Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23](O)=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.Cl.[NH2:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[OH:40]>CO>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23]([NH:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][C@H:36]2[OH:40])=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: O=C(O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Agent: Cl
Solvent: CO
Product: O=C(N[C@@H]1CCC[C@H]1O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O

Procedure:
The titled compound was synthesized using the procedure described above using compound 8. The coupling compound, (1R,2R)-2-aminocyclopentanol hydrochloride, was synthesized by modification of the following procedure: Overman L. E.; Sugai, S., J. Org. Chem. 50, 4154-4155 (1985). The product was a yellow solid, mp 55-57° C., [α20D] −28.5 (c 0.1, MeOH), UV (MeOH) 396 nm (ε 14,100), 319 nm (ε 7444). 1H NMR (CDCl3, 500 MHZ): δ 15.41 (bs, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.60-6.84 (m, 9H), 5.21 (s, 2H), 4.10-3.76 (m, 5H), 2.25-1.73 (m, 6H). 13C NMR (CDCl3, 125 MHZ): δ 181.1, 163.0, 162.1, 160.2, 159.0, 143.7, 141.4, 132.1, 132.1, 132.1, 131.2, 131.1, 131.1, 131.0, 130.5, 130.4, 124.7, 124.7, 122.5, 122.4, 122.3, 121.8, 116.9, 115.5, 115.3, 111.7, 111.7, 111.5, 111.5, 104.4, 104.2, 104.0, 98.1, 79.1, 60.2, 47.5, 32.5, 30.5, 30.4, 21.4. HRMS (M+H)+ calculated mass 527.1794 for C28H26F3N2O5. found 527.1804.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.3 mmol) of [4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 59 mg (1.4 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 380 mg (2.0 mmol) of t-butyl bromoacetate was added to the obtained mixture, and they were stirred at room temperature for 4 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[N:13]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example E.47) (0.39 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.4 g, 76%). MS (ISP) 526.3 [(M+H)+]; mp 163° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].C(N(CC)CC)C.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:21])[CH3:24]
Reactant: NCCS
Reactant: CCOC(=O)CCl
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CSCCNC(=O)OCC
Reaction time: 1 h
Yield: 89.6 %

Procedure:
There was suspended 50 g (0.65 mol) of 2-aminoethanethiol in 660 ml of ethanol and, under cooling with ice, added 65.6 g (0.65 mol) of triethylamine and added dropwise 79.6 g (0.65 mol) of ethyl chloroacetate, and then the mixture was stirred for 1 hour under cooling with ice. Then thereto was added 65.6 g (0.65 mol) of triethylamine and added dropwise 70.6 g (0.65 mol) of ethyl chloroformate, and the mixture was stirred for 1 hour under cooling with ice, and further for hours at room temperature. After the solvent was removed under reduced pressure, the residue was dissolved in chloroform and washed with water, and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give 137 g of the titled compound as oily matter.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:15]
Reactant: CCN(CC)c1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc(C(=O)O)nc1
Temperature: 25 °C

Procedure:
To a stirred solution containing 2.5 g of methyl 5-diethylaminopicolinate in 40 ml methanol is added 40 ml water and 1.04 g of a 50% solution of NaOH in water. The mixture is heated to reflux and allowed to cool to room temperature. This is repeated. The base is neutralized with concentrated HCl, and the solvents removed in vacuo. The residue is dried azeotropically with dioxane. The residue is then extracted into ethanol. Concentration of the ethanol gives 5-diethylaminopicolinic acid as a white crystalline solid, mp 145.5°-147.5° C.
Reaction SMILES: Cl.[NH2:2][C:3]([C:6]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]([OH:24])[N:7]=1)([CH3:5])[CH3:4].CCN(CC)CC.[Cl:32][CH2:33][CH:34]=O.CC(O)=O.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[Cl:32][CH2:33][CH2:34][NH:2][C:3]([C:6]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]([OH:24])[N:7]=1)([CH3:4])[CH3:5]
Reactant: O=CCCl
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(NCCCl)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methanolic solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide hydrochloride (prepared as described in WO2003035076 A1) Et3N (1 eq.), chloroacetaldehyde (2 eq.), AcOH (ca. 1.5 eq.) were added and subsequently NaBH3CN (1.5 eq.). The reaction mixture was stirred at room temperature overnight. To drive the reaction to completion a few drops of TFA were added and stirring was prolonged for a further 1.5 hours. MeOH was removed under reduced pressure to yield the title amine as crude. MS (ES) C17H20ClFN4O3 requires 383. Found: 384 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([Br:45])[C:43]=1[OH:44])[CH2:5][C@H:6]([C:8]([NH:10][C@H:11]([C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:9])[NH2:7].[CH3:46][O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][NH2:55].[O:56]1CCC[CH2:57]1>>[Br:45][C:42]1[CH:41]=[C:4]([CH:3]=[C:2]([Br:1])[C:43]=1[OH:44])[CH2:5][CH:6]([C:8]([NH:10][C@H:11]([C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:9])[NH:7][C:57]([NH:55][CH2:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[O:47][CH3:46])=[O:56]
Reactant: N[C@H](Cc1cc(Br)c(O)c(Br)c1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Reactant: COc1ccccc1CN
Reactant: C1CCOC1
Product: COc1ccccc1CNC(=O)NC(Cc1cc(Br)c(O)c(Br)c1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Temperature: -10 °C

Procedure:
A tetrahydrofuran solution (50 ml) of 1.0 g (1.34 mmol) of 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine was added dropwise over a period of 40 minutes to a suspension of 0.33 g (2.01 mmol) of CDT in 50 ml of tetrahydrofuran cooled to −10 ° C. and stirred. The reaction mixture was then stirred for 2 hours at ambient temperature and mixed with 0.22 ml (1.675 mmol) of 2-methoxy-benzenemethanamine. Then the mixture was refluxed for 2 hours and stirred overnight at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was triturated with ether and the solid obtained (1.1 g; 90% of theory) was suction filtered and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CCN(C(C)C)C(C)C.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: NCCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DIEA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#N)[C:5]([CH3:10])=[CH:4][CH:3]=1.[OH-:11].[K+].Cl.[OH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:14])=[O:11])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C#N
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: Cc1ccc(Cl)nc1C(=O)O
Temperature: 25 °C

Procedure:
6-Chloro-3-methylpyridine-2-carbonitrile (2.95 g, 19.3 mmol) and Potassium hydroxide (3.25 g, 58 mmol) were stirred in refluxing water (60 mL) for 2 hours. The mixture was cooled to room temperature, 30 mL of 2 N HCl was added, followed by the addition of water. The resulting mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]([O:21]CC)=[O:20])[C:8]2=[O:24].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C1COCC1>[Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]([OH:21])=[O:20])[C:8]2=[O:24]
Reactant: CCOC(=O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 60 °C
Yield: 94.8 %

Procedure:
Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate (80 mg, 0.18 mmol) obtained in Step 6 was dissolved in a mixture of ethanol (2 ml) and THF (1 ml), and 1N aqueous sodium hydroxide solution (1 ml, 1.0 mmol) was added. The mixture was stirred with heating at 60° C. for 1 hr. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction solution. The precipitate was collected by filtration, washed with 30% aqueous ethanol and vacuum-dried to give an object product (70 mg, yield 93%) as a white solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:9]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[N:15][N:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1.ClCCl>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[C:9]1[C:8]([C:6]2[S:45][C:1]([CH3:2])=[N:4][N:5]=2)=[C:12]([C:13]2[CH:14]=[N:15][N:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:17]=2[C:18]([F:21])([F:20])[F:19])[O:11][N:10]=1
Reactant: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccncc2)c1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nnc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3ccncc3)c2C(F)(F)F)s1

Procedure:
To a solution of N′-acetyl-3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (0.029 mg, 0.01 mmol) in dioxane (1.5 mL) was added Lawesson's Reagent (23.1 mg, 0.01 mmol). The mixture was stirred at reflux for 30 min. The mixture was then diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Yield: 98.7 %

Procedure:
A solution of t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (0.45 g) in dioxane (3 ml) was treated with triethylamine (0.27 ml) and trimethylsilyl trifluoromethanesulfonate (0.33 ml). The solution was heated at reflux for 30 min and then diluted with water to form a precipitate which was collected by filtration to give 4-[6-(cyclopentylmethycarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.40 g, 99%) as a tan powder; partial NMR (80 MHz, CDCl3): 3.66(s, 3H, CO2CH3), 3.70(s, 2H, COCH2Ar) 3.96(s, 3H, OCH3), 5.29(s, 2H, NCH2Ar). (It will be recognized that this compound is also an example of the invention.)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:14]=[CH:13][N:12]=1)=[O:9])[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:10][C:8](=[O:9])[NH:7][CH:5]([CH3:6])[C:4]([OH:25])=[O:3])[CH:16]=1
Reactant: CCOC(=O)C(C)NC(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)NC(C)C(=O)O)ncn1
Reaction time: 2 h

Procedure:
To a solution of 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-propionic acid ethyl ester (LIV) (470 mg, 1.4 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (0.11 g, 2.7 mmol) in water at ice bath temperature over 30 min and then allowed to stir for 2 hours. THF was evaporated and the aq. solution was acidified with 2N HCl. This aq. phase was then extracted with ethyl acetate (2×100 ml), the separated and combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-propionic acid (compound #32A) as a white solid. Yield: 223 mg, 50.4%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27]OS(C)(=O)=O)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:42]([O:41][C:39]([N:33]1[CH2:38][CH2:37][N:36]([CH2:27][C:12]2[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[CH:11]=2)[CH2:35][CH2:34]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 72.6 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 72.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[N:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[NH:12][C:13](OCC)=[O:14])[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:14])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1ccc(Br)cc1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(Br)cc3c(=O)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Titanium (IV) chloride (2.47 mL, 22.5 mmol) was carefully added to a solution of 1-[(4-bromo-phenylimino)-ethoxycarbonylamino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.84 g, 4.50 mmol) and DCE (45 mL), and the resulting solution was heated to 100° C. for 15 h. The reaction mixture was cooled to room temperature and poured into ice water (50 mL) and DCM (100 mL) was added. The biphasic mixture was stirred for 2 h, and the layers were separated. The aqueous layer was further extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), and concentrated. The residue was triturated from EtOH to yield the titled compound (1.05 g, 64% yield). MS (ESI/Cl): mass calcd. for C14H11BrN4O3, 362.0; m/z found, 363.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.15 (s, 1H), 9.01 (d, J=0.5 Hz, 1H), 8.33 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.99 (dd, J=8.7, 2.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=O)=[O:20])=[C:15]([Cl:23])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.S(Cl)([Cl:28])(=O)=O.[NH2:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:32]1>>[Cl:23][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][C:6]([Cl:28])=[CH:7][CH:8]=3)[N:3]=[CH:2][CH:11]=2)[CH:18]=[CH:17][C:16]=1[S:19]([NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:32]1)(=[O:20])=[O:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCN1CCC(N)CC1
Reactant: O=S(=O)(O)c1ccc(Nc2cc(Cl)nc3ccccc23)cc1Cl
Agent: Cl
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2Cl)CC1

Procedure:
4-(2-Chloro-4-quinolylamino)-2-chlorobenzene sulphonic acid is converted to the corresponding sulphonylchloride hydrochloride and reacted with 4-amino-1-butylpiperidine in a similar manner to that described in Example 1(b) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([O:21][C:32](=[O:34])[CH3:33])[CH2:16]1
Reactant: CC(=O)Cl
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.6 %

Procedure:
Compound 130A (15 mg, 0.045 mmol) was dissolved in 1 mL anhydrous dichloromethane. Triethylamine (32 μL, 0.228 mmol) was added followed by acetyl chloride (6.5 μL, 0.09 mmol). The mixture was stirred at room temperature overnight. The crude product was purified on silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (23 mg, 68% yield).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:34][CH2:33][CH2:32][C:26]2[C:25]3[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=3)[NH:28][CH:27]=2)=[O:18])=[CH:19][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
Thionyl chloride (0.111 mL; 1.52 mmol) was added to a mixture of 4-benzylbenzoic acid (0.100 g; 0.508 mmol) in chloroform (10 mL). The reaction mixture was stirred at 65° C. for 18 hours and evaporated to dryness. The resulting residue was dissolved in chloroform (6 mL) and the solution is cooled to 0° C. A solution of 2-(5-Chloro-1H-indol-3-yl)ethanamine hydrochloride (0.108 g; 0.457 mmol) and triethylamine (0.357 mL; 2.54 mmol) in chloroform (6 ml) was then added and the mixture was stirred for 30 minutes at room temperature. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) to furnish 0.155 g (78%) of 4-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[OH:17][C:18]1[C:10]2[C:11](=[CH:13][CH:14]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[N:12]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1O

Procedure:
Prepared as in Example 1c from 4-phenoxyaniline and diethyl 2-(ethoxymethylene)malonate as a white solid (41%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=8.0 Hz, 3H), 4.18 (q, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.47 (m, 2H), 7.69 (d, J=12.0 Hz, 1H), 12.39 (bs, 1H). MS 310 (MH+).