Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:13]=1.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:8]=3[C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CC(=O)CO2
Reactant: CCCNCCC(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN1CCC(=O)C2=C1COc1ccc(OC)cc12

Procedure:
A mixture of 8.9 g of 6-methoxy-2H-[1]-benzopyran-3-one, 7.46 g of methyl 3-(propylamino)-propionate, 0.8 ml of trifluoroacetic acid in 80 ml to toluene is refluxed for 7 hours in a Dean Stark apparatus; additional 0.8 ml portions of trifluoroacetic acid are added at 2,4 and 6 hours. The reaction mixture is cooled and the solvent is removed in vacuo. The residue is crystallized from ether/methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-1-one, melting point 97°-100°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(O)=O.[ClH:39]>C(O)C>[ClH:39].[ClH:39].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][N:33]1[CH2:32][CH2:31][N:30]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Temperature: 25 °C
Yield: 47.7 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (42.1 g; 215 millimoles) and 61.9 g (215 millimoles) of bis(4-fluorophenyl)methylpiperazine were melted in an oil bath at 100° C., and 10 ml (265 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 30 minutes, and allowed to cool to room temperature. A mixture of 40 ml of conc. hydrochloric acid and 400 ml of ethanol was added, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol-ether gave 55.5 g (yield 47.7%) of 1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])[CH3:2].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([NH:6][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(CBr)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NCC(OCC)OCC
Temperature: 23 °C

Procedure:
A solution of L-phenylalanine ethyl ester (8.37 g, 46.8 mmol, 1 equiv), bromoacetaldehyde diethyl acetal (10.6 mL, 70.1 mmol, 1.5 equiv), and DIEA (16.2 mL, 93.4 mmol, 2.0 equiv) in DMF (100 mL) was heated at 80° C. for 2 d. The resulting solution was cooled to 23° C., taken up in chloroform (200 mL), washed with 10% aqueous potassium carbonate (3×50 mL), dried over potassium carbonate, and concentrated. Purification of the residue by silica gel chromatography yield 7.4 g (54%) of product. 1H NMR (CDCl3) δ 1.13-1.23 (m, 9H), 2.61 (dd, 1H, J=11.8, 5.9), 2.78 (dd, 1H, J=11.8, 5.9), 2.96-3.03 (m, 2H), 3.46-3.53 (m, 1H), 3.55-3.70 (m, 4H), 4.18 (q, 2H, J=7.1), 4.57 (t, 1H, J=5.5), 7.19-7.33 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CS(O[CH:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1)(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(OC2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4.5 grams (0.028 mole) of 3-trifluoromethylphenol and 1.1 grams (0.028 mole) of sodium hydride (60% in mineral oil) in 100 mL of toluene is stirred at ambient temperature for about 20 minutes, and a solution of 6.6 grams (0.028 mole) of 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane (prepared as in Step C of Example 8) in 20 mL of toluene is added dropwise. Upon complete addition, the reaction mixture is heated to reflux where it is stirred for about four hours. The reaction mixture is cooled and concentrated under reduced pressure, yielding 8-(3-trifluoromethylphenoxy)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.CN(C)C=O.S(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([Cl:28])[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1CNC(=O)C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CNC(=O)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
The mixture of diastereoisomers from step 6 were each processed individually to the final products. A solution of 4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]pyrrolidin-2-one (0.41 g, 1.4 mmol) (from Step 6) in methylene chloride (12 mL) was treated with N,N-dimethylformamide (0.011 mL, 0.14 mmol) followed by thionyl chloride (0.21 mL, 2.9 mmol) dropwise and stirred at 20° C. for 30 min. The reaction mixture was added dropwise to ice cooled saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired products [from peak 1 (0.38 g, 87%); from peak 2 (0.39 g, 89%)] along with 17-18% of the styrene that formed from chloride elimination. These mixtures were used without further purification. From peak 1: LCMS for C14H17Cl2FNO2 (M+H)+: m/z=320.1; Found: 320.0. From peak 2: LCMS for C14H17Cl2FNO2 (M+H)+: m/z=320.1; Found: 320.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9](=[O:18])[N:10]([C@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:17])[C:4]=2[C:3]=1[NH2:19].[CH2:20](OC(OCC)OCC)C>Cl>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[N:10]1[C:4]2=[C:3]3[N:19]=[CH:20][NH:1][C:2]3=[N:7][CH:6]=[C:5]2[NH:8][C:9]1=[O:18]
Reactant: CCOC(OCC)OCC
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc(N)c(N)c21
Agent: Cl
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of 6,7-diamino-1-[(1S,2R)-2-methylcyclohexyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (40 mg), orthoformic acid triethyl ester (1 mL) and HCl (20 uL) was stirred at ambient temperature for an hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH2 silica gel, chloroform:methanol=95:5) to give 8-[(1S,2R)-2-methylcyclohexyl]-6,8-dihydrodiimidazo[4,5-b:4′,5′-d]pyridin-7(3H)-one (21 mg) as a white powder.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:13]=1[NH2:22]>>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([Cl:20])[C:14]([Cl:21])=[C:13]2[C:12]=1[NH:11][C:2](=[O:4])[C:1](=[O:8])[NH:22]2
Reactant: Nc1c(N)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrachloro-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.97 g, 20.0 mmol) and 1,2-diamino-3,4,5,6-tetrachlorobenzene (500 mg, 2.03 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the orange solid collected by vacuum filtration and rinsed with cold EtOH (10 mL) and air dried. This solid was recrystallized from abs. ethanol to give 97.0 mg (16%) of an orange solid mp 326°-328° C. (dec). (Lit., >360° ). FT-IR: 3198, 3135 cm-1 (N-H), 1750, 1623 cm-1 (C=O). 1H NMR δ (d6 -DMSO) δ 11.7 (br s, 2H, N-H) EIMS m/z 306 (M+8, 1.7), 304 (M+6, 11.5), 302 (M+4, 47.4), 300 (M+2, 93.9), 288 (M+, 76.7), 274 (50.0), 272 (bp), 270 (79.0), 209 (61.0), 207 (64.0). EIHRMS calc. for C8H2Cl4N2O2 297.8870, found 297.8864.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:30]1[CH:31]=[C:32]([NH:37][S:38]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=1.O>C1COCC1>[Cl:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:31][C:32]=1[NH:37][S:38]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCCCC1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)N4CCCCC4)c3)cc2s1
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
To a microwave vial equipped with a stirbar and charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.16 g, 0.51 mmol), cesium carbonate (0.41 g, 1.3 mmol), Pd Cl2 (dppf)-DCM (0.062 g, 0.076 mmol), N-(5-bromo-2-chloropyridin-3-yl)piperidine-1-sulfonamide (0.150 g, 0.42 mmol) in THF (3 ml) was added water (0.5 ml). The vial was capped and placed into CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired material in the mixture. The organic layer was extracted from the microwave vial by pipet and then diluted the organic with acetonitrile (15 ml) and TFA (0.1 ml). The crude was purified by reverse-phase HPLC. The fractions with desired product were combined and concentrated. The crude was recrystallized from 5:1 EtOAc/Methanol and Hexanes to give N-(6-(6-chloro-5-(piperidine-1-sulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.025 g, 13% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 466 (MH+). Calc'd exact mass for C19H20ClN5O3S2: 465. 1H NMR (400 MHz, DMSO-d6): 1.39 (s, 2H), 1.47 (s, 3H), 1.65 (s, 4H), 2.14 (s, 3H), 2.93 (s, 3H), 7.51 (s, 1H), 7.69 (s, 11H), 7.74 (s, 1H), 7.90 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([S:19]([CH3:22])(=[O:21])=[O:20])C(C2C=CC=C(CCl)N=2)=O)=[CH:6][C:5]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][N:29]3S(C3C=CC=CC=3)(=O)=O)=[C:25]([NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Cl)[N:45]=3)=[O:43])[CH:24]=2)=[CH:4][N:3]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[C:25]([NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[N:45]=3)=[O:43])[CH:24]=2)=[CH:6][C:7]=1[NH:8][S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)N(C(=O)c1cccc(CCl)n1)c1cc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Product: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3cccc(CN4CCOCC4)n3)c3cn[nH]c3c2)cnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
N-{2-Chloro-5-[4-({[6-(chloromethyl)-2-pyridinyl]carbonyl}amino)-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}-6-(chloromethyl)-N-(methylsulfonyl)-2-pyridinecarboxamide (60 mg, 0.061 mmol) and morpholine (0.5 ml, 5.74 mmol) were placed in a vial and heated in a microwave at 90° C. for 15 min. The mixture was concentrated by blow down under a stream of nitrogen. The crude residue was suspended in IPA (2 ml) and 2M NaOH (1 ml) added. The mixture was stirred at room temperature for 2 h. The solvent was removed by blow down and the residue purified by MDAP (Method E) (3×800 μl injections in DMSO, the insoluble salt was filtered off through a filter tube). Product-containing fractions were combined and the solvent removed in vacuo. The residue was dissolved in DCM:MeOH and added to the top of a 1 g silica cartridge that was subsequently eluted with 0-5% MeOH/DCM over 5 column volumes. No separation was observed, hence all fractions were combined and the solvent removed under a stream of nitrogen. The residue was dissolved in DMF/Acetone/Water (0.2 ml:0.2 ml:20 μl) and purified by MDAP (Method E). Product-containing fractions were combined and the solvent removed in vacuo. The resulting oil was triturated with ether to give the title compound as a cream solid (8 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[C:22](=O)[CH2:23][CH3:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:23][CH3:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)N1CC[C@@H]2c3cccc(OC)c3CC[C@@H]21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN1CC[C@@H]2c3cccc(OC)c3CC[C@@H]21
Yield: 93.1 %

Procedure:
0.90 g (0.0232 mol) of lithium aluminum hydride was suspended in 40 ml of THF under argon. A solution of 3.0 g (0.0116 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-propionyl-1H-benzo[e]indole in 50 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 1 hour. 25 ml of a saturated aqueous NH4Cl solution was cautiously added dropwise thereto, the mixture was filtered and the filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with CH2Cl2 /MeOH 49:1 there were obtained 2.65 g (93%) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-propyl-1H-benzo[e]indole as a colorless, oily material.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].N1CCCCC1>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:24]3[S:18][C:19](=[S:20])[NH:21][C:22]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C1CSC(=S)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(Nc1ccccc1)Nc1nc(C=C2SC(=S)NC2=O)cs1

Procedure:
Following a procedure similar to that described in Example 24, the desired compound was prepared from 1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.6 g of rhodanine, 0.75 g of piperidine and 15 ml of ethanol. The resulting product was a yellow-brown powder having the following physical properties.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].C([O:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)C>C1COCC1>[CH3:3][C:4]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:25])=[O:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC1CCc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(CCCCCC(=O)O)CCc2ccccc2C1=O
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a suspension of 0.7 g NaH in 40 mL of dry THF are added 4.0 g 2-methyl-1-tetralon in 20 mL of THF. After stirring for 30 min, 5.5 g ethyl-6-bromo-hexanoate in 10 mL of THF are added and the mixture is refluxed for 6 h. After evaporation of the solvent the residue is dissolved in a solution of 4.16 g potassium hydroxide in 50 mL of MeOH and 20 mL of H2O and heated to reflux over night. After evaporation of the MeOH, the aqueous phase is extracted with ethylacetate, acidified with 2N HCl, and extracted again with ethylacetate. This second extract is evaporated yielding 4.2 g of crude 6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-hexanoic acid (4a). In an analogous manner to that described for the conversion of 3b to 3c in example 3, 4a is converted to the title compound 4c. 4c is an oil MS (APCI): 288.1 (M−1). The enantiomers of 4c were separated by semipreparative HPLC using a Chiracel OJ-R and water/methanol as the mobile phase. Purity was determined by analytical HPLC (Chiracel OJ-R column [15 cm, 4.6 mm, particle size 5 μm] using water 40/ methanol 60 v/v at a flow rate of 0.6 ml/min, injection of 10 μl-samples). Retention time and % ee of each enantiomer was 16.75 min (100% ee) and 20.25 min (87% ee), respectively.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].CCN(CC)CC.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:32](=[O:34])[CH3:33])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(C)=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
To a stirred mixture of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.25 g, 0.76 mmol) and NEt3 (0.01 mL, 0.76 mmol) in THF (10 ml) was added acetyl chloride (0.053 ml, 0.76 mmol) at 0° C. The mixture was stirred at room temperature for 20 min, then the solvent was distilled off; the residue was dissolved in water and extracted with ethyl acetate (3×10 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was triturated with dry diethyl ether and the solid was filtered off to obtain 1-acetyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #13A) (0.208 g, 73%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=1)=[C:16]([NH:22][C:23](=[O:25])[CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1COCC1>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:28][CH:27]=1)[CH:16]([NH:22][C:23](=[O:25])[CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:40][CH:39]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)=C(c1ccc(OC2CCCC2)cc1)c1c(C(=O)OCC)[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc2c1C(c1ccc(OC2CCCC2)cc1)C(NC(C)=O)C(=O)OCC

Procedure:
3-(2-Acetylamino-1-(4-cyclopentyloxyphenyl)-2-ethoxycarbonylvinyl)-5-(4-trifluoromethylphenyl)indole-2-carboxylic acid ethyl ester ('370 mg-, 0.58 mmol; see step (b) above) in MeOH (15 mL) and THF (115 mL) was hydrogenated (rt, 7 bar) over Pd—C (10%, 300 mg) for 6.5 h. The mixture was filtered through Celite® and concentrated to give sub-title compound. Yield 378 mg (1100%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 100 %

Procedure:
1-(tert-Butoxycarbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (14) (6.77 g; 14.1 mmol) is dissolved in methylene chloride (60 mL) at ambient temperature. Trifluoroacetic acid (40 mL) is added in a slow stream, and the solution is stirred for 1.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (300 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×100 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (5.34 g) as a white solid. ESMS: MH+ 379.2
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[OH-].[Na+].O>CO>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:12])=[O:2]
Reactant: COC(=O)c1ccc(C)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl-3-Iodo-4-methylbenzoate (3 g, 109 mmol, 1 eq) dissolved in MeOH (30 ml) was added sodium hydroxide (1.3 g, 327 mmol, 3 eq) followed by the addition of water (15 ml). The above solution was stirred at room temperature for 14 h. The solution was concentrated under vacuum, and then added water. The pH of the reaction was bought to 3 using Conc.HCl. The solid obtained was filtered and dried under vacuum. Yield: 2.7 g (96%). 1HNMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H), 7.45 (d, J=8.00 Hz, 1H), 7.85 (d, J=3.18 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)n1cc(F)c(N)nc1=O
Yield: 55 %

Procedure:
Using the procedure of Example 2, 4-amino-5-fluoro-pyrimidin-2-ol (0.25 g, 1.9 mmol), BSA (1.41 mL, 5.8 mmol) and isopropyl chloroformate (1 M solution in toluene; 2.9 mL, 2.9 mmol) were reacted, and the resulting material was purified via reverse phase chromatography (gradient, CH3CN/H2O) to give isopropyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.225 g, 55%) as a white solid: mp 217-219° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.02-7.99 (m, 2H), 4.97 (septet, J=6.26 Hz, 1H), 1.28 (d, J=6.26 Hz, 6H); ESIMS m/z 216 ([M+H]+).