Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][OH:8])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][O:8][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1COC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (±)-cis-3-ethyl-4-hydroxymethyl-N-toluenesulfonyl-2-azetidinone (3.3 mg) and p-methoxyphenylacetic acid (3.7 mg) in CH2Cl2 (0.6 ml) was added dicyclohexylcarbodiimide (DCC) (5 mg) followed by p-dimethylaminopyridine (DMAP) (1 mg). The mixture was stirred overnight, at room temperature and then purified via preparative tlc on a silica gel plate and developed with CH2Cl2 to yield the titled compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:31])[CH:7](P(OCC)(OCC)=O)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=1)[CH3:4].C(=O)C.[CH2:35]1[CH2:39]O[CH2:37][CH2:36]1>>[CH2:3]([O:5][C:6](=[O:31])[C:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:13][CH:14]=1)=[C:35]([CH2:36][CH3:37])[CH3:39])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)P(=O)(OCC)OCC
Reactant: C1CCOC1
Agent: CC=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)=C(C)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (278.8 mg, 60% in mineral oil, 6.97 mmol) in THF (25 mL) at 0° C. was added a solution of 3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-(diethoxyphosphoryl)-propionic acid ethyl ester (2.5 g, 5.81 mmol) in THF (30 mL). The reaction mixture was allowed to stir at 0° C. for 1 h. To the reaction was added acetaldehyde (512 mg, 11.6 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and then stir for 16 h. Acetaldehyde (2.0 g) was added to the reaction vessel and the reaction mixture was allowed to stir at room temperature for an additional 16 h. The reaction was quenched with the slow addition of saturated aqueous ammonium chloride (30 mL). The mixture was extracted with EtOAc, washed with brine and dried to afford the crude product. The crude product was purified by column chromatography (EtOAc/hexane, 1:8) to give ethyl 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-but-2-enoic acid ethyl ester as a mixture of isomers (1.1 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[C:29]([NH:36][CH2:37][CH2:38][NH2:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:39][CH2:38][CH2:37][NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Example 3, Step A (400 mg, 0.789 mmols) in 5 mL of CH2Cl2, Boc-ethylenediamine (0.137 mL, 0.868 mmol) and triethylamine (0.22 mL, 1.6 mmol) were added. The reaction stirred at room temperature for 2 days, then poured into EtOAc, washed with saturated NaHCO3 solution and brine. The solution was dried over Na2SO4 and concentrated in vac o. Purification by flash chromatograpy using EtOAc:hexane (1:3) gave the titled compound. ESI+ MS: 530 [MH-Boc]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([N:34]=[C:35]=[O:36])[CH2:32][CH3:33]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:35]([NH:34][CH2:31][CH2:32][CH3:33])=[O:36])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CCCN=C=O
Product: CCCNC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}3-propyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and n-propyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.33 min (Grad 2); ES-MS: m/eo=484.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[N:17]([CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:18](=[O:22])[N:19]([CH3:21])[N:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH:24]1([CH2:23][N:17]2[C:18](=[O:22])[N:19]([CH3:21])[N:20]=[C:16]2[CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:7]=[CH:6][CH:5]=3)[CH2:13][CH2:12]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(CCN2CCN(c3cccc(N)c3)CC2)n(CC2CCCCC2)c1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(N2CCN(CCc3nn(C)c(=O)n3CC3CCCCC3)CC2)c1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 5-{2-[4-(3-aminophenyl)piperazino]ethyl}-4-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (D16; 450 mg, 1.129 mmol) in dry pyridine (5 mL), acetic anhydride (0.112 mL, 1.185 mmol) was added at room temperature. The reaction mixture was stirred for 1 h, toluene (30 mL) was added and the solvents were removed in vacuo to afford a light-brown solid. Purification by preparative LC-MS afforded 133 mg (27%) of the title compound as a light brown powder.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[CH3:31][O:30][C:23]1[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:32])[CH:20]=1
Reactant: COc1cccc(-c2cc(C)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.094 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.40 mmol) and methylamine (0.123 g, 4.0 mmol). mp 85-89° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O-:9])=[O:8])=[C:4]([CH3:10])[CH:3]=1.N1C=CC=[CH:13][CH:12]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>ClCCl>[CH3:10][C:4]1[CH:3]=[C:2]([NH:1][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[S:6][C:5]=1[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: c1ccncc1
Reactant: Cc1cc(N)sc1C(=O)[O-]
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)Oc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred mixture of 5-amino-3-methylthiophene-2-carboxylate (11.87 g, 64.08 mmol) and pyridine (5.70 mL, 70.48 mml) in dichloromethane (140 mL) at 0° C. was added dropwise phenyl chloroformate (8.90 mL, 70.71 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes, and then quenched with water (200 mL). The aqueous layer was extracted with dichloromethane (2×200 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford ethyl 3-methyl-5-(phenoxycarbonylamino)thiophene-2-carboxylate as a colorless solid (18.89 g, 96%): MS (ES+) m/z 306.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][OH:14])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-:15].[Na+:16]>C(O)C>[OH2:9].[OH2:15].[Na+:16].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][OH:14])[C:8]([O-:10])=[O:9])[N:6]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(C(=NO)C(=O)[O-])cs1
Product: O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate (syn-isomer) (24.0 g) was suspended in ethanol (26 ml), and 1N aqueous sodium hydroxide (125 ml) was added dropwise thereto for one hour under stirring at 45° C. After the dropwise addition, the mixture was stirred for two hours at the same temperature. The reaction mixture was cooled to 5° C. and stirred for one hour. The precipitate was filtered and collected, washed with ethanol, and dried under vacuum to obtain 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate sodium dihydrate (syn-isomer) (24.6 g).
Reaction SMILES: O.C1(=O)CCCCC1.[N+:9]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]2[CH2:23][O:22][CH2:21][CH2:20][O:19]2)=[CH:14][CH:13]=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)(=O)C>[NH2:9][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]2[CH2:23][O:22][CH2:21][CH2:20][O:19]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCC2COCCO2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C1CCCCC1
Solvent: CC(=O)O
Product: Nc1ccc(OCC2COCCO2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
46.2 g of iron filings, 46 ml of water and 9 ml of glacial acetic acid are stirred for 30 minutes at 95° C. Then 150 ml of cyclohexanone are added and, when the temperature has again risen to 95° C., 36.8 g of (p-nitrophenoxy)methyl-1,4-dioxane (known from British patent specification 749 713) are added in portions. The batch is then stirred for 31/2 hours at 95° C. and, after addition of 9.0 g of sodium carbonate in portions, filtered hot. The residue is washed with cyclohexanone and the filtrate is subjected to steam distillation. After cooling, the product precipitates in the form of white crystals which are separated from a dark oil and recrystallised from water with the addition of animal charcoal. The crystals are dried in vacuo at 60° C., affording 16.3 g (51% of theory) of (p-aminophenoxy)methyl-1,4-dioxane of the formula ##STR33## with a melting point of 86°-87° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([N:11]=[N+:12]=[N-:13])[CH2:9][C:8]([P:14]([O:19][CH2:20][CH3:21])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:7][C@H:6]1[OH:22])(=[O:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(S(O)(=O)=O)(F)(F)F>>[C:1]([NH:4][C@@H:5]1[C@@H:10]([N:11]=[N+:12]=[N-:13])[CH2:9][C:8]([P:14]([O:15][CH2:16][CH3:17])(=[O:18])[O:19][CH2:20][CH3:21])=[CH:7][C@H:6]1[O:22][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(OCC)C1=C[C@@H](O)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Reactant: CCC(CC)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCOP(=O)(OCC)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Yield: 82 %

Procedure:
By a procedure similar to that for 11a, the reaction of alcohol 10b (498 mg, 1.5 mmol) with 3-pentyl trichloroacetimidate (420 mg, 1.8 mmol) in the presence of CF3SO3H (15.6 μL, 0.18 mmol), followed by another batches of the imidate and CF3SO3H, gave the alkylation product 11b (495 mg, 82% yield). Colorless oil; TLC (EtOAc/hexane, 1:1) Rf=0.2; [α]D20=−61.3 (c=0.65, CDCl3); IR (neat) 2100, 1756, 1634, 1246 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.56 (1 H, d, JP-2=21.6 Hz), 5.71 (1 H, d, J=6.9 Hz), 4.52 (1 H, d, J=7.8 Hz), 4.34-4.30 (1 H, m), 4.11-4.01 (4 H, m), 3.31-3.23 (2 H, m), 2.69-2.64 (1 H, m), 2.12-2.08 (1 H, m), 2.01 (3 H, s), 1.51-1.43 (4 H, m), 1.39-1.31 (6 H, m), 0.90-0.81 (6 H, m); 13C NMR (150 MHz, CDCl3) δ 171.0, 141.7, 126.3 (C-1, d, JP-1=182 Hz), 810.9, 73.7, 62.14, 62.10, 54.3, 57.1, 31.0, 26.2, 25.4, 23.6, 16.4, 16.3, 9.6, 9.2; 31P NMR (162 MHz, CDCl3) δ 16.99; HRMS calcd for C17H32N4O5P (M++H): 403.2110, found: m/z 403.2111.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)CCN2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the resulting indoline(180 mg, 0.603 mmol) and acetic acid (0.1 mL) in methanol (5 mL), 37% aqueous formaldehyde (0.054 mL, 0.723 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature under nitrogen for 1 h, and then was cooled to 0° C. again. Sodium cyanoborohydride (95 mg, 1.5 mmol) was added in portions at 0 ° C. The mixture was stirred at room temperature under nitrogen for 3 h and then quenched with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/methanol, 10:1) to afford the N-methyl indoline product, Example 53 as a white solid (140 mg, 74%): mp 63-65° C.; 1H NMR (300 MHz, CDCl3) δ 7.07-7.20 (m, 4H), 6.59 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.0 Hz, 1H), 4.14(t, J=7.9, 5.0 Hz, 1H), 3.58 (d, J=15.0 Hz, 1H), 3.46 (d, J=15.0 Hz, 1H), 3.33 (t, J=8.2 Hz, 2H), 2.93 (dd, J=11.3, 5.0 Hz, 1H), 2.82 (t, J=8.2 Hz, 2H), 2.72 (s, 3H), 2.54 (dd, J=11.3, 7.9 Hz, 1H), 2.42 (s, 3H); CI MS m/z=313 [C19H2iClN2+H]+; IR (KBr) 2940, 2796, 1611, 1594, 1489, 1372, 1286 cm−1; Anal. Calcd for C19H21ClN2: C, 72.95; H, 6.77; N, 8.95. Found: C, 72.70; H, 6.83; N, 8.78.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37].[BH4-].[Li+].C(CN)O.B(Br)(Br)Br>ClCCl.O>[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([NH:39][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:37])[CH3:38]
Reactant: CC(C)(N)Cc1ccc(F)cc1Cl
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: BrB(Br)Br
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: NCCO
Product: CC(C)(Cc1ccc(F)cc1Cl)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: -78 °C

Procedure:
357 mg (1 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 202 mg (1 mmol) of 2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamine are reacted with lithium borohydride analogously to the method for Example 10(d). To debenzylate the ethanolamine thus obtained, it is dissolved in 3 mL of dichloromethane and cooled to −78° C. At this temperature, 2 mL of a 1 molar solution of boron tribromide in dichloromethane is added and the mixture is slowly allowed to come up to ambient temperature. The reaction mixture is combined with 10 mL dichloromethane and 3 mL water and filtered through an EXTRELUT® column. The eluate is freed from solvent and the residue is purified by chromatography. White solid. Yield: 70 mg (13%, trifluoroethyl acetate); mass spectroscopy: [M+H]+=409/11.
Reaction SMILES: CN(CC)C.[CH:6]1([C:9]([N:11]2[CH2:17][CH2:16][CH:15]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][N:14]3[C:13]3[N:29]=[CH:30][CH:31]=[CH:32][C:12]2=3)=O)[CH2:8][CH2:7]1.[OH-].[Na+].FC(F)(F)C(O)=O>O1CCCC1.CO>[CH:6]1([CH2:9][N:11]2[CH2:17][CH2:16][CH:15]3[CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C:13]3[N:29]=[CH:30][CH:31]=[CH:32][C:12]2=3)[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3N(C(=O)C3CC3)CCC2C1
Agent: CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1cnc2c(c1)N(CC1CC1)CCC1CNCCN21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution alane-N,N-dimethylethylamine (0.5 M in toluene, 2.84 mL, 1.42 mmol) was added under nitrogen to an ice-cooled solution of the product of Example 72B (176 mg, 0.473 mmol) in tetrahydrofuran (8 mL). The reaction was stirred with ice cooling for 15 minutes and then warmed to room temperature and stirred for 30 minutes. Methanol (1 mL) was added followed after 5 minutes by addition of 25% NaOH (1 mL). The mixture was stirred for 10 minutes and then concentrated under vacuum. The residue was taken up with brine (10 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic phases were dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in CH2Cl2 (5 mL) and stirred with ice cooling under nitrogen for 10 minutes. Trifluoroacetic acid (1.0 mL, 13 mmol) was added gradually over 0.5 minute, and the reaction was stirred with ice cooling for 1 hour and then warmed to room temperature for 1 hour. The solution was concentrated under vacuum, and the residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous (NH4)2CO3-methanol, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 0.18-0.27 (m, 2H), 0.51-0.60 (m, 2H), 0.93-1.09 (m, 1H), 1.67-1.80 (m, 1H), 1.80-1.94 (m, 1H), 2.73-2.86 (m, 2H), 2.87-3.04 (m, 4H), 3.11-3.28 (m, 3H), 3.41-3.51 (m, 2H), 6.84 (dd, J=7.8, 5.1 Hz, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H), 7.70 (dd, J=5.1, 1.7 Hz, 1H); MS (DCI) m/z 259 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21](=O)[NH2:22])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2c(C(N)=O)cccc12
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCOc1noc2c(C#N)cccc12
Temperature: 5 °C
Yield: 95.3 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzisoxazole (0.10 g) in dimethylformamide (1.0 ml) was added phosphorus oxychloride (0.06 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.09 g, 90%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[S-:18][C:19]#[N:20].[NH4+:21]>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:20]=[C:19]([SH:18])[NH:21][C:10]=2[C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#C[S-]
Reactant: [NH4+]
Reactant: O=C(c1cccs1)C(O)c1ccc(Cl)c(Cl)c1
Solvent: CCCO
Product: Sc1nc(-c2ccc(Cl)c(Cl)c2)c(-c2cccs2)[nH]1

Procedure:
By the procedure described in the second paragraph of Example 2F, 45.0 g (0.16 mole) of 2-(3,4-dichlorophenyl)-2-hydroxy-1-(2-thienyl)ethanone was reacted with ammonium thiocyanate in 1-propanol at reflux to afford 32.6 g of 4-(3,4-dichlorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol m.p. 263°-5°. (recrystallized from 1-butanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH:38]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH:38]=1)[O:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]1
Reactant: COc1ccc(Cl)cc1OCC1CCN(CCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: CO
Product: COc1ccc(Cl)cc1OCC1CCN(CCCN)CC1
Product: Cl
Temperature: 0 °C
Yield: 84.9 %

Procedure:
9.5 g (0.017 mol) of 4-[(5-chloro-2-methoxyphenoxy)methyl]-N-(triphenylmethyl)-1-piperidinepropanamine are suspended in 215 ml of methanol. The reaction mixture is cooled to 0° C. and gaseous hydrochloric acid is bubbled in. The reaction mixture is allowed to return to room temperature and is evaporated to dryness, and the product obtained is recrystallised in an MeOH/AcOEt (50 ml:150 ml) mixture. Yield: 84.9%, M.p. 153°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:36][CH:37]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(=O)c3ccc(C(F)(F)F)cc3)C2)c1
Yield: 87 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester) (51 mg, 0.11 mmol) in CH3CN (5 ml) was added 4-(Trifluoromethyl)benzoyl chloride (35.6 mg, 0.17 mmol) and diisopropylethylamine (40 μl, 0.23 mmol). The reaction was microwaved at 130° C. for 10 minutes, was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (62 mg, 87%). Calcd for C34H35F6NO3 (M+H) 619.64, Found 620.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1([C:11]([O-:13])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1.S(=O)(=O)(O)O.[CH3:22]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1([C:11]([O:13][CH3:22])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CO
Reactant: O=C([O-])C1(Cc2cccc(O)c2)CCCO1
Agent: O=S(=O)(O)O
Product: COC(=O)C1(Cc2cccc(O)c2)CCCO1

Procedure:
To a solution of 2.20 g of 2-(3-hydroxybenzyl)-tetrahydro-2-furancarboxylate in 50 ml of methanol was added 0.5 ml of sulfuric acid, and the mixture was heated under reflux for 18 hours. The solvent was evaporated, and the residue was dissolved in 200 ml of ethyl acetate. The organic layer washed twice with 50 ml of water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give 2.20 g of the title compound from the 7:3 hexane-ethyl acetate fraction.