Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C(Cl)Cl>[CH2:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (10 g., 0.099 mole) and N,N-diisopropylethylamine (87 ml., 0.495 mole) were dissolved in methylene dichloride (200 ml.). The solution was cooled (ice bath) and protected from atmospheric moisture (drying tube), and benzyl chloroformate (14.1 ml., 16.9 g., 0.099 mole) was added over 2 hrs. Water (20 ml.) was added and the solvents were evaporated in vacuo (approx. 1 mm. pressure, solid CO2 cold finger condenser). The residue was shaken together with water (200 ml.) and ethyl acetate (200 ml.), and the mixture was separated. The organic phase was washed with water (4×50 ml.), dried (Na2SO4), and the solvent evaporated to give 1-benzyloxycarbonyl-4-hydroxypiperidine as a colourless oil, I.R.λmax 3800 cm.-1 and 1685 cm.-1.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].C(O)(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)=CCCC(C)CC=O

Procedure:
Prior to the biotransformation, 0.5 ml of permeabilized cells were vortexed with 0.15 ml toluene in 2 ml screw capped glass vials and incubated for 10 min at room temperature. The other components were then added to give 1 ml of aqueous phase with the same composition as the aqueous/NADPH system, with only citral and isopropanol omitted. The reaction was started by addition of 0.05 ml of 0.4 M citral in toluene and the vials were turned vertically on a wheel at 30° C. After 3 h the complete sample was extracted with 0.4 ml freshly prepared solution of 0.15% [v/v] 1-octanol (internal GC standard) in chloroform. After centrifugation 0.4 ml of the lower organic phase (toluene/chloroform mixture) was removed for GC analysis. Strains that formed citronellal were compared in a toluene and a methyl tertiary-butylether (MTBE) two-phase system as detailed below.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:33])[NH:27][C@@H:28]([CH3:32])[CH2:29][O:30][NH2:31])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:33])[NH:27][C@@H:28]([CH3:32])[CH2:29][O:30][NH:31][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: C[C@@H](CON)NC(=O)OC(C)(C)C
Product: C[C@@H](CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 87 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) of Example 9 or 16 and (S)-tert-butyl(1-(aminooxy)propan-2-yl)carbamate (550 mg) described in Reference Example 19, 585.6 mg of the title compound was afforded (yield 87%).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH2:2][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1

Procedure:
In 100 ml of ethanol was dissolved 4.2 g (1.1 eq.) of sodium, and a mixture of 25.0 g of 4-methoxyacetophenone and 27 ml (1.2 eq.) of diethyl oxalate was added dropwise under reflux. After 2 hours' reflux, the resulting crystals were collected by filtration. After 200 ml of 1N hydrochloric acid was added, the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off. The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH2:12][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
With cooling with ice, 4.00 g (0.10 mol) of 65% oily sodium hydride was added to a DMF solution (200 ml) of 7.51 g (0.05 mol) of 4′-methoxyacetophenone and 8.77 g (0.06 mol) of diethyl oxalate, and stirred overnight at 100° C. in a nitrogen atmosphere. Aqueous 2 N hydrochloric acid solution was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water, dried and then concentrated under reduced pressure. Thus concentrated under reduced pressure, the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 12.52 g (yield: 100%) of ethyl 4-(4-methoxyphenyl)-2,4-dioxobutyrate as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]1)(=[O:4])=[O:3].CO.Cl>[Pd].CCOC(C)=O>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)Nc1ccccc1N1CCNCC1

Procedure:
To a round-bottomed flask equipped with stirring was added (methylsulfonyl){2-[4-benzylpiperazinyl]phenyl}amine (42 g, 120 mmol), MeOH, 10% Pd/C (Aldrich)(25 g), and HCO2NH4 (38 g, 610 mmol). After heating at reflux for 2 h, the mixture was filtered through Celite® and washed with CH2Cl2. The combined organic layers were washed with NaHCO3 and concentrated in vacuo to afford a light yellow solid. This was treated with a soln of EtOAc and HCl to afford the salt of the desired compound as the hydrochloride salt (20 g). MS (ESI, pos. Ion) m/z: 256 (M+H); MS (ESI, neg. Ion) m/z: 254 (M−H). Calc'd for C11H17N3O2S: 255.10.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:14]([NH2:16])=O>CC(C)=O>[O:5]=[C:4]1[C:3]2[C:2](=[CH:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=2)[N:1]=[CH:14][NH:16]1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: NC=O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2c(=O)[nH]cnc2c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-amino terephthalic acid (2 g, 11 mmol) and formamide (10 mL) was heated at 180° C. for 5 h. The reaction mixture was cooled to RT and acetone was added. The solid precipitated thus obtained was stirred for 2 h, filtered and dried to give 4-oxo-3,4-dihydroquinazoline-7-carboxylic acid in 80% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[N+:13]([O-])=O)[CH:2]=[CH2:3].[Sn](Cl)Cl>C(O)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH2:13])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: C=CCOc1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 1-allyloxy-5-cyano-2-nitrobenzene (3.6 g, 17.46 mmol) and tin (II) chloride (19.7 g, 87.3 mmol) in ethanol (100 ml) was stirred overnight at rt. The solvent was removed under reduced pressure. The reaction mixture was partitioned between 5% NaHCO3 and ethyl acetate. The mixture was filtered to remove the tin salts and the aqueous was further extracted with ethyl acetate (×4). The combined organic phases were washed with water and brine, dried over MgSO4 Removal of solvent at reduced pressure gave a brown solid (2.82 g) which was recrystallized from t-butyl-methylether/hexane to give the title compound as a pale brown solid. (2.63 g, 93%) MS(ES+) m/e 175 [M+H]+; MS(ES−) m/e 173 [M−H]−;
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1)([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[H-].[Na+].O>COCCOC>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][CH2:11][C:12]1=[O:14])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (5.9 g, 14.6 mmol) in dry 1,2-dimethoxyethane (120 mL) under an argon atmosphere was added sodium hydride (80% suspension in mineral oil, 1.05 g, 43.8 mmol). The mixture was heated to reflux for 4.5 h, then was cooled to room temperature and was stirred for 16 h. Water was added and the reaction mixture was partitioned between ether and acidic water. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a white foam (4.9 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccc(C)nc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)[n+]([O-])c1

Procedure:
Following a literature procedure (Koncewicz, J. and Skrowaezewska, Z., Politec. Wroclaw Rocz. Chem., 1968, 42, 1873-85 (Chem. Ab., 70, 114972u (1968))) 2,5-dimethylpyridine was dissolved in 400 ml glacial acetic acid and 30% hydrogen peroxide (55 mL) was added slowly. The mixture was heated to 70° C. for 48 hours, with addition of more hydrogen peroxide (55 mL) at 5 hours and 20 hours. The reaction mixture was cooled, diluted with water, and the solvents removed to give 141 g of crude 2,5-dimethylpyridine-N oxide as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:14]([CH3:13])(=[O:16])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Yield: 101.8 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (1 g, 4.17 mmol) was treated with methanesulfonyl chloride (480 μl, 6.25 mmol) according to the method described in Preparation 15b to give 1.35 g (97% yield) of the title compound. Purity 96%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Yield: 68.4 %

Procedure:
The title compound (1.95 g, 68% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloro-6,7-dimethoxyquinoline (2.04 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 376 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To trans-tert-butyl-4-(hydroxymethyl)cyclohexylcarbamate (8.0 g, 34.9 mmol) in DCM (180 mL) and DMSO (60 mL) at 0° C. is added DIPEA (24.37 mL, 140 mmol) and pyridine sulfur trioxide (22.21 g, 140 mmol) dissolved in DMSO (60 mL). The mixture is stirred at room temperature for 15 minutes and then is partitioned between 1M HCl and diethylether. The organic phase is separated and washed with 1M HCl, water then saturated brine. The mixture is dried (MgSO4) and solvent evaporated to give the expected product; [MH+MeCN]+ 269.
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][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:23]([C:34](O)=[O:35])[CH2:22]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>C1COCC1>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C@H:23]([CH2:34][OH:35])[CH2:22]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: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1CO
Temperature: 0 °C
Yield: 57.6 %

Procedure:
(2S,4S)-4-(2-([1,2,4] triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.250 g, 0.511 mmol) and THF (5.0 mL) was stirred for 10 minutes (until solution was complete) and cooled to 0° C. BH3—SMe2 (0.242 mL, 2.55 mmol) was added and the mixture was warmed to ambient temperature and for 48 hours. The reaction was carefully quenched with MeOH (1 mL) and concentrated. The residue was taken up in CH2Cl2 (20 mL), water (5 mL) and saturated aqueous Na2CO3 (5 mL). The layers were mixed and separated and the aqueous phase was washed with CH2Cl2 (10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting solid was slurried in 25% CH2Cl2/Et2O and filtered to provide 0.140 g (57%) of the desired product as a yellow solid.
Reaction SMILES: [Na].[C:2]([C:5]1[N:10]=[C:9]([P:11](=[O:30])([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[N:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:8]=[CH:7][CH:6]=1)([OH:4])=[O:3].C([O-])(=O)C.[Gd+3:35].C([O-])(=O)C.C([O-])(=O)C>O>[Gd:35].[C:27]([C:23]1[N:22]=[C:21]([P:11](=[O:30])([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:2]([OH:4])=[O:3])[N:10]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: [Gd+3]
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(P(=O)(c2cccc(C(=O)O)n2)c2cccc(C(=O)O)n2)n1
Agent: [Na]
Solvent: O
Product: [Gd]
Temperature: 90 °C

Procedure:
A reaction flask was equipped with a reflux condenser, agitator, addition funnel, nitrogen source and heating bath. The tris(6-carboxy-2-pyridyl)phosphine oxide sodium salt (310 mg, 0.65 mmol, MW 479) from Example 11 was dissolved warm demineralized water (10 mL) and the resultant solution was filtered and charged to reaction flask. Gadolinium (III) acetate (250 mg, 0.62 mmol, MW 406 for tetrahydrate) was dissolved in warm demineralized water (10 mL) and the resultant solution was filtered and charged to the addition funnel. The bath was heated to 90° C. and the gadolinium acetate solution was added dropwise with agitation over 30 min. Once the addition was complete, the reaction was cooled to ambient temperature and the white solids were isolated by filtration and washed with demineralized water. The solids were dried in vacuo to afford 100 mg of white solids (367 mg theoretical yield for anhydrous complex), and which had the following structural formula: ##STR15##
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:16][C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH:2]([CH3:4])[CH3:3])=[CH:21][N:22]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
2-Bromopropane (1.13 mL, 12 mmol) and potassium carbonate (1.43 g, 10.4 mmol) were added in that order to a DMF (10 mL) solution of 6-bromopyridin-3-ol (1 g, 5.75 mmol), and stirred at 80° C. for 2 hours. The temperature of the solution was restored to room temperature, then this was diluted with ethyl acetate, washed twice with distilled water and once with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give the intended product (1.28 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(=O)=O.CC(C)=O.[Na]>N>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: N
Agent: O=C=O
Agent: [Na]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.9 g/11.8 mmol) was placed in a round bottom flask and cooled to −78 C (external CO2/acetone bath). Ammonia (ca. 20 mL) was condensed into the flask and freshly cut sodium (3 g) was carefully added in small pieces (dark blue color observed) and the reaction allowed to stir for one hour. The reaction was quenched by the addition of solid ammonium chloride followed by careful addition of diethyl ether (30 mL). The reaction was then allowed to warm to room temperature and the ammonia allowed to boil off. Water was then carefully added (50 mL) and the layers separated. The organic layer was extracted with 1 N hydrochloric acid (2×50 mL). The aqueous extracts were basified with 33% aqueous sodium hydroxide and extracted with 10% methanol/methylene chloride (3×50 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated to afford 7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (1.7 g/81%). 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J=8.0 Hz, 1H), 6.68-6.61 (m, 2H), 3.81 (s, 3 H), 2.99-2.82 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.CO[CH:23](OC)[CH2:24][C:25]([CH3:28])(O)[CH3:26]>>[OH:12][C:10]1[C:11]2[CH:23]=[CH:24][C:25]([CH3:28])([CH3:26])[O:1][C:2]=2[C:3]2[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=2[C:9]=1[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: COC(CC(C)(C)O)OC
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3

Procedure:
reacting 5,7-dihydroxy-8-propionyl-4-propylcoumarin with 4,4-dimethoxy-2-methylbutan-2-ol so as to produce 5-Hydroxy-2,2-dimethyl-6-propionyl-10-propyl -2H,8H-benzo[1,2-b: 3,4-b']-dipyran-8one;
Reaction SMILES: [H][H].[CH2:3]([OH:11])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10]>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:3]([OH:11])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC#CCCO
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: CCCC/C=C\CCO

Procedure:
The hydrogen reduction of this 3-octyn-1-ol is carried out by dissolving the compound in n-hexane with addition of 3 to 20% by weight of a Lindlar catalyst and introducing hydrogen at room temperature with agitation (reaction (iii)). Removal of the catalyst by filtration and n-hexane by distillation from the reaction mixture gives cis-3-octen-1-ol in an almost quantitative yield.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].P([O-])([O-])([O-])=O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To a solution of 1.5 g of (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one in 100 ml of dichloromethane, at room temperature and under inert atmosphere, 0.069 g (0.56 moles) of 4-dimethylamino pyridine and 0.5 ml of pyridine are added. To this mixture 0.907 g (6 mmoles) of tert-butyldimethylchlorosilane dissolved in 10 ml of anhydrous dichloromethane are slowly added. The mixture is let under stirring for about 24 hours, then a phosphate buffer at pH 7.5 is added. The organic phase is extracted with dichloromethane and the dichloromethane phase is washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum. Thus, essentially pure (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldimethylsilyl-azetidin-2-one (III, R=TBDMS) is obtained in quantitative yield.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[C:36]([F:37])=[C:35]([O:38][CH2:39][CH3:40])[CH:34]=[CH:33][C:32]=1[CH:41]1[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1.O>C1COCC1>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:41]2[CH2:46][CH2:45][C:44](=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]2)=[C:31]([F:30])[C:36]=1[F:37])[CH3:40]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC(=COC)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (166.1 g) was mixed with THF (500 ml) under an atmosphere of nitrogen, and the solution was cooled to −30° C. Potassium t-butoxide (t-BuOK; 54.4 g) was added in two portions in the temperature range of −30° C. to −20° C. After 30 minutes of stirring at −20° C., the compound (s9) (102.7 g) dissolved in THF (100 ml) was added dropwise in the temperature range of −30 to −20° C. After 30 minutes of stirring at −10° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by column chromatography with a mixed solvent of heptane and toluene (heptane:toluene=1:1 by volume) as an eluent and silica gel as a stationary phase powder to give 1-(4-ethoxy-2,3-difluorophenyl)-4-methoxymethylenecyclohexane. The compound was mixed with formic acid (87%; 55.8 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of heptane and toluene (heptane:toluene=2:1 by volume) to give trans-4-(4-ethoxy-2,3-difluorophenyl)-cyclohexanecarboxaldehyde (s10) (54.6 g). The yield based on the compound (s9) was 50.4%.