Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[F:11][C:12]([F:41])([F:40])[CH:13]([OH:39])[CH:14]([NH:16][C:17](=[O:38])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:37])[C@H:24]([CH3:36])[NH:25][C:26](=[O:35])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:34])[CH3:33])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[F:41][C:12]([F:11])([F:40])[C:13]([OH:3])([OH:39])[CH:14]([NH:16][C:17](=[O:38])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:37])[C@H:24]([CH3:36])[NH:25][C:26](=[O:35])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:34])[CH3:33])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC(C)C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC(C)C(O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (72 μl, 0.83 mmol) in methylene chloride (1 ml) under an argon atmosphere and cooled in a dry ice-acetone bath was added dimethylsulfoxide (0.12 ml, 1.65 mmol) with stirring. After 5 minutes, a solution of the compound of example 57 (0.25 g, 0.55 mmol) in methylene chloride (1.5 ml) was added. The reaction mixture was stirred for 15 minutes, triethylamine (0.50 ml,3.58 mmol) then added and the reaction warmed to room temperature for 30 minutes. The reaction mixture was placed directly onto a silica gel column and eluted with methylene chloride-methanol. Trituration of the resultant oily solid with ether-hexane and filtration gave the above-named product, (50 mg, 0.11 mmol).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19]Br>C1(C)C(C)=CC=CC=1>[BrH:11].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])[C:2]1=[NH:1]
Reactant: BrCCc1ccccc1Br
Reactant: Nc1nc2ccccc2[nH]1
Solvent: Cc1ccccc1C
Product: Br
Product: N=c1n(CCc2ccccc2Br)c2ccccc2n1CCc1ccccc1Br
Yield: 42.2 %

Procedure:
A solution of 5.5 g of 2-aminobenzimidazole and 11.0 g of 2-(o-bromophenyl)ethyl bromide in 250 ml of xylene is heated in a nitrogen atmosphere under reflux for 18 hours. The reaction mixture is cooled and the crystals that separate are filtered and dried. This product weighs 3.7 g and is recrystallized from acetonitrile to give 3.4 g of 1,3-dihydro-1,3-bis[2-(o-bromophenyl)ethyl]-2H-benzimidazol-2-imine hydrobromide, m.p. 248°-249°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12](O)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CS(Cl)(=O)=O.[CH2:21]([N:23](CC)CC)C.[C-]#N.[Na+]>C1COCC1.CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:21]#[N:23])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CC1CCN(c2ccc(N)cc2)C1

Procedure:
1-(4-Nitrophenyl)pyrrolidin-3-ol and methanesulfonyl chloride were allowed to undergo the reaction in THF in the presence of triethylamine. The resulting compound and sodium cyanide were allowed to undergo the reaction in 1-methyl-2-pyrrolidone under heating. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-(4-aminophenyl)pyrrolidine-3-carbonitrile. NMR2: 1.48 (9H, s), 3.12-3.19 (2 H, m), 6.46-6.50 (2 H, m).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1.[H][H]>CO.O.[Pt]=O>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CC(C)Oc1cc(-c2cc[n+](C)cc2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Agent: [I-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(C2CCN(C)CC2)ccc1N
Yield: 96.7 %

Procedure:
A solution of 10 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 280 ml of methanol is hydrogenated in an autoclave on 2.9 g of platinum oxide hydrate, at a hydrogen pressure of 15 bar and at ambient temperature for 4 h. The catalyst is removed by filtration on Clarcel and the mixture is concentrated under vacuum. The residue is taken up in 200 ml of ethyl acetate and washed with 200 ml of 1M sodium hydroxide and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under vacuum, so as to obtain 6.0 g of 4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[O:15])[CH3:14]>>[CH2:7]([N:8]1[C:12]([CH:13]([OH:15])[CH3:14])=[N:11][CH:10]=[N:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Cn2cncn2)cc1
Reactant: CC=O
Product: CC(O)c1ncnn1Cc1ccccc1
Yield: 86 %

Procedure:
1-(1-Benzyl-1H-1,2,4-triazol-5-yl)ethanol was synthesized in a manner similar to that of procedure 21B but using 1-(phenylmethyl)-1H-1,2,4-triazole and acetaldehyde as the starting materials. The product was isolated as a white solid in 86% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:42]#[C:41][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#Cc5ccccc5)n4)cc3)cc2)CC1
Temperature: 40 °C

Procedure:
1-{4′-[4-(6-Bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.386 mmol) was dissolved in toluene along with phenylacetylene (0.051 mL, 0.46 mmol), copper(I) iodide (0.367 g, 1.93 mmol), triethylamine (0.269 mL, 1.93 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.032 g, 0.039 mmol). The reaction was heated to 40° C. for 3 days then cooled, diluted with EtOAc and filtered through a plug of silica gel. The crude material was purified on silica gel to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[N-:12]=[N+:13]=[N-:14].[Na+].Cl.[CH2:17](N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:1]2[N:2]=[N:12][NH:13][N:14]=2)[CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(-c2nn[nH]n2)c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of 3-cyanobenzoic acid (12.3 g, 0.083 mol) in toluene (300 mL) were added sodium azide (16 g, 0.25 mol) and triethylamine hydrochloride (34 g, 0.25 mol) respectively. The reaction mixture was refluxed for 4 hours, cooled to room temperature, and diluted with water (300 mL). The organic phase was separated and the aqueous portion was acidified (pH=1) using concentrated HCl. The precipitate was collected by filtration and oven-dried to give 14 g (89%) of the tetrazole as a white solid. CI-MS: C8H6N4O2 [M+1] 191.0. The product obtained (14 g, 0.074 mol) was suspended in anhydrous methanol followed by the addition of gaseous HCl over a period of 20 minutes. The warm solution was stirred at room temperature for overnight, then concentrated in vacuo. The resulting residue was triturated with diethyl ether and collected by filtration to yield 12.1 g (81%) of the methyl ester intermediate 2. CI-MS: C9H8N4O2 [M+1] 205.2
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O:34][CH:35]1[CH2:39][CH2:38][CH2:37]O1)C.C(O)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].C(N(CC)CC)C>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:20]([CH2:37][CH2:38][CH2:39][CH2:35][OH:34])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CCOC1CCCO1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNCCCCc2ccc(O)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN(CCCCO)CCCCc2ccc(O)cc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-[[2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]amino]butyl]phenol (18 mg in 2 mL tetrahydrofuran) was added 0.050 mL of 2-ethoxytetrahydrofuran followed by 0.25 mL of 30% aqueous acetic acid and the mixture stirred for 30 minutes. At this time 0.35 mL triethylamine was added followed by 10% palladium hydroxide on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 23 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo and partially purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8). Repurification by HPLC (C8, methanol:water, 55:45=0.1% trifluoroacetic acid) gave the title compound (2.8 mg). m/e=485 (M+H)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.[Si:13]([O:20][CH2:21][CH2:22][C@@H:23]1[CH2:35][C:34]2[C:33]3[C:32](Cl)=[N:31][CH:30]=[N:29][C:28]=3[S:27][C:26]=2[CH2:25][CH2:24]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1>[Si:13]([O:20][CH2:21][CH2:22][C@@H:23]1[CH2:35][C:34]2[C:33]3[C:32]([O:11][CH:8]4[CH2:9][CH2:10][CH:5]([N:4]([CH3:12])[CH3:3])[CH2:6][CH2:7]4)=[N:31][CH:30]=[N:29][C:28]=3[S:27][C:26]=2[CH2:25][CH2:24]1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:14])[CH3:15]
Reactant: CN(C)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
NaH (60% dispersion in mineral oil, 63 mg, 3.00 equiv) was treated with trans-4-(dimethylamino)cyclohexan-1-ol (104 mg, 0.73 mmol, 1.40 equiv) in distilled tetrahydrofuran (8 mL) at room temperature under nitrogen. After stirring for min, (12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (200 mg, 0.52 mmol, 1.00 equiv) was added and the resulting solution was stirred overnight at room temperature for 8 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (4:1) to afford 4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]-N,N-dimethylcyclohexan-1-amine (110 mg, 43%) as a light yellow solid. MS (ES): m/z 490 (M+H)+.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:23][CH2:24][C@H:25]2[O:29][C@@H:28]([N:30]3[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:27][C@:26]32[CH2:40][O:39]3)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12](OC)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH3:43][OH:44]>>[CH3:43][O:44][C:12]1[CH:11]=[CH:10][C:9]([C:8]([O:23][CH2:24][C@H:25]2[O:29][C@@H:28]([N:30]3[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:27][C@:26]2([CH2:40][NH2:1])[OH:39])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:41]=[CH:42][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]23CO3)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N
Reactant: CO
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)CN)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 72 h
Yield: 45 %

Procedure:
A saturated solution of ammonia in methanol (9 ml) was added to a solution of 5′-O-(4,4′-dimethoxytrityl)-3′-C,O-methylenethymidine (901 mg; 1.62 mmol) in methanol (3 ml), and the resulting solution stood at room temperature for 3 days. Excess ammonia and methanol was evaporated and the residue purified by chromatography (CH,OH- Hexanes-CHC13, 1:1:8) to yield 414 mg (45%) of 5′-O-(4,4′-dimethoxytrityl)-3′-C-aminomethylthymidine as a colorless solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15]=2[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C(F)(F)F)c4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1

Procedure:
Treatment of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (5.2 g, 11.57 mmol) with sodium azide (3.01 g, 46.3 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.375 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.64 g (69%) of (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 172-174° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.09; H, 4.6; N, 4.03.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[O:15]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=1)[CH2:12]2
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.492 g, 1.6 mmol), 4-phenoxy-benzylamine (0.256 mL, 2.0 mmol), and K2CO3 (0.414 g, 3 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.200 g, 32%). GC-MS: m/z 429 (M)+, 336 (M−93)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([O:19]C(=O)CCCCC)[C@H:10]([CH3:18])[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]([OH:19])[C@H:10]([CH3:18])[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC(=O)OC(NC(=O)OC(C)(C)C)[C@H](C)CCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CCc1cccs1)C(O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)butane (22.0 g, 57.4 mmol) obtained in Example 67(a) was dissolved in a mixture solution of tetrahydrofuran (140 ml) and methanol (280 ml), and a 1N aqueous sodium hydroxide solution (280 ml) was added in an ice bath followed by stirring 30 minutes in an ice bath and subsequently for 1 hour at room temperature. The reaction solution was concentrated in vacuo, and water was added thereto, and after the resulting solution was extracted with dichloromethane, the dichloromethane layer was washed with a saturated aqueous sodium chloride solution. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to afford the title compound (15.5 g, 95% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5](=[CH:8][O:9]C)[CH2:4][CH2:3]1.Cl>C1COCC1.C(OCC)C.[Cl-].[Na+].O.O>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: COC=C1CCC(C)(C)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g, 0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred at room temperature for 24 hr. The reaction mixture was diluted with a mixture of ethyl ether, hexanes, brine and water. The mixture was separated and the aqueous phase was extracted with ethyl ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde as a yellow oil, used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:18](=[O:19])[N:17]2[CH:12]1[S:13][CH2:14][C:15]([C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)=[C:16]2[C:20]([O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:23]([O:22][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:11]([NH:10][C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:18]2=[O:19])=[O:21])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Thien-2-yl-acetyl chloride (1.4 cc) is added to a solution of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-ylmethyl)-thiazol-5-yl]-5-thia-1-azabicyclo [4.2.0]oct-2-ene (6.36 g) in dry tetrahydrofuran (200 cc), and triethylamine (1.58 cc) is then added. The mixture is stirred at 20° C. for 1 hour 20 minutes and is then poured into a 65:35 (by volume) mixture of ethyl acetate and a saturated sodium bicarbonate solution. The organic phase is decanted and then washed successively with distilled water (200 cc), and a saturated sodium chloride solution (200 cc) and dried over anhydrous sodium sulphate. The drying agent is filtered off and washed with ethyl acetate (10 cc) and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 30° C. The residue is purified by chromatography on a column (height: 24 cm, diameter: 3 cm) of silica gel (0.05-0.2 mm), elution being carried out with ethyl acetate (2.5 liters), and 60 cc fractions being collected. Fractions 12 to 35 are combined and concentrated to dryness under reduced pressure (30 mm Hg; B 4 kPa) at 30° C. to give 2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-ylmethyl)-thiazol-5-yl]-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.45 g) in the form of a yellow froth.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[Cl:15]CCCl.CC(O)C>O=P(Cl)(Cl)Cl>[Cl:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: ClCCCl
Reactant: O=[N+]([O-])c1cnc(O)c2ccccc12
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Temperature: 102.5 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
Stir a slurry of 1-hydroxy-4-nitroisoquinoline (62.2 g, 327 mmol) in POCl3 (180 mL) mechanically under nitrogen and heat to 100-105° C. for 1 hour resulting in a homogeneous dark brown solution. Exchange the condenser for a short-path distillation head, and remove excess POCl3 under reduced pressure (ca. 10-30 torr) resulting in a pot temperature of 55° C. To this mixture add 1,2-dichloroethane (150 mL), and warn the mixture to 70° C. to obtain a homogeneous solution. Cool the solution to 15° C., then add i-PrOH (450 mL) over 5 minutes resulting in an exotherm to 33° C. Stir the slurry for 3.5 hours at 15° C. then filter and wash with i-PrOH (3×100 mL). Air-dry the resulting solid overnight to afford 1-chloro-4-nitroisoquinoline (52.08, 76% yield) as a tan solid. (ES+): m/z 209/211 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>C1(=O)CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1ccc(Br)cc1F
Reactant: CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCOc1ccc(Br)cc1F
Reaction time: 7 h
Yield: 83.7 %

Procedure:
A reaction vessel was charged with 19.4 g of 2-fluoro-4-bromophenol, 16.8 g of hexyl bromide, 23.3 g of potassium carbonate and 510 ml of cyclohexanone and the reaction was effected with stirring at 120°-140° C. for 7 hours. The reaction liquid was poured into dilute hydrochloric acid and the mixture was extracted with benzene. The benzene layer was washed with water and dried over Glauber's salt, and the benzene was distilled off. The residue was purified by way of column chromatography on silica gel (eluent: hexane) to obtain 23.4 g (yield 83.6%) of 3-fluoro-4-hexyloxybromobenzene.
Reaction SMILES: [ClH:1].[CH:2](=O)[CH3:3].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1>>[Cl:1][CH:6]([C:11]1[CH:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:2]=1[CH3:3])[CH3:5]
Reactant: Cc1ccc(C)cc1
Reactant: CC=O
Reactant: Cl
Product: Cc1ccc(C)c(C(C)Cl)c1
Reaction time: 1.5 h

Procedure:
Gaseous hydrogen chloride was passed into a cold (5° to 10°), rapidly stirred solution of 240 ml (1.96 m) p-xylene, 54.75 ml (0.98 m) acetaldehyde (I) and 55 ml petroleum ether (30°-60° fraction) until the conversion (monitored by means of nuclear magnetic resonance spectroscopy) of aldehyde I to bis-1-chloroethyl ether (II) was complete. The lower, aqueous phase was removed and 240 ml (1.96 m) p-xylene (III) was added. The reaction mixture was cooled and maintained in the temperature range 0° to 5° while the introduction of hydrogen chloride and rapid stirring were continued. Concentrated sulfuric acid, 54.75 ml (1.03 m), was added during 40 minutes. After the addition was complete, stirring and cooling were continued for 90 minutes. The reaction mixture was then quenched with 200 ml water. The resulting mixture was neutralized with concentrated ammonium hydroxide and the organic phase was collected. Petroleum ether (37 ml) was distilled from the organic phase at atmospheric pressure. Fractional distillation of the remainder of the product mixture at reduced pressure (about 30 mm Hg) afforded 317.6 g (3.00 m) xylene III and 82.3 g (0.49 m) chloride IV. The isolated yield of chloride IV was 50% based on aldehyde I or 53% based on consumed xylene III.