Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13](=[O:15])[CH3:14])C=C.O.C(OCC)(=O)C.C(N(CC)[C:26]1[CH:31]=CC=C[CH:27]=1)C>>[CH2:31]([C:10]1[C:5]([OH:4])=[C:6]([C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[O:11][CH3:12])[CH:26]=[CH2:27].[CH2:31]([C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([OH:4])=[C:6]([C:13](=[O:15])[CH3:14])[CH:7]=1)[CH:26]=[CH2:27]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(OC)ccc1C(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(OC)ccc(C(C)=O)c1O
Product: C=CCc1cc(C(C)=O)c(O)cc1OC

Procedure:
5.60 g of 2′-allyloxy-4′-methoxyacetophenone was dissolved in 10 ml of N,N-diethylaniline. The reaction solution was heated to reflux under nitrogen atmosphere. Approximately 6 hours later, the reaction solution was stood to cool, and then, water and ethyl acetate were added thereto, so as to separate an organic layer. The obtained organic layer was washed with 5 N hydrochloric acid and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 3.37 g of 3′-allyl-2′-hydroxy-4′-methoxyacetophenone and 1.07 g of 5′-allyl-2′-hydroxy-4′-methoxyacetophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11](I)[C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:9]2)=[CH:5][CH:4]=1.[CH3:22][C:23]1[N:28]=[C:27]([O:29][C:30]2[S:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[N:34]=2)[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:33]3[N:34]=[C:30]([O:29][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[N:28]=4)[S:31][CH:32]=3)[C:10]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(Oc2nc(B3OC(C)(C)C(C)(C)O3)cs2)n1
Reactant: COc1ccc(Cn2cc(I)c(C(=O)N(C)OC)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(=O)N(C)OC)n2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
According to Scheme 5, Step 4: A mixture of 1-(4-methoxybenzyl)-4-iodo-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (0.59 mmol, 238 mg), 2-(6-methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.49 mmol, 157 mg), PdCl2(dppf) (49 μmol, 40 mg) and N-ethyl-N-isopropylpropan-2-amine (0.99 mmol, 0.17 mL) in dioxane/water (1:1, 3.3 mL) was stirred at 120° C. for 30 minutes under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (90:10 to 70:30) as eluent to yield 1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide (99 μmol, 46 mg, 15%) as an oil.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](Br)=[CH:24][C:16]([C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])(C)(C)C.[CH:33](=[O:35])[CH3:34]>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][S:20]([CH2:23][CH:33]([OH:35])[CH3:34])(=[O:22])=[O:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC=O
Reactant: CS(=O)(=O)NC(=O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(O)CS(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluoro-N-(methylsulfonyl)benzamide (0.340 g, 0.74 mmol) in anhydrous tetrahydrofuran (5 mL) was added tert-butyllithium (1.7 M solution in pentane, 1.31 mL, 2.22 mmol) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. followed by addition of acetaldehyde (0.21 mL, 3.70 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. After quenched with 1 N hydrochloric acid (5 mL), the mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate gave a residue which was purified by reverse-phase preparative HPLC to afford the title compound as an off-white solid (0.075 g, 24%): 1H NMR (300 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.60 (t, J=8.7 Hz, 1H), 6.93 (dd, J=13.0, 2.2 Hz, 1H), 6.86 (dd, J=8.7, 2.3 Hz, 1H), 5.04 (br s, 1H), 4.17-4.07 (m, 1H), 3.65-3.56 (m, 1H), 3.63 (s, 2H), 3.45 (dd, J=14.3, 5.1 Hz, 1H), 2.02-1.94 (m, 3H), 1.76-1.57 (m, 12H), 1.20 (d, J=6.3 Hz, 3H); MS (ES−) m/z 424.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1
Product: COc1cc(C(=O)CC(Cc2ccc(NC(=O)c3ccccc3)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Yield: 53.4 %

Procedure:
Following the procedure described in Example 154, treatment of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol) with benzoyl chloride (0.039 mL, 0.34 mmol) provided 67 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-benzoyl)aminophenyl)ethylamide as a foam.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:10]=1)(C)(C)C>Cl.O1CCOCC1>[CH2:26]([S:25][C:11]1[N:10]=[C:9]([CH2:8][NH2:7])[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[N:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(SCc2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(SCc2ccccc2)n1

Procedure:
[2-benzylsulfanyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-carbamic acid tert-butyl ester was diluted with 4N HCl in dioxane (20 mL) at rt. After 30 min. the mixture was concentrated and the resulting solid was used without further purification. MS (ESI): mass calcd. for C19H16F3N3S, 373.2; m/z found, 374.2 [M+H]+.
Reaction SMILES: [C:1](/[C:3](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)/[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]>CC(O)=O.[Zn]>[C:1]([CH:3]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1)[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)/C(C#N)=C\c1ccc(-c2ccccn2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C#N)Cc1ccc(-c2ccccn2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A suspension of (Z)-tert-butyl 2-cyano-3-(4-(pyridin-2-yl)phenyl)acrylate (340 mg, 1.110 mmol) and zinc (1089 mg, 16.65 mmol) in AcOH (6.5 ml) was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature and filtered. To the filtrate was added EtOAc and water, and the mixture was basified by aq. NaOH. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 15 to 30% EtOAc/Heptane) and gave the title compound: 150 mg (yield: 44%). LCMS (condition B): 309.2 (M+1); retention time=1.09 min.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:16]
Reactant: CC[O-]
Reactant: ClCc1cc2ccccc2cn1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cc2ccccc2cn1
Temperature: 20 °C
Yield: 88.6 %

Procedure:
A mixture of 3-chloromethylisoquinoline hydrochloride (40 g) and sodium ethoxide (40 g) in ethanol (700 cc) is heated under reflux for 8 hours. After cooling to 20° C., the mixture is filtered and the filtrate is evaporated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (500 cc), the mixture is washed with water (3×100 cc), the organic phase is dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The oily residue is distilled at 110°-114° C. under a pressure of 0.6 mm Hg. 3-Ethoxymethylisoquinoline (31 g), a colourless oil, is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1>C(Cl)Cl.O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:4][C:3]=2[CH2:2][NH:1][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)=[CH:15][CH:14]=1)=[O:26]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)c2cccnc2)c1
Reaction time: 12 h
Yield: 66 %

Procedure:
The product of step C (0.050 g, 0.997 mmol) was dissolved into 1 mL of DCM in a small test tube. Pyridine (0.017 g, 0.219 mmol) and nicotinoyl chloride (0.0195 g, 0.110 mmol) were added, and the reaction mixture was stirred for 12 hours. The reaction mixture was then diluted with methylene chloride and water. The methylene chloride layer was separated and loaded directly onto a biotage 12i column eluting with methylene chloride:MeOH (95:5) to yield tert-butyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-(nicotinamidomethyl)phenyl)-acetate (44 mg, 73% yield) as a clear oil.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=CN=1)[OH:4].C(C1OC=CC=1)(=[O:13])C>>[Cl:1][CH2:2][C@H:3]([C:5]1[O:13][CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: CC(=O)c1ccco1
Reactant: O[C@H](CCl)c1ccccn1
Product: O[C@H](CCl)c1ccco1

Procedure:
As described for the preparation of (1S)-2-chloro-1-pyridin-2-ylethanol, 2-acetylfuran is converted to the title compound, isolated as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([OH:12])[CH2:10][CH3:11].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])=[C:3]([C:9]([OH:12])([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH3:11])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: CCC(O)(c1cccs1)c1cc(Br)ccc1N
Product: CCC(O)(c1cccs1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
The title compound was prepared from 1-(2-amino-5-bromophenyl)-1-thiophen-2-yl-propan-1-ol and chloroacetyl chloride using the procedure described in example 1. 1H-NMR (CDCl3) δ 10.23 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.3 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.29 (dd, J=5.1, 1.0 Hz, 1H), 6.97 (m, 1H), 6.90 (dd, J=3.5, 1.0 Hz, 1H), 4.09 (m, 2H), 2.80 (s, 1H), 2.43 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); MS (ES) m/z 386 (M−H)−; Anal Calc. For C15H15BrClNO2S: C, 46.35; H, 3.89; N, 3.60. Found: C, 46.67; H, 3.80; N, 3.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Ethyl [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (11.06 g) was dissolved in a mixture of tetrahydrofuran (100 mL) and ethanol (100 mL). To the mixture was added 1M aqueous sodium hydroxide solution (37 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M hydrochloric acid (37 mL) was added to the mixture. The resulting yellow suspension was filtered to collect a yellow solid. The solid was dissolved in ethyl acetate-tetrahydrofuran. The solution was dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (9.65 g, 93%) as a yellow solid. MS 462 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:37]([CH2:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:30][CH:31]=1)([OH:41])[CH:38]([CH3:39])[CH3:40])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
Diisopropylamine (44.8 mL, 320 mmol) in THF (125 mL) was cooled to -15° C. n-Butyllithium (1.6 M, 200 mL, 320 mmol) was added over 20 minutes. The solution was cooled to -40° C. and stirred for 20 minutes. Tert-butyl acetate (43 mL, 320 mmol) in THF (90 mL) was added over 30 minutes and the reaction stirred for 30 minutes at -40° C. 1-(4-Benzyloxy-phenyl)-4-methyl-pentan-3-one (21.0 g, 100 mmol) from Example F in THF (125 mL) was added over 10 minutes and the reaction was stirred at -40° C. for 5 minutes. Acetic acid (40 mL, 700 mmol) was added and the reaction warmed to room temperature. The reaction was stripped to dryness and the product was partitioned between ethyl acetate and saturated NH4Cl. The organic layer was washed with water, 5% NaHCO3 and brine. It was dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.O=C1CCCN1CCC(Cl)=O.[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>>[O:11]=[C:9]([CH:29]1[C:30](=[O:33])[CH2:31][CH2:32][O:27][CH2:28]1)[CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CCN1CCCC1=O
Reactant: O=C1CCOCC1
Agent: O=C(Cl)CCN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: O=C1CCOCC1C(=O)CCN1CCCC1=O
Yield: 25.6 %

Procedure:
3-(2-Oxopyrrolidin-1-yl)propanoic acid (519 mg, 3.3 mmol) was heated to reflux in thionyl chloride (0.365 ml, 5.00 mmol) for 30 min. The excess of thionyl chloride was evaporated and the product, (3-(2-oxopyrrolidin-1-yl)propanoyl chloride (3.3 mmol)) used as such in the next step. 1-(3-oxo-3-(4-oxotetrahydro-2H-pyran-3-yl)propyl)pyrrolidin-2-one (202 mg, 15%) was synthesised from dihydro-2H-pyran-4(3H)-one (0.462 ml, 5.00 mmol) and 3-(2-oxopyrrolidin-1-yl)propanoyl chloride (3.3 mmol) by the general procedure for the preparation of diketones.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:13]1[CH:12]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1cccc(-c2ccccc2)c1
Yield: 78.8 %

Procedure:
A mixture of phenylboronic acid (1.000 g, 8.20 mmol), methyl 3-bromophenylacetate (1.691 g, 7.38 mmol), Na2CO3 (1.738 g, 16.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.474 g, 0.41 mmol), toluene (30 mL), and water (5 mL) was heated under reflux for 20 h. The reaction mixture was diluted with water (20 mL) and the volatiles were removed in vacuo. The aqueous solution was washed with EtOAc (4×20 mL). The organic solutions were combined, washed with 1N NaOH (15 mL) followed by water (15 mL). The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (79:1 hexanes:EtOAc to 39:1 hexanes:EtOAc) provided biphenyl-3-yl-acetic acid methyl ester (1.316 g).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH:1]1([CH2:7][N:8]2[CH2:11][CH:10]([CH2:12][O:13][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CN(CC2CCCCC2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCC2CN(CC3CCCCC3)C2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-cyclohexylmethyl-3-azetidinemethanol with 1-fluoro-4-nitrobenzene to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][N:11]([CH2:26][CH2:27][O:28][CH3:29])[N:12]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn[nH]c1-c1cc(Cl)ccc1C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOC)nc1-c1cc(Cl)ccc1C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A solution of ethyl 5-(5-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate (0.2286 g, 0.8636 mmol), cesium carbonate (359.1 mg, 1.102 mmol, 1.276 equiv) and 1-bromo-2-methoxyethane in N,N-dimethylformamide (6 mL) was heated at 50° C. After 2.5 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield 257.7 mg (92%) of ethyl 3-(5-chloro-2-methylphenyl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate, which was carried forward without purification. LCMS (ESI) m+H=323.2.
Reaction SMILES: [O:1]1[CH:5]2[CH:6]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]([CH2:8][OH:9])[CH:2]1[CH:3]=[CH:4]2.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[O:1]1[CH:2]2[CH:7]([CH2:8][O:9][S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:6]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:5]1[CH:4]=[CH:3]2
Reactant: CC(C)(O)C1C2C=CC(O2)C1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2C3C=CC(O3)C2C(C)(C)O)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In 2000 ml of pyridine was dissolved 360 g of 3,6-epoxy-4-hydroxymethyl-5-(1-hydroxy-1-methylethyl)-1-cyclohexene. In a nitrogen stream, the solution was cooled at 5° C., and 400 g of p-toluenesulfonyl chloride was added thereto. The solution was stirred at the temperature for one hour and then at room temperature for 18 hours (at this stage, a corresponding monotosylate, i.e., 3,6-epoxy-4-(1-hydroxy-1-methylethyl)-5-(p-toluenesulfonyloxymethyl)-1-cyclohexene formed in the reaction system). The reaction mixture was then heated at 60° C., and stirred at the temperature for 4 hours (at this stage, pyridine served as the base to induce cyclization so that the end compound formed). After cooling, the reaction mixture was poured into a saturated sodium chloride solution, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with dilute hydrochloric acid, water and an aqueous saturated potassium carbonate solution, dried over magnesium sulfate, and concentrated in vacuum. Vacuum distillation of the concentrate gave 308 g (yield 95%) of the end compound, 3,6-epoxy-2,2-dimethyl-2,2a,3,6,6a,7-hexahydrobenzo[c]furan.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[N:13][OH:14])[NH2:12])=[CH:3]1.[H-].[Na+]>C1COCC1>[CH3:1][N:2]([CH2:10][CH2:9][CH2:8][CH3:7])[CH2:3][CH2:4][CH2:5][C:6]1[O:14][N:13]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:12]=1
Reactant: Cn1cc(C(N)=NO)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(C)CCCc1nc(-c2cn(C)c3ccccc23)no1
Reaction time: 6 h
Yield: 111.9 %

Procedure:
1-Methyl-1H-indole-3-carboxamide oxime (C. J. Swain et al, J.Med. Chem, 1991, 34, 147)(0.250 g, 1.33 mmol) was dissolved in dry THF (8 ml) with stirring and treated with ground 4A° molecular sieves (1 g), under nitrogen. After 30 minutes sodium hydride (80% dispersion in mineral oil) (0.044 g, 1.46 mmol) was added. The mixture was then heated to reflux, after 30 minutes, the mixture was allowed to cool momentarily, and a solution of ethyl-4-N-methylbutylaminobutyrate (0.293 g, 1.46 mmol) in dry THF (2 ml) was added. The mixture was then heated to reflux. After 6 h, the reaction mixture was allowed to cool, and was then filtered. The filter pad was then washed with THF (2×) and the filtrate evaporated under reduced pressure. The residue was then purified by silica-gel chromatography, eluting with ethyl acetate/methanol 20:1 to afford the title compound as a colourless oil (0.243 g, 56%), which was converted to its hydrochloride salt, m.pt, 174°-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13]C(NC)=O>O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH3:12])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CNC(=O)NC
Solvent: O
Product: CNC(=O)c1ccc(F)cc1N
Temperature: 150 °C

Procedure:
A mixture of 2-amino 4-fluoro benzoic acid (2.5 g, 16.13 mmol) and 1,3 dimethyl urea (5.85 g, 66.5 mmol) was heated at 150° C. for 24 hours. The reaction was diluted with water, filtered and extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%)