Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][C:13](=[O:15])[N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11](=[O:24])[CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O.ClCCl>C(O)C>[CH:1]1([C:7]([N:9]2[CH2:10][C:11](=[O:24])[N:12]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([OH:15])[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C1CCCCC1)N1CC(=O)N(CCc2ccccc2)C(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=C(C1CCCCC1)N1CC(=O)N(CCc2ccccc2)C(O)C1
Reaction time: 1 h
Yield: 73 %

Procedure:
15.2 g (0.046 mol) of 4-(cyclohexylcarbonyl)-2,6-dioxo-1-phenethyl piperazine are dissolved in 600 ml of ethanol. In an inert atmosphere, at 0° C., there are added 8.7 g (0.0509 mol) of dihydrated cupric chloride and the mixture is left for 1 hour at 0° C. To the reaction medium, kept at 0° C., are added in portions 8.8 g (0.23 mol) of sodium borohydride and left for 45 minutes at 0° C. The excess of reducing agent is destroyed by adding acetone. The insoluble salts are filtered and the filtrate is evaporated to dryness. The residue obtained is treated with a mixture of water and dichloromethane. The organic phase is decanted, dried over dry sodium sulphate and evaporated to dryness. The residue which is obtained is purified by filtration on a silica bed (elutrient: ethyl acetate). Beige crystals, m.p.=134° C., yield: 73%.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH:20]([C:18]1[N:19]=[C:15]([CH2:14][CH2:13][C:11]2[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=[C:2]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:3]=[C:4]3[CH:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: C1COCCN1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(O)nc3c2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Reaction time: 24 h

Procedure:
The 2-hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4 H-pyrido[1,2-a]-pyrimidin-4-one (500 mg) obtained in (A) was dissolved in methylene chloride (20 ml), added with triethylamine (0.26 ml) and p-toluenesulfonyl chloride (360 mg) and stirred for 24 hours under nitrogen atmosphere. The reaction solution was added with morpholine (0.83 ml) and stirred for 12 hours, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (273 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:39]=[N:40][C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:39]=[N:40][C:41]=1[O:46][CH3:47]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cnc(OC)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cnc1OC
Temperature: 90 °C
Reaction time: 12 h

Procedure:
After adding 38 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.030 ml of triethylamine to a solution of 100 mg of {2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 90° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 1.5 ml of methanol and 0.1 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 3 hours. Next, 1.0 ml of a 5N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 2 hours. After then adding 0.3 ml of acetic acid, the reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5,6-dimethoxypyridin-3-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][C@H:29]([OH:31])[C@@H:28]([OH:32])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][C@H:29]([OH:31])[C@@H:28]([OH:32])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: O[C@H]1CNC[C@@H]1O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@H](O)[C@@H](O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3S,4S)-pyrrolidine-3,4-diol. MS obsd. (ESI+) [(M+H)+] 440, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (s, 1 H), 8.01 (s, 1 H), 7.80-7.78 (d, J=7.6 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.54-7.50 (m, 2 H), 5.83 (s, 1 H), 5.21 (s, 2 H), 4.45 (s, 2 H), 4.22 (s, 2 H), 4.18-4.15 (m, 2 H), 3.67-3.60 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2,6-dimethylbenzoic acid (20.2 g, 134 mmol) in dichloromethane (200 mL) is added DMF (1 mL) followed by oxalyl chloride (14 mL, 162 mmol). On completion of addition, the cold bath is removed and stirring continued for 3 h. The resulting solution is concentrated under vacuum and the residue added slowly to a cooled (0° C.) solution comprising methanol (200 mL) and triethylamine (40 mL). On completion of addition, the reaction mixture is stirred for 30 min. then poured into hydrochloric acid solution (400 mL, 2N) which is then extracted with ether. The ether extract is washed with hydrochloric acid solution (1N), sodium bicarbonate solution and brine then dried over MgSO4 and concentrated to give the title compound which is used without further purification. MS (EI) 164 (M)+.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([O-:16])=[O:15].[F-].[K+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[S:6][C:5]([C:7]3([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: OC1(c2ncc(I)s2)CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)cc1
Temperature: 90 °C

Procedure:
A solution of Example 1B (1.0 g, 3.2 mmol), 4-nitrophenylboronic acid (0.75 g, 4.5 mmol), KF (0.56 g, 9.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.22 g, 0.32 mmol) in a solvent mixture of dimethoxyethane (5 mL) and methanol (5 mL) was heated to 90° C. for 16 h. The reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and H2O (10 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×10 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane; to give the title compound. MS (ESI) m/z 307 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[S:4][N:3]=1.[ClH:20]>ClCCl.CCO>[ClH:20].[CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[S:4][N:3]=1
Reactant: Cc1nsc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1nsc(C2CCCNC2)n1
Temperature: 35 °C

Procedure:
The Boc-protected intermediate 11a (0.87 g, 3.07 mmol) was stirred in dichloromethane (10 mL) and treated with 10 mL of a 2.53 M solution of HCl in EtOH. After warming to 35° C. for 2 hours, the mixture was concentrated under vacuum. The product was precipitated from IPA:MTBE (1:10). The product was recrystallized from IPA:MTBE three times to afford a high purity sample (42 mg) of white solid. MS (ESI) m/z 184 [M+1]+. 1H NMR (CDCl3) δ 1.68-1.91 (m, 3H), 2.13-2.20 (d, 1H), 2.58 (s, 3H), 2.87-2.95 (dt, 1H), 3.14 (t, 1H), 3.25-3.28 (d, 1H), 3.54-3.59 (d, 1H), 3.65-3.73 (m, 1H), 9.10 (s, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[OH-].[K+].NC1C2CCN(CC2)C1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:31]([S:34](=[O:37])(=[O:36])[NH2:35])=[CH:30][C:26]=1[C:27]([Cl:29])=[O:28]>O.O1CCCC1>[OH2:24].[ClH:29].[NH2:35][S:34]([C:31]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[C:26]([CH:30]=1)[C:27]([NH:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1)=[O:28])(=[O:36])=[O:37]
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NC1CN2CCC1CC2

Procedure:
A solution of 3-aminoquinuclidine dihydrochloride (2.5 g, 0.0126 mole) in 25 ml of water was treated with approximately 5 g of KOH and the resultant slurry/solution taken to complete dryness on the rotary evaporator at 50°/35 mm. The dry residue was carefully extracted by repeated triturations with warm tetrahydrofuran until a total volume of 130 ml had been collected and dried over magnesium sulfate. This solution of 3-aminoquinuclidine base was treated with a solution of 2-methoxy-5-sulfamylbenzoyl chloride (2.92 g, 0.0117 mole) in 50 ml of dry tetrahydrofuran by dropwise addition under nitrogen. The resultant very turbid solution was refluxed gently for about 30 min, then freed of tetrahydrofuran by allowing it to evaporate. The residue was taken up in 90% ethanol containing a few drops of ethereal hydrogen chloride, filtered and chilled. The solid produced was then recrystallized again to yield 4.3 g (97%), m.p. 233°-234° C. NMR, MS, and IR were in support of the structure proposed.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:36].[Na+].[CH:38]([NH:40][C:41]1[N:45]([CH2:46][CH2:47][O:48][CH:49]=[O:50])[N:44]=[CH:43][CH:42]=1)=[O:39].O>CN(C)C=O.C(OCC)(=O)C>[I-:36].[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][N+:44]3[N:45]([CH2:46][CH2:47][O:48][CH:49]=[O:50])[C:41]([NH:40][CH:38]=[O:39])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CNc1ccnn1CCOC=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a mixture of benzhydryl 7β-tert-butoxycarbonylamino-3-chloromethyl-3-cephem 4-carboxylate (20 g) and sodium iodide (5.82 g) in N,N-dimethylformamide (20 ml) was added 5-formamido-1-(2-formyloxyethyl)pyrazole (21.34 g) at ambient temperature. After being stirred for 24 hours at the same temperature, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, aqueous sodium chloride solution, and dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7β-tert-butoxycarbonylamino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate iodide (29.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17]O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([NH:27][CH2:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2CNC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To [2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanol prepared in step A of example 1 (0.150 g, 0.60 mmol) in 5 mL of THF at 0° C. was added thionyl chloride (0.22 mL, 5 eq). The reaction mixture was refluxed for 45 minutes and then the solvent and the excess of thionyl chloride were evaporated. The residue was suspended in 5 mL of acetonitrile and tert-butylamine (0.62 mL, 10 eq) was added at 0° C. The solution was stirred 48 h at room temperature, evaporated and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (0.192 g, quantitative yield) m/z (ESI) 307.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[K+]>CN(C)C=O>[CH2:21]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C(CCCc1cccc(O)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-hydroxy-3-(3-benzyloxycarbonylpropyl)benzene (2.0 g), benzylbromide (1.14 ml), potassium bicabonate (1.53 g) and dimethylformamide (20 ml) was stirred for 3 h at room temperature. The mixture was quenched by addition of water and extracted with a mixture of n-hexane:ethyl acetate (3:1). The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (2.55 g) having the following physical data.
Reaction SMILES: [CH:1](=O)[C:2]1C=CC=CC=1.C1(S([C:18]2[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=2[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:22]=2[CH3:35])(=O)=O)CCCCC1>>[CH2:1]([O:34][C:32](=[O:33])[CH2:31][N:23]1[C:24]2[C:29](=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:21]([CH2:20][C:19]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:18]=2)=[C:22]1[CH3:35])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2)c2cc(F)ccc21

Procedure:
Benzaldehyde was used as a starting material, otherwise this compound was prepared in a similar manner to Compound 1, using Procedure K.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:11])[CH3:10].O>CN(C=O)C.CCOC(C)=O>[Br:8][C:23]1[C:24]([NH2:27])=[N:25][CH:26]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([CH:9]([CH3:11])[CH3:10])(=[O:13])=[O:14])=[CH:16][CH:17]=2)[N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (1.926 g, 10.82 mmol) was added to a solution of 5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (3 g, 10.82 mmol) in DMF at ambient temperature. The reaction mixture was stirred at ambient temperature for 30 min and then added to a rapidly stirring water (50 ml). The precipitate was filtered off and dried in vacuo. The solid obtained was slurried in EtOAc, filtered off and dried in vacuo to provide 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine used which was as such without further purification (8 g, 62%). 1H NMR (400.0 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.2 (d, 2H), 7.90 (d, 2H), 7.2 (s, 2H), 3.4-3.5 (m, 1H), 1.20 (d, 6H); LC/MS m/z 358.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 71(b), from benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-hydroxy-piperidine-1-carboxylate by alkylation with 2-bromomethylnaphthalene there was obtained benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 518 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[OH2:8].[C:9]1([CH3:19])C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][CH:19]([CH2:9][OH:8])[CH2:1][O:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: COC(C)(C)OC
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO)CO1

Procedure:
Triol 3-1 (1 eq.) was dissolved in DMF at a concentration of approximately 0.5 M and 2,2-dimethoxypropane (1.16 eq.) and p-toluenesulfonic acid monohydrate (0.03 eq.) were added. The solution was stirred for one or more days, and was quenched with TEA (0.5 eq.). As much solvent as possible was removed in vacuo and the remainder was purified by distillation under vacuum.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethoxybenzoic acid (Acta Chem. Scand., 2, 34-41, (1948)) (22.6 g, 86.6 mmol) in methylene chloride (400 mL) was added dimethylformamide (1.5 mL, 19.4 mmol). Oxalyl chloride (13.0 g, 102.0 mmol) was gradually added to the ice-cold solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure to yield crude crystals of 4-bromo-3,5-dimethoxybenzoyl chloride. To an ice-cold solution of 2-amino-2-methylpropanol (8.40 g, 94.2 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (16.6 mL, 95.3 mmol) and a solution of the crude 4-bromo-3,5-dimethoxybenzoyl chloride in methylene chloride (200 mL). After the mixture was stirred at room temperature for 10 minutes, the mixture was washed successively with water, 8.0 M hydrochloric acid, a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thionyl chloride (47.5 mL, 651.0 mmol) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added ice water and a 2.5 M aqueous sodium hydroxide (600 mL, 1500 mmol), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized form diethyl ether-hexane to yield 2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorless fine needles (melting point: 172.5-174.5° C.) (20.9 g, yield: 77%).
Reaction SMILES: Br[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].C([Mg]Cl)(C)C.O1CCCC1.[CH3:20][C:21]([CH3:27])=[C:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH:23]1[C:22](=[C:21]([CH3:27])[CH3:20])[CH:26]2[CH:25]=[CH:24]1
Reactant: CC(C)=C1C=CC=C1
Reactant: Clc1cccc(Cl)c1Br
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)=C1C2C=CC1c1c(Cl)cccc12
Yield: 87.8 %

Procedure:
A solution of 2-bromo-1,3-dichlorobenzene (22.59 g, 0.1 mol) in dry toluene (100 ml) under a nitrogen atmosphere was reacted at −8 to −15° C. with 2M isopropylmagnesium chloride in tetrahydrofuran (50 ml, 0.1 mol) for 1 hour. Subsequent addition of 6,6-dimethylfulvene (13.03 g, assay 97.8%, 0.12 mol) at 0° C. was followed by heating to reflux temperature for 10 hours. Aqueous work up with saturated aqueous ammonium chloride and ethyl acetate extraction followed by washings with brine and water and drying over sodium sulphate gave the crude material which was purified by chromatography on silica gel in hexane to give the desired product (19.03 g, assay 95.2% by g.l.c., 83.6% yield) as a yellow solid. This reaction is also disclosed in WO 2007/068417.