Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][C:28]1([C:31]#[N:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:23](=[O:25])[NH:27][C:28]2([C:31]#[N:32])[CH2:30][CH2:29]2)[CH2:10]1)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
The carboxylic acid 5A (195 mg, 0.5 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (65.2 mg, 550 μmol), HATU (380 mg, 1.00 mmol) and ethyldiisopropyl amine (262 μL, 1.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature over night. The reaction was concentrated under reduced pressure. The residue was diluted with 5% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with 1M aqueous hydrogen chloride solution and with saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (2S,4R)-tert-butyl 4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)-pyrrolidine-1-carboxylate 6H as a yellow oil (66%). MS ISP (m/e): 354.2 (100) [(M−BOC+H)]+, 398.1 (25) [(M-Isobutylene+H)]+, 454.1 (12) [(M+H)]+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH3:21])=[C:18]([NH2:20])[CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH3:21])=[C:18]([NH:20][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:19]=1)=[O:14]
Reactant: COC(=O)c1cc(N)c(C)s1
Reactant: O=C=NCc1ccccc1
Product: COC(=O)c1cc(NC(=O)NCc2ccccc2)c(C)s1

Procedure:
The title compound was prepared according to the procedure described for Example 13 using benzyl isocyanate (0.4 g, 3.2 mmol) and 5-methyl-4-amino-thiophene-2-carboxylic acid methyl ester from Step 1 to afford 0.77 g of 5-methyl-4-(3-benzyl-ureido)-thiophene-2-carboxylic acid methyl ester. Recrystallization of a sample from acetonitrile gave product with a mp 185-187° C.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4C=CC=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.C(N)C=C>>[CH2:20]([NH:19][C:14]1[N:13]=[C:12]([NH:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]([F:18])=[CH:16][N:15]=1)[CH:21]=[CH2:22]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Solvent: C=CCN
Product: C=CCNc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and allylamine were reacted to yield N2-allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.71 (bs, 1H), 7.37 (d, 1H, J=2.4 Hz), 7.07 (dd, 1H, J=2.4 and 8.7 Hz), 6.75 (d, 1H, J=8.7 Hz), 5.98-5.85 (m, 1H), 5.19 (dq, 1H, J=1.8 and 16.8 Hz), 5.06 (dq, 1H, J=1.8 and 10.5 Hz), 4.24-4.18 (m, 4H), 3.92-3.68 (m, 2H); 19F NMR (CD3OD): −48552; LCMS: ret. time: 19.36 min.; purity: 95%; MS (m/e): 303 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](Cl)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].O.CCOC(C)=O.[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([C:32]#[N:33])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C[C@@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
In a microwave reaction vessel was dissolved (R)-3-(6-chloro-3-nitro-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (0.75 g, 2.14 mmol) in DMF (12 ml). Added the zinc cyanide (0.15 g, 1.29 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.21 mmol). Reaction mixture was degassed using a stream of nitrogen and capped. Reaction was heated in a microwave at 120° C. for 1 hour and then stirred at room temperature for 72 hours. After this time the reaction was poured into water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via silica gel flash column chromatography (12 g silica gel, 5-20% EtOAc/hexanes) to afford 0.70 g (96%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:29]1([C:39]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](OC(=O)c3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Into a 25-mL RB-flask was added N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthalenecarbonyl chloride (100 mg), diisopropylethylamine (0.30 mL) in THF (0.50 mL) at room temperature. After stirring for 16 hrs at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.70 mg, 71.3% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, 1H, J=8.9 Hz), 8.28 (apparent dd, 1H, J=1.5, 7.2 Hz), 8.03 (d, 1H, J=8.7 Hz), 7.88 (dm, 2H, J=8.7 Hz), 7.60-7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90 (apparent d, 1H, J=7.4 Hz), 6.18 (apparent dd, 1H, J=5.7, 7.8 Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.44 (apparent sept, partially hidden, 4H, J=7.5 Hz), 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.6 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: COc1cc2c(nc(CCl)n2C)c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2c(nc(CN3CCCN(Cc4nc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-4,5,6-trimethoxybenzimidazole (75 mg) and homopiperazine (11 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl.CCOCC.[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2([CH2:28][C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24](/[CH:30]=[CH:31]/[C:32]([NH:34][O:35]C4CCCCO4)=[O:33])[CH:25]=3)[O:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2([CH2:28][C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24](/[CH:30]=[CH:31]/[C:32]([NH:34][OH:35])=[O:33])[CH:25]=3)[O:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2)NO
Yield: 83.4 %

Procedure:
1 M HCl in Et2O (5 ml, 5 mmol) was added dropwise to a solution of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (260 mg, 0.55 mmol) in DCM (3 ml). After 1 h a white solid precipitated, which was filtered, washed with DCM, dried under vacuum and purified by preparative HPLC to give 180 mg of (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide as its trifluoroacetic salt.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24]>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH:19]=3)[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Product: Cc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1N

Procedure:
The product of Example 18A (160 mg, 0.57 mmol) was treated with 3-amino-4-methyl-phenylboronic acid (Lancaster, 302 mg, 2.0 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as solid (45 mg, yield, 26%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.65-1.90 (m, 2H), 2.01-2.16 (m, 1H), 2.19 (s, 3H), 2.22-2.29 (m, 1H), 2.74-3.01 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.86 (dd, J=7.51.7 Hz, 1H), 6.95 (d, J=1.7 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 8.73 (s, 2H) ppm. MS (DCl/NH3) m/z 311 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Sn](Cl)(Cl)(Cl)Cl.[N:12]1([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13]1.O>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([C:13]1[N:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: CC(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of isobutyryl chloride (5.4 ml) in DCM (250 ml) was added tin (IV) chloride (5.8 ml) at -10° C. under nitrogen. After stirring for 15 minutes in the cooling bath, 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (10.0 g) was added portion-wise. The reaction mixture was allowed to warm to room temperature, and stir for three days, at which time it was poured into cold water. The layers were separated and the organic phase was washed twice with water, once with 5% HCl (aq.), and subsequently dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, DCM) afforded 2.5 g of the product as a solid, m.p. 147°-149° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:38](I)([CH3:40])[CH3:39]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH:38]([CH3:40])[CH3:39])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)I
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(C(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and isopropyl iodide (0.30 mL) as starting materials, 5-benzyloxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.68 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:19])[C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([O:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:3][CH:4]=3)=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)[C:9](=[O:19])[O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A mixture of 4-(4-hydroxybenzyl)-7-methoxy-3-(4-trifluoromethyl-phenyl)-chromen-2-one (800 mg, 1.88 mmol), pivaloyl chloride (577 μL, 4.69 mmol), imidazole (268 mg, 3.94 mmol) and DMAP (344 mg, 2.81 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. Additional portions of imidazole (268 mg, 3.94 mmol), DMAP (344 mg, 2.81 mmol) and pivaloyl chloride (577 μL, 4.69 mmol) were added and stirring was continued for a further 20 h, for a total reaction time of 38 h. The solvent was removed in vacuo, the residue was dissolved in AcOEt and the organic layer was washed with H2O. The aq layer was extracted with AcOEt (2×) and the combined organic layers were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resultant residue was purified using flash chromatography (silica gel, 5:1 hexanes:AcOEt) to provide the title compound as a white solid (820 mg, 86%). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=8.0 Hz, 2H), 7.43–7.37 (m, 3H), 7.08–7.02 (m, 2H), 7.00–6.93 (m, 2H), 6.88 (d, J=2.5 Hz, 1H), 6.77 (dd, J=2.5, 8.8 Hz, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 1.34 (s, 9H); MS (ESI) m/z 511.0 (M+H)+; HPLC tR 7.58 min.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23](N)=[O:24])=[C:16]2[NH:26][C@H:27]1[CH2:30][C@@H:29]([O:31][CH3:32])[CH2:28]1.ClN1C(=[O:40])N(Cl)C(=O)N(Cl)C1=O>CO>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]([O:40][CH2:11][CH3:1])=[O:24])=[C:16]2[NH:26][C@H:27]1[CH2:30][C@@H:29]([O:31][CH3:32])[CH2:28]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CO[C@H]1C[C@@H](Nc2c(C(N)=O)cnc3ccc(Br)cc23)C1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CO
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1C[C@@H](OC)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DBU (5.36 mL, 35.86 mmol) was added in one portion to a mixture of 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxamide (6.28 g, 17.93 mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (1.667 g, 7.17 mmol) in MeOH (65 mL). The resulting mixture was stirred at r.t. for 18 h. The resulting mixture was evaporated to dryness and the residue was purified by FCC, elution gradient 0 to 10% MeOH in DCM, to afford the desired material (6.48 g, 104%). Data consistent with material produced from alternate synthesis described earlier.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[NH:14][C:13](=[O:19])[C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].[CH3:21]I>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[N:14]=[C:13]([O:19][CH3:21])[C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1[nH]c(=O)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(C)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Temperature: 50 °C

Procedure:
Compound 5-1 (3.2 g; 9.71 mmol), methyl iodide (1.21 mL; 19.4 mmol), silver carbonate (8.03 g; 29.1) mmol) and chloroform (100 mL) were added to a sealed vessel. The contents of the sealed vessel were heated at 50° C. overnight in the absence of light. The reaction mixture was cooled to room temperature, filtered to remove insoluble material, and the filtrate concentrated in vacuo. The crude material was purified via silica gel chromatography (0-15% EtOAc in hexane) to give the title compound. MS M+1=344.8. 1H NMR (CDCl3): 2.58 (s, 3H), 4.06 (s, 3H), 6.96 (m, 1H), 7.20 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5]CC[CH2:2]1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.NC1C=CC(C(OC)=O)=CC=1>>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:7](=[O:8])[CH2:6][CH:1]([CH3:2])[CH3:5])[CH2:11][CH2:12]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: OC1CCNCC1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)CC(=O)N1CCC(O)CC1

Procedure:
The title compound was prepared as described in Example 52A, substituting 3-methylbutanoyl chloride for 2-cyclopentylacetyl chloride and piperidin-4-ol for methyl 4-aminobenzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[Se](=O)=[O:10].[OH2:12]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:7]([OH:10])=[O:12]
Reactant: O=[Se]=O
Reactant: Cc1ccncc1C
Reactant: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cnccc1C(=O)O
Temperature: 185 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a hot (155° C.) solution of 10.7 g (0.1 mol) of 3,4-lutidine in 100 mL diphenylether, was added 18 g (0.16 mol) selenium dioxide in portions. After about 20 minutes, the reaction was heated to 185° C. and allowed to react for approximately thirty minutes. After cooling, the reaction mixture was diluted with water and filtered. The filtrate was extracted with chloroform and the chloroform extracts were then concentrated under reduced pressure to provide 6.0 g of a pale brown solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:5]1)(=O)C.O1CCCC1.CO.O.[OH-].[Li+]>O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C@H:6]2[CH2:7][CH2:8][CH2:9][NH:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CC(=O)N1CCC[C@H](c2ccc(Br)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2CCCNC2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of N-acetyl-(3R)-3-(4-bromophenyl)piperidine (2.88 g, 13.2 mmol) in mixture of tetrahydrofuran (24 ml), methanol (24 ml) and water (12 ml) was added lithium hydroxide monohydrate (3.8 g, 92.4 mmol) and stirred at 95° C. for 2 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give (3R)-3-(4-bromophenyl)piperidine (2.3 g, 87%) as colorless crystals that was used in the next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]([F:36])([F:35])[C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][C@H:10]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:8].[CH3:37][NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C.[I-].[Cl:54]C1C=CC=C[N+]=1C>ClCCl>[ClH:54].[F:35][C:3]([F:36])([F:2])[C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16](=[O:18])[N:38]([CH3:37])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:11][C@H:10]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:8]
Reactant: CNCc1ccccc1
Reactant: C[n+]1ccccc1Cl
Reactant: Cc1ccc(C[C@@H]2CN(CC(=O)O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CC(=O)N(C)Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(carboxymethyl)piperazine hydrochloride (210 mg), N-methylbenzylamine (52 mg) and triethylamine (0.19 ml) in dichloromethane (5 ml) was added 2-chloro-1-methylpyridinium iodide (110 mg) under nitrogen atmosphere at room temperature. The mixture was stirred at the same temperature for 1 hour. After removal of the solvent, the residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (10:1). The eluate was concentrated and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(N-methyl-N-benzylcarbamoyl)methyl]piperazine hydrochloride (190 mg) as a powder.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]([Cl:21])([Cl:20])[CH2:14][O:15][C:16](=[O:19])[CH:17]=[CH2:18].COC(=O)C([Cl:35])CC1C=CC(CO)=CC=1>>[Cl:12][C:13]([Cl:21])([Cl:20])[CH2:14][O:15][C:16](=[O:19])[CH:17]([Cl:35])[CH2:18][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC(Cl)(Cl)Cl
Reactant: COC(=O)C(Cl)Cc1ccc(CO)cc1
Reactant: Nc1ccc(CC(=O)O)cc1
Product: O=C(O)Cc1ccc(CC(Cl)C(=O)OCC(Cl)(Cl)Cl)cc1

Procedure:
The title compound was prepared from 2-(4-amino phenyl)-acetic acid (1.00 g, 6.61 mmol) and acrylic acid 2,2,2-trichloroethyl ester (6.73 g, 33.08 mmol) as described for 2-chloro-3-(4-hydroxymethyl-phenyl)-propionic acid methyl ester. The crude product was purified by flash chromatography using DCM/MeOH 95:5 as the eluent to afford the product as an oil (1.17 g, 47.3%). 1H NMR (300 MHz, CDCl3): δ 7.17-7.33 (m, 4H), 4.73 (s, 2H), 4.52-4.56 (t, 1H), 3.60-3.63 (m, 2H), 3.37-3.42 (dd, 1H), 3.17-3.23 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:32])[CH3:31]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1=C2CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 3 h

Procedure:
A solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (0.9 g, 2.34 mmole) in acetic anhydride (3 mL) and pyridine (6 mL) is stirred overnight at room temperature. Water is added and the mixture is stirred for 3 hours. The solids are collected by filtration to give a brown solid which is purified by flash chromatography (hexane-50% ethyl acetate then ethyl acetate) to give 4-acetamido-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide. This compound has the following structure: ##STR6##