Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C1C[O:17][CH2:16]C1.[Li]CCCC.CN(C=O)C>CCOC(C)=O>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:16]=[O:17])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:9][CH2:8]1
Reactant: Cc1cc(Br)cc2c1OCC2(C)C
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen flushed 50 mL round bottom flask were added 5-bromo-3,3,7-trimethyl-2,3-dihydro-1-benzofuran (0.11 g, 0.46 mmol) and THF (3 mL). A solution of n-BuLi (0.20 mL, 2.5 M solution in hexanes) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then DMF (0.053 mL, 0.68 mmol) was added. The reaction mixture was allowed to warm to room temperature. EtOAc (20 mL) and wet silica gel (5 g silica gel/0.5 mL of water) were added. The resulting mixture was stirred at room temperature for 10 minutes and then filtered. The resulting solid was rinsed with EtOAc. The filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (40 mg) as colorless solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:12][CH:13]=[CH2:14])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].O>CO.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:6]([O:12][CH:13]=[CH:14][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC(=C)C
Reactant: C=COC(=O)C(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: O
Product: C=CC(C)CC=COC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
(Benzene)ruthenium dichloride dimer (14 mg, 0.056 mmol Ru), silver triflate (20 mg, 0.078 mmol) and 2,2-methylenebis(4-phenyl-2-oxazoline) (17.8 mg, 0.058 mmol) were dissolved in 2 ml of methanol. To the mixed solution were added isoprene (2 ml) and vinyl pivalate (1 ml) and the mixture was stirred under heat at 100° C. for 10 hours. The resulting product was poured into water and the separated organic layer was subjected to a GLC analysis. As a result, it was confirmed that a co-dimer was produced with the conversion rate being 72% and the ratio of an isomer being 4:1.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][C:44]=1[F:52]>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[C:44]([F:52])[CH:45]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)c(F)c2)c1
Yield: 40 %

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 4-chloro-3-fluorophenylboronic acid. LC/MS indicated a purity of 92% as measured by UV 214 nM. Yield: 40% (after two steps)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([OH:27])=[O:26])[C:5]2[O:10][C@@H:9]([CH2:11][O:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:8][O:7][C:6]=2[CH:23]=1.[N+:28]([O-])([OH:30])=[O:29]>ClC(Cl)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N+:28]([O-:30])=[O:29])=[C:4]([CH2:24][C:25]([OH:27])=[O:26])[C:5]2[O:10][C@@H:9]([CH2:11][O:12][S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH2:8][O:7][C:6]=2[CH:23]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(Cl)cc(CC(=O)O)c3O2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(Cl)c([N+](=O)[O-])c(CC(=O)O)c3O2)cc1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To 3.0 g (7.3 mmole) of (R)-(7-chloro-3-(toluene-4-sulfonyloxymethyl)-2,3-dihydro-benzo(1,4)dioxin-5-yl)-acetic acid in 50 of dichloroethane in an ice/water bath was added a solution of 3.6 ml (85 mmole) of nitric acid (sp. gr. 1.49) in 50 ml of dichloroethane. The mixture was allowed to come to room temperature and stir overnight. Ice was added to quench the reaction and the mixture was diluted to 300 ml with methylene chloride, washed with water and with saturated brine and dried over sodium sulfate. Concentration in vacuum gave 2.8 g of the title compound as an off-white solid. 1H (DMSO-d6) broad singlet, 12.75 δ (1 H); doublet, 7.80 δ (2 H); doublet, 7.45 δ (2 H);.singlet, 7.15 δ (1 H); multiplet, 4.60 δ (1 H); multiplet, 4.37 δ (2 H); multiplet, 4.15 δ (2 H); singlet, 3.45 δ (2H); singlet, 2.40 δ (3 H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][CH:16]([OH:24])[CH2:17][CH2:18]1)[C@H:13]([OH:26])[CH2:12]3)([O:3][CH3:4])=[O:2].BrN1C(=O)CCC1=O>O1CCOCC1.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=[O:26])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](O)[C@@]4(O)CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 17β-Carbomethoxy-3,β,5α,6β-trihydroxy-androstane (43.5 g, 0.24 mol), as prepared in example 16, in 450 mL of dioxane is diluted with 50 mL of water, and maintained at 25° C. by means of an external cooling bath. To this suspension is added N-bromosuccinimide (22.5 g, 0.25 mol). The mixture is stirred for 8 h. The mixture is cooled in an ice bath and the solid collected by filtration, washed with 50% methanol/water, and air dried to afford 17β-carbomethoxy-6-oxo-3β,5α-dihydroxy-androstane as a white solid, mp 258°-260° C. Anal. Calcd. for C21H32O5 : C, 69.20; H, 8.85. Found: C, 69.38; H, 8.92.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[Cl:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[Cl:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:40][CH3:39])=[O:3])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-N-methyl 3-phenyl-acrylamide CCXVI was prepared from 3-(3-chloro-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [N:1](/[C:4](=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[C:23]1([P:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1/[CH:12]=[CH:11]/[CH:10]=[C:4](/[N:1]=[P:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Add, dropwise, a solution of 5 g of ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate (16.5 mmol) in 60 mL of DCM to a solution of 4.37 g (16.7 mmol) of triphenylphosphine in 40 mL of DCM. Stir the reaction mixture for 2 h at RT, then concentrate under reduced pressure. Solidify the residue obtained in 100 mL of isopropyl ether, then filter on a frit and rinse with 50 mL of isopropyl ether, giving 7.9 g of ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoate in the form of a white solid.
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH2:31]([SH:33])[CH3:32].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1.C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:33][CH2:31][CH3:32])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Reactant: CCS
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CSCC)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step L, 100 mg, 0.224 mmol) was azeotroped three times in benzene on a rotary evaporator. The residue was dissolved in toluene and transferred to a reaction vessel. The vessel was flushed with argon. Ethanethiol (33.1 μl, 0.447 mmol) was added followed by cyanomethylenetributylphosphorane (216 μl, 0.894 mmol). The vessel was sealed and the solution was heated to 100° C. for 4 h. The reaction mixture was diluted with DCM (10 ml) and Si-maleimide (Silicycle, 2.1 g; 0.66 mmol/g; 40-63 microns) was added to scavenge excess thiol. After stirring for about 1 h, the mixture was filtered and the silica gel was rinsed with DCM. The filtrate was concentrated on a rotary evaporator. The residue was dissolved in DCM and loaded directly onto a dry 12 g gold-capped Redisep® column (Teledyne Isco, Lincoln, Nebr.). The column was eluted with a gradient of 0 to 5% MeOH:DCM. The fractions containing the desired product were combined and concentrated to afford the title compound as a colorless film.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Cl[Sn]Cl.O.[CH3:15][CH2:16][O:17]C(C)=O>ClCCCl>[C:16]([C:5]1[NH:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([Cl:1])[CH:6]=1)(=[O:17])[CH3:15]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1[nH]c(C(C)=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) was added to a suspension of SnCl2 (0.238 g, 1.25 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) at 0° C. The reaction was stirred for 10 min. at 0° C. then warmed to room temp over 2 hours. The reaction mixture was poured into water and EtOAc and the organic layer was separated, then washed with 1N sodium hydroxide, dried over MgSO4, filtered and evaporated to a residue. Purification was accomplished on silica with EtOAc and hexanes to afford the title compound (0.034 g, 26%) as a solid, along with methyl 4-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.047 g, 37%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (br. s., 1H), 6.79 (s, 1H), 3.89 (s, 3H), 2.43 (s, 3H). LCMS: m/z 200.0 (M−1).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCO
Product: CCCCCCCCCOC(=O)Cl

Procedure:
288 Parts of nonanol are reacted with phosgene in a similar way to the method described in Example 6 to give 342 parts of nonyl chloroformate as a colourless liquid b.p. 70° C. at 1 mm pressure.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.Cl.C[NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][O:34][CH3:35])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.2 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in dichloromethane (10 ml), N,O-dimethyl hydroxylamine hydrochloride (38 mg; 0.45 mmol) added followed by triethylamine (0.16 ml; 1.1 mmol). The resulting mixture was stirred at ambient temperature for 18 h. The mixture was evaporated to dryness under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The title compound (4 mg; 4%) was obtained by high performance liquid chromatography. 1H NMR (250 MHz; CD3OD) δ: 3.74 (3H, s), 6.00 (2H, s), 6.94 (1H, d,), 7.04-7.08 (2H, m), 7.50-7.70 (2H, m), 7.85 (2H, d), 8.00-8.20 (3H, m), 8.59 (1H, d); m/z (ESMS): 415.1 [M+H]⊕.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C:3]=1[O:4][CH2:5][C:6]#[N:7].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:15]=2)[C:3]=1[O:4][CH2:5][C:6]#[N:7]
Reactant: Cc1cccc(COc2cccc(O)c2)c1OCC#N
Reactant: OCCc1ccccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(COc2cccc(OCCc3ccccn3)c2)c1OCC#N
Reaction time: 2 h

Procedure:
To a solution of [2-methyl-6-(3-hydroxy-phenoxymethyl)-phenoxy]-acetonitrile (135 mg, 0.5 mmol, example 25) and 2-(pyridin-2-yl)-ethanol (126 mL, 0.94 mmol) in THF (2 mL) is added triphenylphosphine (262 mg, 1 mmol) followed by DEAD (118 mL, 0.75 mmol). The resulting solution is stirred for 2 h, then concentrated and the residue purified by flash chromatography (silica, 50% ethyl acetate in hexanes) to give the title compound as an oil. MS (ESI) 375 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[BH4-].[Na+]>CO>[CH3:16][Si:2]([CH3:1])([CH3:15])[C:3]#[C:4][CH:5]([OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(=O)C#C[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(O)C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 200 ml of methanol was added 10 g (41.93 mmol) of the product of Example 5. The reaction mixture was cooled to 0° C. and 0.53 g (14 mmol) of NaBH4 was added portionwise over 5 minutes. After an additional 15 minutes, the reaction was quenched with acetone and the solvent removed under reduced pressure. The residue was partitioned between water and diethyl ether. The aqueous layer was extracted one additional time with diethyl ether and the combined organic extracts were washed 1x with brine and then dried (MgSO4). Thin layer chromatography indicated the crude product to contain both the titled product and its unsilylated analogue. This was used in the next step without further purification.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CC/C=C\CCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C\CCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
Cis-11-tetradecen-1-ol (1 g, 4.72 mmol) and carbon tetrabromide (1.56 g 4.72 mmol) were dissolved in dichloromethane (3 ml) and the solution was cooled in ice bath. A solution of triphenylphosphine (1.24 g, 4.72 mmol) in 2 mL of dichloromethane was added dropwise. After stirring at 0° C. for 15 minutes and at room temperature for 3 h, the solvent was evaporated and the residue was diluted with ether. The ether solution was filtered and concentrated and purified using column chromatography on silica gel eluting with hexane:ethyl acetate (3:1) to give 0.23 g of (Z)-14-bromo-3-tetradecene.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CC(C)[O-].[Ba+2:13].CC(C)[O-]>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Ba+2:13]
Reactant: Oc1ccccc1O
Agent: CC(C)[O-]
Agent: [Ba+2]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (1.37 g, 12.5 mmol) and toluene (25 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, barium(II) isopropoxide (3.20 g (12.5 mmol)) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (catechol-barium complex) was greenish gray in color. The yield amount was 3.08 g (12.5 mmol), and the yield percentage was 100%. Catechol-barium complex was dissolved into acetylacetone until saturated, and then filtered to be used as a coating liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]([O:19][CH3:20])[C@H:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[I:18])[N:8]=1.[CH3:24][O:25]C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[C@@H:4]([CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]([O:19][CH3:20])[C@H:7]([CH2:9][C:10]2[CH:15]=[C:14]([CH:24]=[O:25])[C:13]([O:16][CH3:17])=[CH:12][C:11]=2[I:18])[N:8]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc(OC)cc1I
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(C=O)c(OC)cc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
Formylation of compound 21 by dichloromethyl methyl ether in the presence of stannic chloride was carried out by a known method [(A. H. Lewin, S. R. Parker, N. B. Fleming, and F. Carroll, “Formylation of Arenes by α,α-Dichloromethyl Methyl Ether. An Improved Experimental Procedure” Org. Prep. Proced. Int., 10, pp 201-204 (1978)]. The pyrazine derivative 21 (100 mg, 0.23 mol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0° C. and a 1M solution of SnCl4 (2.6 mL, 2.6 mol) was added drop wise under argon. After completion of the addition of SnCl4, 1,1-dichloromethyl methyl ether (0.21 mL, 2.32 mmol) was added drop wise to the reaction mixture. The solution turned from light yellow to greenish brown upon the addition of the dichloro derivative. The resulting mixture was stirred for 45 min at 0° C. A saturated solution of ammonium chloride (2 mL) was added to quench the reaction and the light brown suspension that resulted was stirred for 30 min at room temperature. The mixture was then extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated, resulting in an oily product. Flash chromatographic purification of this product provided pure 2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2′-iodo-4′-methoxy-5′-formylbenzyl)-(2R,5S)-pyrazine (22) as a yellow oil (51 mg, 48%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[C:8]1([C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Clc1cc(C2=CCCCC2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(C3=CCCCC3)nc3c2CCC3)cc1
Yield: 38.3 %

Procedure:
Following general procedure B1, 4-chloro-2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (1.03 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.150 g, 0.84 mmol) to afford the title compound (0.121 g, 31% over two steps) as an orange oil. MW=376.49. APCI MS m/z 377 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[CH3:32][N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
A solution of Compound 140 (0.100 g, 0.28 mmol) in dichloroethane was added with acetic acid (0.48 mL, 0.84 mmol) and 1-methyl-4-piperidone (0.84 mL, 0.68 mmol). After 20 minutes, the mixture was added with sodium triacetoxyborohydride (0.0827 g, 0.39 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-ethanol to obtain Compound 141 (0.0767 g, 0.17 mmol, 59%).