Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][S:33]([CH3:32])(=[O:35])=[O:34])=[O:12])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 4-[4-chloro-3-(trifluoromethyl)phenoxy]benzamide (Preparation 46, 38 g, 120 mmol) in anhydrous THF (200 ml) was added 1.0M lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide solution in THF (301 ml, 301 mmol) at room temperature via syringe. After 30 minutes stirring, methanesulfonyl chloride (34.5 g, 301 mmol) was added to the reaction mixture, and the resulting mixture was stirred for 18 hours at room temperature. The reaction was quenched by addition of saturated aqueous NH4Cl solution. The solvent was reduced in vacuo and the residue was diluted with EtOAc (100 ml) and water (100 ml). The aqueous phase was acidified with 2N aqueous HCl solution and extracted with EtOAc (3×50 ml). The combined organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give an orange solid. The solid was purified by reverse phase column chromatography eluting with acetonitrile:water (plus 0.1% aqueous formic acid) 5:95 to 100:0. The purified material was partitioned between EtOAc (100 ml) and pH2 aqueous HCl solution. The combined organic phase was washed dried over MgSO4, filtered, and concentrated in vacuo to give 32 g of product as a white solid. The solid was recrystallised in IPA to give 24.9 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:18][OH:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:18][OH:19])[CH2:9][CH2:8]1
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Reactant: NO
Agent: Cl
Product: COc1cccc(CN2CCC(=NO)CC2)c1

Procedure:
1-(3-Methoxybenzyl)-4-piperidone oxime is prepared from 1-(3-methoxybenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:30])[N:6]([CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:7]2=[O:12].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([CH:13]([N:6]2[C:5](=[O:30])[C:4]3[C:8](=[CH:9][CH:10]=[CH:11][C:3]=3[CH2:2][NH:1][C:31](=[O:33])[CH3:32])[C:7]2=[O:12])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(C)=O)c3C2=O)ccc1OC
Temperature: 25 °C
Yield: 55 %

Procedure:
A stirred mixture of 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.92 g, 2.13 mmol) and acetic anhydride (10 mL) was heated at reflux for 40 min and then cooled to room temperature. Excess acetic anhydride was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with 2N hydrogen chloride (20 mL), water (20 mL), brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 75:25) to give N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (0.56 g, 55%) as a white solid: mp 84-86° C.; 1H NMR (CDCl3) δ 7.74-7.62 (m, 3H), 7.13-7.09 (m, 2H), 6.85-6.82 (m, 1H), 6.74-6.69 (m, 1H), 5.92-5.86 (dd, J=4.5, 10.1 Hz, 1H), 4.73 (d, J=6.3 Hz, 2H), 4.59-4.49 (dd, J=10.5, 14.2 Hz, 1H), 4.12 (q, J=6.8 Hz, 2H), 3.84 (s, 3H), 3.81-3.74 (m, 1H), 2.84 (s, 3H), 1.96 (s, 3H), 1.46 (t, J=6.9 Hz, 3H); 13C NMR (CDCl3) δ 170.15, 168.58, 167.77, 149.64, 148.54, 138.05, 135.38, 134.39, 132.07, 129.32, 128.21, 122.73, 120.40, 112.41, 111.37, 64.45, 55.88, 54.61, 48.65, 41.55, 39.42, 23.08, 14.62; Anal. Calcd. for C23H26N2O7S: C, 58.22; H, 5.52; N, 5.90; S, 6.76. Found: C, 57.87; H, 5.52; N, 5.65; S, 6.66.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:22]([O:24][C:25]1[C:26](=O)[C:27](=[O:32])[C:28]=1[O:29]CC)[CH3:23]>C(O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:26]1[C:27](=[O:32])[C:28](=[O:29])[C:25]=1[O:24][CH2:22][CH3:23]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1c(N[C@@H](Cc2ccccc2)C(=O)OC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a stirred solution of L-phenylalanine methyl ester HCl (2.0 mmol, 431 mg) in absolute ethanol (20 mL) was added triethylamine (2.2 mmol, 202 mg; 278 μL) and the resulting solution was stirred at room temperature for 15 minutes. Subsequently, neat 3,4-diethoxy-3-cyclobutene-1,2-dione (2 mmol, 340 mg; 296 μL) was added dropwise and the resulting solution was stirred at room temperature overnight, during which a white solid precipitated out of solution. The volatiles were removed in vacuo and the residue was taken up in EtOAc and partitioned between EtOAc and water. The organics were dried (Na2SO4) and purified by flash chromatography (SiO2 :1) 20% EtOAc/hexane; 2) 30% EtOAc/hexane; 3) 40% EtOAc/hexane) to afford the title compound as a colorless oil (551 mg; 85%).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8]/[C:9](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)/[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.N1C=CC=CC=1>[C:34]1([O:11][C:10](=[O:12])/[C:9](/[CH3:8])=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)C(=O)O
Reactant: Oc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C/C(=C\c1ccc(Cc2cccnc2)cc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of 105 mg of pivaloyl chloride in one ml of methylene chloride was added to a solution of 200 mg of the acrylic acid(prepared as described in Example 15) and 0.1257 ml of triethylamine in 5 ml of methylene chloride at room temperature, and the mixture was stirred at room temperature for one hour. To it were added 1.47 g of phenol and 1.323 ml of pyridine, the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:2) as eluent to give 158 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2N=[N:11][CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].[CH2:16](OC(=O)C1C=CN=C(C)C=1Cl)[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[C:16]([CH3:17])[N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2c(C)nccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 3-chloro-2-methylisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester. Purification by CC (KP-SIL™ from Biotage) using EtOAc/MeOH (8/2) gives the desired product as brown solid;
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:2].C(Cl)Cl.[C:24]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:24]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:3]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:1][CH3:2])=[O:36])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CCN[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)c1ccccc1C(=O)c1ccccc1)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1

Procedure:
Twenty-four grams of trans N-(2-ETHYLAMINOCYCLOHEXYL)-p-TOLUENESULFONAMIDE from Example III,200 ml of methylenechloride, 24ml of triethylamine and 20 grams of ψ-acid chloride of o-benzoylbenzoic acid were mixed together and refluxed 4 hours. The mixture was extracted successively with water, 15% hydrochloric acid, and saturated sodium carbonate solution. The methylenechloride solution was dried over magnesium sulfate, then evaporated to dryness. The residue was slurried with ethyl acetate and filtered. Recrystallization from ethyl acetate afforded trans-2-BENZOYL-N-[2-(p-TOLUENESULFONAMIDO)CYCLOHEXYL]-N-ETHYL BENZAMIDE, mp. 201.5°-204°C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.[NH:32]=[C:33]([NH:35][NH:36][C:37](=O)[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[N:46][N:47]3[CH:52]=[CH:51][C:50]([N:53]4[C@@H:57]([CH:58]([CH3:60])[CH3:59])[CH2:56][O:55][C:54]4=[O:61])=[N:49][C:48]=23)=[CH:40][CH:39]=1)[CH3:34]>ClCCl.CC#N.CCOC(C)=O>[CH:58]([C@H:57]1[CH2:56][O:55][C:54](=[O:61])[N:53]1[C:50]1[CH:51]=[CH:52][N:47]2[N:46]=[CH:45][C:44]([C:41]3[CH:40]=[CH:39][C:38]([C:37]4[NH:32][C:33]([CH3:34])=[N:35][N:36]=4)=[CH:43][CH:42]=3)=[C:48]2[N:49]=1)([CH3:59])[CH3:60]
Reactant: CC(=N)NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4C(C)C)nc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5C(C)C)nc34)cc2)[nH]1
Temperature: 50 °C
Yield: 18.3 %

Procedure:
PS-Triphenylphosphine resin (Biotage, catalog No. 800380, 2.28 mmol/g, 0.167 g, 0.38 mmol)triethylamine (0.132 mL, 0.95 mmol), and CCl4 (40 μL, 0.38 mmol) were added to a suspension of (S)—N′-(1-iminoethyl)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (40 mg, 0.095 mmol) in dichloromethane (3 mL) and MeCN (3 mL), and the reaction mixture was heated to 50° C. for 2 hours. After cooling to ambient temperature, the mixture was treated with EtOAc, washed with water, dried over MgSO4, concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography (4% MeOH in dichloromethane) to afford 7 mg (18%) of (S)-4-isopropyl-3-(3-(4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one. 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.70 (d, 1H), 8.48 (s, 1H), 8.13 (m, 2H), 8.05 (m, 3H), 5.05 (m, 1H), 4.50 (m, 2H), 2.92 (m, 1H), 2.52 (s, 3H), 1.12 (d, 3H), 0.96 (d, 3H); LCMS (APCI+) m/z 404.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (20 g, 0.163 mol, 1 equiv.) in CH2Cl2 (340 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.7 g, 0.18 mol, 1.1 equiv.), acetic acid (2.8 mL, 0.05 mol, 0.3 equiv.) and sodium triacetoxyborohydride (41.4 g, 0.195 mol, 1.2 equ iv.). The reaction was stirred at rt for 16 h. The reaction was quenched with satd. aq. NaHCO3 (3×150 mL) and 1 M NaOH (1×100 mL). The combined aqueous layers were reacidified with 1 M HCl and extracted with CH2Cl2 (2×300 mL). The organic layers were dried, filtered, and concentrated. Purification by column chromatography (5% MeOH/CH2Cl2) yielded product as a white powdery solid (24.4 g, 50%). 1H NMR (500 MHz, CDCl3): 7.16 (d, J=8.5, 2H), 6.74 (d, J=8.5, 2H), 4.37 (s, 0.5H), 4.25 (s, 0.5H), 3.65 (s, 2.5H), 3.52 (s, 0.5H), 3.47 (s, 1H), 3.16 (d, J=10.3, 1H), 2.92 (s, 0.5H), 2.82 (s, 0.5H), 2.72 (s, 0.5H), 2.57 (d, J=9.6, 0.5H), 1.85 (s, 1H), 1.74-1.62 (m, 1H), 1.47 (s, 9H). MS (ESI): mass calcd. for C17H24N2O3, 304.38; m/z found, 305.2 [M+H]+.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O>[CH:9]([C:15]1[S:14][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:12]([CH3:11])[CH:16]=1)=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C=O)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.35 mol (32 mL) of POCl3 was added at 0° C. to a 1.0 mol (77 mL) of DMF (excess of DMF used as solvent). At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 3-methyl-2-phenylthiophene (60 g, 0.35 mol). The resulting reaction mixture was allowed to reach room temperature and after 12 h stirring at the same temperature was heated at 80° C. for 2 days. Then it was poured into a mixture of ice and water, added of sodium acetate and extracted with CHCl3 (3×150 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and evaporated off to dryness. The residue was crystallized. Yield 60.2 g (85%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:39](O)[CH2:40][CH:41]([OH:43])[CH3:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:39][CH2:40][CH:41]([OH:43])[CH3:42])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(O)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCC(C)O
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A stirred solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (2.86 g, 10 mmoles; prepared according to Preparation B), triphenylphosphine (2.62 g, 10 mmoles), (±) 1,3 butandiol (0.90 g, 10 mmoles) in dry tetrahydrofuran (50 ml) was treated dropwise with diethyl azodicarboxylate (1.75 g of 95% purity material, 10 mmoles). The solution was left to stir overnight. After evaporation of the solvent the residue was taken up in methylene chloride. The solution was washed with 0.4N NaOH, water, dried and the solvent evaporated. The residue was chromatographed over deactivated silica using methylene chloride (100), methanol (3), ammonium hydroxide (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated. The residue was crystallized from methylene chloride-pentane to yield 1.05 g (29%) of the title compound. m.p. 136.5°-137.5° C. An additional amount of 0.56 g of material was obtained from the mother liquor after crystallization from toluene, followed by recrystallization from methylene chloride-pentate, and from a dilute solution of ethyl acetate, m.p. 135°-137° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[CH2:10][CH2:11][CH:12]([C:30](N1C(C2C=CC=CC=2)COC1=O)=[O:31])[CH:13]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>COC(C)(C)C>[Si:1]([O:8][CH:9]([C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[CH2:10][CH2:11][CH:12]1[C:30](=[O:31])[N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1cccc(C#N)c1)c1ccc(F)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1cccc(C#N)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Under argon, a mixture of 13 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-fluorophenylamino)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl]benzonitrile 12, 50 ml of bistrimethylsilylacetamide, 0.5 g of tetrabutylammonium fluoride and 100 ml of tert-butyl methyl ether is stirred at room temperature for 10 h. After the reaction has ended, 5 ml of acetic add are added slowly with ice-cooling, and the mixture is concentrated. The residue is separated by silica gel chromatography (ethyl acetate/heptane=⅛). This gives 13:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[C:9](I)=[CH:10][C:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:12][C:5]=2[CH2:4][CH2:3]1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:10][C:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:12][C:5]=2[CH2:4][CH2:3]1
Reactant: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(I)c2CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(-c3ccccc3)c2CC1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
A mixture of 3-methyl-7-(4fluorophenylsulfonyl)-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (0.9 g, 2 mmol), phenylboronic acid (0.4 g, 3 mmol), potassium carbonate (1.6 g, 12 mmol), ethanol (6 ml), water (6 ml), and toluene (25 ml) was degassed, then tetrakis(triphenylphosphine)palladium (0) (100 mg) was added and the mixture heated at 60° C. for 18 h. After cooling the mixture was poured into water (50 ml) and extracted with more ethyl acetate (50 ml). The resulting organic layer washed with brine (100 ml), dried (MgSO4), and evaporated. Isolation using an SCX column and subsequent chromatography on silica eluting with 0 to 10% methanol in dichloromethane containing 0.1M ammonia, gave the title compound as a white foam (0.6 g). 1H NMR δ (d6-DMSO) 2.2 (3H, s), 2.5 (4H, m), 2.8 (2H, m), 3.1 (2H, m), 7.2 (2H, m), 7.4 (5H, m), 7.6 (1H, s), 7.8 (1H, s), and 8.1 (2H, m).
Reaction SMILES: [OH:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[OH-].[NH4+:12]>>[NH4+:12].[OH:1][C:2]([CH3:10])([CH2:8][C:7]([O-:6])=[O:9])[CH2:3][C:4]([NH2:12])=[O:5]
Reactant: CC1(O)CC(=O)OC(=O)C1
Agent: [NH4+]
Agent: [OH-]
Product: CC(O)(CC(N)=O)CC(=O)[O-]
Reaction time: 0.17 h

Procedure:
1.7 g. (0.011 moles) of 3-hydroxy-3-methylglutaric acid anhydride (prepared according to the method of Hilz, et al, Biochem Zeit, 329, 476-489 (1958)) in 30 ml of 15 N ammonium hydroxide is allowed to stand at 25° C. for 10 minutes. The solution is then evaporated to dryness under vacuum and the resulting residue dissolved in 10 ml of warm methanol. Ethyl acetate (10 ml) is then slowly added to the methanol solution. Upon cooling, 1.5 g. of 3-hydroxy-3-methylglutaric acid monoamide, ammonium salt is obtained as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].CC(OC)(C)C.[C:27]1(=[O:32])[CH2:31][CH2:30][CH:29]=[CH:28]1>O1CCOCC1.O.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:29]2[CH2:30][CH2:31][C:27](=[O:32])[CH2:28]2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=C1C=CCC1
Reactant: CC1(C)OB(c2ccc(Br)c(C(F)(F)F)c2)OC1(C)C
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: O
Product: O=C1CC[C@@H](c2ccc(Br)c(C(F)(F)F)c2)C1

Procedure:
2-[4-bromo-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 g, 8.5 mmol) (Preparation 5) and [Rh(R-BINAP)(nbd)]BF4 (155 mg) were dissolved in a de-gassed solution of 2-cyclopenten-1-one (0.70 g) in 1,4-dioxane (12.8 mL), water (2.5 mL), and triethylamine (1.2 mL) in a microwave vial and irradiated in a microwave reactor at 120° C. for 5 min. MTBE was added and the mixture was washed 3 times with water. The organic phase was dried, concentrated under reduced pressure and purified by flash chromatography (100% heptane->70% EtOAc/Heptane) to obtain the title compound. 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J=8.2, 1H), 7.57 (d, J=2.2, 1H), 7.28 (dd, J=8.4, 2.3, 1H), 3.51-3.36 (m, 1H), 2.76-2.64 (m, 1H), 2.56-2.23 (m, 4H), 2.06-1.89 (m, 1H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:15])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:3]>CO.N.[Ni]>[NH2:3][CH2:2][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:15])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NCC(O)COc1ccc(Cl)cc1C#N
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1CN

Procedure:
6.3 gm (0.02 mol) of 1-(2-cyano-4-chlorophenoxy)-2-hydroxy-3-tert.-butylamino propane hydrochloride were dissolved in 100 ml of methanol containing 10 ml of NH3 and the mixture was hydrogenated under normal pressure at 20°C over Raney-nickel. After separation of the catalyst, the solvent was distilled off in vacuo, and the residue was admixed with ether and water. After an addition of a small amount of NaOH, the aqueous phase was separated and the organic phase was washed with water and dried over MgSO4. After distilling off the ether, a solid residue remained which was recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(2-aminomethyl-4-chlorphenoxy)-2-hydroxy-3-tert.-butylamino propane. The base was dissolved in ethanol and ethereal HCl was added thereto. The precipitated crystals of the hydrochloride of the base were isolated to obtain 3.1 gm of the hydrochloride having a melting point of 118° - 120°C.