Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH2:15][CH2:16][CH:17]([SH:19])[CH3:18].C([O-])(O)=O.[Na+]>CCOCC.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([NH:15][CH2:16][CH:17]([SH:19])[CH3:18])=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: CC(S)CN
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A solution of p-nitrobenzyl chloroformate (0.95 g, 4.41 mmol) in Et2O (30 ml) was added dropwise over 45 min. to an ice-cold, stirring mixture of 1-amino-2-propanethiol (0.504 g, 3.94 mmol) in Et2O (100 ml), H2O (11 ml), and 10% aqueous NaHCO3 (10 ml). The resulting mixture was stirred an additional 80 min. at 0°-5°, and then separated into two phases. The organic portion was washed with cold 0.025N HCl (30 ml) and brine (20 ml), dried with MgSO4, filtered, and concentrated under vacuum to a yellow oil (1.28 g). The crude product was purified by preparative TLC on silica gel GF using 20:1 CH2Cl2 -EtOAc as developing solvent to afford an off-white solid (1.00 g). Recrystallization of the chromatographed product from Et2O-petroleum ether gave compound (A3) (0.183 g) as a cream colored solid: mp 54°- 56.5°.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CCOC(=O)c1nnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nnc(C(=O)O)s3)CC2)c(Cl)c1Cl
Yield: 5.2 %

Procedure:
Ethyl 5-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate (Example 219; 0.530 g, 1.2 mmol) and lithium hydroxide (0.117 g, 4.9 mmol) were stirred in dioxane (5 ml) and water (0.5 ml) and heated to 50° C. for thirty minutes. The solution was acidified (pH 4) using 1 N HCl resulting in a precipitate. The solids were collected and purified using semi-preparative HPLC to give the title compound (0.025 g).
Reaction SMILES: FS([C:5]([F:14])([F:13])[C:6](O[Si](C)(C)C)=O)(=O)=O.[Br:15][C:16]1[C:17]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:18][C:19]2[O:23][C:22]([CH:24]=C)=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[C:20]=2[CH:30]=1.[F-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[Br:15][C:16]1[C:17]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:33])=[O:34])=[CH:18][C:19]2[O:23][C:22]([CH:24]3[CH2:6][C:5]3([F:13])[F:14])=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[C:20]=2[CH:30]=1
Reactant: C=Cc1oc2cc(N(C)S(C)(=O)=O)c(Br)cc2c1C(=O)NC
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [F-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: CNC(=O)c1c(C2CC2(F)F)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (31 mg, 0.12 mmol) in toluene (0.5 mL) was added dropwise to a solution of 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-vinylbenzofuran-3-carboxamide (30 mg, 0.07 mmol) and NaF (1 mg, 0.02 mmol) in diglyme (1 mL) at 120° C. over 15 min. The mixture was then stirred at 120° C. for 2 h. The mixture was concentrated in vacuum and the residue was purified by prep-TLC (PE:EA=1:1) to give the product of 5-bromo-2-(2,2-difluorocyclopropyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (7 mg, yield: 22%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 8.02 (s, 1H), 3.74˜3.66 (m, 1H), 3.19 (s, 3H), 3.18 (s, 3H), 2.84 (s, 3H), 2.38˜2.39 (m, 1H), 2.21˜2.17 (m, 1H). MS (M+H)+: 437/439.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:25]1([C:31]2([CH2:34][NH2:35])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:35][CH2:34][C:31]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[CH:11][CH:10]=1
Reactant: NCC1(c2ccccc2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Product: O=C1COc2c(C(O)CNCC3(c4ccccc4)CC3)ccc(O)c2N1

Procedure:
Prepared from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 147 mg (1 mmol) C-(1-phenyl-cyclopropyl)-methylamine. Final purification by chromatography (silica gel; dichloromethane/methanol gradient). Yield: 30 mg (8%); mass spectroscopy: [M+H]+=355.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9](I)([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)I
Reactant: O=c1ccc(Br)c[nH]1
Product: CC(C)n1cc(Br)ccc1=O

Procedure:
5-bromo-1-isopropylpyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one and isopropyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[C:18]1([CH:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCC3c3ccccc3)cnc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 2-phenylpyrrolidine (21 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid as triturated in acetone, filtered, washed with acetone and dried to give the title compound (7 mg, 17%) as a white solid.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.O.[NH2:32]N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH2:32])=[N:12][C:13]=2[CH:18]=1
Reactant: NN
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (750 mg, 1.44 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrate (55%, 0.41 mL, 7.2 mmol) was added and the solution was refluxed for 2 hours. Volatiles were evaporated and the residual white solid was resolidified from ethanol-water and stirred with Raney nickel (preequilibrated under hydrogen) in methoxyethanol (20 mL) for 30 minutes. Catalyst was filtered off and the filtrate made slightly basic with aqueous sodium hydroxide to complete removal of the acetate groups. The solution was neutralized, and volatiles evaporated. The residual solid was recrystallized from ethanol-water to give title compound as pale pink solid (97 mg, 20%), m.p. 283°-284° C. dec.; 1H-NMR(DMSO-d6)δ: 7.61 and 7.30 (both s, 2, aromatic CH), 6.65 (br s, 2, NH2), 5.07 (t, J=4.3 Hz, 1, OH), 4.80 (d, J=7.0 Hz, 1, OH), 4.66 (d, J=3.7 Hz, 1, OH), 4.65-4.50 (m, 1, NCH), 4.45-4.30 (m, 1, OCH), 3.90-4.80 (m, 1, OCH), 3.70-3.40 (two m, 2, OCH2), 2.20-1.80 (m, 3, CH2 and CH of cyclopentane); mass spectrum (CI): 332 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[OH-:14].[Na+]>O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A mixture of water and 2,4-dinitrochlorobenzene is heated to boil. An aqueous sodium hydroxide solution is added dropwise thereto and the mixture is stirred under heating to boil for 1 h to form 2,4-dinitrophenol. Then sodium polysulfide is added dropwise thereto over a period of 3 to 4 h while maintaining a boiling state to promote vulcanization for 24 h under exiling water.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([C:9]([CH2:12]Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[C:3]([OH:14])=[C:4]([C:9]([CH2:12][S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COc1ccccc1S
Reactant: COC(=O)c1c(CBr)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Temperature: 60 °C
Yield: 64.8 %

Procedure:
A mixture of methyl 3-bromo-6-bromomethyl-2-hydroxybenzoate (Intermediate 53, 0.6 g), 2-methoxythiophenol (0.518 g) and potassium carbonate (0.766 g) in THF (10 ml) was stirred and heated at 60° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and water and the separated organic layer was washed with potassium hydroxide solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 3-bromo-2-hydroxy-6-(2-methoxyphenylthiomethyl)-benzoate (0.46 g) as a white solid which was used without further characterisation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1.[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][N:41]1[CH2:42][CH2:43][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[CH2:39][CH2:40]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Yield: 40.8 %

Procedure:
A solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(toluene-4-sulfonyloxymethyl)-cyclopentanecarboxylic acid ethyl ester (example 148, step 1, epimeric mixture, 410 mg), 4-(4-Fluoro-phenyl)-piperidine (cas # 6716-98-9, 291 mg), sodium iodide (1.36 g) and triethylamine (545 mg) in N,N-dimethylformamide (2.8 mL) was stirred at 90° C. over 6 h. The reaction mixture was partitioned between ethyl acetate and an aqueous saturated solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (9:1 to 1:1 v/v) as eluant to afford the title compound (170 mg, 41%) as a yellow liquid. MS (EI): 464.4 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](C(=NO)C)=[CH:12]2)=[O:5].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:4]([NH:6][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:25])(=[O:5])[CH3:3]
Reactant: CC(=NO)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Reaction time: 0.83 h
Yield: 22.6 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyiminoethyl)quinoline (168 mg) in pyridine was added phosphoryl chloride (516 mg) at 4° C., and the mixture was stirred for 50 minutes at the same temperature. The mixture was poured into ice and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol and water to give 3-acetylamino-8-(2,6-dichlorobenzoylamino)quinoline (19 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:13]2[CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]2=[N:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH2:18][CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCc1cc(I)ccc1N=C1NCC2(CCCC2)S1
Reactant: BrC1CCCC1
Product: CCCc1cc(I)ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[NH2:19][C@H:20]([C:22]([NH2:24])=[O:23])[CH3:21].[BH3-]C#N.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:19][C@@H:20]([CH3:21])[C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O

Procedure:
(S)-2-[4-(3-Fluorobenzyloxy)benzylamino]propanamide (Ia) is prepared by reacting 4-(3-fluorobenzyloxy)benzaldehyde (10 mmol), prepared as described in Example 14.1.a., and L-alaninamide hydrochloride (1.37 g, 11 mmol) followed by reduction with NaBH3CN (0.50 g, 8 mmol). After working up the reaction mixture and purification by flash-chromatography, (S)-2[4-(3-fluorobenzyloxy)benzylamino]propanamide is isolated as white solid in 68.7% yield. The product has HPLC purity of 96.2 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (IIa) of 0.15% by weight (see Example 17B).
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:29])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:29])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:16]
Reactant: CCCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC

Procedure:
To a solution of 1.6g of sodium in 100 ml of absolute ethanol, 10 g of p-(1-cyclohexenyl)-phenol in a small amount of absolute ethanol are added at room temperature under anhydrous conditions and with stirring. 10 g of α-bromo-decanoic acid ethyl ester are then added dropwise and the reaction mixture is stirred up for 24 hours at 50° C. The ethanol is subsequently stripped off in vacuo and the residue is partitioned between water and ice-cold N-sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-decanoic acid ethyl ester of the formula ##STR21## in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1c(F)cccc1F
Product: O=C(NCc1c(F)cccc1F)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2,6-difluorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1ccsc1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1ccsc1
Yield: 35.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.55 g of 3-thiophenecarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: OCCN(CCO)CCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Diethanolamine were converted to yield 2-[{5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-(2-hydroxy-ethyl)-amino]-ethanol, MS: 415 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:19][C:18]2[C:5](=[CH:6][C:7]3[C:8](=[O:21])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[O:15][C:16]=3[C:17]=2[CH3:20])[CH2:4]1.CC(C)=[O:24].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[CH3:20][C:17]1[C:16]2[O:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:21])[C:7]=2[CH:6]=[C:5]2[CH2:4][CH:3]([C:2]([OH:24])=[O:1])[O:19][C:18]=12
Reactant: Cc1c2c(cc3c(=O)c4ccccc4oc13)CC(CO)O2
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: Cc1c2c(cc3c(=O)c4ccccc4oc13)CC(C(=O)O)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of 16.1 of the 2,3-dihydro-2-hydroxymethyl-11-methyl-5-oxo-5H-furo[3,2-b]xanthene obtained in Example 25 and 3,000 ml of acetone, a mixture of chromium trioxide (57 g), water (280 ml) and concentrated sulfuric acid (84 g) was added dropwise under agitation. The resulting mixture was left to stand overnight and filtered. The filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from a mixed solvent of methanol and dichloromethane gave 11.1 g of 2,3-dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 297°-299° C. This compound produced a mass spectrum having a molecular ion peak at m/e 296.
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].C(OC(C)C)(C)C.[CH2:25]([NH2:27])[CH3:26]>S(=O)(=O)(O)O>[CH2:25]([NH:27][S:13]([C:2]([F:17])([F:1])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])(=[O:15])=[O:14])[CH3:26]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCN
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N-ethyl-perfluorbutanesulfonamide (C4F9SO2N(H)CH2CH3) was prepared by placing 302 grams perfluorobutanesulfonyl fluoride and 500 mL diisopropyl ether in a two liter three-necked round bottom flask under nitrogen. Next 139.5 grams ethylamine (3.1 equivalents) was slowly added while keeping the temperature below 60° C. After addition was complete the reaction mixture was stirred at 60° C. overnight. Next, 500 milliliters of 6 M sulfuric acid was added. The organic layer was isolated and washed two times with equal volumes of water. The solvent was removed under reduced pressure the give the sulfonamide. The sulfonamides with varying Rf were prepared using this procedure but with the appropriate perfluoroalkanesulfonyl fluoride. The corresponding epoxides were prepared from these sulfonamides in the same manner as described in example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:18]=[O:19])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][OH:19])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2c(cc1OCc1ccccc1)CCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A flamed dried, N2 purged 1-liter , 3-neck flask equipped with a dropping funnel mechanical stirrer, and thermometer was charged with 5-benzyloxy-2,3-dihydrobenzofuran-6-carboxaldehyde (30.00 g, 0.12 moles) and anhydrous toluene (150 ml). The resultant yellow solution was cooled to -65° C. and with efficient stirring a diisobutylaluminum hydride solution in toluene (77 ml of a 25 wt. %) was added dropwise over 30 minutes. Upon complete addition, the reaction mixture Was allowed to warm to room temperature and stirred 1 hour more. The reaction mixture was poured slowly into 2N HCl (300 ml) and crushed ice (400 ml) with rapid stirring. The quenched mixture was extracted sequentially with Et2O (2×300 ml) and EtoAC (2×200 ml). The combined organic layers were washed with brine (2×300 ml), dried over MgSO4, filtered, and the filtrate concentrated in vacuo to afford 5-benzyloxy-6-hydroxymethyl-2,3-dihydobenzofuran as a white precipitate (30.0 g, 97.5%).