Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[N:8]=2)[CH:4]=[N:3]1.[CH:20]1([CH:23]=[CH:24][C:25]#[N:26])[CH2:22][CH2:21]1.CN(C=O)C.C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[C:25]([CH2:24][CH:23]([N:2]1[CH:6]=[C:5]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[N:8]=2)[CH:4]=[N:3]1)[CH:20]1[CH2:22][CH2:21]1)#[N:26]
Reactant: N#CC=CC1CC1
Reactant: COC(=O)c1cc2nccn2c(-c2cn[nH]c2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccn2c(-c2cnn(C(CC#N)C3CC3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.3 %

Procedure:
In a 100 mL flask, methyl 5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate hydrochloride (0.300 g, 1.07 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.300 g, 3.22 mmol) were suspended in DMF (5.36 mL, 1.07 mmol) and DBU (0.722 mL, 4.83 mmol) added in one portion. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted in EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated down to a yellow oil. Purification of the crude material by silica chromatography using a gradient of 50-100% EtOAc afforded methyl 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.127 g, 0.378 mmol, 35.2% yield) as a yellow oil. MS (apci) m/z=337.2 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].Cl>CO>[C:18]1([CH2:17][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to literature (ref. JOC, 1990, 55(1), 111-122) starting from (D)-serine methyl ester hydrochloride (98%, from Aldrich) (D)-serine methyl ester hydrochloride (10 g, 0.065 moles) was suspended in 50 ml of anhydrous methanol and cooled to 0° C. under nitrogen. Triethylamine (9 ml, 0.065 moles) was added dropwise, followed by benzaldehyde (6.6 ml, 0.065 moles). The reaction mixture was then warmed up and stirred at room temperature for 2 hours. Sodium borohydride (4.85 g, 0.13 moles) were added in small portions over 2 hours. The resulting mixture was stirred at room temperature overnight. The mixture was then slowly added to 50 ml of HCl (20% solution) at 0° C. and the resulting solution was washed with diethyl ether (50 ml). The aqueous layer was then brought to basic pH by adding solid potassium carbonate and extracted with diethyl ether (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum to afford the title compound as colourless oil (10.95 g). m/z=210 [M+H]+
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=351 (M+ of free base). α[D]589=−15.49 (c=0.86, methanol).
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:15])=[C:11]([Cl:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1.CON=C1C2C(=CC=C(C)C=2)OCC1>>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:15])[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2cc(C)c(Cl)cc21
Agent: CON=C1CCOc2ccc(C)cc21
Product: Cc1cc2c(cc1Cl)C(N)CCO2

Procedure:
The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 13A for the product of Example 7A. 1H NMR (300 MHz, CDCl3) δ 7.27 (s, 1H), 6.68 (s, 1H), 4.15-4.29 (m, 2H), 3.98 (m, 1H), 2.29 (s, 3H), 2.07-2.17 (m, 1H), 1.75-1.85 (m, 1H). MS (DCI) m/e 198(M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=O)[N:3]=[CH:2]1.Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[NH:19])[NH2:18].[H-].[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>C(O)C.CN(C)C=O.O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:8]1[C:6]([C:4]2[N:3]=[CH:2][O:1][CH:5]=2)=[N:19][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[N:9]1.[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:9]1[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[N:18][C:6]([C:4]2[N:3]=[CH:2][O:1][CH:5]=2)=[N:8]1
Reactant: NNC(=O)c1cocn1
Reactant: N=C(N)c1ccccn1
Reactant: Fc1ccccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1-c1cocn1
Product: Fc1ccccc1Cn1nc(-c2cocn2)nc1-c1ccccn1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxazole-4-carbohydrazide (228 mg, 1.794 mmol) in ethanol (8.9 mL) was added picolinimidamide hydrochloride (283 mg, 1.79 mmol). After heating the orange solution at 100° C. for 50 h, the solvent was removed in vacuo and the residue was azeotroped with toluene (2×4 mL) to give 514 mg of crude material. 187 mg of the crude material (0.75 mmol) was dissolved in N,N-dimethylformamide (3.7 mL) and treated with sodium hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) in a single portion at ambient temperature. After stirring for 20 min, 1-(bromomethyl)-2-fluorobenzene (0.136 mL, 1.12 mmol) was added. The solution was stirred for an additional 45 min, at which point the solution was poured into water (75 mL) and extracted with ethyl acetate (3×50 mL). The organics were combined, washed with water (2×50 mL) and brine (1×50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the crude product as an orange oil. Purification by silica gel chromatography (10-100% ethyl acetate in hexanes) provided 4-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole, I-12 (58 mg, 0.18 mmol, 24% yield over two steps) as a tan solid and 4-(1-(2-fluorobenzyl)-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)oxazole, I-13 (21 mg, 0.06 mmol, 8.7% yield over two steps) as a brown solid.
Reaction SMILES: [N:1]1([C:10]2[CH:23]=[CH:22][C:13]([C:14]([N:16]3[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:14](=[O:15])[C:13]2[CH:22]=[CH:23][C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)[CH2:17]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)c2ccc(-n3cnc4ccccc43)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of (3R)-1-[4-(1H-benzimidazol-1-yl)benzoyl]pyrrolidin-3-ol (2.30 g, 7.48 mmol) in anhydrous dichloromethane at 0° C. is treated with diisopropylethyl amine (2.13 g, 16.46 mmol) and methanesulfonyl chloride (1.29 g, 11.22 mmol), stirred at 0° C. for 2 hours and concentrated to give a crude oil. Purification of this oil by flash column chromatography (silica, methanol:dichloromethane 5:95) provides the title product as a yellow solid, 2.3 g (81% yield), identified by NMR and mass spectral analyses. MS [386.5 m/e (M+H)].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1)[NH2:25]>>[NH2:25][C:24]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[C:22]([F:21])[CH:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3F)ccn2c1=O

Procedure:
Methyl 8-(4-amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound 20 as a yellow solid (87 mg, 64%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:13](Cl)(=O)CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH2:5][CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC(=O)Cl
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CC
Yield: 92.9 %

Procedure:
Under the same conditions as in Example 1, 130 g (1.0 mol) of ethyl acetoacetate in a mixture of 1.2 l of methylene chloride and 300 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 106.5 g (1.15 mol) of propionyl chloride. The subsequent reaction time after the ammonia had been metered in was 4 hours at a pH of 9.3. This gave 134 g (GC purity 72.0%) of ethyl propionylacetate (yield 67.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:6]([O:8][C:13](=[O:14])[NH:12][C:4]=12)=[O:7]
Reactant: O=C(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 10.0 g (60.0 mmol) of 3-methoxyanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.33 g (98%) of the 3-methoxyisatoic anhydride as an off white solid. MS (Cl mode) m/z 176 (M-18, 100%), 194 (M+H, 53%).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:1][C:2]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccc(C(=O)O)c(S)c1
Solvent: c1ccncc1
Product: Cc1ccc2c(=O)nc(-c3ccccn3)sc2c1
Yield: 45.9 %

Procedure:
A mixture of 2-mercapto-4-methylbenzoic acid (2.0 g, 12 mmol), 2-cyanopyridine (1.4 g, 13 mmol) and pyridine (8 ml) was refluxed for 14 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration, subjected to a silica gel column chromatography, eluted with ethyl acetate-methanol (5:1, v/v) and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.4 g, 48%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:9][CH2:10][CH:11]([OH:26])[CH2:12][N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>[Na].C(O)C>[ClH:9].[OH:26][CH:11]([CH2:10][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OC(CCl)CN(C1CCCCC1)C1CCCCC1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: OC(CSc1ccccc1)CN(C1CCCCC1)C1CCCCC1
Yield: 63 %

Procedure:
One mol of thiphenol is dissolved in a solution of 46 g of sodium of ethanol. To the resulting solution there is progressively added 1 mol of an ethanolic solution of (3-chloro-2-hydroxy propyl) dicyclohexylamine hydrochloride. This mixture is then heated for two hours at reflux. After cooling the same, the reaction mixture is filtered and the filtrate evaporated to dryness. The resulting oily residue is taken up in sulfuric ether, through which there is then bubbled gaseous HCl. A white precipitate rapidly forms which is then filtered therefrom and recrystallized in ethanol for a 63 percent yield of white crystals melting at 181° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([I:30])=[C:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:9]([O:11]CC=C)[CH:10]=1)C=C.[Se](=O)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[OH:4][C:5]1[C:6]([I:30])=[C:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:9]([OH:11])[CH:10]=1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1I
Agent: O=C([O-])O
Agent: O=[Se]=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)Cc1c(I)c(O)cc(O)c1C(=O)c1ccc(OC)cc1
Temperature: 75 °C
Yield: 1.8 %

Procedure:
Methyl 3,5-diallyloxy-2-iodo-6-(4-methoxybenzoyl)phenylacetate (80 mg, 0.15 mmol) obtained in Example 15, Step 2 was dissolved in 1,4-dioxane (1.0 mL), and selenium dioxide (36 mg, 0.34 mmol) and acetic acid (0.028 mL; 0.46 mmol) were added thereto, followed by stirring at 75° C. for half a day. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to obtain Compound 15 (1.2 mg, 8.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl)boronic acid (300 mg, 1.72 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (331 mg, 1.89 mmol), K2CO3 (474 mg, 3.44 mmol) and Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) in THF (2 mL) and H2O (1 mL) was heated at 80° C. in a sealed tube for 3 h. The mixture was cooled to rt and partitioned between EA (20 mL) and H2O (20 mL). The aqueous layer was extracted with EA (20 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel elute with PE to give 2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 62.3% yield) as colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][NH:22][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCl
Reactant: NCC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCl)NCC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1

Procedure:
A solution of [1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]methylamine (675 mg, 2.32 mmol) and 4-chlorobutanoylchloride (491 mg, 3.48 mmol) in tetrahydrofuran (3.48 ml) and aqueous 2 N NaOH (1.74 ml) was stirred at ambient temperature for 15 hours. The organic layers were extracted with dichloromethane (10 ml), washed with brine (4 ml) and dried over magnesium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel, 230-400 mesh/30 g/hexane:ethyl acetate=1:1) to give a yellow oil (684 mg/75%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
292.4 g (1 mole) of methyl β-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionate and 383.6 g (1 mole) of oleyl alcohol are initially taken in 50 ml of toluene and are heated at 120° C., so that the toluene has distilled off in the course of one hour. 2.5 g of lithium amide are then added and the methanol which is formed is distilled off at 80° C. The mixture is then heated to 120° C. and is kept at this temperature for 4 hours. The reaction is monitored by thin layer chromatography. When the reaction is complete, the reaction mixture is dissolved in 200 ml of toluene, neutralised with 12 ml of concentrated HCl and then washed with twice 200 ml of water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1

Procedure:
2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LCMS (PS-A3) Rt 6.88 min [M+H]+340. 1H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, br.s).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH:16]=[CH2:17])=[CH:5][CH:4]=1.[O:18]=[C:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[C@H:21]([C:33]([O:35][CH3:36])=[O:34])[CH2:20]1>C1COCC1.C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([CH:16]=[CH2:17])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C@@:19]3([OH:18])[CH2:23][N:22]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])=[O:25])[C@H:21]([C:33]([O:35][CH3:36])=[O:34])[CH2:20]3)=[CH:4][CH:5]=2)[CH:14]=1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1ccc(Cl)cc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Magnesium (0.298 g, 12.27 mmol) was stirred in a round bottom flask under nitrogen for 15 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-5-chloro-2-vinylbiphenyl (3.43 g, 11.68 mmol) in THF (60 mL), was added in dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (3.35 g, 11.67 mmol) in DCM (60 mL) at r.t. and stirred for 1 hr and then quenched with saturated NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (800 mg, 1.593 mmol, 14% yield) as a yellow oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 1.03 (dd, j=9.46, 7.63 Hz, 2H) 2.30-2.48 (m, 1H) 2.63-2.79 (m, 1H) 3.77-3.80 (m, 1H) 3.82-3.86 (m, 3H) 3.95-4.05 (m, 1H) 4.16-4.26 (m, 2H) 4.51-4.67 (m, 1H) 5.20 (d, J=11.90 Hz, 1H) 5.67 (d, J=17.40 Hz, 1H) 6.61 (dd, J=17.40, 10.99 Hz, 1H) 7.26-7.35 (m, 4H) 7.49-7.58 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>O.CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: OCc1cccc(Cl)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
To a mixture of 2-chloro-6-methylpyridine (1.0 g, 7.84 mmol) and dichloromethane (20 mL) was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at 40° C. Water and sodium hydrogencarbonate were added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. Acetic anhydride (20 mL) was added to the resulting residue and stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (4 mL, 20.1 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 30 minutes. Water was added to this mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (200.0 mg, 18%).