Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.F[B-](F)(F)F.[CH3:28][O+](C)C.O>C(Cl)Cl>[CH3:28][O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione is dissolved in methylenechloride and trimethyloxonium fluoroborate added. After stirring at room temperature for a period of two hours, water is added to the reaction mixture, the organic layer is separated, dried over magnesium sulfate and the solvent removed under vacuum. The residue is crystallized from an acetone-hexane solution to yield the desired 19-methoxyandrost-4-ene-3,17-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18]C)=[O:17])=[N:12]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([C:16]([OH:18])=[O:17])=[N:12]1
Reactant: COC(=O)c1nc[nH]n1
Reactant: OB(O)c1ccccc1F
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1ncn(-c2ccccc2F)n1

Procedure:
This intermediate was prepared from 2-fluorophenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=1[NH2:47]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:47][C:46]4[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=4[Cl:44])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4Cl)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 61 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-chloroaniline yielded the title compound (61% yield) as an off-white foam. MS (ISP): m/z=700.4 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCC#Cc1ccc(CN2CCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: OCCCc1ccc(CN2CCCC2)cc1

Procedure:
A solution of 1.65 g (7.66 mmol) 3-(4-pyrrolidin-1-ylmethyl-phenyl)-prop-2-yn-1-ol in 20 mL EtOH is combined with 200 mg 10% Pd/C and hydrogenated in the autoclave at RT and 30 psi H2 until the theoretical uptake of hydrogen is achieved. The catalyst is suction filtered, the filtrate concentrated by evaporation and the residue is purified on silica gel (EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 4 °C
Yield: 63.1 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with phenylacetic acid (10.9 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The product obtained by precipitation in water (13.5 g; m.p. 184° C.) is dissolved in boiling acetonitrile (210 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)phenylacetamide (11.3 g), m.p. 187° C., is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1.[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21].C(O)C>C(O)(=O)C.[Pt]=O>[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21].[NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)ccc1C
Agent: O=[Pt]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc([C@@H]2CCCNC2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.9 %

Procedure:
A 500 mL hydrogenation vessel was charged with 2.0 g platinum(II)oxide and purged with nitrogen. Ethyl 5-(3-pyridyl)-2-methylbenzoate (19.57 g, 81.10 mmol) was added as a solution in 200 mL acetic acid. The suspension was hydrogenated at 45 psi for 18 h. The catalyst was filtered through celite and the filter plug was washed with 200 mL acetic acid. The filtrate was concentrated under reduced pressure. The resultant oil was taken up in 500 mL water and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with ethyl acetate (2×500 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was taken up in 200 mL hot ethanol. L-(+)-tartaric acid (12.17 g, 81.1 mmol) was added into the ethanol solution and was allowed to stir at ambient temperature for 48 h, forming a white precipitate that was collected by filtration. The white solid was recrystallized from hot 5% H2O/ethanol (300 mL) and then from 350 mL hot 20% H2O/ethanol to yield 11.25 g (35%, 95.8% ee) of (S)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-L-tartaric acid salt as a white solid. The mother liquors were combined and concentrated under reduced pressure. The resultant oil was taken up in 300 mL water and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with ethyl acetate (2×300 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was taken up in 200 mL hot ethanol. D-(−)-tartaric acid (6.82 g, 45.4 mmol) was added into the ethanol solution and was allowed to stir at ambient temperature for 48 h, forming a white precipitate that was collected by filtration. The white solid was recrystallized from hot 5% H2O/ethanol (300 mL) and then from 350 mL hot 20% H2O/ethanol to yield 13.51 g (42%, 100% ee) of (R)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid salt as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 82.6 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (0.74 g, 2.9 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.61 g, 2.98 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.96 g of the title compound as a colorless solid (82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)(=[O:12])=[O:11].B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1cccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(O)c2)c(C)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethylphenyl)-N-isobutyl-3-methoxybenzenesulfonamide (431.4 mg, 1.242 mmol) was dissolved in dichloromethane (DCM) (10 mL) and cooled to −78° C. BBr3 in DCM (1M) (6.21 mL, 6.21 mmol) was added dropwise and the reaction put under nitrogen. The reaction was allowed to reach room temperature and left to stir overnight. Water (20 mL) was added dropwise into the reaction mixture, until no more fumes were released. The crude product was then extracted to the organic phase of an aqueous work up between DCM (30 mL) and water (20 mL). The aqueous phase was washed with DCM (2×20 mL). The organic phase was then dried and concentrated in vacuo. The crude product was then dissolved in a minimum of DCM, and loaded onto a silica column before being purified by silica (Si) column chromatography (20 minutes, 0-25% EtOAc in cyclohexane). The relevant fractions were then combined and condensed, to give the desired product, 384.4 mg. LCMS [LCMS1] Rt 1.26 min, m/z (ES+) 334 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:26]=[CH:25][N:24]=[C:23]4[C:18]=3[C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21](=[O:27])[NH:22]4)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][C@H:35]([CH2:38][OH:39])[CH2:34]1>>[OH:39][CH2:38][C@H:35]1[CH2:36][CH2:37][N:33]([C:9]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[CH:26]=[CH:25][N:24]=[C:23]4[C:18]=3[C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21](=[O:27])[NH:22]4)=[CH:14][CH:15]=2)=[O:32])[CH2:34]1.[O:27]=[C:21]1[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[C:18]2[C:23](=[N:24][CH:25]=[CH:26][C:17]=2[NH:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)=[O:32])=[CH:11][CH:12]=2)[NH:22]1
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Product: O=C(Nc1ccccc1)c1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Product: O=C(c1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)N1CC[C@H](CO)C1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 316 and (S)-1-pyrrolidin-3-yl-methanol to provide 317. LC-MS (M+H=407, obsd.=407).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](N1C=CN=C1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1COCC1.C(Cl)CCC>[F:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:27]([CH2:26][C:25]([F:29])([F:28])[F:24])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: O=C(c1ccccc1)c1cc(F)ccc1NC(=O)n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCCl
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a suspension of N-(2-benzoyl-4-fluorophenyl)-1H-imidazole-1-carboxamide (30.00 g, 97.00 mmol) in THF (300 mL) was added 2,2,2-trifluoroethylamine (11.53 g, 116.39 mmol). The reaction was heated to 50° C. After 19 h at 50° C., the reaction was cooled to ambient temperature. Butyl chloride (500 mL) and 10% citric acid (250 mL) were added and the reaction stirred vigorously for 40 min. The precipitate was then isolated by vacuum filtration and placed under vacuum alongside P2O5 for 16 h to give 6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a yellow solid. 1H NMR (CDCl3, 400 MHz) 8.59 (s, NH); d (7.47, J=6.96 Hz, 2H, ArH); 7.36 (m, 3H, ArH); 6.99 (m, 2H, ArH); 6.79 (m, 1H, ArH); 4.39 (m, 1H, CH2); 3.56 (m, 1H, CH2); 3.23 (s, OH); MS (Electrospray): m/z 363.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Br)C.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].Cl>C1COCC1.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[Cl:13])[OH:17]
Reactant: Clc1ccccc1I
Reactant: O=Cc1ccccc1Cl
Agent: CC[Mg]Br
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1ccccc1Cl
Temperature: -12.5 °C
Reaction time: 0.5 h

Procedure:
Under N2, 1-chloro-2-iodobenzene (40 ml, 0.33 mol) was dissolved in THF (360 ml) and cooled to −10 to −15° C. Within 30 min, a 1M solution of ethyl magnesium bromide (344 ml, 0.34 mol) in TBME was added at this temperature. The mixture was stirred at −10 to −15° C. and the reaction was followed by HPLC. After the reaction was complete (15 to 30 min), a solution of 2-chloro benzaldehyde (40.7 ml, 0.36 mol) in TBME (160 ml) was added at −10 to −15° C. within 30 min and the reaction was followed by HPLC. After complete reaction (15 to 30 min), the mixture was hydrolized with dilute HCl until all solids were dissolved at a final temperature of 20 to 25° C. The organic phase was washed with water (2×40 ml) and evaporated to dryness at a temperature of 45 to 50° C. The residue was co-evaporated twice with heptane (80 ml each) and crystallized from hot n-heptane (280 ml at 95 to 100° C.). The product was isolated by filtration after stirring for 1 h at 0 to 5° C. and washed with cold n-heptane (40 ml at 0 to 5° C.). The product was dried under vacuum at 50° C. to constant weight. Yield: 73.4 g (88%). Assay (HPLC): 100% pure vs. standard.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].ON[C:9]([O:11]CC)=[O:10].C([N:16](CC)CC)C>CC(C)=O>[CH2:1]([N:4]1[C:9](=[O:10])[O:11][NH:16][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: CCN(CC)CC
Reactant: C=CCN=C=O
Reactant: CCOC(=O)NO
Solvent: CC(C)=O
Product: C=CCn1c(=O)[nH]oc1=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 158.9 %

Procedure:
To a 500 mL round-bottom flask were added acetone (300 mL), allyl isocyanate (12.0 g, 0.145 mol), N-hydroxyurethane (6.1 g, 0.058 mol) and triethylamine (11.7 g, 0.116 mol) respectively at room temperature under nitrogen with efficient stirring. The reaction mixture was allowed to stir at room temperature for 6 d. The solvent was removed under reduced pressure. The residue was suspended in 100 mL of 1N HCl, extracted with ethyl acetate (3×150 mL). The organic solution was washed with water, brine, dried over MgSO4 and concentrated to a clear yellow oil. The crude product was dried under high vacuum for 4 h to give the title compound as an oil (13.1 g) which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]=[CH:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:11]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](Cl)[C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[O:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]=[CH:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(Cl)c2cccs2)cc1
Reactant: OCCN1CCN(CC=Cc2ccco2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCN2CCN(CC=Cc3ccco3)CC2)c2cccs2)cc1

Procedure:
1.16 g (0.0084 mol) potassium carbonate were added to a solution of 1.00 g (0.0042 mol) 1-(2-hydroxyethyl)-4-[3-(2-furyl)-2-propenyl]piperazine and 1.16 g (0.0084 mol) (4-fluorophenyl)(2-thienyl)methylchloride in 50 ml toluene. The mixture was refluxed for 16 h, then cooled, diluted with 50 ml toluene and washed twice with water. The crude product obtained by evaporation in vacuo was chromatographed on silicagel (elution with dichloromethane/methanol/acetic acid 95/5/3). The combined pure fractions were adjusted to pH 12 by addition of 2N sodium hydroxide solution, subsequently washed with water and brine and concentrated in vacuo. The oily residue was redissolved in acetonitrile and precipitated by addition of an excess of a solution of maleic acid in acetonitrile. 0.340 g (12% of the theoretical yield) of the title compound were obtained as the dimaleate salt, m.p. 169°-71° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:36])[CH2:10][CH2:11][C@@H:12]([NH:20]C(NC2C=CC(C3C=CC=CC=3)=CC=2)=S)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37]([NH:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:45][CH:44]=1)=S)#[N:38]>>[N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:36])[CH2:10][CH2:11][C@@H:12]([NH:20][C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:45][CH:44]=2)=[N:39][C:37]#[N:38])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CNC(=S)Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(CC[C@H](Cc1ccccc1)NC(=S)Nc1ccc(-c2ccccc2)cc1)NCCN1CCCC1
Product: N#CN=C(Nc1ccc(Oc2ccccc2)cc1)N[C@H](CCC(=O)NCCN1CCCC1)Cc1ccccc1

Procedure:
Prepared as in Example 1, step D, from [(R)-1-benzyl-3-(2-pyrrolidin-1-yl-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (Example 31, step A) and 1-cyano-3-(4-phenoxy-phenyl)-thiourea (Example 55, step B). MS (electrospray): mass calculated for C31H36N6O2, 524.29; m/z found, 525.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.37–7.10 (m, 10H), 7.02 (d, J=7.9 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.58 (br s, 1H), 4.21–4.08 (m, 1H), 3.39–3.30 (m, 2H), 2.85 (d, J=6.4 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.53–2.49 (m, 4H), 2.41–2.30 (m, 1H), 2.25–2.18 (m, 1H), 1.84–1.73 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCC(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperadinecarboxylate, 35.2 parts of bis(4-fluorophenyl)bromomethane and 8.6 parts of potassium carbonate is stirred and heated in an oil-bath at 140° C. for 3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, a diluted hydrochloric acid solution and a sodium bicarbonate solution, dried, filtered and evaporated. The forerun is distilled off (bp. till 143° C. at 0.5-1 mm. pressure), yielding ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=C[CH:41]=[CH:40][C:39]=1C.C(N)C=C>C(Cl)Cl>[CH2:39]([NH:38][C:23]([CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[N:17]1)=[O:24])[CH:40]=[CH2:41]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C=CCN
Solvent: ClCCl
Product: C=CCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, allylamine (9 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(2-allylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (9 mg, 16%) as a white solid: ESI-LRMS m/e calcd for C23H29ClN4O4S [M+] 506.19, found 507.34 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.20 (m, 2H, CH2), 1.42-1.94 (m, 8H, 4×CH2), 2.12-2.30 (m, 1H, CH), 2.65 (t, J=6.3 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 3.79-3.84 (m, 2H, CONCH2), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.02-5.07 (m, 1H, vinylic), 5.06-5.09 (m, 1H, vinylic), 6.55 (brm, 1H, NH), 5.67-5.78 (m, 1H, vinylic), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 8.02 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).