Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:19]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:29]=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/CC2CCCCC2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/CC2CCCCC2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 15 mL solution of the obtained tert-butyl 4-((E)-3-cyclohexyl-1-propenyl)-2-(4-fluoroanilino)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 70-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-((E)-3-cyclohexyl-1-propenyl)-2-(4-fluoroanilino)benzoic acid 23 mg of pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18].[I-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CCOCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,6-dimethylphenol (20 g) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride (4.4 g) in DMF (50 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. To the mixture were added bromoethylethyl ether (12.3 ml) and sodium iodide (16.4 g), and the mixture was stirred at 75° C. overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled under reduced pressure to give 5-bromo-2-(2-ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) as colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 0.2 g (0.60 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione in 2 mL of N,N′-dimethylformamide is added 4-piperidin-1-ylmethyl-phenylamine (0.127 mL, 0.67 mmol). The reaction mixture is heated at 120° C. under N2 for 1.5 h. After cooling, ethyl ether is added and left in refrigerator overnight to give dark brown crystal. The crystal is collected and dissolved in 4 mL of dimethyl sulfoxide, followed by addition of 6 mL of 65% MeOH/H2O solution to give a precipitate. The solid is collected and washed thoroughly with water, MeOH, Et2O and hexane, and air-dried to give 0.143 g (48.3% yield) of tan solid: mp 202-203° C., MS (ESI) m/z 488.1 (M+H)+1
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][C:15](=O)[CH2:14]2)=[CH:9][CH:8]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33]>>[NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][CH:15]([NH:31][C@@H:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][CH3:33])[CH:25]=3)[CH3:30])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: NC(=O)CCNC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)NCCC(N)=O)cc3)C2)ccc1F

Procedure:
General procedure B was followed using N-(3-amino-3-oxo-propyl)-4-[(1S)-3-oxocyclopentyl]benzamide as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)-ethylamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 8.39 (t, J=5.6 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.37-7.31 (m, 3H), 7.16 (dd, J=8.6, 1.8 Hz, 1H), 7.10 (dd, J=11.5, 8.2 Hz, 1H), 6.91-6.87 (m, 1H), 6.82 (br s, 1H), 3.83 (s, 3H), 3.77-3.71 (m, 1H), 3.46-3.37 (m, 2H), 2.99-2.87 (m, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.26-2.19 (m, 1H), 1.96-1.85 (m, 1H), 1.78-1.58 (m, 2H), 1.53-1.34 (m, 2H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:24]3[CH2:28][O:27]C(C)(C)[O:25]3)[CH:23]=2)=[N:4][N:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:12]1([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:38][CH2:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)=[N:3][N:4]=[C:5]3[C:18]2[CH:23]=[C:22]([CH:24]([OH:25])[CH2:28][OH:27])[CH:21]=[N:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OCC(c2cncc(-c3nnc(Cl)c4c(-c5ccccc5)cccc34)c2)O1
Reactant: NCc1ccccn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCC(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 100 °C
Yield: 5.1 %

Procedure:
To a solution of 4-chloro-1-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-phenylphthalazine (1.00 g, 2.39 mmol) in toluene (5 mL) was added pyridin-2-ylmethanamine (5.00 mL, 48.5 mmol) the contents were heated at 100° C. for 12 h. The reaction mixture was diluted with DCM (200 mL) and washed with 1.5N HCl (2 ×20 mL). The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by preparative HPLC (Condition 18 as described in general methods) to obtain 1-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)ethane-1,2-diol (55.0 mg, 5.11%) as a white solid. The racemic product (50 mg) was resolved into individual enantiomers by chiral SFC (Condition 29 as described in general methods).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:19]#[N:20])[NH:12][CH:11]=1)[NH:6][CH:7]=O)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4]([CH:5]1[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:19]#[N:20])[NH:12][C:11]=2[CH2:7][NH:6]1)=[O:21])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1c[nH]c2cccc(C#N)c12)NC=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1Cc2c([nH]c3cccc(C#N)c23)CN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.1 %

Procedure:
7.8 g of 4-cyano-N-formyltryptophan ethyl ester is dissolved at 0° C. in 40 ml of phosphorus oxychloride and stirred for 18 hours at room temperature. The solution is then concentrated by evaporation in vacuo, the residue partitioned between water and chloroform and the aqueous phase then extracted. The organic phases are washed with water, dried with calcium sulphate and concentrated by evaporation in vacuo. Chromatography on silica gel with methylene chloride-acetone (1:1) of the residue yields 300 mg of 5-cyano-1,2,3,4-tetrahydro-β-carbolin-3-carboxylic acid ethyl ester of melting point 248° C. in addition to 500 mg of 5-cyano-β-carbolin-3-carboxylic acid ethyl ester of melting point 310° C., by disproportionation of the 5-cyano-3,4-dihydro-β-carbolin-3-carboxylic acid ethyl ester.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([O:15][CH3:16])=[O:14]>CO.[Pt](=O)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]1
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)cc2Cl)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(Cl)cc2Cl)C1
Reaction time: 1.5 h
Yield: 211.7 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)isonicotinate hydrochloride (2.60 g, 8.15 mmol) was dissolved in MeOH (50 mL), added platinum(IV) oxide (0.019 g, 0.08 mmol) and hydrogenated in a Büchi hydrogenator at 5 bar for 90 min. The reaction mixture was filtered and evaporated to give crude methyl 2-(2,4-dichlorophenyl)piperidine-4-carboxylate hydrochloride (2.8 g) as a white solid. MS m/z 288 (M+H)+
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)=[O:18]>>[CH3:3][CH:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(C)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCCCCCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from the product of Example 9 and 4-formylbenzoic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[CH2:12][CH2:11]2)=[O:8])[CH2:3][CH2:2]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:15]2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1CN1CCN(CC(=O)N2CCOCC2)CC1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1CN1CCN(CC(=O)N2CCOCC2)CC1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.1 part of N1 -(morpholinocarbonylmethyl)-N4 -(2-aminobenzyl)piperazine in 3 volume parts of pyridine is added 0.062 part of benzoyl chloride, and the mixture is kept standing at room temperature overnight. Then the pyridine is distilled off under reduced pressure, and resultant residue is chromatographed over silica gel. Ethyl acetate eluates give N1 -(morpholinocarbonylmethyl)-N4 -(2-monobenzoylaminobenzyl)piperazine as oily substance.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[OH:20][CH:21]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23][CH:22]1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N12CCN(CC1)CC2>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH:22]5[CH:21]([OH:20])[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]5)[CH2:31][CH2:32]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CC1(C)OCC(O)C(N2CCNCC2)CO1
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: CC1(C)OCC(O)C(N2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC2)CO1
Yield: 10.5 %

Procedure:
2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated at 140° in 30 ml of dimethyl sulphoxide with 2.5 g (11 mmol) of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine and 2.25 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane for 4 hours, the reaction mixture is concentrated, the resulting oil is diluted with 20 ml of methanol and the pH is brought to 5 with 2N hydrochloric acid. The precipitate which has separated out is recrystallized from glycol monomethyl ether/methanol. 0.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid of melting point 255°-262° (with decomposition) is obtained, and is dissolved in 10 ml of 2N hydrochloric acid, with warming, to split off the protective group. After the solution has been left to stand at room temperature for 1 hour, 0.3 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(1,3,4-trihydroxy-2-butyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid of melting point 262°-268° (with decomposition) has precipitated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:7]1[CH:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=[C:3]([C:11]([F:12])([F:13])[F:14])[C:2]=1[OH:1]
Reactant: CC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(O)c(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
1-(4-Hydroxy-3-trifluoromethylphenyl)ethanone (5 g) was initially charged in acetonitrile (150 ml) at RT while stirring, and cooled to −10° C. At this temperature, N-bromosuccinimide (4.5 g, dissolved in 100 ml of acetonitrile) was added dropwise. Then the cooling bath was removed and the mixture was stirred for a further 5 h. After standing overnight, ¾ of the solvent was drawn off and the residue was admixed with n-heptane/water. The organic phase was removed and washed once with 5% sodium thiosulfate solution and once with water. The precipitate formed was filtered off with suction, washed and dried. 6.9 g of the title compound were obtained in sufficient purity. LC-MS rt: 1.35 min [M+H]+: 283.0 (met. a)
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=2)[CH:19]=[C:18]([N:31]2[C@H:36]([CH3:37])[CH2:35][O:34][C@H:33]([CH2:38][NH2:39])[CH2:32]2)[N:17]=1>C1COCC1>[NH2:15][C:16]1[N:17]=[C:18]([N:31]2[C@H:36]([CH3:37])[CH2:35][O:34][C@H:33]([CH2:38][NH:39][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:32]2)[CH:19]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=2)[N:21]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 124.5 %

Procedure:
Triethylamine (0.05 mL, 0.36 mmol) and pivaloyl chloride (0.04 mL, 0.33 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (99 mg, 0.29 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow foam (154 mg, about 75% pure). LC-MS (ES) m/z=427 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5])C.[OH-].[K+]>CO.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:10]2[S:9][CH:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:13]=1
Reactant: CCOC(=O)c1ncsc1Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncsc1Nc1cccnc1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
A solution of 5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (2.90 g, 11.63 mmol) in methanol (24.00 ml) was treated at room temperature with a solution of KOH (1.95 g, 34.90 mmol) in water (18 ml) and stirred at 65° C. for 2 h 45 min. The methanol was evaporated and the residual slurry acidified to pH 5 with 1N HCl. The mixture was sonicated for 15 minutes, then filtered washing with water. The solid was dried under high vacuum overnight, yielding 5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (2.37 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: CSc1ncc(Cl)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A suspension of 5-chloro-2-(methylthio)pyrimidin-4(3H)-one (24 g, 0.136 mol) in POCl3 (200 mL) was heated at reflux for 2 hrs. The reaction mixture was then cooled to room temperature and was concentrated to remove excessive of POCl3. The residue was then treated with H2O (150 mL) and was adjusted to pH=7˜8 with aq. K2CO3. The resulting mixture was extracted with CH2Cl2 (50 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and dried on vacuum to give title compound (23 g, 86%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:33]([O:36][CH3:37])=[CH:34][CH:35]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N:22](CC)CC)C.ClC(OCC)=O.[NH4+].[OH-]>O1CCCC1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:22])=[O:19])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(N)=O)cc1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid (2.13 g, 7.71 mmol) prepared in 3) was dissolved in tetrahydrofuran (32 ml) in nitrogen atmosphere, and triethylamine (1.16 ml, 8.41 mmol) and ethyl chloroformate (0.726 ml, 8.41 ml) were dropwise added under cooling with ice, followed by stirring for 30 minutes. Then, a 28% ammonia aqueous solution was dropwise added, followed by stirring for 5 minutes. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate twice. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid amide (1.60 g, 76%) as colorless solid.
Reaction SMILES: C([O:3][C:4]([O:6][N:7]=[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:9])=O)C.[OH-].[Na+].Cl>O.C(O)C>[C:10]1([C:8]2[NH:9][C:4](=[O:3])[O:6][N:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)ON=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(-c2ccccc2)no1
Yield: 53.3 %

Procedure:
A solution of N′-[(ethoxycarbonyl)oxy]benzenecarboximidamide (17.0 g, 81.6 mmol) and sodium hydroxide (6.28 g, 157 mmol) in water (380 ml) and ethanol (95 ml) was stirred at room temperature for 3 hours. Thereto 1 N hydrochloric acid (157 ml) was added, and a precipitated solid was collected by filtration and washed with water to give 7.05 g (53.4%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=2)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C[CH2:40][N:41](C(C)C)C(C)C>ClCCl.CN.ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=2)=[N:41][CH3:40])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CN=C(NS(=O)(=O)c1ccc(Cl)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 140 °C
Yield: 14.8 %

Procedure:
Part B: A stirred mixture of N-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (2.36 gram, 5 mmol), PCl5 (1.15 g, 5.5 mmol) and chlorobenzene (50 ml) is heated for 90 minutes at 140° C. After cooling the mixture to room temperature the residue is dissolved in dichloromethane and methylamine.HCl (0.34 g, 5 mmol) and DIPEA (1.74 ml, 10 mmol) are successively added. The resulting mixture is stirred for 16 hours at room temperature, twice washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is further purified by flash chromatography (silica gel, dichloromethane/acetone=99/1 (v/v/), followed by crystallization from diisopropyl ether to give N-[(4-chlorophenyl)sulfonyl]-N′-methyl-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (0.36 gram, 15% yield). Melting point: 134-144° C. Rf (silica gel, diethyl ether=0.4).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]34[CH2:29][CH:17]5[CH2:18][C:19]([NH:21]C(=O)OC(C)(C)C)([CH2:20]3)[CH:15]([CH2:16]5)[CH2:14]4)=[CH:9][CH:8]=2)[C:3]1=[O:30].C(Cl)Cl>[Pd].CO>[NH2:21][C:19]12[CH2:18][CH:17]3[CH2:29][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:5][CH2:6][N:2]([CH3:1])[C:3]5=[O:30])=[CH:12][CH:11]=4)([CH2:14][CH:15]1[CH2:16]3)[CH2:20]2
Reactant: CN1CCN(c2ccc(C34CC5CC(C3)C(NC(=O)OC(C)(C)C)(C5)C4)cc2)C1=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(C34CC5CC(C3)C(N)(C5)C4)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of the compound obtained from step I (0.25 g, 0.56 mmol) in a 1:1-mixture of CH2Cl2 and MeOH (10 mL) was added Pd/C (10% w/w, 0.1 g) and stirred at room temperature under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(3a-aminohexahydro-2,5-methanopentalen-2(1H)-yl)phenyl]-3-methylimidazolidin-2-one (0.15 g) as an off-white solid in 86% yield. M.R. 227-230° C.; m/z (M+1), 312; IR cm-1 3416, 3249, 2964, 1682, 1519, 1485, 1261, 810; 1H NMR (CDCl3+DMSO-d6) 300 MHz δ 8.38 (bs, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 3.76 (t, J=7.4 Hz, 2H), 3.43 (t, J=7.4 Hz, 2H), 2.77 (s, 3H), 2.48-2.40 (m, 2H), 2.22-2.14 (m, 1H), 2.10-2.0 (m, 2H), 2.0-1.86 (m, 4H), 1.80-1.60 (m, 3H).