Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](OC)=[O:31])=[C:24]([F:34])[CH:23]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1COCC1>[F:34][C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:27]=[CH:26][C:25]=1/[CH:28]=[CH:29]/[CH2:30][OH:31]
Reactant: COC(=O)/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(/C=C/CO)c(F)c1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A THF solution of diisobutylaluminum hydride (522 mL of a 1.0 M solution, 522 mmol) was added to a cooled (−78° C.) solution of methyl (2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)acrylate (43 g, 130 mmol) in THF (900 mL). After stirring for one hour at −78° C., additional diisobutylaluminum hydride solution was added (140 mL of a 1.0 M solution, 140 mmol). After another 30 minutes, aqueous citric acid and ethyl acetate were added and the mixture allowed to warm slowly to room temperature. The layers were separated and the aqueous phase extracted with more ethyl acetate. Combined organic phases were washed with H2O, brine and dried (MgSO4), filtered and concentrated to give a red oil. The crude product was purified by column chromatography (0-40% ethyl acetate-hexane) to provide the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(CN2CCOCC2)cc1N
Temperature: 2.5 °C
Yield: 90 %

Procedure:
A mixture of 4-(3,4-dinitro-benzyl)-morpholine (1 mol. eq.) and 5% Pd/C (0.05 wt. eq.) in IMS (33 vol.) was stirred at 0-5° C. while the vessel was charged with hydrogen. The mixture was carefully warmed to 15-20° C. with stirring until the reaction was complete (<24 hours). The mixture was filtered and the filtrate evaporated to dryness to give 4-morpholin-4-ylmethyl-benzene-1,2-diamine (90%). The material was used immediately in the next step. (LC/MS (basic method): Rt 1.64, [M-N(CH2CH2)2O−]+ 121).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[CH3:29]>CN(C)C=O>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]([O:11][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=2[CH3:29])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(C)(C)C)c1

Procedure:
3-t-Butylphenol (7.5 g) and potassium carbonate (6.9 g) are added to a solution of 1-chloro-2,5-dimethyl-4-nitrobenzene (9.5 g) in dimethylformamide (60 ml) under an inert atmosphere. The reaction mixture obtained is refluxed for 5 h and then partitioned in a water/diisopropyl ether mixture. The organic phase is washed with a basic aqueous solution and then with water at pH 7. Drying over magnesium sulphate and then addition of carbon black, followed by filtration through Celite gives, after concentration, the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:25]3[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=3[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:25]4[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=4[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 4-chlorophenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 26).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Br:11]Br.N>CC(O)=O>[Br:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1ccc2nc[nH]c2c1
Agent: N
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 5-aminobenzimidazole (0.3 g, 2.3 mmol) in 30 ml of AcOH was added bromine. (0.055 ml, 1.1 mmol) in a portion and resulting reaction mixture was stirred for 0.5 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a dark brown solid which was subjected to silica gel column chromatography (NH3 saturated 10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: Clc1ccc2c(N3CCNCC3)ccnc2c1
Yield: 65.4 %

Procedure:
4,7-Dichloroquinoline (9.9 g, 50 mmol) and piperazine (43.1 g, 500 mmol) in EtOH (200 mL) are reacted according to method B yielding 8.10 g of the product.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
1-(3-Methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (1.44 g) was dissolved in 50 ml of methanol and 25 ml of 20% aqueous NaOH was added. The reaction mixture was stirred at 50° C. for 1.5 h until there was no starting material checked by TLC. The reaction mixture was concentrated to about 20 ml, 200 ml of water was added. The resulting solution was neutralized with 5 M hydrochloric acid to pH 2 and the precipitates formed were collected by filtration, washed with water and dried to give 1-(3-methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid (1.29 g, 99%). 1H NMR (DMSO-d6) δ 13.12 (br. s, 1H), 8.27 (d, 1H), 7.26 (d, 1H), 4.36 (t, 2H), 1.59 (dd, 2H), 1.50 (dt, 1H), 0.88 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 1.04 g (7.14 mmol) of 2-bromo-1-chloroethane (purity: 98 wt. %), 0.85 g (6.04 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetonitrile. The resulting mixture was reflued under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added 20 mL of n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate as a white crystalline product.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl>O>[CH3:16][O:17][CH2:18][O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1
Temperature: 30 °C
Yield: 79.1 %

Procedure:
Into a reactor, 40 g of p-bromophenol and 200 ml of DMF (dimethylformamide) were charged, to which 10 g of a 60% NaH (sodium hydride) were gradually added to give a solution. To the solution, 18 g of methoxymethyl chloride were added dropwise with stirring at a temperature of 30° C. or lower, and reacted overnight at room temperature to give a reaction solution. The reaction solution was poured into water, extracted with benzene, washed with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was distilled under reduced pressure to give 38.4 g (Y., 79.3%) of 4-bromopheny methoxymethyl ether.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[F-].[K+]>CS(C)=O.CCOC(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 150 °C
Yield: 59.8 %

Procedure:
A solution of 4-fluorobenzonitrile (1.00 g, 8.26 mmol) and morpholine (0.77 mL, 9.08 mmol) in dimethyl sulfoxide (40 mL) was treated with 37% KF on alumina, and the mixture was heated at 150° C. for 5 h. After cooling, the mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with water (3×), brine (1×), and then dried with magnesium sulfate. The extract was concentrated and the residue was purified by chromatography (SiO2, 20 to 30% EtOAc in hexanes) yielding 930 mg (60%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CS(C)=O.O>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv) in DMSO (5 mL), and morpholine (1070 mg, 12.30 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 120° C. in an oil bath. The resulting solution was diluted with 100 mL of H2O. The solids were collected by filtration. The product was obtained as 617 mg (79%) of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccnc(N)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
A solution of 2-amino-4-methyl-3-nitropyridine (Aldrich 10 Chemical Co., 500 mg) in methanol (3 mL) was treated with palladium hydroxide on carbon (50 mg) and stirred under a hydrogen atmosphere (1 atm) at room temperature for 6 h. The mixture was filtered through a pad of celite filter aid and the solvent removed by rotoevaporation to give the title compound (340 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
To a mixture of 4benzyloxybenzoic acid (2.28 g, 10 mmole) in 20 ml dried dichloromethane were added five drops of DMF and 2.5 ml thionyl chloride. The mixture was refluxed for three hours and evaporated under reduced pressure. Yield: 2.45 g=100%
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O1CCOCC1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CC(C)([O-])C.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1COCCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1cncc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 41.1 %

Procedure:
To a solution of [3,5-dibromopyridine (1000 mg, 0.004 mol) in 1,4-dioxane (8 mL, 0.1 mol), morpholine (400 mg, 0.004 mol) and sodium tert-butoxide (400 mg, 0.004 mol) were added. The reaction was bubbled with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.0002 mol) was added and nitrogen was bubbled through for couple of minutes. The mixture was heated at 80° C. overnight. The reaction was allowed to cool to rt and was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a crude residue. The crude product was purified by FCC on silica gel eluting with 1:1, EtOAC:Hexane gave to give 4-(5-bromopyridin-3-yl)morpholine as a viscous oil (400 mg, 40%). 1H NMR (400 MHz, CDCl3): 8.2 (s, 1H), 8.1 (s, 1H), 7.2 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([C:20]3([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:14]2[C@H:13]([NH:27]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([C:20]3([C:23]([F:26])([F:24])[F:25])[CH2:21][CH2:22]3)=[N:18][N:19]=[C:14]2[C@H:13]([NH2:27])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Reaction time: 1.5 h
Yield: 122.7 %

Procedure:
Hydrochloric acid (4.0 M in dioxane; 5 mL, 20.0 mmol) was added to a solution of tert-butyl {(6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl}carbamate (440 mg, 0.93 mmol) in 1,4-dioxane (5 mL). After 1.5 h, the reaction mixture was concentrated to give the bis hydrochloride salt of the title compound (425 mg). MS 347.1 (M+1).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[NH4+]>CO.O>[N:8]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7])=[N+:9]=[N-:10]
Reactant: C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NC1CCCCC1O
Temperature: 72 °C

Procedure:
A mixture of cyclohexene oxide (2 g, 20.4 mmol), sodium azide (1.86 g, 30.6 mmol), and ammonium chloride (2.16 g, 40.8 mmol) in methanol/water (61 mL/6 mL) was heated to 72° C. for 16 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give pure product. (2.3 g, 80%). EI-MS m/z 242 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].[BH4-].[Na+]>C(O)C.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][CH2:12][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: OCCNCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Substituted benzaldehyde (0.01 mol), such as 4-chloro benzaldehyde (1.4 g), was dissolved in dry ethanol (30 mL) and ethanolamine (0.61 g, 0.01 mol) was added. The reaction mixture was stirred overnight at 60° C. The ethanol was evaporated under reduced pressure to give a colorless oil. The oil was then dissolved in dry methanol (30 mL) and cooled in ice. Sodium borohydride (NaBH4, 0.57 g, 0.015 mol) was added slowly in portions, and the resulting solution was left overnight at room temperature. The solvent was evaporated in vacuo, and the residue was dissolved in water, and extracted with CH2Cl2 (3×20 mL). The organic layers were combined and dried with Na2SO4, filtered and evaporated in vacuo to give colorless oily residue, which was purified by column chromatography (silica gel CH2Cl2:MeOH=9:1) to give 2-(4-chlorobenzylamino)-ethanol (II-1, 1.83 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (10.0 g, 41 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (1.2 equiv) was added, followed by methanesulfonyl chloride (1.2 equiv). The mixture was stirred at room temperature for 48 hours, then diluted with DCM (100 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (11.9 g, 37 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=2)[O:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (30.82 mmol) of 2,2-dimethylchroman (Compound 56) in 50 ml of nitromethane was treated, under nitrogen, with 2.53 g (32.35 mmol) of acetyl chloride followed by 4.4 g (33 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 3 hours and then cooled in an ice-bath and treated slowly with 50 ml of 6M HC1. The mixture was diluted with water and extracted with ether. The ether extracts were washed successively with saturated NaHCO3 solution, water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a white solid. PMR (CDCl3) : & 1.36 (6H, s), 1.84 (2H, t, J~6.8 Hz), 2.54 (3H, s), 2.82 (2H, t, J~6.8 Hz), 6.80 (1H, d, J~8.4 Hz), 7.69-7.76 (2H, m). MS exact mass, m/e 204.1140 (calcd. for C13H16O2, 204.1150).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-mercaptophenol (49.7 mg, 0.39 mmol) in tetrahydrofuran (2 mL) was added cesium carbonate (128 mg, 0.39 mmol) and ethyl bromoacetate (44 μL, 0.39 mmol) and the reaction was stirred at 50° C. overnight. The reaction was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc to afford ethyl 2-(4-hydroxyphenylthio)acetate (507).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([C:17]=2[C:19]([OH:21])=O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1>>[CH:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([C:17]=2[C:19]([Cl:3])=[O:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12

Procedure:
Thionyl chloride (20 me) was added to 2.2 g of 9-acridinecarboxylic acid, followed by heating under reflux for 5 hours. After the thionyl chloride was distilled off under reduced pressure, 20 ml of methylene chloride were added further. Distillation was repeated twice under reduced pressure, whereby 2.4 g of the compound (2) were obtained (yield: stoichiometric).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[O:18]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(COc1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of 23.3 g. (0.1 mol.) of α-bromo-p-chloroacetophenone, 10.0 g. (0.1 mol.) of phenol and 14.5 g. (0.1 mol.) of potassium carbonate in 65 ml. of dry acetone is refluxed for 12 hours. The reaction mixture is cooled, poured into 500 ml. of water and the precipitate formed is collected by filtration and recrystallized from ethanol to give α-phenoxy-p-chloroacetophenone.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCO2)cc1
Reaction time: 2 h
Yield: 65 %

Procedure:
To (S)-(tetrahydrofuran-2-yl)methanol (2.0 g, 20 mmol) in CH2Cl2 (10 mL) at about 0° C. was added p-toluenesulfonyl chloride (4.2 g, 22.00 mmol), followed by drop-wise addition of triethylamine (5.6 mL, 40.0 mmol). The resulting solution was kept at 0° C. for 2 hours, and then at room temperature for another 2 hours. The reaction mixture was concentrated to dryness and diethylether (200 mL) and water (100 mL) were added. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to yield the title compound (2.3 g, 13.00 mmol, 64%) as a colorless oil, which was used in the next step without purification.