Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][OH:25])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:25][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
At a temperature of 0° C., p-toluenesulfonylchloride (6.0 g, 30.4 mol) was added portionwise to a stirred solution of (S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9 g, 24.3 mmol) and pyridine (14.6 ml, 181 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 30 minutes at 0° C. and then allowed to stand for 15 hours at ambient temperature. Then dichloromethane (50 ml) was added. The solution was washed with water (4×50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (9.83 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1) to afford 8.07 g (83.4% of theory) of (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil. 1H NMR (400 MHz, DMSO): δ 1.29 and 1.35 (s, 9H), 1.72 (m, 3H), 1.92 (m, 1H), 2.43 (s, 3H), 3.18 (m, 2H), 3.83 (m, 1H), 4.03 (m, 2H), 7.49 (d, 2H), 7.78 (d, 2H). MS [M+H]+ 256. [α]23D=−39.1 (c 5.98, CHCl3).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:21])[C:14]([O:16]C(C)(C)C)=[O:15].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl.C1(OC)C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:21])[C:14]([OH:16])=[O:15]
Reactant: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of 2-[(1,3-dioxo-2H-isoindol-2-yl)-oxy]-2-propenoic acid, t-butyl ester (49.9 g, 0.173 mole) in methylene chloride (300 ml) and anisole (150 ml) was treated with trifluoroacetic acid (300 ml). After stirring overnight at room temperature, 800 ml of dry toluene was added and the reaction mixture was concentrated in vacuo. The residue was triturated twice with hexane to give 39.6 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 1-methylpiperazine (0.605 ml, 5.45 mmol) in DMF (6.25 ml) was added 4-fluoronitrobenzene (0.750 ml, 7.07 mmol) and potassium carbonate (1.13 g, 8.18 mmol) and the reaction mixture stirred at 90° C. overnight. The reaction was then cooled to room temperature, diluted with DCM and washed with water. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel silica chromatography using a 0-10% MeOH in DCM gradient to afford 1-methyl-4-(4-nitrophenyl)piperazine (1.03 g, 4.66 mmol, 85%) as a yellow solid. 1H NMR (DMSO) δ 2.37 (3H, s), 2.58 (4H, t), 3.45 (4H, t), 6.82 (2H, d), 8.12 (2H, d). LCMS (1) Rt: 1.63 min; m/z (ES+) 222.
Reaction SMILES: Cl[C:2](=[N:11][N:12]=[C:13](Cl)[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[F:10].O.[NH2:24][NH2:25]>O1CCCC1>[F:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[C:2]1[N:24]=[N:25][C:13]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:12][N:11]=1
Reactant: NN
Reactant: Fc1cccc(F)c1C(Cl)=NN=C(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1-c1nnc(-c2c(F)cccc2F)nn1

Procedure:
To a solution of 0.9 g of bis[chloro-(2,6-difluorobenzylidene)]hydrazine [prepared in the preceding step b.)] in 18 ml of tetrahydrofuran of 40° C. temperature, 0.59 ml of hydrazine hydrate is dropped over 1 minute. After filtering the precipitate is washed with water and dried to give 0.5 g of desired product as yellow crystals. The melting point is 225.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[O:17][C:18](=[O:20])[CH3:19].COC1C=CC2[C@H]3CC[C@@]4(C)[C@H]([C@@H]3CCC=2C=1)CCC4=O>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[O:17][C:18](=[O:20])[CH3:19]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
The procedure described in Example 1 hereinbefore was repeated but an equal amount of 3-methoxy-13β-methyl-17β-acetoxygona-1,3,5(10)-triene was substituted for the 3-methoxy-13β-methylgona-1,3,5(10)-trien-17-one that was used in that example. After distilling off the dichloromethane from the electrolyzed solution at a subatmospheric pressure and crystallizing from the remaining solution, 2.0 grams of 3-methoxy-13β-methyl-17β-acetoxygona-1,3,5(10),9(11)-tetraene having a melting point of 110°-113° C., was obtained. After recrystallization of the compound from a mixture of dichloromethane and methanol it had a melting point of 114°-116° C. and a specific optical rotation of +95° at a temperature of 25° C. for the sodium D line.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Yield: 81.7 %

Procedure:
9-Benzyl-6-chloro-9H-carbazol-4-ol (0.0616 g, 0.20 mmol), 2-diethylaminoethylchloride hydrochloride (0.0517 g, 0.30 mmol), potassium carbonate (0.0863 g, 0.62 mmol), sodium iodide (0.0027 g, 0.018 mmol) and DMF (1 mL) are heated at 85° C. for 3.5 h. After the mixture had cooled, it is partitioned between water and ether. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (60 mL) using methanol/dichloromethane (1/99 to 2/98 to 4/96) to give 0.0665 g (82%) of the title compound; mp 96-97.5° C.; MS (ESI+) for C25H27ClN2O m/z 407.3 (M+H)+; IR (drift) 2966, 1583, 1466, 1453, 1340, 1268, 1242, 1149, 1124, 1069, 795, 780, 745, 718, 708 cm−1; 1H NMR (CDCl3) δ1.16, 2.75, 3.12, 4.34, 5.47, 6.69, 6.97, 7.08, 7.21-7.38, 8.34. Anal. Calcd for C25H27ClN2O: C, 73.79; H, 6.69; N, 6.88. Found: C, 73.39; H, 6.73; N, 6.78.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[C:53]([CH3:54])=[CH:52][CH:51]=[C:50]1[CH2:55][NH2:56]>>[CH3:48][N:49]1[C:53]([CH3:54])=[CH:52][CH:51]=[C:50]1[CH2:55][NH:56][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: Cc1ccc(CN)n1C
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(C)n1C
Yield: 57 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1,5-dimethyl-1H-pyrrol-2-yl)methanamine, the title compound was obtained as a beige solid in 57% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.08 (s, 1H), 6.00 (d, J=3.2 Hz, 1H), 5.81 (d, J=3.2 Hz, 1H), 5.67 (t, J=4.4 Hz, 1H), 4.53 (d, J=4.4 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.49-3.39 (m, 5H), 2.48 (s, 3H), 2.21 (s, 3H); MS (ES+) m/z 463.1 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]1(C)C=CC=CC=1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[CH3:12])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: Cc1ccccc1
Reactant: CSc1ncc(CO)c(N)n1
Product: CSc1ncc(C(C)=O)c(N)n1
Yield: 72 %

Procedure:
By substituting 1-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanol (Example 34) for (4-amino-2-methylsulfanyl-pyrimidin-5-yl)-methanol in Example 3 and conducting the reaction at 80° C. in toluene, 3.74 g (72%) of the product as a solid is obtained.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[CH3:11]>C(O)(=O)C>[CH3:11][C:10]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([CH3:22])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=Nc2ccccc2C1(C)CCCCCC(=O)O
Yield: 61.7 %

Procedure:
To a stirred solution of phenylhydrazine hydrochloride (Aldrich, 7.2 g, 0.05 mol) in acetic acid (50 ml) was added 7-acetyloctanoic acid (11 g, 0.06 mol). The reaction mixture was heated under reflux for 4 hrs. The solution was cooled. (No clear precipitate was observed). Acetic acid was removed under reduced pressure. The resulting yellow liquid was chromatographed on a silica gel column using chloroform/methanol mixture as solvent. Pure 6-(2,3-dimethyl-3H-indol-3-yl)hexanoic acid (8.0 g, 61%) was obtained as pale yellow oil which crystallized on standing, m.p. 115-118° C.; IR νcm−1=2927, 2860, 2526, and 1709. 1H NMR, CDCl3, δ, 7.6 (d, 1H, J=7 Hz, 4-H); 7.2-7.4 (m, 3H, aromatic protons); 2.25 (s, 3H, —CH3); 2.1-2.2(t, —CH2COOH); 1.72-1.94 (m 2H, —CH2); 1.4-1.45 (m, 2H, —CH2); 1.23-1.05 (m, singlet merged in m, 5H, —CH2, —CH3); 0.55-0.85 (m, 2H, —CH2). TLC, Rf=0.22 (silica gel, methanol-chloroform, 5:95).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:36][CH3:37])[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:36][CH3:37])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCNCC1
Yield: 50.2 %

Procedure:
tert-Butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate (0.040 g, 0.079 mmol) was added to a mixture of trifluoroacetic acid and DCM (1:1) for 30 minutes, and the reaction was concentrated. Ethyl acetate was added and the suspension was filtered through a Waters filter (to remove any errant silica gel), and the filtrate was concentrated. DCM was added followed by precipitation with HCl dissolved in diethyl ether, evaporated, co-evaporated in diethyl ether to yield 16 mgs of the desired product as a yellow solid (95% pure by LC). MS ESI (+) m/z 404 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:6]([CH:8]1[CH2:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]1=O)=O.O.[NH2:27][NH2:28].C(O)(=O)C>C(O)C>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[CH2:15][C:11]4[S:12][CH:13]=[CH:14][C:10]=4[C:9]=3[NH:28][N:27]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: NN
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1Cc2sccc2C1=O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2n[nH]c3c2Cc2sccc2-3)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
5-(3,5-Bis-trifluoromethyl-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.07 g, 4.1 mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol), glacial acetic acid (0.8 mL) and ethanol (10 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(3,5-Bis-trifluoromethyl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.58 g, 1.5 mmol) as white solid in 37% yield.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=O.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]#[N:5])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)[C@@H]1CCCN1
Product: N#C[C@@H]1CCCN1C(=O)CCl

Procedure:
In a similar procedure as employed in a patent (WO98/19998), L-proline amide (10.0 g) was reacted with chloroacetyl chloride (7.0 ml) and then subjected to dehydration reaction to give the title compound (7.7 g, yield (Y.:51%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:16]([C:17]3[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([F:25])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:16]([C:17]3[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:25])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)O)c(F)cc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 126.3 %

Procedure:
To a solution of methyl 4-(4-chlorophenoxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoate (Preparation 31, 194 mg, 0.50 mmol) in THF (10 mL) was added aqueous lithium hydroxide solution (1M, 2.51 mL, 2.51 mmol) and the mixture stirred for 72 hours at room temperature under a nitrogen atmosphere. The reaction was then concentrated in vacuo to afford the title compound as a white solid (236 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1([C:23]#[C:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:7][CH2:6][C:5]2[C:8]([CH3:22])=[C:9]([O:14]CC3C=CC=CC=3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1>[Ni].C(O)C.C(OCC)(=O)C>[CH3:13][C:10]1[C:11]([CH3:12])=[C:4]2[C:5]([CH2:6][CH2:7][C@:2]([CH2:23][CH2:24][CH2:25][C@@H:26]([CH2:27][CH2:28][CH2:29][C@@H:30]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:37])[CH3:38])([CH3:1])[O:3]2)=[C:8]([CH3:22])[C:9]=1[OH:14]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C#CCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 6 h
Yield: 101.2 %

Procedure:
A mixture of [2S-(4R*,8R*,)]-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-1-tridecynyl)-6-(phenylmethoxy)-2H-1-benzopyran, (200 mg, 0.39 mmol) and 40 mg of Raney Nickel in 5 mL of ethanol and 5 mL of ethyl acetate was hydrogenated at 25° C. and atmospheric pressure for 6 h. Workup in the usual manner and purification of the crude product by chromatography on silica gel (eluent 1:5 ether-hexanes) gave 170 mg of (2R,4'R,8'R)-α-tocopherol as a pale yellow oil, identical in all aspects with a known sample.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][O:19][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
88.7 g (515.41 mmol) of (2-chloroethyl)diethylamine hydrochloride are added at ambient temperature to a suspension of 71.7 g (515.41 mmol) of p-nitrophenol and 284.94 g (2.061 mol) of potassium carbonate in 600 mL DMF and the reaction mixture is heated to 80° C. for 8 hours. The reaction mixture is evaporated down and the residue poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the filtrate is evaporated down. Yield: 110.52 g (90% of theory); C12H18N2O3 (M=238.28); Rf value: 0.52 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: Cl.N1(C(=O)CC2C=CC(N3C=NN=N3)=CC=2)CCNCC1.[N:22]1([C:28]([O:30]C(C)(C)C)=O)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[C:35]([C:37]1[C:42]([F:43])=[CH:41][C:40]([CH2:44]C(O)=O)=[C:39]([F:48])[CH:38]=1)#[N:36]>>[F:43][C:42]1[CH:41]=[C:40]([CH2:44][C:28](=[O:30])[N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[C:39]([F:48])=[CH:38][C:37]=1[C:35]#[N:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(F)c(CC(=O)O)cc1F
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Product: N#Cc1cc(F)c(CC(=O)N2CCNCC2)cc1F

Procedure:
2,5-difluoro-4-[2-oxo-2-(piperazin-1-yl)ethyl]benzonitrile was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from tert-butyl piperazine-1-carboxylate and (4-cyano-2,5-difluorophenyl)acetic acid. LC/MS: [(M+1)]+=266.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:15][CH2:14]2)=[O:12])=[N:7][CH:6]=1.Br.Br[CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[S:9][C:8](=[N:10][C:11]([C:13]2([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])[N:7]([CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:6]=1
Reactant: CCN(CC)CCBr
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CC2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCn1cc(Cc2ccccc2Cl)sc1=NC(=O)C1(c2ccc(OC)cc2)CC1
Yield: 20 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-benzyl)-thiazol-2-yl]-amide (39.9 mg, 0.100 mmol) and (2-bromo-ethyl)-diethyl-amine hydrobromide (26.1 mg, 0.100 mmol) were dissolved in 1 mL of tetrahydrofuran. Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added and the reaction was subjected to microwave irradiation for 10 minutes at 100° C. The solvent was evaporated to dryness and the crude mixture was purified by reverse-phase preparative liquid chromatography to yield 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-benzyl)-3-(2-diethylamino-ethyl)-3H-thiazol-2-ylidene]-amide (10 mg, 0.020 mmol, 20%) ESI-MS m/z calc. 497.2. found 498.3 (M+1)+. Retention time of 2.64 minutes. 1H NMR (400 MHz, CD3CN) δ 1.07-1.17 (m, 8H), 1.54-1.59 (m, 2H), 2.88-2.94 (m, 4H), 3.19-3.24 (m, 2H), 3.80 (s, 3H), 4.07 (s, 2H), 4.24 (t, J=6.4 Hz, 2H), 6.86-6.91 (m, 2H), 6.97 (s, 1H), 7.26-7.47 (m, 6H) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid [5-(2-chloro-benzyl)-thiazol-2-yl]-(2-diethylamino-ethyl)-amide (14 mg, 0.028 mmol, 28%) ESI-MS m/z calc. 497.2. found 498.3 (M+1)+. Retention time of 2.65 minutes. 1H NMR (400 MHz, CD3CN) δ 1.08-1.17 (m, 6H), 1.30-1.37 (m, 2H), 1.51-1.57 (m, 2H), 2.55-2.59 (m, 2H), 3.00-3.05 (m, 4H), 3.79 (s, 3H), 4.26 (s, 2H), 4.42 (t, J=3.0 Hz, 2H), 6.90-6.95 (m, 2H), 7.16-7.23 (m, 2H), 7.27-7.50 (m, 5H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[NH2:5][CH2:4][CH2:3][CH:2]([O:1][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(O)CC#N
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(CCN)OC1CCCCO1
Yield: 93.6 %

Procedure:
A mixture of 3-hydroxycaprylonitrile (5.2 g., 36.8 millimole), dihydropyran (3.8 g., 45 millimole), and p-toluenesulfonic acid.hydrate (catalytic amount) is stirred at 25° C. for 16 hours, then diluted with ether (100 ml.). The resulting solution is washed with 5% aqueous sodium hydroxide (25 ml.) and water (2×25 ml.), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo affords the title compound as a pale yellow oil (7.9 g., 95%), pmr (CDCl3) δ0.93 (3H, t), 2.54 (2H, q) and 4.68 (H, m).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[N:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:14]3[N:15]=[C:16]([NH2:20])[N:17]=[CH:18][C:19]=3[C:11]=2[CH:10]=[CH:9][N:8]=1)(=O)=O.[CH2:28]1COCC1.C[Mg]Br>CN1CCCC1=O>[CH:21]1([N:13]2[C:14]3[N:15]=[C:16]([NH2:20])[N:17]=[CH:18][C:19]=3[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:28])[C:12]2=3)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCOC1
Reactant: Nc1ncc2c3ccnc(OS(=O)(=O)C(F)(F)F)c3n(C3CCCC3)c2n1
Agent: C[Mg]Br
Solvent: CN1CCCC1=O
Product: Cc1nccc2c3cnc(N)nc3n(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A flame-dried two-necked flask was charged under argon with compound 86 (0.100 g, 0.25 mmol), ferric acetylacetonate (0.0044, 0.012 mmol), THF (2 ml) and N-methylpyrrolidone (0.1 ml). Methylmagnesium bromide (0.27 g, 2.2 mmol, 3M in ether) was added via syringe to the resulting red solution. A yellow precipitate formed immediately. The reaction was stirred at room temperature for 30 min and quenched with 5% NaHCO3, then extracted into DCM The resulting organic solution was washed with brine, dried and concentrated. Purification by flash chromatography (10% methanol/DCM/1% NH4OH) gave compound 87 as a light yellow solid (0.036 g, 54%). LCMS-ESI (POS), M/Z, M+1: Found 268.1, calculated 268.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(2,4-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.6 Hz), 7.98 (2H, d, J=8.1 Hz), 7.80–7.70 (1H, m), 7.39 (2H, d, J=8.1 Hz), 7.34 (1H, dd, J=8.9, 2.6 Hz), 7.14–6.87 (3H, m), 6.73 (1H, d, J=8.9 Hz), 5.45–5.27 (1H, m), 3.90 (3H, s), 1.55 (3H, d, J=6.9 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.