: 23 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
tert-Butyl (1SR,7SR)-1-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A9a) (29 mg; 0.06 mmol) was dissolved in dichloromethane (3 ml) and at 23° C. trifluoroacetic acid (TFA) (0.8 ml) was added. The yellow solution was stirred for 2 hours at 23° C. The reaction mixture was extracted with sat NaHCO3 solution and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated to give a light yellow oil which was chromatographed on 10 g SiO2—NH2 with dichloromethane+dichloromethane/methanol 19:1 to give the 5-chloro-pyridine-2-carboxylic acid [3-((1SR,7SR)-3-amino-4-thia-2-aza-bicyclo[5.1.0]oct-2-en-1-yl)-4-fluoro-phenyl]-amide (13.34 mg; 58%) as an off white solid. MS (ISP): m/z=391.0 [(M+H)+] and 393.1 [(M+2+H)+].
Reaction SMILES: [OH:1]/[CH:2]=[C:3](/[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)\[C:4](OC)=O.[NH2:19][C:20]([NH2:22])=[S:21]>CO>[CH3:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][C:3]2[C:2](=[O:1])[NH:19][C:20](=[S:21])[NH:22][CH:4]=2)=[CH:10]1
Reactant: NC(N)=S
Reactant: COC(=O)/C(=C\O)Cc1cn(C)c2ccccc12
Solvent: CO
Product: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)c2ccccc21
Temperature: 50 °C
Yield: 18.3 %

Procedure:
To the solution of methyl (2Z)-3-hydroxy-2-[(1-methyl-1H-indol-3-yl)methyl]-2-propenoate (0.790 g, 3.22 mmol) in methanol (10 mL) was added thiourea (0.25 g, 3.28 mmol). The mixture was heated at 50° C. for 6 h. After cooling to room temperature, purification via reverse phase flash chromatography then afforded the title compound (200 mg, 0.590 mmol, 18.31% yield). LCMS: rt=2.36 min, [M+H+]=272
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:8]=1[CH3:15].C(OCC)(=O)C.[OH-].[Na+]>CCCCC>[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH3:15]
Reactant: COc1ccc(C)c(OC)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
The starting material 2,4-dihydroxytoluene was prepared by adding boron tribromide (3.1 ml, 3.2 mmol) to a solution of 2,4-dimethoxytoluene (1 g, 6.5 mmol) in pentane (10 ml) at −70° C. The reaction mixture was allowed to warm to ambient temperature and the mixture stirred for a further 2 hours. Ice water and ethyl acetate were then added and the aqueous layer basified to pH9.5 with 2M aqueous sodium hydroxide solution. After stirring for 10 minutes, the organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/ethyl acetate (9/1) to give 2,4-dihydroxytoluene (759 mg, 94%) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:17]=[N+:18]=[N-:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCN=[N+]=[N-])CC1

Procedure:
To 1-4 (27.9 g, 0.082 moles) dissolved in DMSO (400 ml) was added sodium azide (5.61 g, 0.086 moles) at room temperature and the resulting solution was heated at 65° for 2 hrs. The cooled reaction mixture was diluted with 250 ml EtOAc, extracted with 2×100 ml portions of water, 2×50 ml portions of brine and then dried (MgSO4). Solvent removal provided 1-5 as a pale yellow oil, Rf 0.5 (silica gel, 20% acetone/hexane). ##STR13##
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:35](O)[CH3:36]>O1CCCC1>[CH2:35]([CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:11]([NH:10][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:32])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])[CH3:36]
Reactant: CCOC(=O)COc1ccc(CC(NS(=O)(=O)c2ccc(C)cc2)c2cccnc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(CC(NS(=O)(=O)c2ccc(C)cc2)c2cccnc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-[2-(4-toluene sulfonamido)-2-(3-pyridyl)ethyl]phenoxyacetate (90 mg) was dissolved in 2 ml of ethanol and 2 ml of tetrahydrofuran, followed by addition of 0.30 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature for one hour. The solvent was concentrated under reduced pressure, and neutralized with 2N hydrogen chloride. Then, the crystalline deposited was taken out by filtration, to yield 80 mg of ethyl 4-[2-(4-toluene sulfonamido)-2-(3-pyridyl)- ethyl]phenoxyacetic acid.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[C:25]1[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]1)=[N:19][CH:18]=2.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.[Pd]>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=[C:5]1[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[C:25]1[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]1)=[N:19][CH:18]=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccc2cnc3ccccc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2sc(-c3ccc4cnc5ccccc5c4c3)cc2c1
Yield: 78 %

Procedure:
Benzo[b]thiophene-2-ylboronic acid (884 mg, 5.0 mmol) and 9-chlorophenanthridin (1.0 g, 4.8 mmol) were dissolved in tetrahydrofuran (30 ml), and palladium catalyst (160 mg, 0.14 mmol) and 2M sodium carbonate solution (20 ml) were added, followed by refluxing under a N2 atmosphere for 5 hours. The reaction solution was added to H2O and the mixture was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 1.15 g, yield: 78%).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27]([C:30](=O)[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1>>[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27](/[C:30](=[N:8]/[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)/[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\Nc1ccccc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 32 %

Procedure:
The title compound was prepared from phenyl hydrazine and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 32% yield as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 8.86 (dd, 1H), 8.32 (d, 1H), 7.98 (m, 3H), 7.78 (d, 1H), 7.61 (s, 1H), 7.47 (q, 1H), 7.30 (m, 4H), 6.83 (t, 1H), 4.57 (s, 2H), 2.31 (s, 3H). LCMS (method C): [MH]+=411, tR=4.57 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>ClCCl>[C:16]([NH:15][C@H:14]1[CH2:13][CH2:12][N:11]([C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH2:10][C@H:9]1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N[C@H]1CCNC[C@H]1OCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@H](NC(=O)c2ccccc2)[C@H](OCc2ccccc2)C1
Reaction time: 3 h

Procedure:
To a stirred solution of 40 parts of cis-N-[3-(phenylmethoxy)-4-piperidinyl]benzamide in 153 parts of tetrahydrofuran were added 323 parts of a sodium hydroxide solution 1N. Then there was added dropwise a solution of 15.4 parts of ethyl carbonochloridate in 58 parts of tetrahydrofuran at a temperature below 5° C. Upon completion, stirring was continued for 3 hours while cooling in an ice-bath (temp. below 5° C.). Dichloromethane was added and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and crystallized from acetonitrile. A first fraction was filtered off, yielding 30.2 parts of cis-ethyl 4-(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate; mp. 139.2° C. The mother liquor was concentrated. The precipitated product was filtered off, yielding a second fraction of 5 parts of cis-ethyl 4-(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate.