Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[Br:21])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[Br:21])=[N:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2sccc2Br)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Stir a mixture of 4-(3-bromo-thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 21a) (41.5 g, 0.11 mol), hydroxylamine hydrochloride (15.4 g, 0.23 mol) and pyridine (190 mL) at ambient temperature overnight. Pour the reaction into water (500 mL) and extract with dichloromethane (3 times). Wash the combined extracts with saturated CuSO4 solution (2 times), dry (MgSO4) and concentrate to a green solid. Dissolve the solid in toluene (175 mL) and let stand at ambient temperature for 3 h. Collect the resulting crystals that form and wash with toluene (60 mL). Concentrate the filtrate and again dissolve the residue in toluene and proceed to collect additional crystals to obtain a total yield of 25 g (58%) of the title compound as a light, green solid.
Reaction SMILES: [C:1]([C:3]1[C:11]([C:12]#[N:13])=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CC(C)([O-])C.[K+]>CO>[CH2:15]([N:8]1[N:7]=[C:6]2[CH:10]=[C:11]([C:12]#[N:13])[C:3]([C:1]#[N:2])=[CH:4][C:5]2=[N:9]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCBr
Reactant: N#Cc1cc2nn[nH]c2cc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCn1nc2cc(C#N)c(C#N)cc2n1
Temperature: 25 °C

Procedure:
5,6-Dicyano-1H-benzotriazole (169 mg, 1.0 mmol), 1-bromooctane (195 mg, 1.0 mmol), potassium tert-butoxide (113 mg, 1 mmol), and methanol (5 mL) were mixed in a round-bottomed flask equipped with a condenser. The reaction mixture was refluxed overnight. The mixture was cooled down to room temperature and methanol was removed with a rotary evaporator. The resulting mixture was then extracted with CHCl3 and the organic phase was washed with water and dried over Na2SO4. The resulting off-white solid was purified by column chromatography (80 mg, 30%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([O:26][CH2:13][CH:11]([OH:12])[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: O=C(OCC1CO1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Yield: 25.7 %

Procedure:
A solution of oxiran-2-ylmethyl benzoate (3.0 g, 16.8 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoic acid (6.0 g, 20.2 mmol), and tetrabutylammonium bromide (542 mg, 1.7 mmol) in anhydrous toluene was heated to 90° C. for 18 hrs. The reaction mixture was concentrated to dryness under reduced pressure, diluted with ethyl acetate, and washed with water twice followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:1 ethyl acetate/hexane) of the residue afforded 2.05 g (26%) of 2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24]Cl>CC(C)=O>[Br:21][CH2:22][CH2:23][CH2:24][O:13][C:11]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[NH:7][C:2]([CH3:14])([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: ClCCCBr
Reactant: CC1(C)NC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2ccc(OCCCBr)cc2O1

Procedure:
A mixture of 38.6 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one, 55.2 g of potassium carbonate, 47.2 g of 1-bromo-3-chloro-propane and 600 ml of acetone is refluxed for 24 hours. Filtering, concentrating the filtrate to 1/3 of the original volume and cooling yields 7-(3-bromopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one with a melting point of 111°-113°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][CH:16]3[CH2:18][O:19][CH2:20][CH:15]3[N:14]=2)=[CH:8][C:3]=1[C:4]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:5]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1cc(C2=NC3COCC3N2)c(C)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C2=NC3COCC3N2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Into around-bottom flask, was placed a solution of 2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-c]imidazol-2-yl)benzoic acid (compound 466.5, 80.0 mg, 0.250 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 82.0 mg, 0.350 mmol, 1.20 equiv), 4-dimethylaminopyridine (76.0 mg, 0.620 mmol, 2.00 equiv), and EDC.HCl (116 mg, 0.610 mmol, 2.00 equiv) were added and the resulting solution was stiffed overnight at room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with brine (3×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (15% CH3CN up to 50% in 9 min, up to 100% in 1 min, down to 15% in 1 min); Detector, Waters 2489 254 nm & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (13 mg, 12%). m/z (ES+) 429 (M+H)+. 1H-NMR (300 MHz, CD3OD): δ 7.70 (d, 2H), 7.53-7.36 (m, 4H), 5.09 (s, 2H), 4.17 (d, J=10.8 Hz, 2H), 3.77 (d, J=10.5 Hz, 2H), 3.60-3.44 (m, 1H), ˜3.3 (m, partially overlapped with water, 1H), 3.10-2.92 (m, 2H), 2.48 (s, 3H), 2.45 and 2.35 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.10-1.97 (m, 1H), 1.92-1.52 (m, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]#[N:21])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:6][CH:5]=1.[OH-:25].[Na+]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([C:20]([NH2:21])=[O:25])=[C:18]([CH3:19])[C:13]=3[N:12]=[C:11]2[CH2:23][CH3:24])=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: CCc1nc2c(C)c(C#N)c(C)cc2n1-c1ccc(CCCl)cc1
Agent: [Na+]
Product: CCc1nc2c(C)c(C(N)=O)c(C)cc2n1-c1ccc(CCCl)cc1
Yield: 83 %

Procedure:
A solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (Example 329, step 6,997 mg, 2.95 mmol) in CH2SO4 (50 ml) was stirred at 80° C. for 15 h. The mixture was poured onto ice and was neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with brine (300 ml), then dried (Na2SO4). The solvent was removed to afford 871 mg (83%) of the title compound as white solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(OCC)(=O)C>O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:35][CH2:34][CH2:33][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCCNCCN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 35.2 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (5.812 g, 15 mmol) obtained from step 6 of Example 1 and 2-morpholin-4-yl-ethylamine (10.725 g, 82.5 mmol) was dissolved in water bath at 30° C. and stirred for 5.5 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (100 ml) and saturated brine (100 ml), stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (100 ml×4), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-methyl-5-[3-(2-morpholin-4-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 10a (2.238 g, yield 87%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[CH2:21][C:22](Cl)=[O:23].[H-].[Na+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[NH:1][C:22](=[O:23])[CH2:21][O:12][C:3]=2[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2
Yield: 93.7 %

Procedure:
Using methyl 4-amino-3-hydroxybenzoate (2 g, 12 mmol), triethylamine (2.17 mL, 16 mmol) and chloroacetyl chloride (1.13 mL, 13 mmol) in THF (70 mL) followed by sodium hydride (1.0 g of a 60% suspension in oil, 24 mmol) to yield the title compound as a brown solid (2.33 g, 94%). δH (DMSO-d6) 3.81 (3H, s), 4.65 (2H, s), 6.99 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1.5 Hz). 7.59 (1H, dd, J 8.5, 1.9 Hz), 11.10 (1H, br s). LCMS (ES+) 208 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[OH:30])[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]2([NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2O)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2OS(C)(=O)=O)cc1F
Reaction time: 16 h

Procedure:
N-[(1R)-1-(3,3′-difluoro-2′-hydroxy-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide (0.040 g, 0.093 mmol) and triethylamine (0.019 g, 0.187 mmol) were dissolved in CH2Cl2 (2 mL) and cooled to −78 C. To this solution was added methanesulfonyl chloride (0.012 g, 0.103 mmol) and the reaction was allowed to stir for 16 hours. The reaction was concentrated under reduced pressure, diluted with methanol and purified by reverse phase chromatography using a gradient from 95/5H2O/CH3CN to 5/95H2O/CH3CN. Product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: C21H19F5N2O5S requires: 507.1076, found: 507.1002. 1H NMR (400 MHz, (CD3)2SO) δ 9.79 (s, 1H), 8.30 (d, J=7.5 Hz, 1H), 7.44-7.54 (m, 3H), 7.30-7.39 (m, 3H), 5.23 (qn, J=7.5 Hz, 1H), 2.99 (s, 1H), 1.4.2 (d, J=7.5 Hz, 3H), 1.32-1.38 (m, 2H), 0.92-1.06 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C:41]#[CH:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:39][CH2:40][C:41]#[CH:42])=[O:35])=[CH:37][CH:38]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: C#CCN
Product: C#CCNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 77.5 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 44 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a similar manner as described in Example 211,a mixture of 2.39 g N-methyl-[4-(2-butynyloxy)phenyl]sulfonamide], methyl alpha-bromo(4-chlorophenyl)acetate, and powdered potassium carbonate in DMF was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)acetate as a yellow oil which was then used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Cl[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:13](=[O:14])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2)[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(Cl)c1ccccc1SCl
Solvent: c1ccncc1
Product: Cc1ccnc(-n2sc3ccccc3c2=O)c1
Temperature: 50 °C
Yield: 37.1 %

Procedure:
Using the method of Fischer and Hurni (Arzneimittel Forsch., 1964;14:1301) 5.4 g (0.05 mol) of 2-amino-4-methylpyridine in 50 mL of pyridine at 10° C. was reacted with 10.3 g (0.05 mol) of 2-chlorosulfanylbenzoyl chloride. The mixture was heated to 50° C. and maintained at that temperature for 2 hours. The mixture was cooled to 25° C. and filtered. The solid was recrystallized from benzene to give 4.5 g of the title compound, mp 195-196.5° C.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2OC(=O)[S:22][N:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(OCC)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[S:22][N:21]=2)=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=c1oc(-c2ccc([N+](=O)[O-])cc2)ns1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)c1snc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)OC
Yield: 25.2 %

Procedure:
Dimethyl acetylenedicarboxylate (85.26 g, 0.6 mol) and 5-(p-nitrophenyl)-1,3,4-oxathiazol-2-one (33.63 g, 0.15 mol) were heated as given above for 15 hours. Crystallization of the brown solid from methanol (2X) gave little improvement in purity. The brown solid was decolorized in ethyl acetate solution and recrystallized (3X) to give 12.2 g (0.0378 mol, 25.2%) of dark gold solid, m.p. 142°-143°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Cl[CH2:14][CH:15]1[CH2:17][O:16]1>CN(C=O)C.[OH-].[Na+]>[OH:16][CH2:17][CH:15]1[O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[O:1][CH2:14]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)OCC(CO)O2
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a cold (5° C.) solution of 3,4-dihydroxybenzaldehyde (3.20 g, 23.2 mmol) in DMF (70 mL) is carefully added NaH (1.96 g 55% in mineral oil, 48.5 mmol) in portions. The temperature rises to 12° C. Upon completion of the addition, the cooling is removed and a solution of 2-chloromethyl-oxirane (2.57 g, 27.7 mmol) in DMF (3 mL) is added. The reaction mixture is stirred at it overnight. The mixture is diluted with 1N aq. NaOH (150 mL) and extracted with EA (2×200 mL). The organic extracts are washed with 1 M aq. NaOH (2×200 mL) and water (200 mL), combined, dried over MgSO4, filtered and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptene/EA 5:1 to 1:1 to afford the title aldehyde (0.53 g) as a solid. LC: tR=0.69 min. 1H NMR (D6-DMSO): δ 9.77 (s, 1H), 7.41 (dd, J=2.3, 8.2 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 5.10 (t, J=5.9 Hz, 1H, D2O exchangeable), 4.37 (dd, J=2.3, 11.1 Hz, 1H), 4.30-4.23 (m, 1H), 4.05 (dd, J=7.6, 11.1 Hz, 1H), 3.67-3.60 (m, 2H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>C1COCC1>[N:41]1([C:38]2[CH:37]=[CH:36][C:35]([NH:34][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:40][CH:39]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (34 mg, 0.1907 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 73% yield (0.069 g, 0.1141 mmol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[Na].C(=O)([O-])O>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na]
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCCCCCOC1CCCCO1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
5-chloro-1-pentanol (12.26 g, 0.1 mol) was dissolved in dry dichloromethane (400 mL). 3,4-Dihydro-2H-pyrane (12.62 g, 0.15 mol) and pyridine toluene-4-sulphonate (1.26 g, 5 mmol) was then added and the reaction mixture was stirred magnetically in a nitrogen atmosphere at room temperature over night. Sodium-hydrogen-carbonate, saturated solution (150 mL) was added and the phases were separated. The aqueous phase was then extracted with dichloromethane (4×25 mL). The combined dichloromethane phases were washed with water (2×20 mL) and then dried (MgSO4). Dichloromethane was then distilled out on a rotary evaporator and yielded 19.6 g (95%) of a pale yellow oil. NMR indicated a pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC[C@H](O)CO
Reactant: COc1cscc1OC
Product: CCCCCCCCC1COc2cscc2O1

Procedure:
Chiral 2-n-octyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with (S)-1,2-decanediol and purified to a purity of 99.24% as described in INVENTION EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited a specific rotation of −88° at 25° C. and 436 nm in hexane.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH:19]2[CH2:22][N:21](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:20]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18][CH:19]2[CH2:22][N:21]([C:1]([Cl:4])=[O:2])[CH2:20]2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(SC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
A stirred mixture of 8.5 g (0.086 mole) of phosgene and 12 g (0.086 mole) of potassium carbonate in 200 ml of methylene chloride was cooled in a water bath under nitrogen atmosphere while 26.3 g (0.072 mole) of 3-[(4-chlorophenyl)thio]-1-diphenylmethylazetidine in 100 ml of methylene chloride was added dropwise. After the addition, the reaction mixture was stirred for 20 hr then treated with enough ice to form a thick paste. The methylene chloride solution was decanted, filtered through Whatman phase separating paper and concentrated in vacuo. The residue (40 g) was triturated 3 times at -78° C. with 30/60 petroleum ether and allowed to warm to 0° C. before decanting the petroleum ether. The fine granular solid which remained was collected by filtration to yield 14.1 g (75%) of crude product. A sample was recrystallized from hexanes for analysis, m.p. 47°-48° C.
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:5]([F:8])([F:7])[F:6]>C1COCC1>[F:6][C:5]([F:7])([F:8])[CH2:4][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Oc1ccccc1C(Cl)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccccc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium borohydride (.930 g) was added to a solution of 2-(1-chloro-2,2,2-trifluoroethyl)phenol (2.6 g) in THF (30 ml). The reaction mixture was then stirred for 14 hrs at room temperature under an atmosphere of nitrogen, after which time the reaction was quenched with 1N HCl (50 ml) and partitioned between 1N HCl (100 ml) and ethyl acetate (200 ml), the organics were separated and dried over magnesium sulfate, filtered and solvent evaporated in vacuuo to afford title compound as a semi solid (2.4 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.06 Hz 2H), 6.80 (m, 1H), 7.00 (m, 1H), 7.25 (m, 2H).