Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[O:30]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:35][C@H:32]2[CH2:33][CH2:34][O:30][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Reactant: O[C@H]1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(O[C@H]5CCOC5)c34)cc2o1
Temperature: 75 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), (S)-tetrahydrofuran-3-ol (1.1 equiv) in 1,4-dioxane (0.2 M) was added sodium tert-butoxide (1.1 equiv). The reaction was stirred at 75° C. for 5 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-90%) ethyl acetate in hexane) to give the title compound (90% yield) as yellow solid; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 9H) 0.84-0.90 (m, 2H) 1.99-2.10 (m, 1H) 2.26 (dtd, J=13.96, 8.25, 8.25, 6.25 Hz, 1H) 2.63 (s, 3H) 3.53-3.62 (m, 2H) 3.73-3.81 (m, 2H) 3.84 (d, J=10.54 Hz, 1H) 3.93 (dd, J=10.54, 4.30 Hz, 1H) 5.57 (s, 2H) 5.72-5.80 (m, 1H) 7.59-7.64 (m, 1H) 7.66 (d, J=8.59 Hz, 1H) 7.89 (s, 1H) 7.91 (d, J=0.78 Hz, 1H); MS (ESI) m/z 501.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[Cl:17])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:19]1([CH2:25][C:26]2[S:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:29]2[S:30][C:26]([CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[Cl:17])=[O:9]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1Cl
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: Nc1ncc(-c2ccc(CN3CCOCC3)s2)cc1C(=O)Nc1ccncc1Cl

Procedure:
Reaction of 2-amino-5-bromo-N-(3-chloro-4-pyridyl)pyridine-3-carboxamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A33”; HPLC/MS: 1.25 min, [M+H]=343;
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:16][C:17]1[S:18][NH:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[C:12]([NH:16][C:17]1[S:18](=[O:9])[NH:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)([O:14][CH3:15])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2NS1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2NS1=O
Reaction time: 0.25 h

Procedure:
A solution of 240 mg of m-chloroperbenzoic acid in 10 ml of dioxan was introduced, while stirring, into a solution of 0.54 g of 3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine in 50 ml of dioxan. The mixture was stirred for 15 minutes, then it was diluted with 100 ml of water, neutralized with sodium carbonate solution, and subsequently the whole was shaken with ethyl acetate. After washing out the ester extract with sodium chloride solution, the ester solution was strongly concentrated, and the separated 3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine-S-oxide was isolated by way of filtration. The yield was 120 mg.
Reaction SMILES: C[C:2]#[C:3][C:4]([O-:6])=[O:5].C[Si]([N:11]=[N+:12]=[N-:13])(C)C.[CH3:14]O>>[NH:11]1[CH:2]=[C:3]([C:4]([O:6][CH3:14])=[O:5])[N:13]=[N:12]1
Reactant: CO
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC#CC(=O)[O-]
Product: COC(=O)c1c[nH]nn1
Temperature: 105 °C
Reaction time: 72 h

Procedure:
Methylpropiolate (20 g) and trimethylsilyl azide (68.6 g) were added to a pressure-resistant tube, and the mixture was stirred for 72 hours at 105° C. After allowing the mixture to be cooled to room temperature, methanol was added to the mixture, and the solvent was removed under reduced pressure, and the obtained residue was washed with diethylether/methanol to give methyl 1,2,3-triazole-4-carboxylate (22.7 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:25][N:16]([CH2:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OCC

Procedure:
600 mg (1.8 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared as in Example 1(e)), 10 ml of toluene, 300 μl (1.8 mmol) of diethyl malonate and 50 mg (0.35 mmol) of piperidine acetate are introduced into a three-necked flask under a stream of nitrogen. This mixture is refluxed for 6 hours, while separating out the water formed using Dean-Stark apparatus. The reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is separated out after settling has taken place, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (75/25). After evaporation of the solvents, 700 mg (84%) of expected product are collected.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH:12]=[O:11]
Reactant: O=C1CCCN1CCO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCN1CCCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.87 mL, 10 mmol) was added dropwise to a solution of DMSO (0.71 mL, 10 mmol) in CH2Cl2 (7 mL) cooled to −78° C. After stirring 15 min at this temperature, 1-(2-hydroxyethyl)-2-pyrrolidinone (1 g, 7.7 mmol) was added dropwise. The mixture was stirred 30 min at −78° C. and Et3N (2.8 mL, 20 mmol) was added dropwise. After allowing the reaction to warm to rt, a solution of NaHCO3 was added and the mixture was extracted with CH2Cl2 (6×). The combined organic layers were dried and concentrated to give the product as an oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(F)cnc1Cc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorobenzyl)nicotinic acid (step 3) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.49 (1H, d, J=2.8 Hz), 8.01–7.97 (2H, m), 7.44 (1H, dd, J=7.9, 2.8 Hz), 7.27 (2H, dd, J=4.6, 4.0 Hz), 7.14–7.09 (2H, m), 6.93–6.86 (2H, m), 6.08 (1H, br.s), 4.56 (2H, d, J=5.9 Hz), 4.29 (2H, s), 3.92 (3H, s); MS (ESI) m/z 397 (M+H)+, 395 (M−H)−.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([NH2:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:11][C@H:12]([C:23]([NH2:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: [H][H]
Reactant: NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Yield: 96.8 %

Procedure:
To methanol (300 mL) solution of the compound obtained in Example 125 (3.6 g) was added 5% palladium/carbon (0.36 g) in an argon atmosphere, and the mixture was stirred for 16 hours at room temperature in a hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under a reduced pressure, to give the captioned compound (2.1 g, 95%) as an oily product.
Reaction SMILES: C.Cl[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C=O>[C:4]1([C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Yield: 103.5 %

Procedure:
After the portionwise addition of 18.1 g (65.1 mmol) of chlorotriphenylmethane methane to a 150 ml dimethylformamide solution of 10.0 g (65.1 mmol) of 4-piperidone monohydrate hydrochloride and 20.0 g (198 mmol) of triethylamine at 60° C. under stirring, the resulting mixture was stirring further for 5 hours at the same temperature. The triethylamine hydrochloride precipitated by cooling was filtered out and the filtrate was concentrated under reduced pressure. To the residue was added 150 ml of water, followed by extraction with 300 ml of ethyl acetate. The organic layer was then washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, whereby 23.0 g (yield: 98.3%) of 1-triphenylmethyl-4-piperidone were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[NH:5]1.[CH3:17][C:18]([O-:20])=O.[Na+].[BH-](O[C:32]([CH3:34])=[O:33])(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:5]1[CH2:3][CH2:4][N:5]1[C:18](=[O:20])[C:17]2=[CH:9][CH:6]=[CH:7][CH:8]=[C:34]2[C:32]1=[O:33]
Reactant: COCC1CCC(c2ccccc2OC)N1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COCC1CCC(c2ccccc2OC)N1CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 173 %

Procedure:
To a solution of 2-methoxymethyl-5-(2-methoxyphenyl)-tetrahydropyrrole (226 mg, 1.02 mmol) in CH2Cl2 was added NaOAc (88 mg, 1.07 mmol), N-phthalimidoacetaldehyde (203 mg, 1.07 mmol) and NaB(OAc)3H (326 mg, 1.54 mmol) and the resulting suspension was stirred at ambient temperature for 17 hours. H2O was added followed by 1N NaOH until pH was 10, the aqueous layer was extracted with CHCl3 (×4), and the combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (5% MeOH-0.5% NH3.H2O-94.5% CH2Cl2) to afford the title compound as a yellow oil (348 mg, 86%). MS m/z: 395 (M+H)
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].C1(=O)OCC1.C([NH-])C=C>>[CH2:16]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: O=C1CCCCO1
Reactant: C=CCCCCCCBr
Agent: C=CC[NH-]
Agent: O=C1CCO1
Product: C=CCCCCCCC1CCCOC1=O
Yield: 63 %

Procedure:
13.25 g of tetrahydro-3-(7-octenyl)-2H-pyrane-2-one of interest was prepared in the same manner as in Example 1 except that 10.01 g (100.0 mmol) of δ-valerolactone and 22.93 g (110.0 mmol) of 8-bromo-1-octene were used instead of β-propiolactone and allyl amide described in Preparation Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH:18]=[CH:19][C:20]([OH:22])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10](/[CH:18]=[CH:19]/[C:20]([N:30]([CH:31]([CH3:33])[CH3:32])[NH:29][C:27](=[O:28])[C:26]3[CH:34]=[CH:35][CH:36]=[C:24]([F:23])[CH:25]=3)=[O:22])=[CH:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cc(C=CC(=O)O)c2ccc(F)cc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1cccc(F)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing 3-(1-(tert-butoxycarbonyl)-6-fluoro-1H-indol-3-yl)acrylic acid (200.0 mg, 0.66 mmol), 3-fluoro-N′-isopropylbenzohydrazide (192.8 mg, 0.98 mmol) and HATU (376.6 mg, 0.98 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.16 ml, 0.98 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (50% EtOAc) for refinment and dried so that white (E)-tert-butyl 6-fluoro-3-(3-(2-(3-fluorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (180.0 mg, 56.4%).
Reaction SMILES: [CH:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:31][CH2:32][NH:33][C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH:12]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:11])[C:8]([O:10][CH2:31][CH2:32][NH:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Reactant: OCCNc1ncccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(OCCNc1ncccn1)C(O)(c1ccccc1)C1CCCCC1

Procedure:
To a mixture of α-cyclohexylphenylglycolic acid (1 g) and N,N-carbonyldiimidazole (0.69 g) in DMF (10 ml), 2-(2-hydroxyethyl) aminopyrimidine (0.6 g) and DBU (0.65 g) were added. The mixture was treated according to the method described in Example 3a, affording 2-(2-pyrimidyl)aminoethyl α-cyclohexylphenylglycolate, which was heated with ethanolic HCl to afford 1,5 g of the hydrochloride. M.p. 167°-168° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][CH2:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>>[Cl:12][CH2:13][CH:14]([CH3:18])[C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: Fc1ccccc1
Reactant: CC(CCl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CCl)C(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of 22.7 g. (0.17 mole) of anhydrous aluminum chloride and 9.6 g. (0.10 mole) of fluorobenzene is added 14.1 g. (0.10 mole) of β-chloroisobutyrylchloride over 30 minutes at 20°-25°C. The mixture is aged for 30 minutes at 20°-25°C and then quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-chloro-4'-fluoro-2-methylpropiophenone.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([O:21][C:22]([C:24]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:14]2>CC#N>[CH:22]([O-:23])=[O:21].[CH3:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([CH2:2][N+:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([O:21][C:22]([C:24]1([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:14]2)=[O:4]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: CN(C(=O)CBr)c1ccccc1
Solvent: CC#N
Product: CN(C(=O)C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)c1ccccc1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-bromo-N-methyl-N-phenyl-acetamide ((Example 39a) (38 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in 1 mL MeCN was stirred at room temperature for 48 h. The volatiles were evaporated and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane. Further purification by reverse phase HPLC eluting with 20-90% MeCN/H2O containing 0.1% formic acid gave the title compound (17 mg) as a colourless gum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>O1CCCC1.CCCCCC>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Br
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of 23.0 g (120 mmole) of 4-bromochlorobenzene in 150 ml of dry tetrahydrofuran was cooled to -78° C. under nitrogen and 78 ml (120 mmole) of 1.55 M n-butyllithium in hexane was added dropwise at a rate to maintain temperature below -60° C. After stirring an additional 15 minutes, 14.0 ml (120 mmole) of 2-bromo-benzaldehyde was added and the reaction was stirred for 15 minutes. The reaction was quenched at -78° C. with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 75 ml portions of 1.0 M sodium bisulfite, followed by 50 ml of 1.0 M sodium hydroxide, 100 ml of water, and 50 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 35.3 g (99%) of crude 2-bromo-α-(4-chlorophenyl)benzyl alcohol as a pale yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: CS(=O)(=O)Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Methane sulfonyl chloride (43 μL, 0.55 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E72); MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(S)n[nH]1
Solvent: c1ccncc1
Product: O=C(Nc1nc(S)n[nH]1)c1ccccc1
Reaction time: 0.42 h

Procedure:
To a suitably equipped reaction vessel was charged 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole and 500 mL of pyridine. A total of 147.5 g (1.05 mole) of benzoyl chloride was added with vigorous stirring over 25 min, during which time the temperature rose from 24° to 59° C. The mobile, pale yellow slurry obtained was heated at reflux with stirring. The solid material dissolved and then, after about 40 additional min, a white solid began separating. An additional 200 mL of pyridine was added to aid mixing and the reaction was continued at 117°-122° C. for a total of 7 hr. The thick, white slurry obtained was filtered, washed with water and with methylene chloride, and dried to obtain 186 g (84 percent of theory) of the title compound, m.p. 311°-312° C. (dec.).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][Cl:18])[C:8]=2[CH:7]=[N:6]1>>[ClH:18].[OH:19][CH:16]([CH2:17][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:15][O:14][C:13]1[C:8]2[CH:7]=[N:6][S:5][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: OC(CCl)COc1cccc2sncc12
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1cccc2sncc12
Product: Cl

Procedure:
Using isopropylamine and 1-(1,2-benzisothiazol-4-yloxy)-3-chloro-propan-2-ol as the starting materials, 4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole hydrochloride is obtained by the method described in Example 6. The compound is identical with that obtained as described in Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1)(=[O:3])[CH3:2].[I:11]I.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[I-:11].[Br:10][C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH2:2][N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: II
Solvent: O
Product: O=C(C[n+]1ccccc1)c1cccc(Br)n1
Product: [I-]
Temperature: 100 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A reaction vessel was charged with 11.0 g of 2-acetyl-6-bromopyridine, 14.0 g of iodine, and 45 mL of pyridine, followed by heating and stirring at 100° C. for 5 hours. After cooling to room temperature, 100 mL of water was added thereto and purification by recrystallization was performed. The reaction product was vacuum-dried at 70° C. for 12 hours to obtain 13.8 g (yield, 62%) of [2-(6-bromopyridin-2-yl)oxoethyl]pyridinium iodide as a brown powder.