Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(Cl)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Acetone (320 ml), 75 g (450 mmol) of ethyl bromoacetate, and 40.0 g (310 mmol) of 3-chlorophenol were mixed together, then 69.8 g (505 mmol) of potassium carbonate was added. The mixture was mechanically stirred and heated to reflux for 4 h, and after cooling to room temperature, was poured into 350 mL of ethyl acetate. To this was then cautiously added 400 mL of 1 M HCl, taking care to avoid excess foaming. The layers were separated and the aqueous layer was extracted with portions of ethyl acetate (3×200 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and the resulting solid was recrystallized from hexane to afford 58 g (87%) of 10 as a white solid, m.p.=39-40° C. 1H NMR δ 7.20-7.08 (m, 1 H), 6.95-6.82 (m, 2 H), 6.75-6.70 (m, 1 H), 4.53 (s, 2 H), 4.21 (q, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([O:20][CH3:21])=[CH:9][C:10]([C:18]#[N:19])=[C:11]([N:13]=[CH:14][N:15](C)C)[CH:12]=1.C(O)(=O)C.N[C:27]1[CH:31]=[C:30]([CH2:32][C:33]([OH:35])=[O:34])[NH:29][N:28]=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]2[C:10]([C:18]([NH:19][C:27]3[CH:31]=[C:30]([CH2:32][C:33]([OH:35])=[O:34])[NH:29][N:28]=3)=[N:15][CH:14]=[N:13]2)=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCCl
Reactant: Nc1cc(CC(=O)O)[nH]n1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCCCl
Reaction time: 1 h
Yield: 73.9 %

Procedure:
N′-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamide (464 g, 15 mmol) in acetic acid (13.5 ml, 225 mmol) was reacted with (3-amino-1H-pyrazol-5-yl)acetic acid (2.22 g, 15.8 mmol) at reflux for 1 hour. The mixture was cooled, diluted with ethanol (25 ml) and the resultant precipitate recovered by suction filtration. The solid was stirred in water for 1 hour, collected by suction filtration and dried to yield (3-([7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino)-1H-pyrazol-5-yl)acetic acid (4.5 g, 74% yield):
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]([OH:35])CO)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=[O:35])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(O)CO)O3)ccc1OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C=O)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of [8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (417 mg, 0.86 mmol) in THF (10 mL) was added NaIO4 (468 mg, 2.19 mmol) and H2O (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and partitioned between sat. aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, filtered and concentrated in vacuo to yield 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carbaldehyde (384 mg, 99%) as a white solid. ESI-MS m/z calc. 450.3. found 451.3 (M+1)+; Retention time: 1.33 minutes (3 min run).
Reaction SMILES: [CH:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.CC(=O)OCC>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][C:15]=1[F:22]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(c1ccc(N)c(F)c1)C1CCCCC1

Procedure:
Ethyl 2-cyclohexyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mixture of EtOH and EA (420 mL) and hydrogenation was carried out in an H-cube (1 bar, 25° C., 1 mL/min and 0.25 mol/L). Following removal of the solvent and drying, 5 g of the desired product were obtained (quantitative conversion).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (320 mg, 75%).
Reaction SMILES: [CH3:1][C@@H:2]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])=[CH:17][CH:16]=1)[C:3](N1CCOCC1)=[O:4].C1C[O:39]CC1.[OH-].[Li+]>CO.O>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([C:21]2[N:20]([CH2:19][C:18]3[CH:34]=[CH:35][C:15](/[CH:14]=[CH:13]/[CH2:12][O:11][C@H:2]([CH3:1])[C:3]([OH:4])=[O:39])=[CH:16][CH:17]=3)[CH:24]=[CH:23][CH:22]=2)=[O:26])=[CH:32][CH:31]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2cccn2Cc2ccc(/C=C/CO[C@H](C)C(=O)N3CCOCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)c2cccn2Cc2ccc(/C=C/CO[C@H](C)C(=O)O)cc2)cc1
Yield: 85 %

Procedure:
The compound of Example 68-1 (213 mg, 0.45 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide (0.9 ml), followed by stirring under reflux for 7 hours. The reaction mixture was diluted with water and washed with diethyl water. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (155 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:31]C)[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=1.Cl.[CH3:34]O>O1CCOCC1>[CH3:34][O:30][C:28](=[O:29])[CH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:31])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])=[CH:26][CH:25]=1
Reactant: CO
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCc3ccc(CC(=O)O)cc3)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from step (viii) (13 g) was dissolved in methanol (100 ml) and 4N—HCl in dioxane (10 ml) added. The reaction mixture was stirred at rt for 24 h. The resultant was concentrated under reduced pressure and aqueous NaHCO3 added to pH 8. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 11 g.
Reaction SMILES: [OH:1]O.[C:3]([C:5]1[C:6]([CH3:17])=[C:7]([C:12]([S:15][CH3:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:4].[OH-].[Na+]>C(O)C.O>[CH3:11][O:10][C:8]([C:7]1[C:6]([CH3:17])=[C:5]([CH:14]=[CH:13][C:12]=1[S:15][CH3:16])[C:3]([NH2:4])=[O:1])=[O:9]
Reactant: COC(=O)c1c(SC)ccc(C#N)c1C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Temperature: 65 °C

Procedure:
Hydrogen peroxide (30%, 18 ml) was added dropwise with stirring to a solution of methyl 3-cyano-2-methyl-6-methylsulphenylbenzoate (10.0 g) in ethanol (100 ml) in an atmosphere of nitrogen. A solution of sodium hydroxide (0.43 g) in water (2 ml) was added dropwise and the resultant rapid exotherm was controlled by ice cooling. After the exotherm had ceased the mixture was stirred and heated at 65° C. for 0.5 hours. The orange solution was poured into a mixture of ice and water (400 ml) and it was extracted with ether (3×100 ml). The combined organic extracts were washed with water (100 ml), aqueous ferrous sulphate solution (100 ml), water (2×100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) as an orange oil, NMR (CDCl3) 2.3(s,3H), 2.4(s,3H), 3.9(s,3H), 6.5(bs,2H), 6.95(d, 1H), 7.25(d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26]([NH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([F:20])([F:18])[F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a mixture of ethyl 7-amino-5-(trifluoromethoxy)-1H-indole-2-carboxylate (2.53 g) and pyridine (50 mL) was added thiophene-2-sulfonyl chloride (1.94 g) at 0° C., and the mixture was stirred at room temperature for 4 hr, and concentrated. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained crystals were washed with diisopropyl ether to give the title compound (3.40 g, yield 89%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 196-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[F:30][C:29]([F:31])([F:32])[C:26]1[CH:25]=[CH:24][C:23]([C:21](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[CH3:20])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Oc2ccc(N=C(C)c3ccc(C(F)(F)F)cc3)cn2)cc1

Procedure:
Ethyl 4-(5-aminopyridin-2-yloxy)benzoate (16.0 g, 62 mmol) was dissolved in toluene (300 mL). To the resulting solution were added 4-trifluoromethylacetophenone (11.7 g, 62 mmol) and (±)-camphor-10-sulfonic acid (1.08 g, 4.65 mmol), and refluxed overnight. The reaction solution was concentrated under reduced pressure, to thereby yield 26.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]=[CH2:20])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:25][S:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:28])=[O:27].[CH3:37][S:38]([OH:40])=[O:39].[Na]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][CH2:20][S:38]([CH3:37])(=[O:40])=[O:39])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:25][S:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:27])=[O:28]
Reactant: CS(=O)O
Reactant: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1
Agent: [Na]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(CCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 251 using N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (0.135 g, 0.247 mmol) and methane sulfinic acid, sodium salt (0.126 g, 1.234 mmol), the title compound was obtained as a solid (127 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.72 (s, 1H), 8.54 (d, J=5.49 Hz, 1H), 7.52 (m, 3H), 7.44 (m, 2H), 6.48 (d, J=5.49 Hz, 1H), 3.54 (m, 2H), 3.28 (m, 2H), 3.04 (s, 3H), 1.42 (s, 9H); MS (ESI): 627 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:21](=[O:22])[NH:20][C@H:4]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:3])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)N[C@@H](C)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with (S)-1-isocyanato-ethyl)-benzene (25 mg) to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure I. This product (25 mg) was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 882.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][CH:60]([O:63][CH2:64][C:65](O)=[O:66])[CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:68]([F:71])([F:70])[F:69])([O-:49])=[O:48]>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:65](=[O:66])[CH2:64][O:63][CH:60]3[CH2:61][CH2:62][CH:57]([NH:56][C:53]4[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[C:51]([C:68]([F:70])([F:69])[F:71])[CH:52]=4)[CH2:58][CH2:59]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Cc1cc(N2CCNCC2)nc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)COC3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 4-methyl-2-(piperazin-1-yl)quinoline (100 mg, 0.44 mmol) in dichloromethane (20 ml) was added EDAC.HCl (126 mg, 0.66 mmol, 1.5 eq), HOBt (88.8 mg, 0.66 mmol, 1.5 eq), triethylamine (133 mg, 1.31 mmol, 3 eq) and 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (190 mg, 0.52 mmol, 1.2 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC with 50% ethyl acetate in dichloromethane to afford 1-[4-(4-methylquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoro-methyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (117 mg, 47%); (ES, m/z) [M+H]+ 572.20; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54-7.62 (m, 1H), 7.32-7.38 (m, 1H), 6.87 (s, 2H), 6.63-6.67 (m, 1H), 4.48 (d, J=7.5 Hz, 1H), 4.28 (s, 2H), 3.75-3.85 (m, 7H), 3.39-3.52 (m, 2H), 2.65 (s, 3H), 2.16 (d, J=9.9 Hz, 1H), 1.46-1.53 (m, 2H), 1.25-1.36 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31](O)=[O:32])[CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1.CS([O-])(=O)=O.ClC1C=CC=C[N+:41]=1C.N>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([NH2:41])=[O:32])[CH:29]=3)[NH:24][CH:23]=2)[CH2:20][CH2:21]1
Reactant: C[n+]1ccccc1Cl
Reactant: COc1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(C(=O)O)cc45)CC3)c2c1
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: CN1CCCC1=O
Product: COc1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(C(N)=O)cc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.1 g of 3-[1-(4-(5-methoxyindol-3-yl)butyl)-4-piperidyl]indole-5-carboxylic acid are suspended in 100 ml of N-methylpyrrolidone. 3.2 g of 2-chloro-1-methylpyridinium methanesulfonate are then added and the mixture is stirred at room temperature for 12 hours. Dried NH3 gas is passed into the resulting solution until it is saturated and it is stirred again for 10 hours. Working-up in a conventional manner gives 3-[1-(4-(5-methoxyindol-3-yl)butyl)-4-piperidyl]indole-5-carboxamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>ClCCl>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1cccs1
Temperature: -5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Chloropropionyl chloride (12 mL, 130 mmol) in dry dichloromethane (50 mL) was added dropwise at −5° C. to a stirred suspension of aluminium chloride (18.8 g, 141 mmol) in dry dichloromethane (100 mL). The resulting suspension was allowed to stir at −5° C. for 10 mins before a solution of thiophene (10 g, 118 mmol) in dry dichloromethane (50 mL) was added dropwise. The resulting orange solution was stirred at −5° C. for 1 hr before being carefully dropped onto crushed ice (200 g). The organic phase was separated and dried (MgSO4), the solvent was then passed through a pad of celite/charcoal to remove any colour. Removal of the solvent in vacuo resulted in the title compound as a colourless oil (20 g, 100%); δH (300 MHz, CDCl3) 7.75 (1H, d, Ar), 7.68 (1H, d, Ar), 7.15 (1H, m, Ar), 3.90 (2H, t, J=7 Hz, CH2), 3.38 (2H, t, J=7 Hz, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]#[N:9])=[N:5][NH:6][CH:7]=1.C1C(=O)N([I:17])C(=O)C1>CN(C)C=O>[I:17][C:7]1[NH:6][N:5]=[C:4]([C:8]#[N:9])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1c[nH]nc1C#N
Solvent: CN(C)C=O
Product: COc1c(C#N)n[nH]c1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 4-methoxy-1H-pyrazole-3-carbonitrile (compound 280.7, 200 mg, 1.62 mmol) in N,N-dimethylformamide (15 mL) was added NIS (549 mg, 2.44 mmol). The reaction mixture was stirred for 2 h at 70° C., then quenched with 20 mL of Na2S2O3 (sat.). The aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:6) as the eluent to furnish 330 mg (82%) of the title compound as a white solid.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:29][S:26]([CH:23]2[CH2:25][CH2:24]2)(=[O:28])=[O:27])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)C1CC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. LCMS (M+H) calcd for C15H18FN2O6S: 373.1; found: 373.0. 1H NMR (500 MHz, CDCl3) δ: 1.13 (m, 2), 1.44 (m, 2), 2.95 (m, 1), 3.68 (s, 3), 4.79 (s, 2), 6.55 (s, 1), 7.02 (m, 2), 7.29 (m, 2), 8.95 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 6.45, 31.41, 48.31, 63.22, 92.45, 115.71, 115.88, 130.25, 130.32, 131.09, 159.44, 159.74, 161.70, 163.67, 170.98.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.44) (3.12 g, 10.6 mmol) and commercially available 4-iodo-imidazole (2.27 g, 11.7 mmol) according to the general procedure IVa. Obtained as an off-white solid (4.0 g, 83%). MS (ISP) 451.0 [(M+H)+]; mp 202° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[C:10]([NH:14][NH2:15])(=[O:13])[CH2:11][CH3:12]>C(O)C>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:1](=[N:15][NH:14][C:10](=[O:13])[CH2:11][CH3:12])[CH3:2]
Reactant: CCC(=O)NN
Reactant: CC(=O)c1cnccn1
Solvent: CCO
Product: CCC(=O)NN=C(C)c1cnccn1
Yield: 64.2 %

Procedure:
A mixture of 6.11 gm (0.05 mole) of 2-acetylpyrazine, 4.41 gm (0.05 mole) of propanoic acid hydrazide and 100 ml of absolute ethanol is refluxed 10 hr. The mixture is cooled. The white crystals which deposit are collected and dried to yield 6.17 gm (64%) of the title compound having a melting point of 181.3° C.