Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][S:58](Cl)(=[O:60])=[O:59]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:58]([CH2:57][C:51]1[CH:52]=[CH:53][C:54]([Cl:56])=[CH:55][C:50]=1[Cl:49])(=[O:60])=[O:59])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)cc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 98 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added [(2,4-dichlorophenyl)-methyl]sulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 98% yield.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH:3]([CH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (15 g, 52.8 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 2.11 g, 52.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (12.6 g, 52.8 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (15.4 g, 66%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH2:38][N:1]5[CH2:2][CH2:3][CH:4]([C:7]6[CH:16]=[N:15][C:14]7[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=7)[N:8]=6)[CH2:5][CH2:6]5)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:18][CH2:19]1
Reactant: O=Cc1ccc(-c2nc3nc(C4CC4)nn3cc2-c2ccccc2)cc1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cn3nc(C4CC4)nc3nc2-c2ccc(CN3CCC(c4cnc5ccccc5n4)CC3)cc2)cc1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
125.3 mg (0.59 mmol) 2-Piperidine-4-ylquinoxaline are dissolved in 5.2 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.59 mmol) 4-(2-cyclopropyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (intermediate example 4.0) and 0.06 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 137 mg (0.65 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for four hours. Saturated NaHCO3 is added to the reaction mixture, the precipitate is filtered off and purified by chromatography on silica gel (dichloromethane/methanol). 157.8 mg (47.5%) of the pure product are obtained.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:40])[CH3:39])=[O:19])(=O)=O.[CH3:41][NH:42][CH3:43]>C(#N)C.O1CCCC1.C(OCC)(=O)C>[CH3:41][N:42]([CH3:43])[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:39])[CH3:40])=[O:19]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)CC#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of intermediate 183, 3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate (0.100 g, 0.18 mmol) in acetonitrile (5 ml) was treated at 22° C. with 0.3 ml (0.6 mmol) of a 2 M solution of dimethylamine in tetrahydrofuran and the resulting mixture was stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.080 g (88% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 2.43 (6H, s, 2×NCH3), 3.58 (2H, broad s, CH2), 4.05 (4H, m, 2×CH2), 4.70 (2H, d, J=6.0 Hz, NCH2), 5.30 (2H, s, OCH2), 7.01 (1H, m, aromatic), 7.18 (1H, dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32–7.38 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.79 (1H, broad t, NH). HRMS (ESI+) calculated for C29H32FN4O4 [M+H+]: 519.2408. Found: 519.2407.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[O:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[O:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][C:3]=2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:28])[CH2:23][CH2:22]1
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C1CCOCC1
Yield: 78.2 %

Procedure:
A solution of tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (1.2 g, 4.13 mmol, 1.0 eq.), tetrahydro-2H-pyran-4-carboxylic acid (0.65 g, 4.96 mmol, 1.2 eq.), HATU (3.14 g, 8.27 mmol, 2.0 eq.) and Hünigs base (1.80 mL, 10.33 mmol, 2.5 eq.) in DMF (15 mL) was stirred for 18 h at room temperature. The reaction mixture was diluted with water. The solid was isolated by filtration and washed with hexanes to afford tert-butyl (2-(tetrahydro-2H-pyran-4-carboxamido)-4-(thiophen-2-yl)phenyl)carbamate (1.3 g, 78% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[Cl:11][C:12]1[N:17]=[C:16](S(C)(=O)=O)[CH:15]=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([O:9][CH2:8][CH2:7][OH:10])[CH:15]=[CH:14][N:13]=1
Reactant: OCCO
Reactant: CS(=O)(=O)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCOc1ccnc(Cl)n1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (0.89 g, 6.45 mmol) was added at room temperature to an oven-dried, nitrogen cooled flask containing a suspension of ethylene glycol (1.3 mL, 23.4 mmol) in DMF (29 mL) and the mixture was then stirred for 15 minutes. 2-Chloro-4-(methylsulfonyl)pyrimidine (1.13 g, 5.86 mmol) was then added. The solution was stirred for 1.5 h at room temperature, then diluted with EtOAc (30 mL) and washed with 1:1 water:brine (3×50 mL). The organic extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford 2-[(2-chloropyrimidin-4-yl)oxy]ethanol as a pale yellow solid. MS ESI calcd. for C6H8ClN2O2 [M+H]+ 175. found 175.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: COCCn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 51 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 25% ethyl acetate/hexanes to 45% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (85 mg, 63%) as a white foam: [α]30589=−24.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C20H25N3O2Cl2 (M+H)+ 410.1397, observed 410.1396; 1H NMR (300 MHz, DMSO-d6) δ 1.09 (m, 2H, CH2), 1.38-1.79 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.4 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.12 (t, J=5.4 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.34 (dd, Jm=2.1 Hz, Jo=8.4 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.59 (d, Jo=8.4 Hz, 1H, Ar), 7.59 (d, Jm=2.1 Hz, 1H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C1CCCCC1.O.C([O-])([O-])=[O:17].[Na+].[Na+]>CCCCCC>[CH3:1][CH:2]1[O:17][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: CC1CCCCC1=O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CC1CCCCC(=O)O1
Reaction time: 3 h

Procedure:
3.15 g of 2-methylcyclohexanone and 3.85 g of cyclohexane percarboxylic acid, dissolved in n-hexane, are kept at 50° C. for 3 hours under agitation. The reaction product is treated with H2O, then neutralized with a solution of Na2CO3 and finally extracted with ethyl acetate. After solvent distillation, one obtains 3.3 g of 7-methyl-2-oxepanone, identified by mass spectrometry (EI, 70 eV), yielding the following m/e values: 128, 98, 80, 69, 55, 42.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH:23]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]=[C:43]=[O:44])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:2]=[O:3].[NH2:45][C:46]1[NH:47][C:48]([CH3:53])=[CH:49][C:50](=[O:52])[N:51]=1>N1C=CC=CC=1>[CH2:13]([CH:12]([CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH:45][C:46]1[NH:47][C:48]([CH3:53])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:1][C:2]([NH:45][C:46]1[NH:47][C:48]([CH3:53])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCC(CCCCCCCCN=C=O)C(CCCCCCCCCC)CCCCCCCCN=C=O
Reactant: Cc1cc(=O)nc(N)[nH]1
Solvent: c1ccncc1
Product: CCCCCCCCCCC(CCCCCCCCNC(=O)Nc1nc(=O)cc(C)[nH]1)C(CCCCCCCCCC)CCCCCCCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Reaction time: 24 h
Yield: 89.7 %

Procedure:
In a 250 mL round-bottomed flask fitted with a reflux condenser was added 11,12-bis(8-isocyanatooctyl)docosane (diamer diisocyanate, Cognis Corp.) (11.74 g, 19.03 mmol) and 2-amino-6-methylpyrimidin-4(1H)-one (5 g, 40.0 mmol) in Pyridine (50 mL) to give a white suspension. The mixture was heated to 95 deg/C. under argon and stirred for 24 h. The pyridine was removed and the residue was taken up in chloroform. The hazy solution was filtered and the resulting clear solution was concentrated to about 100 ml and the viscous solution was poured into a rapidly stirring solution (1.5 L) of MeOH upon which a white solid formed. The white powder was collected by vacuum filtration and dried at 50 deg for 24 h to give 1,1′-(9,10-didecyloctadecane-1,18-diyl)bis(3-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea) (14.8 g)
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:27]([S:30](Cl)(=[O:32])=[O:31])([CH3:29])[CH3:28]>CCCCCC.C(Cl)Cl>[C:1]1([C@@H:7]([CH3:10])[CH2:8][NH:9][S:30]([CH:27]([CH3:29])[CH3:28])(=[O:32])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](CN)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccccc1
Reaction time: 0.75 h
Yield: 92 %

Procedure:
To a solution of the (2R)-2-phenylpropylamine (1.2g, 8.87mmol) in hexane (16.0 mL) was added triethylamine (2.47 mL, 17.74 mmol) and dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5° C., then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with IN HCl (20.0 mL) and extracted organic with methylene chloride (25.0 mL). Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1%) an oil; 1H nmr (CDCl3, 300 MHz) δ 1.25 (d, 3H, J=6.9Hz), 1.29(d, 3H, J=6.9Hz), 1.30 (d, 3H, J=7.2 Hz), 2.98 (m, 1H), 3.05 (m, 1H), 3.22 (m, 1H), 3.36 (m, 1H), 3.89 (b, 1H), 7.23 (m, 2H), 7.34 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(2-tolyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave the crude product which was purified by column chromatography giving the pure product (gum). This gum was dissolved in 5 ml of NH4OH, concentrated and dried under high vacuum to get the ammonium salt of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide in 67% yield, m.p. 180-184° C. (NH3+ salt).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC#N.O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:2]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1H-pyrazol-3-yl)phenol (500 mg, 3.125 mmol), K2CO3 (517.5 mg, 3.75 mmol) and ethyl 2-bromoacetate (417.5 mg, 2.5 mmol) in MeCN (20 mL). The mixture was stirred at room temperature for 2 h, at which time TLC showed the completion of the reaction. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1F
Product: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1F

Procedure:
Ethyl 4-amino-2-fluorobenzoate (17 g), 4-chlorobenzaldehyde (14 g), and 100 ml of absolute alcohol are heated on a steam bath for 10 minutes. Upon cooling, the mixture is filtered. The residue is dried and then dissolved in 200 ml of hot ethanol and 4 g of sodium borohydride is added in portions with stirring. The mixture is then heated under reflux, with stirring, for 3 hours, cooled, added to ice water and filtered to yield ethyl 4-(p-chlorobenzylamino)-2-fluorobenzoate as a solid.
Reaction SMILES: CC1(C)O/[C:5](=[CH:7]/[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])/[CH2:4][O:3]1.[NH:15]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16]>C(O)(C)C>[Cl:23][C:22]1[C:17]([N:15]2[C:8]([OH:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][C:5]([CH2:4][OH:3])=[N:16]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: NNc1ncccc1Cl
Reactant: COC(=O)C(=O)/C=C1\COC(C)(C)O1
Solvent: CC(C)O
Product: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of methyl (3E)-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate (20 g, 0.1 mol) and 2-hydrazino-3-chloropyridine (21.4 g, 0.15 mol) in 150 ml of isopropanol was stirred for 8 hours at RT. The precipitate was filtered off and washed with hexane. This gave 27.6 g (85%) of the product as a pale yellow solid with a m.p. of 113-115° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:13].[CH:15](O)([OH:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC.C(OCC)C>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:5]3([O:17][CH2:15][CH2:16][O:13]3)[CH2:6][CH2:7][S:8][C:9]2=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: COC(OC)OC
Product: Cc1cc(Br)c(C)c2c1SCCC21OCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
58.4 g (0.22 mol) of 6-bromo-5,8-dimethyl-4-thiochromanone were dissolved in 380 ml of trimethyl orthoformate, admixed with 555 g (8.9 mol) of ethanediol and 0.2 g of p-toluenesulfonic acid monohydrate and stirred at 80° C. overnight. The mixture was subsequently allowed to cool, diluted with 500 ml of diethyl ether and washed with a 1:1 mixture of 1 M aqueous sodium hydroxide solution and sat. NaCl solution (2×500 ml) and subsequently with sat. NaCl solution (300 ml). The organic phase was dried over MgSO4 and concentrated using a rotary evaporator. The residue was taken up in 50 ml of heptaneldiethyl ether (9:1) and stored in a cold place. The crystals which had precipitated overnight were filtered off with suction, washed with cold heptane and dried.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[O:32]1[CH2:37][CH2:36][CH:35]([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:34][CH2:33]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A light suspension containing N-hydroxylphthalimide (18.4 mmol, 3.0 g), triphenylphosphine (18.4 mmol, 4.82 g), tetrahydro-4H-pyran-4-ol (18.4 mmol, 1.75 mL) and anhydrous THF (50 mL), were transferred to a flask containing di-tert-butyl azodicarboxylate (20.2 mmol, 4.66 g) under nitrogen. Over 2 hours the reaction stirred at room temperature and changed from a dark orange to yellow in appearance. The solvent was removed under vacuum and replaced with trifluoroacetic acetic acid (10 mL). The reaction was stirred for 30 minutes and the TFA was removed under vacuum. The crude residue was then dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, 5% aqueous solution of potassium carbonate, brine and dried over magnesium sulfate. The solvent was removed under vacuum and the residual triphenylphosphine oxide was crystallized and filtered using hexanes and ether. The solvent was again removed and the crude solid was purified by silica gel chromatography (2:1 hexanes/ethyl acetate) and recrystallization using methylene chloride and hexanes providing 1.69 g (37%) of a white crystal. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84-7.82 (2H,m), 7.75-7.73 (2H,m), 4.46-4.40 (1H,m), 4.08-4.02 (2H,m), 3.50-3.44 (2H,m), 2.04-1.98 (2H,m), 1.92-1.84 (2H,m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:41][CH2:42][CH2:43][C:44]#[N:45]>C(OCC)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH:45][CH2:44][CH2:43][C:42]#[N:41])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: N#CCCN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Reaction time: 0.08 h

Procedure:
(S)-2-t-Butoxycarbonylamino-3-biphenyl-4-yl-propionic acid (J. Org. Chem., 1992, 57, 379; 20 g, 58 mmol) in ethyl acetate (300 mL) and methylene chloride (75 mL) is cooled under nitrogen to 0° with an ice bath and treated with N-methylmorpholine (6.5 mL, 58 mmol). Isobutyl chloroformate (7.6 mL, 58 mmol) is added dropwise. After 5 minutes of stirring, 3-aminopropionitrile (4.52 g, 64 mmol) in methylene chloride (50 mL) is added over 4 minutes. Stirring is continued for 1 hour at 0° then for 4 hours at room temperature. Ethyl acetate (300 mL) is added and the solution is successively washed with cold water (100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with ether (150 mL). The solid is filtered off, washed with cold ether and dried under high vacuum to give (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide as a colorless crystalline solid, m.p. 163°-164°; [α]D =+3.58° (c 1, CHCl3).