Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH:18]([CH3:20])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])(=O)C.[Na+].[CH3:26][O:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:18]([CH3:20])[CH3:19])[C:2]=2/[CH:31]=[CH:30]/[C:29]([N:28]([O:27][CH3:26])[CH3:33])=[O:32])=[CH:12][CH:13]=1
Reactant: C=CC(=O)N(C)OC
Reactant: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 0.75 h

Procedure:
2 g (6.02 mmol) of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole and 10 ml of DMF are introduced into a 50 ml three-necked round-bottomed flask, which has been purged with nitrogen and is equipped with a magnetic stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen delivery line, and degassing is carried out for 45 min. by introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from WO-A-99/47474 and 0.539 g (6.59 mmol) of sodium acetate are then added and degassing is carried out for a further 15 min. 1.08 g (8.43 mmol) of N-methoxy-N-methylacrylamide (prepared analogously to a procedure of S. Nahm, Tetrahedron Letters 22, 3815 (1981)) are subsequently added and the suspension is heated at reflux for 1.75 hours. A further 0.5 g (4.34 mmol) of N-methoxy-N-methylacrylamide is added and refluxing is carried out for 1.5 hours. Cooling is then carried out followed by dilution with 50 ml of water and extraction three times with 50 ml of ethyl acetate. The combined organic phases are washed three times with 50 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. Purification by means of flash chromatography (hexane/ethyl acetate=2:1) yields a yellow solid that is pure according to NMR. Recrystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:23][C:24](=[O:26])[CH3:25].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[NH:23][C:24](=[O:26])[CH3:25])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: CC(=O)Nc1ccncc1I
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 23.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 200 mg, 0.912 mmol) was reacted with N-(3-iodo-pyridin-4-yl)-acetamide (262 mg, 1.003 mmol), 1,4-dioxane (10 mL), copper iodide (17.3 mg, 0.09 mmol), trans-1,2-diamino cyclohexane (31.4 mg, 0.273 mmol) and potassium phosphate (581 mg, 2.73 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 75 mg of the product (23.36% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([OH:9])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:7]([C:6]2[S:5][C:4]([CH2:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (80 mg, 0.24 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (86 mg, 0.27 mmol), N,N-diisopropyl ethyl amine (210 μL, 1.21 mmol) and 4-aminotetrahydropyran (27 mg, 0.27 mmol). The resulting reaction mixture was stirred overnight and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (97 mg, 97%) as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:28]3[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=4)[CH2:26][CH2:27]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Yield: 85 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.500 g, 2.22 mmol), (4-fluorophenyl)piperidin-4-ylmethanone (0.620 g, 2.55 mmol) and triethylamine (0.7 mL, 5 mmol) in acetonitrile (20 mL) was heated to reflux overnight. The solvent was removed in vacuo. The residue was diluted with water, then extracted with ethyl acetate. The residue obtained upon the evaporation of solvent was purified by column chromatography. The title compound was obtained as a white solid in 85% yield (0.270 g). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=9.0 Hz, 1H), 8.02-7.93 (m, 2H), 7.65 (d, J=9.0 Hz, 1H), 7.2-7.11 (m, 2H), 6.98 (d, J=9.0 Hz, 1H), 4.55-4.44 (m, 2H), 3.63-3.49 (m, 3H), 3.32-3.19 (m, 2H), 2.5-1.8 (m, 2H), 1.7-1.44 (m, 4H), 0.8-0.67 (m, 1H), 0.52-0.41 (m, 2H), 0.15-0.07 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 200.1, 167.5, 164.1, 163.2, 161.4, 159.9, 158.9, 151.8, 144.6, 132.0, 131.0, 130.9, 129.4, 128.0, 126.9, 116.1, 115.8, 112.2, 44.5, 43.1, 40.0, 39.6, 34.5, 34.3, 27.9, 8.64, 8.6, 4.2. MS (ES+) m/z 397 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38]Cl)=[O:35]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[N:2]3[CH2:38][CH2:37][O:36][C:34]3=[O:35])=[CH:17][CH:16]=2)=[O:20])=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C(Cl)OCCCl
Agent: Cl
Product: O=C(Nc1ccc(-n2cnc3c(N4CCOC4=O)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and 2-chloroethyl chloroformate by using the same method as in Example 107.
Reaction SMILES: COC(=O)[C@@H]1CCCN1C(=O)CCCCCCCCCCC/C=C\CCCCCCCC.[C:33]([OH:56])(=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].Cl.[NH2:58][CH2:59][C:60]([NH2:62])=[O:61].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:33]([NH:62][C:60](=[O:61])[CH2:59][NH2:58])(=[O:56])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: NCC(N)=O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)NC(=O)CN
Yield: 44 %

Procedure:
In a manner similar to (i), erucic acid (2.12 g) was converted to its acid chloride, to which was added glycine amide hydrochloride (692 mg). The mixture was stirred in THF (5 ml)-water (3 ml) in the presence of potassium carbonate (2 g) at room temperature for three hours. The solvent was concentrated, and the residue was washed with water and methylene chloride. Resulting precipitates were air-dried, followed by recrystallization from ethanol to afford colorless crystals [1.08 g (yield 44%)], m.p. 128 to 130° C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]([C@@H:9]3[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(OC(=O)C)(=O)C.[Br:26]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:26][C:7]1[N:6]([C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC[C@@H]1C=C[C@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: OC[C@@H]1C=C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Yield: 14.8 %

Procedure:
(±)-cis-[4-(5,6-Dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol (1.55 g, 5.47 mmol) was acetylated in pyridine (17 mL) with acetic anhydride (0.6 mL) at ambient temperature for 2 days. Volatiles were removed in vacuo and the residual oil partitioned between chloroform and aqueous sodium bicarbonate. The chloroform solution was dried (sodium sulfate) and concentrated to dryness. The residue was dissolved in dry dioxane (10 mL) and the solution brought to reflux. N-bromosuccinimide (930 mg, 5.23 mmol) was added all at once. The dark solution was cooled after 4 minutes of reflux. Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Elution with 2-5% methanol-chloroform gave fractions containing starting material (1.05 g) followed by fractions containing title compound as a dark oil (0.28 g). The recovered starting material was again treated with N-bromosuccinimide and the crude product chromatographed. All product-containing fractions were combined and rechromatographed on silica gel with elution by hexanes-ethyl acetate to give the acetate of title compound as a yellow oil (0.62 g). Deacetylation was carried out as in Example 4. Volatiles were evaporated in vacuo from the neutralized solution and the residue was chromatograped on silica gel. Elution with 2% methanol-chloroform gave (±)-cis-[4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-2-cyclopenten-1-yl]methanol as off-white powder (293 mg, 15%), after resolidification from hexanes-ethyl acetate, m.p. 126°-128.5° C.; 1H-NMR(DMSO-d6) δ: 8.09 and 7.95 (both s, 1 each, aromatic CH), 6.24-6.20 and 5.98-5.94 (both m, 2, CH=CH), 5.81-5.76 (2 m, 1 each, CH2O), 4.96 (t, J=4.9 Hz, 1, OH), 3.02-2.95 (m, 1, CH), 2.67-2.51 (m overlapping solvent, 1/2CH2), 2.0-1.8 (m, 1, 1/2CH2); mass spectrum (CI) consistent with structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3ccccc3)c3ccccc23)cc(OC)c1OC

Procedure:
Substantially the same procedure as in Example 7 was repeated using Compound 1 (1.69 g) obtained in Example 1 and benzoyl chloride (1.16 ml) to give Compound 8 (0.91 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: COC(=O)c1c(Oc2ccc(Cl)cc2[N+](=O)[O-])c2ccccc2n1Cc1ccccc1

Procedure:
In the same way as described in example 5, methyl-3-[2-nitro-4-chlorophenoxy]-indole-2-carboxylate was alkylated with benzyl bromide. Analytical material was obtained by recrystallization from ethanol, mp. 120°-1°.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]1([C:20]#N)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S(=O)(=O)(O)[OH:36]>C(Cl)Cl>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]1([CH:20]=[O:36])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: CN(C)CCC1(C#N)c2ccccc2CCc2ccccc21
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: CN(C)CCC1(C=O)c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (101) (4.15 g, 14.3 mmol) in 50 mL of CH2Cl2 stirred at −78° C. and maintained under a nitrogen atmosphere was added diisobutylaluminum hydride (20.6 mL of a 1.0M solution in CH2Cl2; 20.6 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes, warmed to 0° C. and left stir an additional 4 hours. The solution was poured into 35 mL of saturated aqueous ammonium chloride. The resulting gelatinous mixture was stirred vigorously for 15 minutes, then 65 mL of 1.5N sulfuric acid was added and the mixture stirred overnight. The mixture was extracted with CH2Cl2 (3×), and the combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried the over sodium sulfate, filtered, and evaporated do dryness. The resulting oil was purified by chromatography on silica gel with 96/4/0.4 of methylene cloride/methanol/ammonium hydroxide. The product fractions were evaporated to dryness to yield the title product as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:26])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]([Cl:38])=[CH:35][CH2:36]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:26][CH2:36][CH:35]=[C:34]([Cl:38])[Cl:33])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1)[CH3:2]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a mixture of 0.6 g of 3-ethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]-5-methylphenol, 0.22 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added dropwise a solution of 0.31 g of 1,1,3-trichloro-1-propene dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.5 g of 3-ethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]-5-methyl-1-(3,3-dichloro-2-propenyloxy)benzene (71% yield), nD23.5 1.5150.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)([Cl:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:39]([Cl:41])=[O:40])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2)c(OC(C)C)c1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of cis-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole (5 g, 10.98 mmol, example 2) in methylene chloride (50 mL) cooled to 0° C. were added triethylamine (3 mL, 21.96 mL) and phosgene (8.7 mL, 16.47 mmol, ˜20% solution in toluene), respectively. The reaction mixture was stirred at 0° C. for 30 min then the excess reagents and solvent were removed under reduced pressure. The residue was taken in methylene chloride (˜100 mL) and the solution was filtered through a plug of silica gel (˜50 g). The silica gel was washed with 20% ethyl acetate in hexanes. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel, eluting with 5%, 10%, 20% ethyl acetate in hexanes) to give rac-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride as white solids (4.31 g, 76%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[CH2:23][N:22]([CH2:24][CH2:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[C@H:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:20]=1.I[CH3:38]>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[CH2:23][N:22]([CH2:24][CH:25]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])[CH3:38])[C@H:21]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:20]=1
Reactant: CCS(=O)(=O)CCN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)C(C)CN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 0.74 mL, 0.74 mmol, 4.0 equiv) was added to a solution of (2S)-4-(2,5-difluorophenyl)-1-[2-(ethylsulfonyl)ethyl]-2-phenyl-2,5-dihydro-1H-pyrrole (70 mg, 0.185 mmol, 1 equiv) in THF (5 mL) at −78° C., then stirred for 1 h. Iodomethane (0.035 mL, 0.56 mmol, 3.0 equiv) was added and the resulting mixture was warmed to 0° C. and stirred for 30 minutes. The mixture was then partitioned between saturated potassium bisulfate solution and ethyl acetate (2×40 mL). The combined organic layers were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography (CH2Cl2 initially, grading to 4% EtOAc in CH2Cl2) to give (2S)4 (2,5-difluorophenyl)-1-[2-(ethylsulfonyl)propyl]-2-phenyl-2,5-dihydro-1H-pyrrole (38-1) as a single diastereomer (colorless oil). 1H NMR (500 M, CDCl3) δ 7.38-7.28 (m, 5H), 7.08-6.92 (m, 3H), 6.29 (br s, 1H), 4.66 (br s), 4.37 (dd, 1H, J=12.5, 4.9 Hz), 3.84 (br d, 1H, J=13.0 Hz), 3.36 (dd, 1H, J=13.7, 7.1 Hz), 2.99 (m, 1H), 2.84 (m, 2H), 2.77 (dd, 1H, J=13.9, 7.3 Hz), 1.31 (d, 3H, J=7.1 Hz), 1.19 (t, 3H, J=7.6 Hz). LRMS m/z (M+H) 392.4 found, 392.1 required.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=O)=[C:4](Cl)[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1COCC1>[Cl:8][C:6]1[C:5]2[N:9]=[CH:10][S:22][C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncsc2n1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 124.6 %

Procedure:
To a solution of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (12 g, 57 mmol) in THF (250 mL) was added Lawesson's reagent (17.5 g, 43 mmol). The reaction mixture was stirred at 65° C. for 30 minutes. The reaction mixture was then filtered, and the filtrate was concentrated. The crude yellow solid obtained was triturated using diethyl ether to afford the title compound (10 g, 93.4%) as a pale yellow solid. LCMS (ES+) 186.95 (M+H)+, RT 1.31 minutes (method 1).
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:17]1([NH:9][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(NN(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 94 %

Procedure:
1,1-Diphenylhydrazine hydrochloride (1.2 equiv., 0.6 mmol, 135 mg), bromobenzene (1.0 equiv., 0.5 mmol, 0.05 mL), Pd(OAc)2 (0.01 equiv, 0.005 mmol, 2 mg), BINAP (0.01 equiv., 0.005 mmol, 3 mg), and NaOtBu (2.8 equiv., 1.4 mmol, 134 mg) and toluene (3 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (˜1 min.) and then heated to 80° C. for 4 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (5% EtOAc/Hex) to give the title product as a white solid (123 mg, 0.47 mmol, 95% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:25]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:26]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)C12CC3CC(CC(C3)C1)C2
Yield: 56.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), adamantanecarbonyl chloride (1.1 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided adamantane-1-carboxylic acid (6,7,8,9-tetrahydro-dibenzofuran-2-yl)-amide (0.98 g). Mp 247-248° C.; Anal. Calcd. for C23H27NO2: C, 79.05; H, 7.79; N, 4.01; Found: C, 78.75; H, 7.73; N, 3.75.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)#[CH:17]>C(#N)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
Heat a suspension of 3,5-dibromopyridine (4.00 g, 16.88 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.59 g, 0.84 mmol) and copper (I) iodide (0.32 g, 1.69 mmol) in triethylamine (4.7 mL, 33.8 mmol) to 80° C. Add a solution of 1-ethynyl-4-fluorobenzene (2.03 g, 16.88 mmol) in acetonitrile (34 mL), stir for 2 h, cool to room temperature and dilute with ethyl acetate. Wash with an aqueous saturated solution of sodium bicarbonate, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a 1% solution of ethyl acetate in 1:1 chloroform:hexanes, and then recrystallize from methanol to give the title compound (2.4 g, 51.5%).