Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28]N)([O-:18])=[O:17]>CC#N>[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O-:28])([O-:18])=[O:17].[NH2:16][N+:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCc1cc[n+](N)cc1
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 203.9 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyloxy)methyl)pyridine (8.9 g, 39.7 mmol) and O-(2,4-dinitrophenyl)hydroxylamine Y-3 (7.9 g, 39.7 mmol) in MeCN (27 ml) was stirred at 40° C. for 24 h, then concentrated to afford the title compound (17.1 g), used in next step without further purification. MS (m/z): 239(M−183)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.Cl.[F:13][C:14]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15]1>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:17][CH2:18][C:14]([F:19])([F:13])[CH2:15]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1F)N1CCC(F)(F)C1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and 3,3-difluoropyrrolidine, hydrochloride salt and triethylamine (2 molar equivalent).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:12][CH:11]=1)=[O:9].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1.Cl>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.C(Cl)Cl>[C:36]([CH:35]1[CH2:34][C:33](=[O:39])[O:9][CH:8]1[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:12][CH:11]=1)([OH:38])=[O:37]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C=O)cc23)c(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2cccc3ccc(C4OC(=O)CC4C(=O)O)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (4.54 g) was added to a mixture of methyl 4-[7-formylnaphth-1-ylmethyl]-3-methoxybenzoate (5.00 g), succinic anhydride (2.99 g), zinc chloride (6.11 g) and methylene chloride (50 ml). During the addition, the reaction was cooled with an ambient temperature bath. The mixture was stirred for 18 h and poured into a vigorously stirred solution of 1:1 ethyl acetate:2N hydrochloric acid (500 ml). The organic layer was washed (water, brine) and dried (MgSO4). After the evaporation of solvent and dissolving the residue in saturated sodium bicarbonate, the solution was washed with ether. The aqueous solution was neutralized with 6N hydrochloric acid, acidified to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed (water, brine), dried (MgSO4) and evaporated to give methyl 4-[7-(3-carboxy-2,3,4,5-tetrahydro-5-oxofuran-2-yl)naphth-1-ylmethyl]-3-methoxybenzoate (6.16 g, 95%, as a mixture of diastereomers) as a pale yellow foam; MS(CI), m/e=434(M+H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:16]=[C:17](/[C:21](/[CH2:25][CH3:26])=[CH:22]/[CH2:23]O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>ClCCl>[Cl:1][CH2:23]/[CH:22]=[C:21](/[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)\[CH2:25][CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC/C(=C\CO)c1cccc([N+](=O)[O-])c1
Solvent: CSC
Solvent: ClCCl
Product: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) in dichloromethane (1.2 l) at 0° C. was added dropwise over 20 minutes dimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwise over 20 minutes at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-penten-1-ol (Preparation 14, 80 g, 0.39 mol) in dichloromethane (300 ml). The mixture was warmed to room temperature over 1 h, stirred at room temperature for 16 h, then partitioned between water (2 l) and dichloromethane (1 l). The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (2 kg), eluting with 10:1 hexane/diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (54 g, 62%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3].C=CC1C=C[NH+]=CC=1.[Br-:21].[Br-].[Br-]>CO>[CH2:11]1[O:12][C:6]2[CH:5]=[C:4]([C:2]([CH2:1][Br:21])=[O:3])[CH:9]=[CH:8][C:7]=2[O:10]1
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: C=Cc1cc[nH+]cc1
Solvent: CO
Product: O=C(CBr)c1ccc2c(c1)OCO2
Yield: 37.8 %

Procedure:
To a solution of 2.5 g (15.23 mmol) of 3,4-methylenedioxy acetophenone in 200 mL of anhydrous methanol was added 61 mmol (20 g) of poly(4-vinylpyridinium tribromide), Aldrich Chemical Co., and allowed to reflux for 2.5 h. The solution was filtered and concentrated. 1-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one (1.4 g, 38% yield) was obtained methylene chloride/hexanes as off-white crystals. 1H-NMR (DMSO-d6; 300 MHz) δ 8.2 (s, 1H), 8.07 (s, 1H), 7.61-7.64 (m,2H), 7.01-7.04 (dd, J=1.2 Hz and 7.1 Hz, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[O-:12][C:13]#[N:14].[K+].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:14][C:13]([NH:24][C:19]1[N:20]=[C:21]([CH3:23])[CH:22]=[C:17]([CH3:16])[N:18]=1)=[O:12])(=[O:10])=[O:9]
Reactant: Cc1cc(C)nc(N)n1
Reactant: N#C[O-]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1

Procedure:
A slurry of 23.8 g (0.10 mole) 2-chlorobenzenesulfonyl chloride, 16.2 g (0.2 mole) potassium cyanate, 15.5 g (0.11 moles) 4,6-dimethyl-2-pyrimidinamine in 150 ml acetonitrile was stirred at reflux for 5 hours. The reaction was cooled to 25° and filtered. The solids were dissolved in water, filtered, and the filtrate acidified to give a solid A. The reaction filtrate was distilled in vacuo to remove solvent. The residue and Solid A were combined, dissolved in 200 ml of 5% sodium hydroxide and extracted with methylene chloride. The aqueous layer was then acidified, the solids collected, washed with water and dried to give 18.9 g (50.6% of theory) of the title compound. The m.p. and IR spectrum of the title compound were identical to those of an authentic sample prepared as described in U.S. Pat. No. 4,169,719.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].C>Cl>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:11]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
0.47 g of N-{4-[4-(3-nitro-phenyl)-thiazol-2-ylsulphamoyl]-phenyl}-acetamide was suspended in 10 ml of 6N hydrochloric acid and heated to boiling overnight. The cooled mixture was treated with 35 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 50 ml of 40% ethanol yielded 0.16 g of 4-amino-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:13]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2)=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc3[nH]ncc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOC[C@H](O)CO)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (135 mg, 0.26 mmol) in methanol (4 mL) was added hydrochloric acid in dioxane (2 mL, 4N, 8 mmol). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as an off white solid (94 mg, 75%). LCMS (Method A): RT=7.67 min, [M+H]+=487. 1H NMR (DMSO-d6, 400 MHz) 13.20 (1H, s), 11.67 (1H, s), 9.94 (1H, s), 7.66 (1H, dd, J=10.30, 1.92 Hz), 7.47 (1H, d, J=8.79 Hz), 7.45-7.41 (1H, m), 7.22 (1H, s), 7.01 (1H, d, J=8.78 Hz), 6.92 (1H, t, J=8.64 Hz), 3.92-3.85 (1H, m), 3.76-3.58 (2H, m), 3.41-3.31 (2H, m).
Reaction SMILES: BrCCCCCCCCCC[O:12]C1C=CC(C(O)=O)=CC=1.C1(C=CC=C(O)C=1)O.[CH2:30]([O:41][C:42]1[CH:58]=[CH:57][C:45]([C:46]([O:48][C:49]2[CH:54]=[CH:53][C:52]([CH:55]=[O:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40].[O-]Cl=O.[Na+]>>[CH2:30]([O:41][C:42]1[CH:58]=[CH:57][C:45]([C:46]([O:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([OH:12])=[O:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40]
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Reactant: C=CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: C=CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (1.71 g, 16 mmol), 13 (5.07 g, 13 mmol), NaH2PO4·H2O (5.32 g, 39 mmol), NaClO2 (6.71 g, 74 mmol). Yield 5.34 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (12 H, m, CH2), 1.83 (2 H, m, O—CH2—CH2), 2.04 (2 H, m, CH2═CH—CH2), 4.05 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.82 (1 H, m, CH2═CH), 6.99 (2 H, d, 3J=8.9 Hz, Ar—H), 7.34 (2 H, d, 3J=8.6 Hz, Ar—H), 8.16 (2 H, d, 3J=8.9 Hz, Ar—H), 8.20 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.9, 29.1, 29.3, 29.4, 29.5, 33.8, 68.4, 114.1, 114.4, 121.0, 122.0, 126.5, 131.9, 132.4, 139.2, 155.5, 163.8, 170.6.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH:15][CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[S:13][CH:14]=1)(C)C.[H-].[Na+].Br[CH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29].[CH2:34]1[CH2:38]OC[CH2:35]1>>[CH:34]([C:8]1[CH:9]=[CH:4][C:5]([C:10]2[N:11]=[C:12]([N:15]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[C:28]#[N:29])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:7]=1)([CH3:38])[CH3:35]
Reactant: C1CCOC1
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)c1ccccc1-c1csc(NCc2cccs2)n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)Cc3ccccc3C#N)n2)cc1
Reaction time: 3 h

Procedure:
2-({[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-methyl)-benzonitrile was prepared by stirring (4-(-isopropyl-phenyl)-thiazol-2-yl)-thiophen-2-ylmethyl-amine (100 mg, 0.31 mmol), NaH (26 mg, 60%, 0.62 mmol), and 2-bromomethylbenzonitrile (72 mg, 0.372 mmol) in THF (50 mL) at room temperature. After 3 h, the reaction mixture was concentrated under high vacuum. The crude product used without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7]P(=O)(OCC)OCC)([O-:3])=[O:2].O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.[H-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH:7]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of diethyl (3-nitrobenzyl)phosphonate (8.4 g, 0.031 mol) and tert-butyl 4-oxopiperidine-1-carboxylate (6.12 g, 0.031 mol) in dry tetrahydrofuran (120 mL) was treated with a 60% suspension of sodium hydride in oil (1.36 g, 0.034 mmol). The resulting mixture was stirred at room temperature for 4 h, then partitioned between dichloromethane (500 mL) and water (500 mL). The organic extract was dried (Na2SO4) and evaporated in vacuo to give the title compound (9.86 g, 100%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([OH:26])=[O:25].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([O:26][CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:25]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)O)CC[C@H]4[C@@H]3CC[C@@H]12
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)OC(c5ccccc5)c5ccccc5)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetic acid (3.5 mg) in CH2Cl2 (0.2 ml) under N2 was added diphenyldiazomethane (ca. 20 mg) in portions during 15 minutes. The reaction stirred at room temperature for 2 hours, then additional diphenyldiazomethane (ca. 5 mg) was added and the reaction was allowed to stir overnight. The mixture was purified via preparative TLC on a silica gel plate (1000μ) developed with EtOAc to yield diphenylmethyl 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetate, (Rf=0.4/EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20]C(C)=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:28](Cl)[CH2:29]Cl.[CH:32]1[CH:33]=[CH:34][C:35]2[N:40](O)N=[N:38][C:36]=2C=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:28]([CH3:29])=[CH:22][C:23]=2[C:24]([N:40]2[CH2:32][CH2:33][CH2:34][C@@H:35]2[CH2:36][N:38]2[CH2:6][CH2:7][C@H:2]([F:1])[CH2:3]2)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCl
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC[C@@H]2CN2CC[C@H](F)C2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.28 mmol), EDC (120 mg, 0.63 mmol), HOBt (40 mg, 0.3 mmol) in DMF (4 mL) was added TEA (0.15 mL) and (S)-3-fluoro-1-(R)-1-pyrrolidin-2-ylmethyl-pyrrolidine (95 mg, 0.55 mmol). The mixture was stirred at rt for 20 hours. The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15](Cl)[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][C:35]2[C:36](=[O:42])[NH:37][C:38](=[S:41])[NH:39][CH:40]=2)[CH:31]=[N:30]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([S:41][C:38]3[NH:39][CH:40]=[C:35]([CH2:34][C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[C:36](=[O:42])[N:37]=3)[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CC(Cl)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Sc1nc(=O)c(Cc2cnn(C)c2)c[nH]1)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 130 °C
Yield: 5.6 %

Procedure:
To a suspension of 1-chloro-4-{[4-(1-chloroethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (150 mg, 0.448 mmol) and K2CO3 (124 mg, 0.895 mmol) in DMF (3 mL) was added 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (99 mg, 0.448 mmol). The mixture was heated with a microwave reactor at 130° C. for 15 min. Purification via reverse phase flash chromatography and MDAP then afforded the title compound (13 mg, 5.58% yield). LCMS: rt=3.65 min, [M+H+]=521
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C>C(O)(C)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:35])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]([NH:3][OH:2])=[NH:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:9][CH:10]=1
Reactant: [NH3+]O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C(=N)NO)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
199 mg of hydroxylammonium hydrochloride were added to a solution of 200 mg of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (8) and 0.45 ml of triethylamin in 15 ml of isopropanol. The mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 463.51 (C26H26F1N3O4); MS (ESI): 464.19 (M+H+).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18]>C1COCC1>[F:15][C:16]([F:24])([F:23])[C:17]([C:2]1[O:6][C:5]([C:7](=[O:9])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(Br)o1
Solvent: C1CCOC1
Product: CCCCC(=O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2-furoic acid (191 mg 1 mmol) in THF (8 ml), was added n-butyllithium in hexanes solution (2.5 M, 1.2 ml, 3 mmol) at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 30 minutes. Hexafluoroacetone (1.2 g, 7.3 mmol) was bubbled into the reaction mixture and the resulting solution was stirred for another 30 minutes at −78° C. The reaction mixture was allowed to warm to r.t. and then quenched with H2O. Solvent was evaporated, and the residue was dissolved in EtOAc. The organic layer was washed with H2O and brine, dried (MgSO4) and evaporated. The residue was purified by preparative TLC (hexanes:ethyl acetate, 2:1) to afford the title compound (109 mg) as a yellow oil. 1H NMR δ0.93 (t, 3H), 1.38 (m, 2H), 1.68 (m, 2H), 2.80 (t, 2H), 7.19 (d, 1H), 7.80 (d, 1H); ESIMS: m/z 319 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1c(F)ccc(C=O)c1Cl
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1c(F)ccc(/C=C/C(=O)O)c1Cl
Temperature: 90 °C
Reaction time: 3.67 h

Procedure:
To a mixture of 2-Chloro-4-fluoro-3-methoxybenzaldehyde (17.6 g, 93.3 mmol) and malonic acid (18.6 g, 179 mmol) was added pyridine (60 mL) followed by piperidine (1.6 mL, 19 mmol). The mixture was heated in a 90° C. oil bath giving a clear yellow solution. After 220 minutes, the hot solution was poured into 500 mL of ice cold 2.5N HCl with stirring. The resulting solid was isolated by filtration, washing thoroughly with water. Drying under vacuum gave (2E)-3-(2-chloro-4-fluoro-3-methoxyphenyl)acrylic acid as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=O.[NH2:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=1>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:26])[CH2:23][CH2:24][CH2:25][C:20]=3[NH:19][C:6]([CH3:7])=[C:5]2[S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: NC1=CC(=O)CCC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CC1=C(S(C)(=O)=O)C(c2ccc(Cl)c(Cl)c2)C2=C(CCCC2=O)N1

Procedure:
A solution of methanesulfonylacetone (135 mg, 1.00 mmol), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol (7 mL) was heated to reflux for 24 hours and cooled. The solid that precipitated was collected, washed with ethanol, dried, and triturated with methanol to provide the title compound. MS (APCI) m/e 386 (M+H)+, 388 (M+H)+; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.21 (m, 2H), 2.32 (s, 3H), 2.50 (m, 2H), 2.73 (s, 3H), 4.94 (s, 1H), 7.18 (dd, 1H), 7.34 (d, 1H), 7.53 (d, 1H), 9.48 (br s, 1H), Anal. Calcd for C17H17Cl2NO3S: C, 52.86; H, 4.44; N, 3.63. Found: C, 52.91; H, 4.31; N, 3.55.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].CO[C:13](OC)([CH3:15])[CH3:14].O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1>>[C:13](=[C:8]([OH:9])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]([OH:3])[C:1](=[C:19]([CH3:24])[CH3:20])[OH:10])([CH3:15])[CH3:14]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: COC(C)(C)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)=C(O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=C(C)C

Procedure:
In a 5 L round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were placed 1000 g of xylitol, 1916 g of 2,2-dimethoxypropane, and 37.5 mg of p-toluenesulfonic acid monohydrate and, with introduction of nitrogen thereinto, the reaction was carried out at 65° C. The solvent of the reaction solution was removed by distillation and purification by distillation (b.p. 108° C./0.15 mmHg) was performed to obtain an isomer mixture of 1,2,3,4-diisopropylidenexylitol (formula (5)) and 1,2,4,5-diisopropylidenexylitol (formula (6)). 1H-NMR (CDCl3, internal standard TMS) δ (ppm): 1.37-1.44 (12H, m, —C(CH3)2), 3.59-3.65 (1H, m, —CH—O—), 3.81-3.90 (2H, m, —CH2—O—), 3.98-4.01 (1H, m, —CH—O—), 4.04-4.10 (2H, m, —CH2—O—), 4.11-4.23 (1H, m, —CH—O—) 1H, m, —CH—O—)