Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[Na+]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNCCCOc1ccccc1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCOc1ccccc1
Yield: 84.7 %

Procedure:
A solution of 486 mg of 11β-fluor-7α-(5-iodopentyl)-estra-1,3,5(10)-triene-3,17β-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 600 mg of methyl-(3-phenoxy-propyl)-amine for 3 hours at a bath temperature of 80° C. Then, the batch is added to saturated sodium chloride solution, extracted with ether, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with methylene chloride/methanol/ammonia. 443 mg of 11β-fluoro-7α-{5-[methyl-(3-phenoxy-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam [α]D=+47° (c=0.5 in CHCl3).
Reaction SMILES: C(OC([NH:8][C:9]1([C:25](O)=[O:26])[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>>[F:28][C:29]([F:37])([F:38])[C:30]1[CH:31]=[C:32]([NH:33][C:25]([C:9]2([NH2:8])[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:16])=[O:17])[CH2:11][CH2:10]2)=[O:26])[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Product: NC1(C(=O)Nc2cccc(C(F)(F)F)c2)CCN(S(=O)(=O)c2ccccc2Cl)CC1

Procedure:
In analogy to the procedure of the synthesis of [4-(4-tert-Butyl-phenylcarbamoyl)-1-(toluene-4-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (example 77, step 2) the title compound was prepared from 4-tert-Butoxycarbonylamino-1-(2-chloro-benzenesulfonyl)-piperidine-4-carboxylic acid through amide coupling with 3-trifluoromethyl-aniline (commercially available) followed by the removal of the protecting group with HCl in dioxane to afford the title compound after purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. MS (m/e): 462.1 [(M+H)+].
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:10][O:11][CH3:12])=[CH:17][CH:16]=1
Reactant: COCCl
Reactant: Oc1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.33 ml of N,N-diisopropylethylamine and 900 μl of methoxymethyl chloride were added to a chloroform (20 ml) solution of 2 g of 4-iodophenol, and stirred overnight at room temperature. With cooling with ice, aqueous saturated ammonium chloride solution was added to it, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 1.08 g of the entitled compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]2[C:32]([C:33](O)=[O:34])=[CH:31][N:30]=[C:27]2[S:28][CH:29]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[N:26]4[C:27]([S:28][CH:29]=[C:25]4[CH3:24])=[N:30][CH:31]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1csc2ncc(C(=O)O)n12
Product: Cc1csc2ncc(C(=O)NC[C@@H]3C[C@@H]4C[C@@H]4N3C(=O)c3nc(N)sc3-c3cccc(F)c3)n12

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 3-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.76 min; [M+H]+=497.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH3:23]
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
To a solution of 3,5-dichloro-thiophenol (0.50 g, 2.71 mmol) in dichloromethane (8 ml) at 0° C. were added triethylamine (0.49 ml, 3.55 mmol) and a solution of ethyl bromoacetate (0.33 ml, 2.93 mmol) in dichloromethane (2 ml). The resulting solution was stirred at 0° C. for 20 min and then at room temperature for 1 hour. The reaction mixture was then washed sequentially with water and with 1 N aq hydrochloric acid. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo to yield a light yellow oil (0.72 g, 100%); 1H NMR (300 MHz, CDCl3): 7.26 (2H, d), 7.20 (1H, t), 4.21 (2H, q), 3.65 (2H, s), 1.26 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 36.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10.0 g) and 4-butylaniline (10.0 g) as starting materials, (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (6.83 g) was obtained. melting point: 60–61° C.
Reaction SMILES: C[O:2]C1C=CC(C(O)=O)=CC=1[N+]([O-])=O.ON1C(=O)CCC1=O.[CH:23]1([N:29]=[C:30]=[N:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:32]1([NH:31][C:30](=[O:2])[NH:29][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1.97 g (10 mmoles) of 4-methoxy-3-nitrobenzoic acid was dissolved in 50 ml of acetonitrile. 1.15 g (10 mmoles) N-hydroxysuccinimide was added with agitation. Finally 2.063 g (10 mmoles) of N,N′-dicyclohexylcarbodiimide were added and the mixture agitated. After 2 hours at approx. 20° C. a precipitate of dicyclohexyl-urea had formed. The solution was filtered through a Gooch 3G funnel. The formation of ester was determined by t.l.c. of the filtrate (CHCl3/MeOH=9:1, v/v). Observation under U.V. revealed the ester as a dark spot of Rf approx. 0.9. After evaporation of the acetonitrile a whitish-yellow powder remained in the flask. The powder was redissolved in 50 ml of hot isopropanol. Approximately 2 spatula-tips activated charcoal were added and the solution was boiled in a boiling water-bath for about 5 minutes. The boiling solution was quickly poured through a sintered glass filter (G4, previously heated by a passage of hot isopropanol) into a hot flask. The solution was allowed to cool down overnight. White, needle-like crystals were formed (m.p. approx. 145–152° C.) having the expected t.l.c. properties.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OCC)OCC.[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=[CH:3][C:2](=[O:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOP(=O)(CC(=O)c1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.255 mL, 301 mg, 1.17 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 45 mg, 1.13 mmol) in THF (7 mL) at rt. After 15 min, a portion (1.8 mL) of the clear solution was removed and discarded, and the remainder cooled in an ice bath. 1-(tert-Butoxycarbonyl)-4-piperidinecarboxaldehyde (177 mg, 0.830 mmol, from Step B) was added in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing. After 16 h at rt, the mixture was then partitioned between ether (40 mL) and 2.5 N aq. NaOH (20 mL). The organic layer was washed with sat'd NaCl (20 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 10% EtOAc in hexane, to give 201 mg of 1-(tert-butoxycarbonyl)-4-(3-oxo-3-phenylprop-1-enyl)piperidine as a colorless oil. Hydrogenation of this material using 5% Pd/C in 95% ethanol at atmospheric pressure yielded the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[CH2:31]([O:36][C:37](Cl)=[O:38])[CH2:32][CH2:33][CH2:34][CH3:35]>O1CCOCC1>[CH2:31]([O:36][C:37](=[O:38])[NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:22]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cn1cncc1C(=NOCc1nccc(N)n1)c1ccccc1
Reactant: CCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCOC(=O)Nc1ccnc(CON=C(c2ccccc2)c2cncn2C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 9.5 %

Procedure:
To a solution of 2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.65 mmol) in 1,4-dioxane (10 mL) were sequentially added triethylamine (0.18 mL, 1.30 mmol) and chloroformic acid pentyl ester (0.38 mL, 2.60 mmol). After stirring at room temperature for 19 h, the mixture was concentrated in vacuo, diluted in ethyl acetate (50 mL), washed with water (20 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification on silica gel afforded pentyl{2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}carbamate [26 mg, yield 9%; HPLC/MS: m/z=423 (M+H); log P(HCOOH)=2.66].
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:41])[CH2:37][C:38]([NH2:40])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:41])(=[O:39])[NH2:40]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN(CC(N)=O)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(N)=O)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 539.0 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.49 (DCM/MeOH/NH3aq, 9:1).
Reaction SMILES: [OH-].[K+].[CH:3]1([C:6]([C:12]2[S:16][C:15]([SH:17])=[N:14][CH:13]=2)([OH:11])[C:7]([F:10])([F:9])[F:8])[CH2:5][CH2:4]1.Br[C:19]1[CH:28]=[C:27]2[C:22]([C:23]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1>CO>[CH:3]1([C:6]([C:12]2[S:16][C:15]([S:17][C:19]3[CH:28]=[C:27]4[C:22]([C:23]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[CH:24][C:25](=[O:29])[O:26]4)=[CH:21][CH:20]=3)=[N:14][CH:13]=2)([OH:11])[C:7]([F:8])([F:10])[F:9])[CH2:5][CH2:4]1
Reactant: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Reactant: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(-c2cccnc2)c2ccc(Sc3ncc(C(O)(C4CC4)C(F)(F)F)s3)cc2o1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Powdered KOH (0.111 g, 1.98 mmol) was added to a solution of (−)-1-cyclopropyl-2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanol (0.507 g, 1.98 mmol) in dry MeOH (2 mL). When a solution was obtained, the reaction mixture was concentrated to dryness. Dry toluene was then added and the mixture was concentrated to dryness again. The residue was dissolved in NMP (2 mL) and 7-bromo-4-pyridin-3-yl-2H-chromen-2-one (0.500 g, 1.65 mmol) was added and the resulting mixture was stirred at 120° C. for 16 h. Once cooled, the mixture was directly applied onto a column of silica gel and chromatographed (acetone/toluene 5:95 to 20:80), affording the title compound. 1H NMR (500 MHz, CDCl3): δ 8.76 (brd, 1H), 8.68 (d, 1H), 7.85 (s, 1H), 7.79 (brd, 1H), 7.50 (m, 2H), 7.31-7.36 (m, 2H), 6.39 (s, 1H), 3.05 (br s, 1H), 1.48 (m, 1H), 0.71 (m, 2H), 0.62 (m, 1H), 0.56 (m, 1H); [α]D=−31.1° (c=1.05, EtOH).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])(=O)=O)=CC=1.[Br:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:35]>CN(C)C=O>[Br:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[CH:29][C:28]=1[CH3:35]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCCC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1Br
Temperature: 50 °C

Procedure:
Cs2CO3 (850 mg) is added to a solution of 2-(2-oxopyrrolidin-1-yl)ethyl 4-methylbenzenesulfonate (390 mg) and 4-bromo-3,5-dimethylphenol (200 mg) in N,N-dimethylformamide (4 mL). The mixture is heated to 50° C. for 12 hours and partitioned between diethylether and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (ethyl acetate) to give the title compound. Yield: 210 mg; Mass spectrum (ESI+): m/z=312 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17](=[S:20])[NH:18][NH2:19]>C(O)C.ClCCl>[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17]1[S:20][C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:19][N:18]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: COCOCC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COCOCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of 2-(methoxymethoxy)-1-phenylethanone (600 mg, 3.33 mmol) in ethanol/dichloromethane (12 mL, 3:1) was added 2,5-difluorobenzothiohydrazide (627 mg, 3.33 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to afford the product (734 mg, 63%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.Br.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19]>ClCCl.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH:19][C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1cccc(O)c1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Yield: 78.1 %

Procedure:
To a solution of trans-3-(3-pyridyl)acrylic acid (179 g) in dichloromethane (4.8 L), triethylamine (584 ml) and pivaloyl chloride (148 ml) were sequentially added under ice-cooling and stirring and stirred for 15 minutes. Subsequently, 3-hydroxyphenethylamine hydrobromide (263 g) was added at the same temperature and stirred for 2 hours. After the solvent was distilled out under reduced pressure, water was added to the residue and the precipitated crystal was filtered, washed with water and recrystallized in ethanol to yield the titled compound (251.4 g, 78%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl.CCOC(C)=O>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([C:17](=[O:18])[CH3:19])[CH2:14][CH:15]=2)[O:6]1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (Intermediate G3, 1.4 g, 5.70 mmol) was suspended in DCM (15 mL) at 0° C., then TEA (2.384 ml, 17.10 mmol) and AcCl (0.405 ml, 5.70 mmol) were added The reaction was allowed to warm up to rt and stirred for further 30 min, then the reaction volume was reduced to 1/3 of the initial volume and the residue diluted with AcOEt (150 ml). Organic phase was washed twice with water, once with 0.2 M HClaqueous and once with saturated NaClaqueous, anhydrified over Na2SO4 and solvent removed under reduced pressure to give the title compound (1.24 g, 87% yield) as yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:28][CH2:27][CH2:26][C@:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[N:9]3C(=O)N[C@@H](C3C=CC=CC=3)C)[C:6]=2[CH:7]=1.C[O-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:28][CH2:27][CH2:26][C@:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]3)[C:6]=2[CH:7]=1
Reactant: C[C@@H](NC(=O)N1C(=O)NC(=O)[C@]12CCOc1ccc(F)cc12)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C1NC(=O)[C@]2(CCOc3ccc(F)cc32)N1
Yield: 36 %

Procedure:
In like manner, when pure (4R)-6-fluoro-2,3- dihydro-3'-[(R)-1-phenylethylcarbamoyl]spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione [the (R)(R)-diastereomer product of Example 1] and sodium methoxide were reacted together in accordance with this same procedure (using the same molar proportions as before), there was eventually obtained (after work-up) a 36% yield of pure (4R)-(-)-6-fluoro-2,3-dihydro-spiro-[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione in the form of a white crystalline solid melting at 235°-237° C.; [α]D25° 31 54.1° (c=1 in methanol). This product was also substantially identical in every respect with the corresponding final product first reported as 1-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione [m.p. 241°-243° C.; [α]D25° -54.8° (c=1 in methanol)] by R. Sarges in Example I of U.S. Pat. No. 4,130,174.
Reaction SMILES: [C:1]([O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:11]=1[O:23][CH3:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[C:1]([O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[O:19][C:20]([C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[CH:21][CH:22]=2)=[CH:12][C:11]=1[O:23][CH3:24])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC(=O)c1ccccc1
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1OC(=O)c1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
4-(Furan-2-yl)-2,6-dimethoxyphenyl benzoate was reacted with N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure described for the synthesis of Example 12 except that the reaction was warmed to only 0° C. Purification by chromatography (EtOAc-hexanes) provided 2,6-dimethoxy-4-(5-(2-methoxy-2-(4-morpholinophenyl)acetyl)furan-2-yl)phenyl benzoate as a yellow solid (0.257 g, 50% yield). MS: m/z 558.2 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>CC(O)=O>[OH:5][C:6]1[CH:14]=[C:13]([OH:15])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cold stirred solution of nitric acid (70%, 28 mL) and AcOH (30 mL), is added portionwise 2,4-dihydroxybenzoic acid (7.7 g, 49.9 mmol). The mixture is stirred at 0° C. for 15 min and then slowly warmed to room temperature. The reaction becomes very exothermic and is cooled again in an ice bath to keep the mixture at approximately room temperature. The mixture is stirred at room temperature for 18 h. The resulting precipitate is filtered, washed with water, air dried, then washed with DCM and dried under reduced pressure to afford 2,4-dihydroxy-5-nitrobenzoic acid as a solid: (M−H)−=198.1.
Reaction SMILES: [CH2:1]([CH:7](O)[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:14]>>[CH2:1]([CH:7]1[CH:8]([OH:12])[CH:9]=[CH:10][C:11]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC(O)c1ccco1
Reactant: O
Product: CCCCCCC1C(=O)C=CC1O
Yield: 65 %

Procedure:
In the same apparatus as in Example 1, α-n-hexylfurfuryl alcohol (30 parts) and water (1500 parts) were charged, and the resultant mixture was stirred at 100° C., during which the pH was maintained at 4.6 to 5.0 until the starting compound was consumed. The reaction mixture was treated as in Example 1, followed by purification with chromatography to give 2-n-hexyl-3-hydroxy-4-cyclopentenone in a yield of 65 %.