Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]1=[O:19]>C1COCC1.[Cl-].[NH4+].[Zn]>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH2:2][C:3]1=[O:19]
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reaction time: 3 h

Procedure:
Zinc (100 g, 1.54 mol) was added to a solution of 3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueous ammonium chloride (220 mL). After 3 h, the reaction was filtered and concentrated in vacuo. The residue was partitioned between EtOAc and H2O which resulted in the formation of a white precipitate. Both layers were filtered through a Celite pad and the layers were separated. The aqueous layer was washed with EtOAc (2×) and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated. The crude product was filtered through a plug of silica gel eluting with EtOAc:CH2Cl2-1:9 and the eluant was concentrated under reduced pressure to provide the title compound. MS: m/z=265 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.O1CCOCC1>[CH2:18]([O:25][C:26]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1

Procedure:
A 1L 3-neck flask was charged with 25.09 (160 mmol) trans-4-aminomethyl-cyclohexanecarboxylic acid, 77.4 g (560 mmol) K2CO3, 250 mL dioxane and 250 mL water. The suspension was stirred, then 28.5 mL (200 mmol) benzylchloroformate was added dropwise. The reaction mixture was then stirred at room temperature for 6.5 hours then poured into 800 mL water and acidified (slowly) with 1N HCl. The resulting white precipitate was filtered and dried-45.6 g.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46]>CN(C)C=O.C(OCC)(=O)C>[CH2:46]([N:22]1[C@@H:19]2[C@H:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C@@:16]1([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:15]([O:14][CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=1)[CH2:21][CH2:20]2)[CH:45]=[CH2:44]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 2.1 g, 4.0 mmol), potassium carbonate (1.7 g, 12.0 mmol) and allyl bromide (0.42 ml, 4.8 mmol) in dimethylformamide (10 ml) were stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and washed with water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10% ethyl acetate/iso-hexane, (1.8 g, 80%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1.[C:17](OC=C)(=[O:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(CC(C)C)=O>[C:17]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3]1)(=[O:19])[CH3:18]
Reactant: COc1cccc(CC2=CC(O)CC2=O)c1
Reactant: C=COC(C)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Product: COc1cccc(CC2=C[C@H](OC(C)=O)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone (9 g, 41.26 mmol) was dissolved in isobutyl methyl ketone (90 mL), and vinyl acetate (8.4 g, 97.57 mmol) and Lipase derived from Pseudomonas cepacia (0.9 g) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the Lipase and the filtrate was evaporated. The resulting residue was dissolved in PhCH3 (150 ml), and triphenylphosphine (6.5 g; 24.78 mmol) and AcOH (1.61 g, 26.81 mmol) were added to the solution. Then diisopropylazodicarboxylate (5 g, 24.72 mmol) was added to the mixture at 5° C. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-methoxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 10 g (yield: 93%, 95% ee by HPLC using a chiral column)
Reaction SMILES: C1C([N+]([O-])=[O:8])=CC=C(O)C=1.[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[C:18]([NH:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
The above product (0.75 g, 0.0024 mole) is dissolved in 50 ml ethyl acetate. This is cooled to -5° C. and p-nitrophenol is added followed by the portionwise addition of dicyclohexylcarbodiimide. The reaction mixture is stirred at -5° C. for 2 hours. The formed dicyclohexylurea is filtered off. After concentrating to a 10 ml volume, the reaction mixture is cooled overnight. More dicyclohexylurea is formed. This is filtered and the filtrate is concentrated in vacuo to yield 0.95 g of active ester, (the p-nitrophenyl ester of N-[N-[2-(mercaptomethyl)-4-methyl-1-oxopentyl]glycyl]glycine).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])(=O)=O.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([O:16][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[CH:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-[1,1′-biphenyl]-2,4-diol (14.6 g) and 2,6-dimethylpyridine (10.2 mL) in toluene (100 mL) was added triisopropylsilyl trifluoromethanesulfonate (21.1 mL) at −15° C., and the mixture was stirred at −15° C. for 20 min. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a white amorphous solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added morpholine (30 μL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 40.3 mg of the title compound (70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:10][Mg]Br.CCOCC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH3:10]
Reactant: O=Cc1ccncc1Br
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1ccncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-bromo-pyridine-4-carbaldehyde (2.0 g, 10.8 mmol) in dry THF (45 mL) is added methyl magnesium bromide solution in Et2O (3M; 3.9 mL, 11.8 mmol). The mixture is stirred at 0° C. for 1 h then warmed and stirred at room temperature for 1 h. Saturated aqueous NH4Cl solution is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to afford 2.1 g of 1-(3-bromo-pyridin-4-yl)-ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH:7]([CH2:14][CH2:15][CH3:16])[CH2:6]2.[Br:17]Br.C1CCN2C(=NCCC2)CC1>CC#N>[Br:17][C:8]1[C:7]([CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[OH:13]
Reactant: CCCC1CC(=O)c2ccc(OC)cc2C1
Reactant: BrBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCc1cc2cc(OC)ccc2c(O)c1Br

Procedure:
Treatment of 6-(methyloxy)-3-propyl-3,4-dihydro-1(2H)-naphthalenone (93) (0.50 g, 2.29 mmol) with bromine followed by DBU in CH3CN gave 0.62 g of compound 94 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=7.4 Hz, 3H), 1.65-1.75 (m, 2H), 2.79 (t, J=7.7 Hz, 2H), 3.90 (s, 3H), 6.06 (s, 1H), 7.00 (d, J=2.4 Hz, 1H), 7.08 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.17 (s, 1H), 8.07 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 295 (M+H)+, m/z 293 (M−H)−.
Reaction SMILES: [C:1]1([CH2:11][NH:12][CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:25]=[N:24][CH:23]=2)[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>C(Cl)Cl>[CH3:48][O:47][C:45]([N:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[CH:25]=[N:24][CH:23]=1)[C@@H:15]([CH3:18])[CH2:16][CH3:17])=[O:46]
Reactant: COC(=O)Cl
Reactant: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CN(Cc1cccc2ccccc12)C(=O)OC)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 2 (40 mg, 0.083 mmol) in CH2Cl2 (1 ml) and triethylamine (24 μl, 0.17 mmol) at 0° C. was added methyl chloroformate (39 μl of a 2.1 M solution in CH2Cl2, 0.082 mmol). The reaction was stirred at room temperature for 3 hr, the solvent evaporated in vacuo and the residue purified by preparative HPLC (C-18; 95:5 to 5:95 water:CH3CN containing 0.1% trifluoroacetic acid; gradient elution). Lyophilisation of the collected fractions afforded the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][O:18][CH3:19])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 97.3 %

Procedure:
Potassium carbonate (2.4 g, 17.3 mmol) was suspended in N,N-dimethyl formamide (15 mL). 4-bromophenol (1.00 g, 5.78 mmol) and 1-bromo-2-methoxyethane (0.964 g, 6.94 mmol) were added into the reaction sequentially and the resulting mixture was stirred at 60° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and evaporated to give the title compound (1.3 g, 99%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC>C(Cl)Cl>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:5]4[O:4][C:3]([N:2]([CH3:1])[CH2:13][CH:14]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]5)=[N:7][C:6]=4[CH:8]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(C5CCCCC5)cc4)ccc3o2)C1
Yield: 49.4 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.040 g, 0.154 mmol), 4-cyclohexylbenzoic acid (0.047 g, 0.230 mmol), HATU (0.058 g, 0.154 mmol), polystyrene-bound diisopropylamine (0.385 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (20 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography (12 g column, eluting with 10% 2M NH3 in MeOH/CH2Cl2) to yield a colorless oil. The oil was dissolved in CH2Cl2 and hexane added. The mixture was concentrated and dried under high vacuum to yield the desired product as a white solid (0.034 g, 50%). mass spectrum (m/e): 447.3 (M+1). 1H NMR (400 MHz, CD3OD): δ 7.89-7.85 (m, 2H), 7.71 (d, J=2.0 Hz, 1H), 7.39-7.28 (m, 4H), 3.59 (m, 2H), 3.23 (s, 3H), 2.83-2.58 (m, 6H), 2.39 (s, 3H), 2.13-2.01 (m, 1H), 1.94-1.84 (m, 4H), 1.83-1.76 (m, 1H), 1.67-1.57 (m, 1H), 1.57-1.41 (m, 4H), 1.40-1.28 (m, 1H).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[C:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=[CH:9][CH:8]=1.[Cl-].[NH4+].CCCCCC>O1CCCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:20])([CH3:19])[O:16][C:17]2=[O:18])[C:1]#[C:2][CH3:3])=[CH:22][CH:23]=1
Reactant: CC#C[Mg]Br
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0.5M tetrahydrofuran solution of 1-propynylmagnesium bromide (800 mL) was added dropwise a solution of 5-(4-hydroxybenzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dion e (47.3 g) obtained in Substep 1 in tetrahydrofuran (650 mL) under argon atmosphere at 11° C. over 40 minutes, followed by stirring the reaction mixture at room temperature for 1 hour. Then, to the reaction mixture were added successively aqueous ammonium chloride solution (34 g/l L) and hexane (1 L), followed by removing the organic layer. After adding saturated aqueous potassium hydrogen sulfate solution to the aqueous layer and adjusting a pH to 1, the aqueous layer was extracted with ethyl acetate twice. The organic layer was dried and concentrated to give 5-[1-(4-hydroxyphenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxan e-4,6-dione (54.8 g).
Reaction SMILES: [Cl:1][C:2]1[C@H:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH:7]=1.[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12]>>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11](=[NH:12])[O:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH:7]=[C:2]1[Cl:1]
Reactant: O[C@@H]1CCCC=C1Cl
Reactant: N#CC(Cl)(Cl)Cl
Product: N=C(O[C@@H]1CCCC=C1Cl)C(Cl)(Cl)Cl

Procedure:
In Scheme A step c, (R)-2-chloro-cyclohex-2-enylalcohol is contacted with trichloroacetonitrile to give (R)-2,2,2-trichloro-1-(2-chloro-cyclohex-2-enyloxy)-ethylideneamine.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1.Cl>C1COCC1>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.9 %

Procedure:
Cinnamoyl chloride (89.2 g, 535 mmol) was dissolved in THF (170 mL) and added dropwise to a 0° C. solution of 2-fluoroaniline (54.1 g, 486 mmol) and pyridine (39.35 mL, 486.5 mmol) dissolved in THF (170 mL). The mixture was allowed to warm to ambient temperature after the addition and stirred for 15 hours. A solution of 2M HCl was added (1250 mL) and the mixture was stirred at ambient temperature for 8 hours, during which the initial oil solidified to a light pink solid. This material was collected by filtration, washed with several portions of water, and air-dried to provide the desired product (119.5 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([O:14][CH3:15])[CH:6]=1.CCOC(C)=O>CN(C=O)C>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(SC)ccc1C(C)=O
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
Sodium thiomethoxide (3.35 g, 47.8 mmol) was dissolved in dry DMF (35 ml) under a blanket of nitrogen. The solution was cooled to −15° C. and 1-(4-fluoro-2-methoxyphenyl)ethanone (6.7 g, 39.8 mmol) was added in portions. After 10 min at −15° C. the reaction mixture was brought to 0° C. for 1.5 h. EtOAc was added and the organic phase was washed three times with aqueous HCl (10%), dried (Na2SO4) and evaporated under reduced pressure to dryness. Purification by flash column chromatography (isooctane/EtOAc 4:1) gave the pure title compound (6.3 g, 81%). MS m/z (rel. intensity, 70 eV) 196 (M+, 37), 182 (11), 181 (bp), 166 (7), 138 (10).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered into this solution then at a pH of 10.5, over the course of three hours, were 70.2 g (0.5 mol) of benzoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol), and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution) and adjusted to a pH of 1.5 to 3 at 65 to 70° C. using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.) and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 119.1 g (98.3% of theory). According to HPLC and NMR measurement, the product was free from benzoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].[Cl:7][C:8]([Cl:12])([Cl:11])[C:9]#[N:10]>CCOCC>[Cl:7][C:8]([Cl:12])([Cl:11])[C:9](=[NH:10])[O:6][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCO
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 80% sodium hydride (945 mg., 31.5 mmol.; washed twice with 25 ml. of hexane) in dry. ether (30 ml.) was treated dropwise with a solution of 2-propen-1-ol (21.4 ml., 18.3 g., 315 mmol.), in dry ether (45 ml.), stirred for 20 minutes at room temperature under argon and then cooled to 0° C. (ice-salt bath). Trichloroacetonitrile (30 ml. or 42.3 g., 0.30 mole) was added over a period of 15 minutes and the brownish solution was stirred at 0° C. for 40 minutes, at 10° C. for 10 minutes and at room temperature for 10 minutes. The reaction mixture was concentrated to a syrup, treated with a solution of methanol (1.2 ml.) in pentane (30 ml.) and stirred vigorously for 5.0 minutes. The light brown precipitates were filtered off, washed with pentane (2×30 ml.) and the combined flitrates concentrated down to a light brown liquid. The liquid was redissolved in pentane (30 ml.), stirred for a few minutes, and the resulting suspension filtered, and the precipitates obtained washed with pentane (30 ml.), repeating the procedure at least one more time. The clear filtrate was concentrated and dried in vacuo to give 54.0 g. of title compound as a light red-colored liquid. This material was stored as a solution in hexane at 10° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[K+]>CO>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCCBr)cc1
Yield: 39.4 %

Procedure:
As expressed in the following reaction scheme, hydroquinone (1) (4.5 g) and 1,6-dibromo hexane (2) (10 g) were dissolved in methanol (100 ml) at room temperature. Adding potassium hydroxide (2.3 g) to the mixture solution, the resulting solution was refluxed at 60° C. overnight. Then, after lowering the solution to room temperature and evaporating methanol, the product was extracted three times with water (100 ml) and ethyl acetate (100 ml). After removing water with magnesium sulfate and evaporating the solvent, the product was refined by column chromatography (eluent: ethyl acetate/hexane=1/5) thereby obtaining 4.4 g of 4-(6-bromohexyloxy)phenol (3).