Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:19][NH:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
Tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (1.0 g, 4.38 mmol) was dissolved in DCM (40 ml) and treated with 36.5% formaldehyde solution (326 μl, 4.38 mmol) followed by acetic acid (1 drop). The reaction mixture was stirred for 20 mins and treated with sodium triacetoxyborohydride (93 mg, 0.438 mmol). The resulting mixture was stirred at ambient temperature for 16 hrs and quenched with 2M NaOH (40 ml). The mixture was extracted with DCM (2×100 ml) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate as an oil;
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[S:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]2OCC[O:48]2)[C:44]([CH3:52])=[CH:43][C:42]=1[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]=[O:48])[C:44]([CH3:52])=[CH:43][C:42]=1[O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-(1,3-dioxolan-2-yl)-4-methylphenyl]-5-thio-D-glucopyranose (11.1 g, 13.5 mmol) in tetrahydrofuran (100 mL), 6N hydrochloric acid (100 mL) was added under ice cooling and stirred at room temperature for 12 hours. After addition of water under ice cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (10.1 g, quant.) as a light-yellow oily compound.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:7]1[S:8][C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])=[O:6])C.Cl>CC(C)=O.O>[Cl:12][C:11]1[C:10]([Cl:13])=[C:9]([Cl:14])[S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(=O)c1sc(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C(=O)c1sc(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of (3,4,5-trichlorothiophen-2-yl)-oxo-acetic acid ethyl ester (0.25 g, 0.86 mmol) in acetone (6 ml), water (2 ml), and conc. HCl (6 ml) was stirred under reflux for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature then evaporation of acetone gave rise to solids which were collected, washed with water and dried. (3,4,5-trichlorothiophen-2-yl)-oxo-acetic acid was thus obtained as a light yellow solid (99 mg, 50%). MS (M−H)−: 258.74; 13C NMR (75 MHz, DMSO-d6) δ174.16, 162.74, 134.73, 130.43, 125.92, 125.26. IR (KBr) cm−1 3547.5, 2855.3, 2515.5, 1924.8, 1716.3, 1667.1, 1405.7, 1339.7, 1305.4
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (1.0 g) in pyridine (10 ml) is added dropwise methanesulfonyl chloride (0.92 g) at ice-bath temperature. After stirring for 1 hour at ice-bath temperature, the mixture is stirred for 30 minutes at room temperature, and then cooled. After addition of water (1 ml), the mixture is stirred for 30 minutes at ice-bath temperature, and ice bath is removed. The mixture is stirred for 30 minutes at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract is washed successively with 10% hydrochloric acid, water, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (1.1 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:4].[C:37]([N:44]([CH3:50])[C@H:45]([C:47](O)=[O:48])[CH3:46])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:40]([O:39][C:37]([N:44]([CH3:50])[C@@H:45]([CH3:46])[C:47]([NH:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:4])=[O:48])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 88.5 %

Procedure:
Amine 5 (12.57 g, 25.5 mmol) is then coupled with BOC-N-methyl-L-alanine (5.18 g, 25.5 mmol) using DIEA (22.3 mL, 0.13 mol), HBTU (10.64 g, 28.1 mmol) and HOBt (3.79 g, 28.1 mmol) in DMF (550 mL) under the same conditions as in step 1 above. Purification is carried out by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 50% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (15.30 g, 89% yield): 1H NMR δ (CDCl3) 7.28-7.38 (br m, 5H), 7.03-7.19 (br m, 4H), 6.73 (br s, 1H), 6.02-6.35 (br m, 1H), 5.05-5.26 (br m, 4H), 3.84-4.82 (br m, 5H), 2.68-3.56 (br m, 9H), 1.70-2.07 (br m, 5H), 1.47 (s, 9H), 0.60-1.33 (br m, 8H); LCMS (APCl+) 679.0 (MH+), 579.0 (MH+-BOC, 100%); HPLC(C18 column) 99.4%.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]2[CH2:31][C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:26]([NH:29][C:30](=[O:32])/[C:31]/2=[CH:17]\[C:14]2[NH:13][C:9]3[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=3[C:15]=2[CH3:16])=[N:27][CH:28]=1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ncc(Br)cc43)c(C)c2C1=O
Yield: 33.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 14 (23 mg, yield 33.8%) as an orange solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH:4]1[C:9]([OH:11])=[O:10].[CH3:12]O>>[CH3:12][O:10][C:9]([C@H:4]1[C@@H:3]([OH:2])[CH2:8][CH2:7][CH2:6][NH:5]1)=[O:11]
Reactant: O=C(O)C1NCCCC1O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1NCCC[C@@H]1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Hydrogen chloride gas was bubbled through a suspension of 3-hydroxy-piperidine-2-carboxylic acid (0.54 g, 0.370 mol) in MeOH (100 mL) cooled to 0° C. for 10 min. The resulting clear solution was stirred at rt for 4 h, then evaporated carefully under reduced pressure (white precipitates formed during the concentration). The resulting white solid was dried overnight under vacuum to afford 0.86 g of the title compound as an off-white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[C:9]([I:16])[CH:8]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[F:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:14])=[C:9]([I:16])[CH:8]=1
Reactant: CC(O)c1cnc(F)cc1I
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(OS(C)(=O)=O)c1cnc(F)cc1I
Reaction time: 4 h
Yield: 64.2 %

Procedure:
Add methanesulfonyl chloride (1.93 g, 16.8 mmol) to a solution of 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethanol (1.5 g, 5.6 mmol) and diisopropylethylamine (2.2 g, 16.8 mmol) in DCM (50 mL) at 0° C. Continue to stir the mixture at 0° C. to RT for 4 h. Dilute the reaction mixture with diluted sodium carbonate. Extract the product into chloroform. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo. Purify the crude by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a white solid (1.24 g, 64%). MS (ES) m/z 346 [M+1]+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:21](=O)[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:8]1=2)=[O:6])([CH3:3])[CH3:2]>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:23]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccnc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccnc1
Temperature: 70 °C
Yield: 21.6 %

Procedure:
Add a solution of borane-THF complex in THF (1.0 M, 0.2 mL, 0.2 mmol) to 5-[(3,5-Bis-trifluoromethyl-benzoyl)-pyridin-3-yl-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (90.1 mg, 0.139 mmol) in THF (1.6 mL). Heat in a sealed tube (70° C.) for 14 h. Add saturated aqueous sodium bicarbonate (5 mL) and extract with EtOAc (3×5 mL). Dry (MgSO4), concentrate, and purify via column chromatography (silica gel; 10% to 20% to 25% EtOAc:hexanes) to give 19 mg (22%) of the title compound as a yellow solid. APCI MS m/z 634 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](I)[CH:3]=1.[Li]C(CC)C.CCCCCC.C(=O)=O.[CH3:24][C:25]([CH3:27])=[O:26].B(F)(F)F>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:24][C@H:25]([OH:26])[CH3:27])[CH:3]=1
Reactant: Cc1ccc(F)cc1I
Reactant: CC(C)=O
Agent: FB(F)F
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(F)cc1C[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven dried 3-necked round bottom flask (rbf), which contained a magnetic stirring bar, was sealed with rubber septum having a thermometer. While cooling to rt, the flask was evacuated and backfilled with argon. This sequence was repeated 3 times. In the flask, a solution of 4-fluoro-2-iodo-1-methylbenzene (25 g, 105.9 mmol) in anhydrous THF (800 mL) was stirred at −78° C. in a dry ice/acetone bath under argon gas. After 30 min, 1.4 M sec-BuLi in hexane (83.2 mL, 116.5 mmol) was added dropwise at that temperature for 20 min. After adding, the mixture was stirred at −78° C. in the dry ice/acetone bath for 30 min, and stirred more for 30 min without the bath. And then, the solution was cooled again in the dry ice/acetone to −78° C. and a solution of R-(+)-propylene (8 g, 137.7 mmol) in 50 mL anhydrous THF was added dropwise at the temperature for 10 min. And then, the mixture was cooled to −105° C. and 46.5% solution of BF3 in diethyletherate (19.6 mL) was added dropwise. And the mixture was stirred at −78° C. for 2 h, and then quenched slowly by sat. NH4Cl at −78° C. and stirred at ambient temperature for overnight. Water (20 mL) was added and extracted with EtOAc, dried over anhydrous MgSO4, evaporated and purified by column chromatography (DCM/hexane 9/1) to give (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (F-1) as pale yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21](=O)[CH2:22][C:23](=O)[CH3:24])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.[CH:50]1([NH:54][NH2:55])[CH2:53][CH2:52][CH2:51]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:21]1[N:54]([CH:50]2[CH2:53][CH2:52][CH2:51]2)[N:55]=[C:23]([CH3:24])[CH:22]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O
Reactant: NNC1CCC1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as colorless oil. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C>C(Cl)(Cl)Cl>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NCCCN2CCOCC2)cc1
Solvent: ClC(Cl)Cl
Product: Nc1ccc(S(=O)(=O)NCCCN2CCOCC2)cc1
Yield: 701.4 %

Procedure:
The mixture of 3.4 g (0.001 mol) of 4-acetamido-N-(3-morpholinopropyl)benzene sulphonamide XIII and 4 ml of 17% acid was heated for 3.5 hours until slight boiling under stirring. The mixture was cooled to the room temperature and neutralized to chloroform. The solvent was distilled off from the solution and the distillation residue-oil was macerated with ether. Afforded 2.1 g of (71%) 4-amino-N-(3-morpholinopropyl)benzenesulphonamide XIV. Colourless solid, m.p. 96-97° C. Lit. [8] reports 95° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27]O)[CH3:23].CS(Cl)(=O)=O>CN(C=O)C>[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCN(CC)CCCO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(C(C)=O)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H2O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1–4% MeOH/DCM).
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[Na+].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1.Cl>CN(C=O)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])([CH3:16])[CH3:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)c1ccc(S(=O)[O-])cc1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)no1
Temperature: 50 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a solution of 160 mg (0.55 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide in DMF (3 mL) were added 181 mg (0.71 mmol) of 4-methanesulfonyl-benzenesulfinic acid sodium salt in one portion. Pyridine (48 μL) was added and the reaction was stirred at 50° C. for 18 h. The mixture was acidified with 1M aqueous HCl solution (1 mL) and extracted with diethyl ether (3×3 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by column chromatography (silica, eluent heptanes, 0-20% ethyl acetate) to afford 47 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-propionamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](I)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.Cl>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
Mix 1-fluoro-3-iodo-5-nitro-benzene (1 g, 3.75 mmol), tributyl(1-ethoxyvinyl)stannane (1.5 g, 4.15 mmol) and Pd(dppf)Cl2 (78 mg, 0.1 mmol) in toluene (5 mL) under N2. Stir at 100° C. under N2 atmosphere for 3 hrs. Cool to room temperature, add 1N HCl solution (5 mL) and stir for 20 min. Load directly onto silica gel column and purify by chromatography (EtOAc:PE=3:7) to give the title compound (660 mg, 96%).
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:4]1[CH3:28].C([O-])(=O)C.[NH4+:33]>C(O)C>[NH2:33][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:4]1[CH3:28]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CO)C2=O
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CN)C2=O

Procedure:
A mixture of 5.0 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, benzyl ester and 5.0 g. of ammonium acetate in 200 ml. of ethanol is heated to reflux for 35 min. The reaction mixture is concentrated to dryness and the residue taken up in 200 ml. of chloroform. The chloroform solution is then washed successively with water (1 × 100 ml.), 1N aqueous sodium hydroxide (2 × 100 ml.) and brine (1 × 100 ml.), dried over magnesium sulfate and concentrated to dryness. The residual oil is crystallized from ethyl acetate, 3.34 g., m.p. 143°-149.5°C. and 1.3 g. recrystallized from the same solvent, 660 mg., m.p. 144°-146.5°C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH3:33][N:34]1[C:38]([CH3:39])=[C:37]([CH2:40][NH2:41])[C:36]([CH3:42])=[N:35]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:41][CH2:40][C:37]1[C:36]([CH3:42])=[N:35][N:34]([CH3:33])[C:38]=1[CH3:39])=[O:4]
Reactant: Cc1nn(C)c(C)c1CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nn(C)c(C)c1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (1,3,5-trimethyl-1H-pyrazol-4-yl)methanamine-HCl (18.33 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)acetamide (17.2 mg, 0.031 mmol, 44.8% yield): LCMS=553.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.28 Hz), 7.50-7.69 (8H, m), 5.10 (1 H, s), 4.19 (2 H, d, J=5.27 Hz), 3.65 (3 H, s), 2.17 (3 H, s), 2.12 (3 H, s); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: CCOC(O)C(OCC)=O.C(N)(=O)C=C.C([O:18][CH:19]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[C:26]([NH:25][CH:19]([OH:18])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:29])[CH:27]=[CH2:28]
Reactant: C=CC(=O)NC(OCC)C(=O)OCC
Agent: C=CC(N)=O
Agent: CCOC(=O)C(O)OCC
Product: C=CC(=O)NC(O)C(=O)OCC
Reaction time: 2.5 h

Procedure:
Ethyl glyoxylate hemiacetal obtained from Example A in the amount of 29.5 parts (0.2 mole) is employed along with 14.3 parts (0.2 mole) of acrylamide following the procedure of Example I. The reaction is run at 70°-85° C. for 2.5 hours. Analysis of the product by 13C NMR shows a 90% conversion with a 90% selectivity to ethyl acrylamidoglycolate ethyl ether are also found.