Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:16][CH2:15]3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[C:25]([OH:35])(=[O:34])[C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>C(OCC)(=O)C>[C:25]([OH:35])(=[O:34])[C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:18][CH2:19]3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: COCCN1CCN(C[C@H]2CCN(c3ccc(Cl)cc3)C2=O)CC1

Procedure:
To a hot solution of 66.6 g of 1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidinone in 350 mL of ethyl acetate was added a hot solution of (R)-(-)-mandelic acid in 120 mL of ethyl acetate. After cooling, the precipitated crystals were filtered, washed with ethyl acetate and dried in vacuo to give 36.4 g of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12](=[O:27])[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:12]([OH:27])[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)C(O)C=C[C@@H]1N2Cc1ccccc1
Reaction time: 1 h

Procedure:
Sodium borohydride (450 mg, 11.8 mmol) was added to a stirred suspension of (1R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 2; 3.5 g, 8.1 mmol) in methanol (40 ml) at +5° C. The reaction mixture was stirred for 1 hour and quenched with saturated NaHCO3 and concentrated in vacuo to removed methanol. The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a 4.4:1 mixture of epimeric alcohols. The diastereoisomers were separated by flash chromatography followed by crystallisation.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:6]=2[CH:5]=1>C(O)C>[CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:6]=2[CH:5]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc2cc([N+](=O)[O-])ccc2s1
Solvent: CCO
Product: CN(CCc1ccc(N)cc1)Cc1cc2cc(N)ccc2s1

Procedure:
A mixture of the product of (B) above (1.0 g) and stannous chloride dihydrate (6.07 g) in ethanol (100 ml) was heated under reflux for 8 hours and then evaporated. An excess of 20% aqueous sodium hydroxide solution was added and the mixture was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol (99:1) gave impurity and then further elution with dichloromethane/methanol (98:2) gave, after collection and evaporation of appropriate fractions, the product as an oil (0.30 g) which was used immediately in the procedure of Example 6.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[N:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH:15]=[N:14]2)=[CH:11][CH:12]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:27][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:16]3[CH:15]=[N:14][N:13]([C:10]4[N:9]=[N:8][C:7]([NH2:6])=[CH:12][CH:11]=4)[CH:17]=3)=[CH:19][NH:20]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(CNc2ccc(-n3cc(-c4c[nH]c5cc(F)ccc45)cn3)nn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1ccc(-n2cc(-c3c[nH]c4cc(F)ccc34)cn2)nn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A mixture of N-(2,4-dimethoxybenzyl)-6-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)pyridazin-3-amine (80 mg; 0.18 mmol) and anisole (2.0 mL) in TFA (2.0 mL) was stirred at 120° C. for 2 hours in a microwave reactor. The reaction mixture was concentrated, and purified by a silica gel column chromatography (PE/EtOAc=4/1 to 2/1) to afford 30 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:33])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: COCCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 88.2 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 49 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:12][CH2:13][CH:14]([NH2:17])[CH2:15][CH3:16]>C(#N)C>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:17][CH:14]([CH2:15][CH3:16])[CH2:13][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCC(N)CC
Solvent: CC#N
Product: CCC(CC)NCCNC(=O)OC(C)(C)C

Procedure:
By using 1.0 g of tert-butyl(2-bromoethyl)carbamate, 2.5 mL of pentan-3-amine, and 10 mL of acetonitrile as starting materials, the reaction similar to Preparation Example 9 was performed, thereby obtaining 890 mg of tert-butyl[2-(pentan-3-ylamino)ethyl]carbamate.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[F:8][C:7]1[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14]
Reactant: CC1CCCNC1
Reactant: CCC#CCOc1ncnc(Cl)c1F
Product: CCC#CCOc1ncnc(N2CCCC(C)C2)c1F
Reaction time: 3 h
Yield: 89 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.29 g of 3-methylpiperidine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.23 g of 5-fluoro-4-(3-methylpiperidino)-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (10)).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1>COC(O)C>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=3)[N:20]=2)=[CH:11]1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Agent: COC(C)O
Product: OCCc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Temperature: 160 °C
Yield: 84.2 %

Procedure:
A mixture of compound 1f (4.00 g) and 2-(4-aminophenyl)-ethanol (2.96 g) in 1-methoxyethanol (30 mL) was heated at 160° C. for 17 hrs in a pressure tube. The mixture was then cooled, quenched with water and extracted with mixed THF and ethyl acetate. The combined organic phase was washed with brine and concentrated. The residue was subjected to silica column and eluted with 2-6% methanol in dichloromethane to give compound 1 (3.01 g, yield 84%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.89 (d, J=8.0 Hz, 1H), 8.26 (dd, J=5.2 Hz, 2.0 Hz, 2H), 8.22 (s, 1H), 7.59 (m, 2H), 7.20 (m, 4H), 3.78 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H). MS (ESI) m/z: 332 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[O:4].[Mg].Br[C:8]1[CH:15]=[CH:14][CH:13]=[C:10]2[CH2:11][CH2:12][C:9]=12.[Cl-].[NH4+]>O1CCCC1>[CH:3]([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]2[CH2:11][CH2:12][C:9]=12)=[O:4]
Reactant: Brc1cccc2c1CC2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cccc2c1CC2
Temperature: 25 °C
Yield: 90 %

Procedure:
The procedure is that of Evans, J. Chem. Soc. (1956), pages 4691-4693. Dimethylformamide (15 mL) is added dropwise to a stirred solution of Grignard reagent prepared from 4.8 g of magnesium and 18.3 g of 4-bromobenzocyclobutene in 40 mL of tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting mixture is warmed slowly to room temperature and poured into 100 mL of saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the organic extract is washed with water and brine and then dried over anhydrous magnesium sulfate. After removing solvent, the product is distilled under reduced pressure to give 11.9 g (90%) of 4-formylbenzocyclobutene, b 90° C./3.5 mm.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[C:19]1([CH:25]2[CH2:26][CH2:27][N:28]([C:2]([Cl:1])=[O:4])[CH2:29][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.68 g (2.26 mmol) triphosgene in 6,8 mL dichloromethane at −80° C. is added 0.52 mL (6.5 mmol) pyridine. Then 1.05 g 4-phenylpiperidine (6.5 mmol) is added over a period of 10 minutes. The reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. 4.5 mL 1N hydrochloric acid is added for hydrolization. The organic phase is separated, washed with saturated sodium bicarbonate solution and dried with sodium sulfate. After evaporation of the solvent the crude product is purified via column chromatography on silica gel using dichloromethane as eluent
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]([CH:24]1[CH2:26][CH2:25]1)([CH3:23])[CH2:19][C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[CH2:19][C:18]([NH:17][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH2:15][F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH:24]1[CH2:26][CH2:25]1)[CH3:23]
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Reactant: CC(N)(CC(N)=O)C1CC1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCCF)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)pyridine-2-carboxylic acid (example 146b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (65 mg, 56%) as; MS (ESI, m/z): 350.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])[N:6]=[C:5]([N:23]([CH3:25])[CH3:24])[N:4]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C>[Br:26][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([N:23]([CH3:25])[CH3:24])=[N:6][C:7]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOCCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Solvent: CC#N
Product: COCOCCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Temperature: 23 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 1.41 g (3.99 mmol) of 4-methoxy-6-(10-(methoxymethoxy)decyl)-N,N-dimethylpyrimidin-2-amine in 10 mL of acetonitrile were added 852 mg (4.79 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 23° C. and protected from light for 5 h. The reaction mixture was concentrated under diminished pressure and the residue was dissolved into 100 mL of ethyl acetate. The organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 9:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 910 mg (53%); silica gel TLC Rf 0.65 (9:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.31-1.26 (br m, 10H), 1.54-1.64 (m, 4H), 2.67 (dd, 2H, J=7.6, 7.6 Hz), 3.11 (s, 6H), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.92 (s, 3H) and 4.59 (s, 2H); 13C-NMR (CDCL3) δ 26.18, 27.59, 29.34, 29.40, 29.40, 29.47, 29.55, 29.72, 36.68, 36.93, 53.96, 55.04, 67.85, 91.16, 96.35, 160.06, 165.05 and 169.04; mass spectrum (APCI+), m/z 432.1857 (M+H) (C19H35N3O3Br requires 432.1862).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)C(=O)O)cc21
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of methyl 2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionate (3.00 g, 6.11 mmol) in tetrahydrofuran (20.0 ml) and methanol (20.0 ml) was added 2N aqueous sodium hydroxide solution (10.00 ml, 20.00 mmol) at room temperature, and the mixture was stirred overnight. To the reaction mixture were successively added 2N hydrochloric acid (11.00 ml, 22.00 mmol), water and methanol, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionic acid (2.60 g, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.FC(F)(F)C1C=CC=C(C=C)C=1.[H-].[Na+].Cl[CH2:39][C:40]1[N:44]=[C:43]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[O:42][N:41]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=3)[CH2:11][N:10]([CH2:39][C:40]3[N:44]=[C:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)[O:42][N:41]=3)[C:9]2=[O:23])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Agent: C=Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN3C[C@H](c4cccc(C(F)(F)F)c4)N(c4ccc(Cl)cc4)C3=O)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-1-(4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (40 mg, 0.117 mmol, prepared by following the same procedure as described in example 151 using 1-(trifluoromethyl)-3-vinylbenzene as the starting material.) in anhydrous DMF (2 mL) is cooled down to 0° C. in an ice bath when NaH (17 mg, 60% in mineral oil, 0.423 mmol) is added into the solution portion wise. After the addition, the mixture is stirred at 0° C. for 10 min when a solution of 3-(chloromethyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole (31.6 mg, 0.141 mmol) in DMF (1 mL) is added into the mixture. The resulted mixture is allowed to warm up to room temperature and stir for 1 h. The residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) δ 7.95 (d, J=9.2 Hz, 2H), 7.62 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.48-7.39 (m, 2H), 7.31 (d, J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 5.50 (dd, J=9.2, 6.0 Hz, 1H), 4.68 (m, 2H), 4.07 (t, J=9.2 Hz, 1H), 3.78 (s, 3H), 3.41 (dd, J=9.0, 6.0 Hz, 1H); HPLC-MS calculated for C26H21ClF3N4O3 (M+H+) 529.1, found 529.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Yield: 65.4 %

Procedure:
Pd/C 10% (0.25 g) was added to the suspension of tert-butyl 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.10 g; 3.31 mmol) in a mixture of methanol (100 mL) and ammonium formate (2/1 g; 42.97 mmol). The mixture was refluxed for 20 hours and was filtered through celite. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% ethyl acetate in dichloromethane) to give 0.65 g (61%) of the title compound as a pink solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18]>>[CH2:1]([S:8][C:9]1([CH2:15][NH:16][C:30]([NH:29][C:21]2[C:20]([CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=2[CH:26]([CH3:28])[CH3:27])=[O:31])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1(SCc2ccccc2)CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(SCc2ccccc2)CCCCC1
Yield: 45.1 %

Procedure:
Similarly to Example 1(c), by reaction of 120 mg (0.51 mmol) of C-(1-benzylsulfanyl-cyclohexyl)-methylamine with 125 μl (0.61 mmol) of 2,6-diisopropylphenylisocyanate. 101 mg of 1-(1-benzylsulfanyl-cyclohexylmethyl)-3-(2,6-diisopropyl-phenyl)-urea is obtained in the form of a white solid. (m.p.=156° C., Yields 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[F:16][C:17]1[CH:18]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36](Cl)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:20]=[C:21]([F:28])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:28][C:21]1[CH:20]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=3)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:18]=[C:17]([F:16])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: COc1ccc(B(O)O)cc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc1C(F)(F)F
Yield: 32.1 %

Procedure:
4-Methoxy-3-trifluoromethylbenzeneboronic acid (34 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (30 mg, 0.078 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (80 mg, 0.25 mmol) as described above to give the title compound (13 mg, 32%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cccc(Oc2ccc(Br)cn2)c1
Solvent: CCCCCCC
Product: CCOP(=O)(Cc1cccc(Oc2ccc(Br)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
5-Bromo-2-(3-(chloromethyl)phenoxy)pyridine (3.08 g, 10.3 mmol) from Step 2 was treated neat with triethylphosphite (2.65 mL, 15.5 mmol) and heated to 150° C. After 5 h, the reaction mixture was removed from the heating bath and treated slowly with heptane until an oil precipitated out of solution. Ethyl acetate was added until mixture became homogenous. Heptane was slowly added again (at a cooler temperature) until a white precipitate formed. After the addition of more heptane and stirring for 15 min, the precipitate was filtered to afford a white solid (3.35 g, 81% yield). MS (APCI) M+1=400.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.02 Hz, 6H) 3.17 (d, J=21.64 Hz, 2H) 3.98-4.08 (m, 4H) 6.84 (d, J=8.77 Hz, 1H) 7.00-7.05 (m, 1H) 7.08 (q, J=2.21 Hz, 1H) 7.15-7.20 (m, 1H) 7.35 (t, J=7.90 Hz, 1H) 7.77 (dd, J=8.58, 2.53 Hz, 1H) 8.21 (d, J=2.73 Hz, 1H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][S:55]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH3:67])[CH:59]=2)(=[O:57])=[O:56])=[C:50]([CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=2)[CH:49]=1>O1CCCC1>[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[C:60]([O:66][CH3:67])[CH:59]=2)(=[O:57])=[O:56])[C@@H:35]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]2)=[C:50]([CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=2)[CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2ccccn2)cc1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2Cc2ccccn2)[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Reaction time: 0.5 h
Yield: 162.3 %

Procedure:
0.91 ml of diisopropylazodicarboxylate is added at room temperature to 1.21 g of triphenylphosphine in solution in 25 ml of tetrahydrofuran. After 30 minutes, 0.86 g of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate is introduced. After 30 minutes, 1.29 g of N-[4-chloro-2-(pyridin-2-ylmethyl)phenyl]-3,4-dimethoxybenzene-sulfonamide are added and the mixture is left for 18 hours at room temperature. The reaction medium is concentrated and chromatographed on silica gel in order to obtain 2.94 g of the expected product.