Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH2:10]Br)=[CH:4][C:3]=1[Cl:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[C@@H:33]3[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]3)[C:27](=[O:34])[N:26]([CH:35]3[CH2:40][CH2:39][N:38](C4C=CC([N+]([O-])=O)=CC=4)[CH2:37][CH2:36]3)[N:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>O>[ClH:8].[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH2:10][N:38]2[CH2:39][CH2:40][CH:35]([N:26]3[N:25]=[C:24]([C:18]4[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=4)[C@@H:33]4[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]4)[C:27]3=[O:34])[CH2:36][CH2:37]2)=[CH:4][C:3]=1[Cl:13]
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Solvent: O
Product: COc1ccc(C2=NN(C3CCN(CC(=O)c4cc(Cl)c(N)c(Cl)c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: Cl

Procedure:
Prepared from (4-Amino-3,5-dichloro-phenyl)-2-bromo-ethanone and starting compound A1 as described for compound 11. After the addition of water, the mixture is extracted with diethyl ether. The ether solution is dried over magnesium sulfate. After the addition of a saturated solution of hydrochloric acid in ether, the compound precipitates. Crystallisation from tetrahydrofurane. M.p. 206° C. (decomposition).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](Cl)=[S:20])[CH:15]=[CH:16][CH:17]=1.Cl.CCOCC>[OH-].[Na+]>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[S:20])[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1cccc(CC(=S)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(CC(=S)Nc2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 957.3 %

Procedure:
3-Methylbenzenethiol and butyl bromoacetate were reacted by a conventional method and then hydrolyzed to obtain 3-methyl-α-phenylthioacetatic acid. 3-Methyl-α-phenylthioacetatic acid was reacted with thionyl chloride by a conventional method to obtain 3-methyl-α-phenylthioacetyl chloride. Anthranilic acid 5.6 g (4.1 mmol) was dissolved in 10% aqueous sodium hydroxide solution 32 ml and to this solution, 3-methyl-α-phenylthioacetyl chloride (99° C./3.3 mmHg) 8.9 g was added dropwise at 0° C. The resulting solution was stirred at room temperature for 20 minutes and neutralized with 10% hydrochloric acid solution. To this solution, ether was added, and deposited crystals were collected by filtration and washed with hot water to obtain N-(3-methylphenylthioacetyl)anthranilic acid (melting point: 148° to 150° C.) 11.2 g (yield: 25%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([C@@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:28][C@H:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)[CH:21]=2)[CH3:27])=[O:10])=[CH:11][CH:12]=1
Reactant: C[C@H](N)c1cccc(N2CCN(C)CC2)c1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1ccc(F)cc1)c1cccc(N2CCN(C)CC2)c1
Yield: 73.5 %

Procedure:
A solution of 4-fluorocinnamic acid (17 mg, 0.1 mmol), (S)-1-[3-(4-methylpiperazin-1-yl)-phenyl]ethylamine (preparation 42, 24 mg, 0.11 mmol), EDC (28 mg, 0.15 mmol), DMAP (12 mg, 0.1 mmol) and triethylamine (40 mg, 0.4 mmol) in dichloromethane (2 ml) was stirred overnight. The reaction mixture was purified by fresh chromatography over silica gel with 5% methanol in dichloromethane to give the title compound as a solid (27 mg 74% yield).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[CH:27]=3)[CH:37]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in 1-methylpyrrolidin-2-one (7.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with toluene and diisopropyl ether to give the title compound (256 mg, 84%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[C:24]([O:28][C:29](=[O:43])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)([CH3:27])([CH3:26])[CH3:25]>C(O)CCCC>[C:24]([O:28][C:29](=[O:43])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:2]3[N:11]=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)[C:9]4[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=4)[N:3]=3)[CH2:39][CH2:38]2)=[CH:32][CH:31]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: COc1cc2nc(Cl)nc(Nc3ccc(C)cc3)c2cc1OC
Solvent: CCCCCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(Nc3ccc(C)cc3)c2cc1OC
Temperature: 120 °C
Yield: 85.4 %

Procedure:
2-chloro-6,7-dimethoxy-N-(4-methylphenyl)-4-quinazolinamine (0.099 g, 0.3 mmol) prepared according to the procedures described in Gazit et al (Bioorg Med Chem, 1996, 4:1203) was added to a solution of (49) (0.10 g, 0.37 mmol) in n-pentanol (5 mL) at 25° C. The mixture was heated to 120° C. and maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.146 g (85.3%) of the title compound: TLC (Rf =0.40; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 12.41 (br s, 1H), 10.71 (br s, 1H), 8.08 (s, 1H), 7.63 (d, 2H, J=8.7), 7.57 (s, 1H), 7.55 (d, 2H, J=8.3), 7.24 (d, 2H, J=8.3), 6.63 (d, 2H, J=8.8), 6.44 (d, 1H, J=6.9), 4.41 (d, 2H, J=12.9), 3.91 (s, 3H), 3.89 (s, 3H), 3.73 (m, 1H), 3.42 (m, 2H), 2.31 (s, 3H), 2.03 (d, 2H, J=10.8), 1.49 (s, 9H), 1.41 (m, 2H); 13C NMR (DMSO) δ 165.2, 157.2, 155.2, 151.3, 150.7, 146.9, 136.6, 134.7, 130.9, 129.0, 124.0, 117.7, 111.2, 104.6, 102.3, 99.3, 79.0, 56.5, 56.1, 47.9, 43.7, 30.8, 28.0, 20.6; HRMS (FAB) m/z 570.3070 (M+H)+ (C33H39N5O4 requires 570.3080); Anal. (C33H39N5O4 ·1HCl) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:18])([CH2:16][SH:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].[C:21]1(C)[CH:26]=CC(S(OCCCC)(=O)=O)=[CH:23][CH:22]=1>CN(C)C=O.O>[CH2:26]([S:17][CH2:16][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:18])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[CH2:21][CH2:22][CH3:23].[ClH:1]
Reactant: CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O[C@@](CS)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSC[C@](O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Product: Cl
Reaction time: 18 h
Yield: 1386 %

Procedure:
To a solution of (R)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-3-mercapto-2-propanol (II) (3 g) in dry N,N-dimethylformamide (20 ml) were added a 50% dispersion of sodium hydride in paraffin (1 g) and n-butyl p-toluenesulfonate (2.3 g) at 0°-5° C. in nitrogen atmosphere. The mixture was stirred at 0°-5° C. for 1 hour and at 20°-25° C. for 18 hours. The reaction mixture was diluted with water (200 ml) and extracted with dichloromethane. Treatment of the extract in the same manner as in Example 4 gave (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (I: n=3) hydrochloride (2.5 g). Yield, 63.8%. M.P., 168°-169° C. [α]D20 -88.8° (c=1, methanol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]
Reactant: Oc1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCCCCOc1ccc2ccccc2c1
Reaction time: 4 h

Procedure:
A mixture of 2-naphthol (17.5 g), 1-(p-toluenesulphonyloxy)-8-chlorooctane (32.0 g), anhydrous potassium carbonate (32.0 g) and dimethylformamide (200 ml) was stirred at 60° for 4 hours. Water and ether were then added, and the ethereal solution was washed with water and dilute aqueous potassium hydroxide, then dried and evaporated. The residue was chromotographed on silica gel, eluting with 3:2 hexane:dichloromethane, to afford the title compound as a solid, mp 35°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([N:17]([CH3:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10](C3NC(=O)ON=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-:39].[Na+].Cl.[CH3:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([N:17]([CH3:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:42]([OH:43])=[O:39])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: CO
Reactant: CN(c1ccccc1)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: Cl
Agent: [Na+]
Product: CN(c1ccccc1)c1nc2cc(C(=O)O)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.174 step 2, 160 mg, 0.339 mmol) in methanol (2 mL) in a sealable tube was added 30% sodium hydroxide solution (4 mL). The tube was sealed and heated to 80° C. for 14 hours. The reaction mixture was cooled to room temperature and neutralized with the addition of 1.5 M HCl solution. The solution was extracted with ethyl acetate (4×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Kromasil C18, water/acetonitrile+0.1% TFA modifier) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (TFA salt). MS ES/APCI calc'd. for C27H28ClN6O2 [M+H]+ 490. found 490. 1H NMR (400 MHz, DMSO-d6): δ 12.79 (bs, 1H), 8.78 (d, J=12.8 Hz, 2H), 8.30 (s, 1H), 7.82 (s, 1H), 7.26 (t, J=7.6 Hz, 2H), 6.96-6.87 (m, 3H), 3.40-3.30 (m, 2H), 3.21 (s, 3H), 1.46-1.42 (m, 2H), 1.26-1.01 (m, 4H), 0.86-0.84 (m, 3H), 0.73-0.71 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](O)[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.C(N(CC)CC)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:31](=[O:32])[NH:30][CH3:29])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1
Reactant: O=c1cc(Oc2c(Cl)cccc2Cl)c2cc(O)ccc2o1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,6-dichlorophenoxy)-6-hydroxycoumarin (0.5 g, 1.55 mmole) in dimethyl formamide, under nitrogen, at room temperature is treated with triethylamine (0.7 mL, 5 mmole), then treated with CH3NCO (0.5 mL, 5.5 mmole) and allowed to stir at room temperature for about 1 hour. When the reaction is complete by HPLC analysis, the reaction mixture is poured onto water and extracted with methylene chloride. The extracts are concentrated in vacuo to give a residue. The residue is crystallized from methylene chloride/hexane to afford the title product as white crystals, 0.382 (71% yield), mp 292°-299° C., identified by 1HNMR, 13CNMR and IR analyses.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)C(O)=O)=[N:4][NH:3]1.[N:22]1([C:29](OC(C)(C)C)=[O:30])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:22]1([C:29]([C:15]2[CH:14]=[C:13]([CH:21]=[CH:20][CH:19]=2)[CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][N:4]=2)=[O:30])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCCNCC1
Yield: 97 %

Procedure:
The synthesis was carried out according to the method described in (a) above using 3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A) and tert-butyl 1-homopiperazine carboxylate to yield 4-[3-([1,4]diazepane-1-carbonyl)benzyl]-2H-phthalazin-1-one (3) as a grey crystalline solid (5.3 g, 97%); m/z [M+1]+ 363 (97% purity); δH 2.6-3.8 (10H, m), 4.4 (2H, s), 7.2-7.5 (4H, m), 7.7-8.0 (3H, m), 8.2-8.3 (1H, m), 12.6 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:15](OCC)([O:19]CC)[O:16]CC>O1CCCC1>[CH2:8]([C:5]1[N:6]=[CH:7][C:2]([B:15]([OH:19])[OH:16])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCOB(OCC)OCC
Reactant: CCc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(B(O)O)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromo-2-ethylpyridine (3 g, 16.12 mmol, 1.00 equiv) and tetrahydrofuran (200 mL). To the resulting mixture was then added n-BuLi (8.4 mL, 2.5 M) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. in an ethanol/N2 bath. To the resulting mixture was then added triethyl borate (4.7 g, 32.19 mmol, 2.00 equiv) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, overnight at room temperature. The reaction was then quenched by the addition of methanol (20 mL) and water (0.5 mL). The resulting mixture was then concentrated under vacuum. The resulting solution was diluted with methanol (10 mL). The resulting residue (10 mL) was purified by Flash-Prep-HPLC (reversed column) with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, A:water with trifluoroacetic acid (0.05%); B: MeCN=1/100 increasing to A:water with trifluoroacetic acid (0.05%); B: MeCN=20/100 within 25 min; Detector, UV 254 nm to yield of (6-ethylpyridin-3-yl)boronic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH:5]([Br:19])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CON=C(CCC1CCCC1)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(c1ccc(Cl)cc1)C(Br)CC1CCCC1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (1.120 g, 4.214 mmol) in carbon tetrachloride were added N-bromosuccinimide (812 mg, 4.425 mmol) and benzoyl peroxide (102 mg, 0.4 mmol). The resulting mixture was heated at reflux for 12 h. Upon cooling to room temperature, the solids were filtered and washed with diethyl ether. The filtrate was washed with aqueous solution of sodium bicarbonate, sodium thiosulfate and brine. It was then dried with anhydrous sodium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 1–2% ethyl acetate in hexanes yielded 2-bromo-1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (1.16 g, 80%) as yellow oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26](I)=[C:25]([F:30])[CH:24]=1>[Cu](I)I.C(NCC)C>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C:15]#[C:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10]2)=[C:25]([F:30])[CH:24]=1
Reactant: Fc1cc(-c2ccccc2F)ccc1I
Reactant: C#C[C@H]1CC[C@H](CCCCCCC)CC1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCCCCCC[C@H]1CC[C@H](C#Cc2ccc(-c3ccccc3F)cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(trans-4-heptylcyclohexyl)acetylene (28.40 mmol), 2′,3-difluoro-4-iodobiphenyl (28.40 mmol), tetrakis(triphenylphosphine)palladium(0)dichloromethane (0.85 mmol), copper iodide (1.43 mmol), and diethylamine (200 ml) is stirred for 4 hrs at room temperature. The reaction mixture obtained is extracted with toluene (200 ml) twice. The extract is washed with water (150 ml) three times and dried over anhydrous magnesium sulfate. The toluene solution is concentrated under reduced pressure, purified by silica-gel chromatography, and further recrystallized to give the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:18]=[CH:17][C:16]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:29]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cc(OC2CCCCO2)ccc1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (1.43 g, 7.94 mmol), [2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methanol (2.37 g, 7.94 mmol) and tributylphosphine (2.97 mL, 11.9 mmol) in toluene (120 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (3.00 g, 11.9 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (60 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (3.05 g, yield 83%).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[C:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8].CO[C:14]1[CH:19]=CC(O)=C[CH:15]=1>>[C:6](=[O:9])([O:7][CH3:8])[O:11][CH2:2][C:3](=[CH2:4])[CH3:5].[CH3:5][C:3](=[CH2:4])[CH2:2][O:7][C:6](=[O:11])[O:9][CH2:10][C:14]([CH3:19])=[CH2:15]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)CCl
Reactant: COC(=O)OC
Product: C=C(C)COC(=O)OC
Product: C=C(C)COC(=O)OCC(=C)C
Reaction time: 2 h
Yield: 0.7 %
Yield: 15.3 %

Procedure:
The reaction conditions of Example 37 are substantially repeated employing 3-chloro-2-methyl-l-propene (181.1 g, 2.0 moles), dimethyl carbonate (450.0 g, 5.0 moles), 30.0 g of DOWEX® MWA-1 beads and p-methoxyphenol (1.0 g, 0.08 mole). After 2 hours at 150° C., distillation gives 37.7 g (15.3 percent yield based on 3-chloro-2-methyl-1-propene) of methallyl methyl carbonate, b.p. 89° C.-90° C. (100 torr) and 1.2 g (0.7 percent yield based on 3-chloro-2-methyl-l-propene) of bis(2-methylallyl)carbonate, b.p. 87° C.-88° C. (17 torr).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.FC(F)(F)C(O)=O.N>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC1(N)COC1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of tert-butyl {[3-(dibenzylamino)oxetan-3-yl]methyl}carbamate (13.0 g, crude), 20% palladium hydroxide on carbon (2.0 g) and trifluoroacetic acid (0.5 mL) in methanol (20 mL) was stirred overnight under hydrogen atmosphere (1 bar). After being basified with ammonia solution in methanol, the resulting mixture was filtered and concentrated in vacuo to afford 5.8 g of the crude product, which was used for the next step without any purification.
Reaction SMILES: [CH3:1][O:2][CH2:3]OC1C=C([C@@H](N2CC[C@H](OCOC)C2)CO)C=CC=1.CO[CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33](O)[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:45][NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>>[CH3:1][O:2][CH2:3][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@H:33]([N:46]([C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH3:45])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: COCOc1cccc([C@H](O)CN2CC[C@H](OCOC)C2)c1
Reactant: COCOc1cccc([C@H](CO)N2CC[C@H](OCOC)C2)c1
Product: COCCOc1cccc([C@@H](CN2CC[C@H](OCOC)C2)N(C)c2ccc(C(=O)OC)cc2)c1
Yield: 60 %

Procedure:
This was prepared from the mixture of 2-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).