Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CO>C1COCC1.CCOCC.[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:20][CH:21]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of the title compound from Example 10 Step B (450 mg, 1.55 mmol) in THF (8 mL) was added DIBAL-H (3.10 mL, 1.50 M in heptane, 4.65 mmol). After 30 min, the reaction mixture was transferred to a 0° C. bath and was held at this temperature for 45 min, whereupon it was quenched by addition of MeOH (0.63 mL, 15.5 mmol). The resulting mixture was diluted with ether and saturated aqueous sodium/potassium tartrate, and the mixture was stirred rapidly until a clear phase separation was achieved. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 231.1 [M−OH]+; 1H NMR (500 MHz, CDCl3) δ 7.29 (d, J=7.5 Hz, 2H), 7.24 (d, J=7.5 Hz, 2H), 4.65 (s, 2H), 3.98 (s, 4H), 2.59-2.54 (m, 1H), 1.87-1.66 (m, 8H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:5]([O:31][CH3:32])=[CH:6][C:7]2[O:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:9](=[O:29])[C:8]=2[CH:30]=1.[CH:33](O)=O.C=O.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[CH3:2][O:3][C:4]1[C:5]([O:31][CH3:32])=[CH:6][C:7]2[O:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:33])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:9](=[O:29])[C:8]=2[CH:30]=1
Reactant: COc1ccc(CCNCCCN2COc3cc(OC)c(OC)cc3C2=O)cc1OC
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCN(C)CCCN2COc3cc(OC)c(OC)cc3C2=O)cc1OC
Reaction time: 0.17 h
Yield: 90 %

Procedure:
8 g (18.5 mmol) of base of the compound P are dissolved with cooling in 2.1 ml (56 mmol) of formic acid, stirred for 10 min, then treated at 25° C. in 1.6 ml of 40% strength formaldehyde (23 mmol) and then taken for 10 min to an oil bath preheated to 80° C. The mixture is cooled, taken up in methylene chloride and alkalinized with caustic soda solution. The phases are separated, the aqueous phase is re-extracted with the same solvent and the organic phases are combined, washed with saline solution and then dried and evaporated. The residue is converted to hydrochloride as in Example 2, to give the compound B, possessing the same characteristics as those described in Example 2, in a 90% yield.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reaction time: 1 h
Yield: 377 %

Procedure:
To a solution of the product (4.5 g, 2.48 mmol) from Step 2 in dioxane (2 mL) was added 4M HCl in dioxane (8 mL) at rt and the resulting mixture was stirred for 1 h at that temperature. The solvent was removed in vacuo to obtain a thick oil. The oil was triturated with ether to obtain a white solid (2.5 g). The solid was recrystallized with toluene (20 mL) to obtain the title product (1.8 g, 53%) as a crystalline solid: MS; m/z 268 (M+H): 1H NMR (400 MHz, DMSO-d6); δ 1.73 (m, 1H), 1.89 (m, 1H), 1.98 (m, 1H), 2.09 (m, 1H), 3.18 (m, 2H), 3.87 (m, 1H), 3.88 (s, 2H), 4.13 (dd, 1H, J1=7.2 Hz, J2=6.4 Hz), 4.19 (dd, 1H, J1=8.8, J2=3.2 Hz), 6.91 (d, 2H, J=6.8 Hz), 7.15-7.20 (m, 5H), 7.27 (m, 2H): HPLC (UV); 97.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18].[CH3:27][C:28]1([CH3:45])[O:32][CH:31]([CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30][O:29]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:33][CH:31]2[CH2:30][O:29][C:28]([CH3:45])([CH3:27])[O:32]2)[CH:22]=[CH:21][C:20]=1[F:26])=[O:18]
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OCC(COc2ccc(F)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)O1
Temperature: 110 °C
Reaction time: 0.83 h

Procedure:
Compound 512 (54 mg, 0.14 mmol) was dissolved in acetonitrile (4 mL) in a reaction vial. Compound 506 (61 mg, 0.21 mmol) and K2CO3 (30 mg, 0.21 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 110° C. for 50 min. in a microwave oven, followed by reflux in a oil bath for 24 h. The reaction mixture was concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:7 to 1:3) as the eluent, affording the title compound as a yellow oil. 13C NMR (CDCl3) δ 190.6, 159.1 (dd), 154.7, 154.5 (d), 154.4 (dd), 147.8, 134.7, 132.9, 129.6, 127.9 (d), 124.4 (dd), 124.2 (dd), 120.6 (d), 117.1 (d), 116.0, 115.1 (d), 112.9, 111.6 (dd), 109.9, 104.9 (dd), 73.9, 69.6, 66.6, 26.8, 25.4
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:9]1[S:13][C:12]([SH:14])=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Br[C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:23][C:24](=[O:29])[O:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[C:21]3[C:26](=[C:27]([CH3:28])[C:18]([S:14][C:12]4[S:13][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:15])([F:1])[F:16])=[CH:10][N:11]=4)=[CH:19][CH:20]=3)[O:25][C:24](=[O:29])[CH:23]=2)=[CH:35][CH:34]=1
Reactant: OC(c1cnc(S)s1)(C(F)(F)F)C(F)(F)F
Reactant: Cc1c(Br)ccc2c(-c3ccc(F)cc3)cc(=O)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c(Sc2ncc(C(O)(C(F)(F)F)C(F)(F)F)s2)ccc2c(-c3ccc(F)cc3)cc(=O)oc12

Procedure:
Employing the procedure of Example 1, Step 3 using 1,1,1,3,3,3-hexafluoro-2-(2-mercapto-1,3-thiazol-5-yl)propan-2-ol, (0.332 g, 1.2 mmol), 7-bromo-4-(4-fluorophenyl)-8-methyl-2H-chromen-2-one (0.430 g, 1.3 mmol) and potassium carbonate (0.404 g, 2.9 mmol) in NMP, the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 8.21 (s, 1H, OH), 7.97 (s, 1H), 7.36-7.72 (m, 6H), 6.50 (s, 1H), 2.67 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C:3]#[C:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH3:7].[Si:22](C1NC=CN=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:7][C@@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH2:5][C:4]#[C:3][C:2]([CH3:20])([O:1][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH3:21]
Reactant: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: ClCCl
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 4 h
Yield: 93 %

Procedure:
860 mg (2.96 mmol) of (4aR,5R,8aR)-5-((R)-5-hydroxy-1,5-dimethyl-hex-3-ynyl)-4a-methyl-octahydro-naphthalen-1-one in 23 ml of abs. CH2Cl2 was treated with 3.89 ml (26.6 mmol) of TMS-imidazole and kept at RT for 4 h. Pouring onto crushed ice, twofold extraction with ether, washing with water and brine, and drying over sodium sulfate left a crude product, which was purified by flash chromatography (SiO2, hexane/AcOEt=9/1). Thereby, 998 mg of the title compound was obtained as colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(N(C)C)=O.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cnnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cnn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL), and the reaction mixture was stirred at 100° C. for 3 hours. After such time, the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS (m/e): 333.4 (M+H+, 100%)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[O:9]1[CH:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:27]1[C:24]1[CH:23]=[CH:22][C:21]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCC=Cc1ccc(CCCCCCCCC)cc1
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(C2OC2CCCC)cc1
Reaction time: 20 h

Procedure:
6.76 g of m-chloroperbenzoic acid (90% content) in 100 ml of dichloromethane are added to a solution of 6.32 g of 1-(4-nonylphenyl)-hex-1-ene (mixture of cis- and trans-isomers) from the preceding stage in 150 ml of dichloromethane while cooling to 0°-5°, and the whole is stirred for 20 hours at 20°. The reaction mixture is washed in succession with 10% strength (w/v) sodium sulphite solution, 5% strength (w/v) sodium carbonate solution and 3 portions of water, dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (19:1) yields in succession the trans- [1(RS),2(RS)-] and the cis-[1(RS),2(SR)-]-isomer in the form of colourless oils.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[K+].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][O:11][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC#Cc2ccc(Cl)cc2)cc1
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-(4-chloro-phenyl)-prop-2-yn-1-ol (3.3 g) and toluene-4-sulfonyl chloride (3.7 g) in diethyl ether (100 ml) which is pre-cooled to −15° C. is added powdered potassium hydroxide (2.8 g) in small portions during 10 minutes. The reaction mixture is stirred at 0° C. during 90 minutes. Then water (200 ml) is added and the mixture is extracted with diethyl ether (2×100 ml) and washed with brine (50 ml). The organic layers are collected, dried (Na2SO4) and evaporated. Toluene-4-sulfonic acid 3-(4-chloro-phenyl)-prop-2-ynyl ester is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][CH:5]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][C@@H:23]([CH3:25])[NH:22][CH2:21][C@@H:20]1[CH3:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][C@@H:23]([CH3:25])[N:22]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=2)[CH2:21][C@@H:20]1[CH3:26])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(F)nc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)nc1

Procedure:
A mixture of 6-fluoronicotinic acid methyl ester (200 mg, 1.29 mmol) and (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was heated at 120° C. in DMSO (2.0 mL) with potassium carbonate (178 mg, 1.29 mmol) for 2 h. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (5.0 mL). The organic layer was washed with water (2×5.0 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate as a yellowish oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCOCC1>[CH3:26][O:25][C:23]([C:22]1[CH:27]=[CH:28][C:19]([CH2:18][CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[CH:20][CH:21]=1)=[O:24]
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 4.44 g (111.0 mmol) of sodium hydride (60% strength dispersion in mineral oil) are added a little at a time to a solution of 27.28 g (148.09 mmol) of diallyl malonate in 220 ml of anhydrous dioxane. The mixture is stirred at 40° C. for 30 min, and a solution of 18.00 g (74.04 mmol) of methyl 4-(2-bromoethyl)benzoate is then added at room temperature. The reaction mixture is then heated at 110° C. for 16 hours. After addition of 25 ml of saturated ammonium chloride solution, most of the dioxane is removed on a rotary evaporator. The residue is taken up in 200 ml of ethyl acetate and 100 ml of water. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After distillative removal of a large proportion of the excess diallyl malonate, the crude product is pre-purified on 100 g of silica gel 60 (mobile phase: cyclohexane/dichloromethane 2:1, then cyclohexane/ethyl acetate 4:1). The desired product is then isolated by preparative HPLC. This gives 11.60 g (22% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([F:32])[F:33])=[CH:28][CH:29]=2)=[O:23])=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(OC(F)F)cc1

Procedure:
Prepared by Method E using (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.3 g, 1.13 mmol) and 2-bromo-1-[4-(difluoromethoxy)phenyl]ethanone (0.315 g, 1.19 mmol) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[NH4+]>O>[C:10]1([CH2:9][CH2:8][NH:16][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccncc1
Reactant: NCCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CCNc2ccncc2)cc1
Yield: 16 %

Procedure:
A mixture composed of 2.0 g (0.0176 m) of 4-chloropyridine and 4.3 g (0.0352 m) of phenethylamine was heated under nitrogen to 160°-165° C for one hour. The mixture was then cooled and 200 mL of a 50/50 mixture of ammonium hydroxide in water was added. The product was extracted into CH2Cl2, which was then concentrated to dryness. The resulting material was purified by HPLC on silica gel, eluting with ethyl acetate to provide 0.560 g of the title product.
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[S:9][CH3:10])[CH3:3].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][CH:2]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[S:9][CH3:10])[CH3:3]
Reactant: CSc1ccsc1C(C)O
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOC(C)c1sccc1SC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)3-methylthiothiophene (13.5 g, 0.077 mol) in dry methylene chloride (100 ml) was added methoxyethoxymethyl chloride (11.5 g, 0.092 mol) followed by N,N-diisopropylethylamine (12.1 g, 0.092 mol) with cooling. The solution was stirred at room temperature for 18 hours. Some starting material remained upon work up at this point. The material was recycled as above using 1/2 the above quantities of methoxyethoxymethyl chloride and N,N-diisopropylethyl amine. After 5 hours at room temperature the reaction was completed. The solution was washed with water, dilute HCl, saturated NaHCO3 solution and again with water. Then it was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Pure product was obtained as a yellow oil (17.6 g, 87%). TLC confirmed the purity and NMR and mass spectrometry (M/Z=262) supported the structure.
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>>[I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([Cl:32])=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(I)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(I)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 28.3 g of diethyl 4-iodobenzoylmalonate, 14.6 g of diisopropylethylamine and 20 ml of phosphorus oxychloride was stirred at 100° C. for 2 hours and then poured over ice. The reaction mixture was extracted with diethyl ether, and the extract was dried over magnesium sulfate, treated with activated carbon, filtered and then concentrated at atmospheric pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 20.14 g of the title compound as a pale yellow liquid.
Reaction SMILES: [OH-].[K+].O.C(O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16]>C(Cl)Cl>[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CCCOc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)CCCOc1cccc(F)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of KOH (0.24 g, 4.28 mmol) in mixed solvents of water (3 mL) and ethanol (3 mL) under N2 was added ethyl 4-(3-fluorophenoxy)butanoate (0.30 g, 1.33 mmol) in one portion and the mixture was stirred at 40° C. for 4 h. It was then cooled to rt and 20 mL of DCM was added. The organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (0.25 g, 96%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(O)CCCC1>C1(C)C=CC=CC=1>[C:1]([O:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)CCCCC
Agent: OC1CCCC1
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OC1CCCC1
Yield: 70 %

Procedure:
Likewise, refluxing a toluene solution containing one equivalent of hexyl hexanoate, 2 equivalents of cyclohexanol and 1 mol % of the PNN complex 1 under argon atmosphere for 20 h resulted in 84% conversion of hexyl hexanoate as determined by GC analysis, with the exclusive formation of the ester cyclohexyl hexanoate in 83% yield (Table 30, entry 2). Notably, unlike the traditional transesterification methods, this reaction does not form an alcohol product; rather, an irreversible incorporation of both the acyl and alkoxo parts of the starting ester into the product ester takes place. While 2 equivalents of the alcohol with respect to the ester are sufficient, somewhat higher yields are obtained when 3 equivalents of alcohol were used. Thus, reaction of 3 equivalents of cyclohexanol with hexyl hexanoate resulted after 26 h in 96% conversion with 95% yield of cyclohexyl hexanoate, as observed by GC, and confirmed by GC-MS by comparison with an authentic sample (Table 30, entry 3). The pure product was isolated by evaporation of the solvent followed by passing through a basic alumina plug and analysis by NMR and GC-MS. Use of the PNP complexes 2 or 3 resulted after 20 h in 58% or 17% yield of cyclohexyl hexanoate, respectively. Studying the scope of this new reaction with regard to the secondary alcohol, reaction of hexyl hexanoate with cyclopentanol in the presence of 1 mol % 1 was carried out. After 26 h reflux in toluene, cyclopentyl hexanoate (70% yield) was formed, with 71% conversion of hexyl hexanoate (Table 30, entry 4). Similarly, upon reaction of hexyl hexanoate with excess of 1-phenylethanol, 50% conversion of hexyl hexanoate with the formation of 49% of the acylated product was observed (Table 30, entry 5). The lower conversion of the ester is a result of facile dehydrogenation of 1-phenylethanol to acetophenone (49%). Because of the expected easy dehydrogenation of the isopropyl alcohol to acetone, transesterification with this alcohol was performed in a closed vessel, to retard this dehydrogenation process. Thus, heating hexyl hexanoate with excess of isopropyl alcohol resulted after 19 h in 83% conversion of hexyl hexanoate with the formation of isopropyl hexanoate in 67% yield (entry 6). The reaction of hexyl hexanoate and 3-pentanol led to 91% conversion of the ester with formation of 3-pentyl hexanoate in 90% yield after 26 h reflux (entry 7).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([SH:51])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C.[C:61]([O:65][C:66]([N:68]1[CH2:72][CH2:71][CH:70]([C:73]2[CH:78]=[CH:77][C:76](Br)=[CH:75][C:74]=2[CH3:80])[CH2:69]1)=[O:67])([CH3:64])([CH3:63])[CH3:62].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:61]([O:65][C:66]([N:68]1[CH2:72][CH2:71][CH:70]([C:73]2[CH:78]=[CH:77][C:76]([S:51][C:48]3[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=3)=[CH:75][C:74]=2[CH3:80])[CH2:69]1)=[O:67])([CH3:64])([CH3:63])[CH3:62]
Reactant: Cc1cc(Br)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Sc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)c(C)c2)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (336 mg, 0.3674 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (425 mg, 0.7347 mmol), 4-methoxy-benzenethiol (361 μL, 2.939 mmol) and DIPEA (0.538 mL, 5.878 mmol) were added to a solution of 3-(4-bromo-2-methyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.939 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated at reflux for 18 hours, then cooled to room temperature, and a solution of 10% KHSO4/Na2SO4 was added. The mixture was extracted with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 95/5) to give 0.91 g (77% yield) of 3-[4-(4-methoxy-phenylsulfanyl)-2-methyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.