Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(CN)cc1
Yield: 86.2 %

Procedure:
To solution of methyl (2E)-3-(4-cyanophenyl)acrylate (18 g, 0.096 mol) in methanol (200 ml) was added Pd/C (1.8 g) and hydrogenated under a pressure of 50 psi of hydrogen for 12 h. The catalyst was filtered off and the filtrate was concentrated to a residue. The residue was purified by chromatography (SiO2, chloroform/methanol 9/1) to yield the title compound as a liquid (16 g, 86%). TLC:CHCl3/MeOH (9/1); Rf: 0.3
Reaction SMILES: [H-].[Li+].C([Al+]CC(C)C)C(C)C.[H-].C([O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[O:25][CH2:26][CH2:27][CH3:28])CC>C1COCC1>[Cl:24][C:20]1[C:19]([O:25][CH2:26][CH2:27][CH3:28])=[C:18]([CH2:17][OH:16])[CH:23]=[CH:22][CH:21]=1
Reactant: CCCOC(=O)c1cccc(Cl)c1OCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
Diisobutylaluminum lithium hydride (30.7 mL of a 1.0 M in hexanes, 30.7 mmol) was added dropwise to an ice-cold solution of 3-chloro-2-propoxybenzoic acid propyl ester (2.63 g, 10.2 mmol) in THF (20 mL). After the addition was complete, the ice bath was removed and the mixture stirred at ambient temperature for 18 h. The reaction was cooled to 0° C. and HCl (1N, 100 mL) was added until all the resulting solids returned to solution. The solution was extracted with Et2O (3×100 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) filtered and concentrated to yield the title compound (1.12 g, 56%) as a light yellow oil: 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.33 (m, 2H), 7.13 (t, J=7.7 Hz, 1H), 5.22 (t, J=5.6 Hz, 1H), 5.56 (d, J=5.6 Hz, 2H), 3.84 (t, J=6.4 Hz, 2H), 1.76-1.71 (m, 2H), 1.01 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=C)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:8]1[CH2:31][CH:30]([CH2:32][OH:34])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(CO)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (135 mg, 0.30 mmol) in DCM (4 mL) and methanol (1 mL) at −78° C. was bubbled ozone until the solution turned faint blue. NaBH4 (91 mg, 2.41 mmol) and methanol (˜2 mL) was added under an atmosphere of nitrogen and the reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo, quenched with 4N HCl/dioxane, concentrated in vacuo, then diluted with methanol-water (1:1), microfiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HCl modifier) to give [8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (50 mg, 34%). ESI-MS m/z calc. 452.6. found 453.5 (M+1)+; Retention time: 1.18 minutes (3 min run).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][O:6][CH:7]=1.C(OCC)(=O)[CH2:19][C:20]([O:22]CC)=[O:21].[H-].[Na+].Cl>O1CCCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:4]2[C:3]([CH2:2][CH2:19][C:20]([OH:22])=[O:21])=[CH:7][O:6][N:5]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2nocc2CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1conc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 4-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole (2.90 g) in tetrahydrofuran (100 ml) was added to a mixture of diethyl malonate (5.35 g), sodium hydride (60%, oil, 1.30 g) and tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[3-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (2.49 g, yield 79%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 173–174° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([OH:26])=O.Cl.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:39][CH2:38][CH2:37][C@H:36]2[CH2:40][OH:41])[CH2:31][CH2:30]1>>[OH:41][CH2:40][C@@H:36]1[CH2:37][CH2:38][CH2:39][N:35]1[CH:32]1[CH2:33][CH2:34][N:29]([C:24]([C:3]2[C:4]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:15])[F:16])[CH:8]=3)[C:2]=2[CH3:1])=[O:26])[CH2:30][CH2:31]1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Yield: 78 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (Example 160D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol dihydrochloride gave the title compound in 78% yield as a light yellow foam. MS: 530.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:39])[CH2:29][CH2:30][C@H:31]([NH2:38])[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:40]([C:43]1[C:44]([CH:56]=O)=[CH:45][C:46]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:47][CH:48]=1)([O-:42])=[O:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28](=[O:39])[CH2:29][CH2:30][C@H:31]([NH:38][CH2:56][C:44]2[C:43]([N+:40]([O-:42])=[O:41])=[CH:48][N:47]=[C:46]([O:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:45]=2)[CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: N[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCOCC1)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[[4-amino-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester (1.9 g, 3.5 mmol) and 5-nitro-2-phenoxy-pyridine-4-carboxaldehyde (0.86 g, 3.53 mmol) in 1,2 dichloroethane (100 mL) was stirred at room temperature for 4 hours, and then NaBH(OAc)3 (1.4 g, 6.6 mmol) was added. The resulting mixture was stirred at room temperature overnight. Then 1N NaOH was added, and the reaction mixture was then poured into EtOAc (200 mL). The organic layer washed with aq. NaCl, dried with MgSO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography (1:1 heptane/EtOAc) to yield 4-{(2-benzyloxy-ethyl)-[4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-amino}-cis-cyclohexanecarboxylic acid benzyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH:8]=[CH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.CN(P(N(C)C)(N(C)C)=O)C.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1C=CCOc2ccc(Br)cc21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1CC(c2ccccc2)COc2ccc(Br)cc21
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 7-bromobenzo[b]oxepin-5(2H)-one (1.33 g, 5.6 mmol), CuBr—SMe2 (60 mg, 0.3 mmol) and HMPA (2.058 g, 11.5 mmol) in THF (30 mL) was added phenylmagnesium bromide (3.0 M, 3.7 mL) at −78, the mixture was stirred at −78 for 1 hour. The mixture was quenched by HCl (10%, 5 mL), extracted with ethoxyethane, and then washed with NaHCO3, brine, dried over Na2SO4, concentrated and purified by column chromatography to give 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (300 mg, 17%). 1H-NMR(CH2D2): 3.11 (m, 2H), 3.49 (m, 1H), 4.28 (m, 2H), 6.93 (m, 1H), 7.17 (m, 1H), 7.23 (m, 4H), 7.45 (m, 1H), 7.83 (m, 1H)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH:16]=[C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH3:27])[C:18]=3[CH3:28])[O:14][C:13]2=[O:29])=[C:4]1[CH3:30])[CH3:2].[CH2:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[CH3:42])[CH3:32].OO>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:29])[O:14][C:15]([C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH2:31][CH3:32])[C:34]=3[CH3:42])([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH3:27])[C:18]=3[CH3:28])[CH:16]=2)=[C:4]1[CH3:30])[CH3:2]
Reactant: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Reactant: CCn1c(C)cc2ccccc21
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)(c3c(C)n(CC)c4ccccc34)OC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 5.5 g (0.0138 mole) of 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone, 8.0 g (0.05 mole) of 1-ethyl-2-methylindole, 100 ml of acetic anhydride and 0.25 ml of 30 percent hydrogen peroxide was stirred approximately eighteen hours at room temperature. The solid was collected by filtration and a small sample showed an infrared maximum at 1800 cm-1 and a smaller maximum at 1745 cm-1. The solid and the filtrate were recombined, and stirred eighteen hours at approximately 60° C. The solid was collected by filtration and dried at 60° C. in vacuo to obtain 3,5,5-tris(1-ethyl-2-methyl-3-indolyl)-2(5H)-furanone (Formula III: R=R2 =CH3CH2 ; R1 =R3 =CH3 ; Y=Y1 =H) as a white solid which melted at 232°-234° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OCCO2)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Br[C:18]([C:20]([F:23])([F:22])[F:21])=[CH2:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([C:20]([F:23])([F:22])[F:21])=[CH2:19])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: Fc1ccc(B2OCCO2)cc1C(F)(F)F
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 70 °C
Yield: 23.2 %

Procedure:
The mixture of 2-(4-fluoro-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (2.34 g, 10 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.10 g, 12 mmol), Pd(Ph3P)2Cl2 (0.281 g, 0.4 mmol) and K2CO3 (2.76 g, 20 mmol) in THF (30 mL) and H2O (15 mL) was heated at 70° C. overnight. Then the reaction mixture was cooled down to rt, added water and extracted with ethyl acetate, washed with brine, dried with Na2SO4, concentrated to dryness to afford the crude product. It was further purified by column chromatography eluted with PE to afford the desired product (0.6 g, yield 23.3%) as light yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.69-7.62 (m, 2H), 7.27-7.21 (t, 1H), 6.05 (d, 1H), 5.80 (d, 1H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22][C:23]2[C:24](B(O)O)=[CH:25][C:26]3[C:27]([CH3:36])([CH3:35])[CH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[C:31]=3[CH:32]=2)=[CH:19][CH:18]=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:6]=1[C:24]1[C:23]([O:22][CH2:21][C:20]2[CH:40]=[CH:41][C:17]([Cl:16])=[CH:18][CH:19]=2)=[CH:32][C:31]2[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:35])[C:26]=2[CH:25]=1
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)c(OCc3ccc(Cl)cc3)cc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C=CC(=O)O)ccc3O)c(OCc3ccc(Cl)cc3)cc21
Yield: 32.5 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 2.05 g (5.5 mmol) of 3-(4-chlorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained above, 590 mg (30%) of the expected compound were obtained in the form of a white solid having a melting point of 152°-154° C.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:21][NH:20][C:19](=O)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12][N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][C:9](=O)[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>COCCOC>[CH:1]1([CH:7]2[CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(=O)NCC(C3CCCCC3)NC(=O)CN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: C1CCC(C2CNCCNCCNCCNCCN2)CC1
Temperature: 25 °C
Reaction time: 39.5 h
Yield: 42 %

Procedure:
5-Cyclohexyl-1,10,13-tris(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecan-3,8-dione prepared as in Example 30D (4.841 g, 6.386 mmol) was placed in a 2-necked flask under argon. Dry 1,2-dimethoxyethane (dme, 100 ml) was added, giving a suspension. After placing the reaction flask in a cold water bath, lithium aluminum hydride in dme (0.5M, 100 ml, 50 mmol) was added over a 10 min period giving an almost clear solution. Additional dme (50 ml) was added and the flask was removed from the water bath and heating with a mantle was started. After a few minutes of heating, more lithium aluminum hydride solution (40 ml, 20 mmol) was added, and heating to reflux was continued. The solution quickly became yellow and opaque. Overnight the refluxed solution became mostly white and heterogeneous. After 39.5 h, the reaction mixture appeared milky with a slight tint of yellow. Heating was stopped and the reaction mixture was cooled to room temperature. It was quenched, after placing the reaction flask in a water bath, by careful addition of water (2.2 ml) over a 10 min period. The reaction was exothermic with gas evolution. Next, 15% aqueous sodium hydroxide solution (2.2 ml) was rapidly added, then water (6.5 ml). After stirring for 1 h, tetrahydrofuran (135 ml) was added with continued stirring. The mixture was thick with a white precipitate. Fifty min later the mixture was filtered under an inverted funnel through which N2 was flowing, and the filtrate was removed on the rotary evaporator to give a viscous liquid. After pumping on the vacuum line, this residue was recrystallized under argon from acetonitrile with cooling to -20° C. Three successive batches of a slightly sticky white solid were obtained which were combined and recrystallized from hexanes under argon with cooling to -20° C. to give 0.796 g (42% yield): mp 67°-69.5° C. (under nitrogen); 1H NMR (CDCl3) δ 0.84-1.32 (several m, 5 H), 1.40-2.0 (several m, 11 H), 2.28-2.46 (m, 2 H), 2.50-2.97 (several m, 17 H); Exact mass (M+H)+ : calcd, 298.2971; Found, 298.2973 (C16H36N5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1>[C:2]1([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:11]=2)[OH:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of bromobenzene (0.3 mol) in THF (300 ml) was added dropwise to a mixture of magnesium (0.32 mol) in THF (20 ml). The mixture was stirred and refluxed for 1 hour. A mixture of 4-biphenylcarboxaldehyde (0.3 mol) in THF (500 ml) was added dropwise. The mixture was stirred and refluxed for 2 hours, at room temperature overnight, poured out into a saturated NH4Cl solution and extracted with DCM. The organic layer was separated, washed three times, dried, filtered and the solvent was evaporated. The residue was triturated in hexane, filtered off and purified over silica gel on a glass filter (eluent: CH2Cl2 100%). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 31 g of (±)-α-phenyl(1,1′-biphenyl)-4-methanol (interm. 23).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].CS(O[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.O>COCCOC>[C:21]1([CH2:20][O:19][CH2:18][CH2:17][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1ccc(COCCOCCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
Sodium hydride (80% dispersion in oil, 1.68 g) was added portionwise to a solution of 2-pyridineethanol (6.88 g) in 1,2-dimethoxyethane (50 ml) and stirred under nitrogen for 18 h at room temperature. A solution of 2-(phenylmethoxy)ethanol methanesulphonate (8.25 g) in 1,2-dimethoxyethane (100 ml) was added and the mixture stirred at room temperature for 7 h, then poured into water (400 ml) and extracted with diethyl ether (3×200 ml). The ethereal extracts were washed with 2N hydrochloric acid (250 ml). The aqueous phase was re-extracted with diethyl ether (100 ml) and the aqueous phase carefully basified with 8% sodium bicarbonate to pH8. Extraction with diethyl ether (2×200 ml) and drying and evaporation in vacuo of the organic extracts gave an oil. Purification by FCC eluting with System F (4.1→1.1) gave the title compound (2.71 g) as an oil. T.l.c. (diethyl ether) Rf 0.54
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1>CC(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=1[Cl:3]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c(Cl)s1
Reaction time: 168 h

Procedure:
A solution of bromine (634 uL, 12.3 mmol) in AcOH (2.5 mL) was added dropwise to 5-chloro-2-thiophenecarboxylic acid (2 g, 12.3 mmol) and FeCl3 (399 mg, 2.50 mmol) in AcOH (25 mL) at 25° C. The reaction mixture was warmed to reflux where additional bromine (634 uL, 12.3 mmol) and FeCl3 (399 mg, 2.50 mmol) were added. After 7 d, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 242 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[OH-].[Na+].[H][H]>O.[Pd]>[OH:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
A solution of 3-benzyloxy-2-methylbenzoic acid (50 g, 0.21 mol) and sodium hydroxide (9 g, 0.225 mol) in 700 g of water and 2 g of 5% Pd/C catalyst (50% water-moist) are added to a 21 steel autoclave with an aerating stirrer. 10 bar of hydrogen are injected at a temperature of 50° C. and a stirring speed of 800 rpm. Consumed hydrogen is replaced by repeated injection. After 20 min, the absorption of hydrogen falls off. The catalyst is filtered off at room temperature by means of a pressure filter. 760.7 g of a crude solution are obtained, from which 7.7 g of toluene are separated off in a separating funnel. A total of 22.2 g of hydrochloric acid (37% strength) are added to the crude solution, then the solution is cooled to 0° C. The precipitated solid is filtered off with suction and washed twice with 50 g of water. After drying, 18.0 g of 3-hydroxy-2-methylbenzoic acid having a melting point of 147° C. are obtained. After concentration of the mother liquor, a further 9.6 g of substance can be obtained, such that the total yield is 27.6 g or 88.1% of theory.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH3:14])=[N:8][NH:9]2.O.NN>C(O)C.[Pd]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH3:14])=[N:8][NH:9]2
Reactant: Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2cccc(Oc3ccc(N)cc3F)c12
Temperature: 80 °C

Procedure:
75 mg (0.26 mmol) of 4-(2-fluoro-4-nitrophenoxy)-3-methyl-1H-indazole (from example II) are dissolved in 3 ml of ethanol, and 261 mg (5.22 mmol) of hydrazine hydrate and 10 mg of 10% palladium on activated carbon are added. The mixture is heated at 80° C. for two hours and then filtered through kieselguhr. The filtrate is concentrated under reduced pressure.