Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11].[NH2:13][CH2:14][C:15]([OH:17])=[O:16].O>C(O)(=O)C>[CH3:12][C:2]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)CC1C(=O)CCCC1=O
Reactant: NCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(n1CC(=O)O)CCCC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(2-oxopropyl)cyclohexane-1,3-dione (prepared by evaporation of an ethanolic solution to dryness under vacuum) (20.0 g, 119 mmol) and glycine (17.9 g, 238 mmol) in acetic acid (100 mL) was heated under reflux for 1.5 h then allowed to cool to r.t. Water (100 mL) was then added and the mixture evaporated to a thick oil in vacuo. Acetone (200 mL) and water (40 mL) were added to the residue and the mixture stirred for 30 mins at r.t., after which the solid was collected by filtration and the filtrates retained. The solid was slurried with further acetone (100 mL) and water (20 mL) at r.t. then removed by filtration. The combined filtrates were concentrated in vacuo then dissolved in aqueous sodium hydroxide (1M, 200 mL), adding a small amount of 10M sodium hydroxide to bring the pH to 14. After washing with ethyl acetate (2×100 mL), the mixture was acidified by the addition of aqueous hydrochloric acid (5M, 60 mL) then sodium chloride (50 g) was added. After stiffing for 4 h, the solid product was collected by filtration, washed with acetone (2×25 mL) then dried under vacuum at 40° C. to afford the title compound as an orange-brown solid; 7.45 g (30%); purity 99.1 area % by HPLC; m/z: 208 (MH+); 1H-NMR: 13.2 (1H, br s), 6.02 (1H, s), 4.67 (2H, s), 2.65 (2H, t, J=6.2 Hz), 2.29-2.24 (2H, m), 2.10 (3H, s), 2.02-1.95 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1)=[O:38])[CH3:35]>>[CH2:34]([O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]4[N:11]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[C:30]([F:32])([F:31])[F:33])=[O:13])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)=[O:28])[CH2:40]1)=[O:38])[CH3:35]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CCOC(=O)C1CCCN(C(=O)C2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)C1

Procedure:
This compound was prepared from 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid and piperidine-3-carboxylic acid ethyl ester using the same method describer in earlier example. LC-MS showed a single peak with a retention time of 3.62 min. LRMS calcd for C31H33F3N4O5 (M+H) 599.24, obsd 599.2
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].BrC[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[I:37]>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:28]=3[I:37])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1ccc(I)c(CCBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1.28 mmol) as described in Example 66 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.06 (d, J=8.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 (s, 2 H), 7.61 (s, 1 H), 7.33 (dd, J=8.2, 1.4 Hz, 1 H), 5.79 (d, J=7.8 Hz, 1 H), 4.91 (d, J=16 Hz, 1 H), 4.40 (d, J=16 Hz, 1 H), 4.16-4.06 (m, 1 H), 0.83 (d, J=6.4 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[C-:10]#[N:11].[Na+]>C(C#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:10]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1)#[N:11]
Reactant: [C-]#N
Reactant: OCc1ccc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1ccc(CO)nc1
Temperature: 110 °C
Yield: 47.8 %

Procedure:
(5-Bromo-pyridin-2-yl)-methanol (1.0 g), NaCN (521 mg), Pd(PPh3)4 (612 mg), and CuI (200 mg) were taken up in degassed EtCN and heated at 110° C. (4 h). The solution was partitioned between EtOAc and 10% NH4OH (aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/2 hexanes/EtOAc, SiO2) gave 341 mg (48%) of (5-cyano-pyridin-2-yl)-methanol as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]=1[CH2:29][NH:30]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].[ClH:38]>C(OCC)(=O)C>[ClH:38].[NH2:30][CH2:29][C:7]1[N:8]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:9](=[O:24])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]1[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=1)=[CH:12][CH:11]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
2-[4-Butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid hydrochloride (0.13 g, 92.9%) as crystals.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[S:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[S:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Yield: 54 %

Procedure:
A solution (0.07 M) of ethyl 4-cyclohexyl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (2 N solution, 4 eq.). The mixture was heated to reflux for 6 hours. After cooling down, the reaction was concentrated and acidified to pH 1 with aqueous HCl (6 N). The resulting mixture was dissolved with DMSO and purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; linear from 95% A to 5% A in 10 min) to afford the title compound (54%) as a solid.
Reaction SMILES: C(O[C@H:5]1[C@@H:9]([NH:10][C:11](=[O:28])[C@H:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][O:6]1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:41][OH:42]>O1CCCC1>[CH2:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][O:6][CH:5]1[O:42][CH2:41][C:40]([O:44][CH2:45][CH3:46])=[O:43])=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CO
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended (2S,3S)-2-acetoxy-3-[[N-benzyloxycarbonyl-(L)-leucyl]amino]tetrahydrofuran (0.8 g) and following addition of p-toluenesulfonic acid (0.02 g) and ethyl glycolate (5 ml), the mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column, elution being carried out with ethyl acetate-hexane (1:1, v/v). From the eluate was obtained ethyl [(3S)-3-[[N-benzyloxycarbonyl-(L)-leucyl]amino]tetrahydrofuran-2-yl]oxyacetate (0.6 g) as an oil. This oil was dissolved in methanol (5 ml) followed by addition of potassium carbonate (0.1 g)-water (5 ml) and the mixture was stirred at room temperature for 3 hours. This reaction mixture was neutralized with 1N--HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried ((MgSO4) and the solvent was distilled off. The residue was dissolved in ethanol (20 ml) and following addition of 1N--NaOH (0.6 ml), the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to provide sodium [(3S)-3-[[N-benzyloxycarbonyl-(L)-leucyl]amino]tetrahydrofuran-2-yl]oxyacetate (chemical formula below) (0.35 g, 41%). As recrystallized from methanol-ether, colorless powder, m.p. 125°-127° C., optical rotation [α]D +50.7° (c=0.33, dimethyl sulfoxide)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH3:21][NH:22][CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]([CH3:23])[CH3:21])[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: CNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and dimethylamine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (635 mg) in N,N-dimethylformamide (100 mL) was added potassium phosphate (918 mg) and dimethylamine (1.3 ml, 2 molar soln.). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered. Concentrated HCl (0.3 mL) was added to a solution of the product in dioxane (150 mL) to precipitate the hydrogen chloride salt (400 mg), mp>300° C. 1H-NMR (300 MHz, DMSO-d6), 11.63 (br s, 1H), 10.92 (br s, 1H), 8.63 (s, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.91 (t, J=9.0 Hz, 1H), 7.69 (m, 2H), 7.38 (d, J=9.0 Hz, 1H), 4.19 (br s, 2H), 2.91 (br s, 6H). Anal. (C17H17N3O2.HCl 0.9 H2O), Calc for: C, 58.67; H, 5.73; N, 12.07; Cl, 10.19. Found: C, 58.91; H, 5.59; N, 11.80; Cl, 9.95.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][P:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])=[CH:14][CH:15]=2)[C:10]([C:27]2[N:28](C(OC(C)(C)C)=O)[C:29]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:31][CH:30]=3)=[N:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:39]1([CH2:38][CH2:37][O:36][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([C:10]2[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([CH3:26])([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:19])[CH:12]=4)[NH:8][N:9]=2)=[CH:35]3)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OP(C)(=O)c3ccccc3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CP(=O)(Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A solution of 10.5 mg of 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-5-(methylphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester in a mixture of 500 μl of dichloromethane and 500 μl of trifluoroacetic acid is agitated at ambient temperature for 4 hours. The reaction medium is evaporated under a stream of nitrogen and then redissolved in 1.4 ml of DMSO. The solution obtained is stirred at 60° C. for 3 days and then purified by LC/MS to obtain 5.1 mg of methylphenylphosphinic acid 3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-yl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C1(C)C=CC=CC=1>[O:11]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[CH:8]([C:26](=[O:27])[NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[C:9]#[N:10]
Reactant: Cn1cccc1C(=O)CC#N
Reactant: O=C=Nc1cccnc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1cccnc1
Reaction time: 8 h

Procedure:
To the suspension of 12.9 g of 1-methyl-β-oxo-2-pyrrolepropionitrile (U.S. Pat. No. 4,256,759) in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine are added 10.8 g of 3-pyridyl isocyanate while stirring. After all solids are dissolved, the solution is allowed to stand at room temperature overnight. The mixture is evaporated to dryness, the residue taken up in methanol and the solution is neutralized to pH ca. 6 with 3 N hydrochloric acid and diluted with 600 ml of water. The resulting precipitate is collected, washed with water, and dried to yield the β-oxo-α-(3-pyridylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1.[C:17](=O)([O-])[O:18]CC.C[O-].[Na+]>CO>[OH:13][CH2:12][CH:11]1[O:14][C:17](=[O:18])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=2)[CH2:10]1
Reactant: CCOC(=O)[O-]
Reactant: OCC(O)CNc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1OC(CO)CN1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
59 G. OF 1-(M-TRIFLUOROMETHYL PHENYLAMINO)-2,3-PROPANEDIOL AND 118 G. OF ETHYL CARBONATE ARE INTRODUCED INTO A DISTILLATION APPARATUS. The mixture is progressively heated to about 110° C. when dissolution is obtained. Then, 12 ml. of a 5% solution of sodium methylate in methanol is added thereto. The distillation of the ethanol formed during the course of the reaction is then observed. Upon completion thereof any excess ethyl carbonate is removed under reduced pressure and the residue obtained is crystallized in isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:22]2[CH2:24][CH2:23]2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:4]([F:25])[CH:3]=1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:45])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:22]2[CH2:24][CH2:23]2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:45])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:4]([F:25])[CH:3]=1
Reactant: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 150 mg (0.25 mmol) of the compound from Example 230 in analogy to the synthesis of the compound from Example 235. 75 mg (77% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([NH2:27])=[CH:22][CH:23]=3)[CH2:18]2)[CH2:15][CH3:16])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl.CCN(C(C)C)C(C)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][N:14]([CH2:15][CH3:16])[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([NH:27][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:22][CH:23]=3)[CH2:18]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(N)cc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid isopropylamide (200 μL of 0.25 M in acetonitrile, 50 μmol) was added 220 μL of a 0.25 M solution of 4-fluorobenzoyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2 and concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile:water (0.1% TFA)) to afford 4-({ethyl-[7-(4-fluoro-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide (13.1 mg) 7 [M+H]+=495.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Li+]>O1CCCC1.O>[C:10]([O:9][C:7]([NH:6][CH2:5][CH:4]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:3]([OH:22])=[O:2])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To 3-tert-Butoxycarbonylamino-2-(3,4-dichloro-phenyl)-propionic acid methyl ester (17.11 g, 0.049 mol) in tetrahydrofuran-water (200 ml of each) was added lithium hydroxide (1.18 g, 0.049 mol). The reaction mixture was stirred at room temperature for 6 hours. THF was removed in vacuo and the pH was adjusted to pH 4 with 2M hydrochloric acid. The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The title compound was obtained as a foam in 89% yield (14.67 g). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (9H, s), 3.22–3.35 (1H, m), 3.35–3.50 (1H, m), 3.76 (1H, t), 6.84 (1H, t), 7.24 (1H, m); 7.48 (1H, s), 7.58 (1H, d), 12.85 (1H, s); MS (ES+): m/e=334.2 (8%); MS (ES−): m/e=332.2 (100%), 334.1 (65%), 336.1 (10%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([N:9]=[C:10]=[S:11])[CH:3]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(Cl)c(Cl)cn1
Solvent: ClCCl
Product: S=C=Nc1cc(Cl)c(Cl)cn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 4,5-dichloropyridin-2-amine (0.25 g, 1.53 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.36 g, 1.56 mmol). The reaction was stirred at 40° C. for 3 hours, then cooled to room temperature. The crude material was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 4,5-dichloro-2-isothiocyanatopyridine (0.26 g, 1.27 mmol, 83% yield) as a yellow powder. The product was carried directly to the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[N:4]([C:31]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:32])[CH2:3]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC1(C)CNc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)N2CC(C)(C)c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc32)CC1

Procedure:
N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-nitro-benzamide (Example 7, Step A)(300 mg, 0.96 mmol) was treated with 4-methyl-piperazine-1-carbonyl chloride (200 mg, 1 mmol) in the presence of DIEA (40 mL) in THF overnight at 65° C. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with H2O and brine, then dried over Na2SO4. The organic solution was concentrated in vacuo to yield the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=3)=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.200 g, 0.47 mmol) and triethylamine (0.08 mL, 0.56 mmol) in CH2Cl2 was added 4-chlorobenzoyl chloride (0.07 mL, 0.56 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated and used directly in the hydrolysis step.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])=[CH:11][CH:10]=1
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(F)cc1

Procedure:
To a solution of 4.9 g. (0.05 mole) of 2-imino-1-methylpyrrolidine in anhydrous benzene is added 6.85 g. (0.05 mole) of p-fluorophenylisocyanate, dissolved in anhydrous benzene, dropwise with stirring. The mixture is stirred at room temperature overnight, then filtered and the filtrate taken to dryness in vacuo. The residue is triturated with isopropanol. The solid which forms is collected, 1-p-fluorophenyl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 113°-115° C. Recrystallization from ethyl acetate yields the pure product, m.p. = 115°-116° C.