Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>C(OC(C)C)(C)C.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCCCC1
Solvent: CC(C)OC(C)C
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in diisopropyl ether (60 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and stirred for 15 minutes. The separated organic layer was dried with sodium sulfate and treated with carbon. The diisopropyl ether was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (50 ml) and stirred for 20 minutes at room temperature, filtered. The solid obtained was dried to obtain 3.4 gm of maraviroc amorphous form.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[CH2:12]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([Cl:21])=[O:20])[CH2:13]1.CC(C)=O>FC(F)(F)C(O)=O>[CH:14]1([CH2:17][CH2:18][C:19]([C:6]([CH2:7][C:8](=[O:10])[O-:9])([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[OH:11])=[O:20])[CH2:15][CH2:16][CH2:12][CH2:13]1.[Cl-:21]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: C[N+](C)(C)CC(O)(CC(=O)[O-])C(=O)CCC1CCCC1
Product: [Cl-]

Procedure:
Carnitine chloride (1.97 g; 0.01 moles) was dissolved in trifluoroacetic acid (10 cc). To the resulting solution 3-cyclopentanpropionyl chloride (1.60 g; 0.01 moles) was slowly added under stirring. The resulting mixture was kept under stirring at 45° C. overnight. The mixture was then cooled, acetone (40 ml) was added and the mixture was kept under stirring for 2 hours in ice. The precipitate thus formed was filtered off and to the filtrate ethyl ether was added. The white solid which precipitated was dissolved in ethanol-acetone (5:1) and once again precipitated with ether.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](\[CH3:13])/[C:10]([OH:12])=[O:11].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23]O)[CH3:21])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1CCCCC1.CCCCCC>[CH3:21][CH:20]([CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])[CH2:22][CH2:23][O:11][C:10](=[O:12])/[C:9](/[CH3:13])=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(C)=CCCC(C)CCO
Reactant: C/C(=C\c1ccccc1O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CCCC(C)CCOC(=O)/C(C)=C/c1ccccc1O
Yield: 60.5 %

Procedure:
A solution of 6.0 g of (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid, 5.3 g of citronellol and 1 g of p-toluene-sulfonic acid in 150 ml of cyclohexane was refluxed for 6.5 hours using a water separator. Then the reaction mixture was cooled down, diluted with hexane and washed to neutrality with saturated sodium bicarbonate and water. The organic phase was dried, filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography to yield 6.45 g of a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1([F:15])[CH2:14][O:13][CH2:12]1.[CH:16]1([CH2:19][OH:20])[CH2:18][CH2:17]1.CC([O-])(C)C.[Na+]>CN(C=O)C.C1COCC1>[CH:16]1([CH2:19][O:20][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]2([F:15])[CH2:14][O:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: OCC1CC1
Reactant: O=C(O)c1ccc(C2(F)COC2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Temperature: 50 °C
Yield: 21.7 %

Procedure:
6-Chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid (Example 134 e, 44 mg, 190 μmol) and cyclopropylmethanol (CAN 2516-33-8, 17.8 mg, 20.0 μL, 247 μmol) were dissolved in DMF (1.32 mL). A solution of sodium 2-methylpropan-2-olate (42.0 mg, 437 μmol) in THF (800 μL) was added and the mixture was heated to 50° C. for 3 h and for additional 3 h to 70° C. After cooling to ambient temperature, the reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by thin layer chromatography (2 mm SiO2, dichloromethane/MeOH 19:1, elution with EtOAc) to give the title compound (11 mg, 22 mg) as colorless oil, MS (ESI) m/e=268.2 [MH+].
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][CH:25]1[O:30][CH:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:27]3[CH2:26][CH:25]([CH3:24])[O:30][CH:29]([CH3:31])[CH2:28]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: CC1CNCC(C)O1
Solvent: CCCCO
Product: CC1CN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC(C)O1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 90 μL of 2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)nicotinamide. MS (Q1) 423.4 (M)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([N:14]1[CH:18]=[CH:17]N=[CH:15]1)(N1C=CN=C1)=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][NH:37][C:38]([C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)CNCC2)=[O:39]>ClCCl.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([N:14]1[CH2:15][CH2:47][C:48]2[C:17](=[CH:42][CH:41]=[C:40]([C:38](=[O:39])[NH:37][O:36][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][O:30]3)[CH:49]=2)[CH2:18]1)=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCCO
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COCCCOC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.069 ml 3-methoxypropanol in 4 ml dichloromethane are treated with 117 mg carbonyldiimidazole and 10 mg p-toluenesulfonic acid. After 2 h at ambient temperature, 200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide are added and the reaction mixture is stirred overnight at ambient temperature. Subsequently, the mixture is treated with 2 ml of water and the organic phase is separated. The aqueous phase is extracted twice with 5 ml dichloromethane, dried and evaporated. 100 mg of colorless oil are obtained.
Reaction SMILES: [N+](C1C([N+]([O-])=O)=C(C)C=C[C:5]=1[O:14]CC1OC1)([O-])=O.C(NCC(OC1C=CC=CC=1OC)C)C1C=CC=CC=1.[ClH:39].Cl.Cl.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([CH3:50])[CH:46]=[CH:45][C:44]=1[O:51][CH2:52][CH:53]([OH:68])[CH2:54][NH:55][CH2:56][CH:57]([O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[O:66][CH3:67])[CH3:58]>C(O)C.[Pd]>[ClH:39].[OH:68][CH:53]([CH2:54][NH:55][CH2:56][CH:57]([O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[O:66][CH3:67])[CH3:58])[CH2:52][O:51][C:44]1[C:43]2[NH:42][C:5](=[O:14])[NH:49][C:48]=2[C:47]([CH3:50])=[CH:46][CH:45]=1
Reactant: Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: COc1ccccc1OC(C)CNCC(O)COc1ccc(C)c(N)c1N
Agent: [Pd]
Agent: COc1ccccc1OC(C)CNCc1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1OC(C)CNCC(O)COc1ccc(C)c2[nH]c(=O)[nH]c12

Procedure:
30.5 g. 2,3-Dinitro-1-(2,3-epoxypropoxy)-4-methylbenzene and 32.6 g. N-benzyl-2-(2-methoxyphenoxy)-propylamine are boiled under reflux for 3 hours in 500 ml. ethanol. The reaction mixture is then hydrogenated in the presence of 10 g. 10% palladium-charcoal in 1 liter ethanol at 50° C. and 30 bar. The catalyst is filtered off and the filtrate is acidified with 2 N hydrochloric acid, clarified with active charcoal and evaporated to dryness. There are obtained 59 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2-methoxyphenoxy)-propylamino]-propoxy}-4-methylbenzene trihydrochloride.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:23][C:11]2=[N:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:15]([CH3:16])=[C:10]2[C:9]=1[NH:24][C:25]([NH:27]C(=O)C1C=CC=CC=1)=[S:26])=O)C.CN(C)C=O.I[CH2:42][CH3:43]>C(O)C>[CH2:42]([S:26][C:25]1[NH:27][C:6](=[O:5])[C:8]2[S:23][C:11]3[N:12]=[C:13]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[C:15]([CH3:16])[C:10]=3[C:9]=2[N:24]=1)[CH3:43]
Reactant: CCI
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)cc(C)c2c1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCSc1nc2c(sc3nc(-c4ccccc4)cc(C)c32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
10.5 ml (10.5 mmol) 1 M sodium hydroxide solution is added to 2.00 g (4.2 mmol) 3-(3-benzoylthioureido)-4-methyl-6-phenyl-thieno[2,3-b]-pyridine-2-carboxylic acid ethyl ester in 25 ml ethanol and refluxed for 30 min. Following the addition of 10 ml N,N-dimethylformamide, 5 ml (5 mmol) sodium hydroxide solution (1M) and 0.50 ml iodoethane (6.2 mmol) the next step is stirring at room temperature for 30 min. The precipitate precipitated following acidification with dilute hydrochloric acid is sucked off, washed with water, suck dried and dried in vacuo at 50° C. 1.23 g (83%) 2-ethylthio-9-methyl-7-phenyl-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidin-4-one is obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:17][CH3:18])[CH:8]=2)[N:3]=1.[CH2:19]([Mg]Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([C:2]1[C:11]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:17][CH3:18])[CH:8]=2)[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Mg]Cl
Reactant: COc1ccc2nc(Cl)c(C3OCCO3)cc2c1
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(OC)cc2cc1C1OCCO1
Temperature: 70 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
To a solution of 2-chloro-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44002 (1.41 g, 5.31 mmol) in dry THF (27 mL) at 0° C. under N2 in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added Fe(acac)3 (197 mg, 0.547 mmol) followed by dropwise addition of n-butylmagnesium chloride (2.0 M in THF, 12.4 mL, 24.8 mmol). After complete addition, the mixture was stirred for 5 h at 70° C. then cooled to RT and quenched with water (10 mL). THF was then removed at 40° C. under vacuum and the resulting mixture was extracted with CH2Cl2 (50 mL). The organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:EtOAc=100:0 to 95:5) gave 2-butyl-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44042 as an orange oil (867 mg, 57% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][CH2:27][CH:28]=1)CCC>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3[O:24][CH2:25][CH2:26][CH2:27][CH:28]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Product: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)OCCC1

Procedure:
Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane. Orange oil. MS (m/e): 292.1 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH3:23])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1ccccc1CN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C)cc3)c2)o1

Procedure:
2′-Methyl-N-(2-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-methylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.01,(1H, t), 8.01,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.26,(1H, m), 7.18-7.15,(3H, m), 4.48,(2H, d), 2.56,(3H, s), 2.33,(3H, s), 2.31,(3H, s). LCMS; retention time 3.47 min, MH+ 398.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[C:15]#[C:16][Si](C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:15]([C:6]1[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=[CH:10][C:5]=1[C:4]([N:3]([O:2][CH3:1])[CH3:22])=[O:21])#[CH:16]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100.1 %

Procedure:
To a suspension of N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethynyl-nicotinamide (148 g, 0.449 mmol) in THF (1 ml) and CH3OH (0.5 ml) was added a solution of 1N-NaOH (0.5 ml) and the mixture was stirred for 50 min at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 2-ethynyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (116 mg, 99%).
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OC(=[Se])c1ccccc1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [Se]=C(Nc1ccccc1)c1ccccc1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6 g (0.0206 mol) 2-benzylselenobenzoic acid in 60 ml dichloromethane is treated at -10° C. with 2.64 g (0.0206 mol) chloromethylenedimethyliminium chloride (Vilsmeier's reagent). After stirring for 30 minutes at 0° C. the clear reaction mixture is treated dropwise within 15 min with a solution of 1.9 g (0.04 mol) aniline and 4.21 g (0.0416 mol) triethylamine in 60 ml dichloromethane. After stirring for 48 h at room temperature the clear yellow solution is extracted with 1N HCl (100 ml) followed by water until it is neutral, the organic phase is dried over Na2SO4 and then evaporated to dryness in vacuum. The solid crude product is recrystallized from 2-propanol (220 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[OH-].[Na+:26]>C(O)(C)C>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[Na+:26]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 87.9 %

Procedure:
5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (3.0 g, 0.0083 mole) is dissolved in iso-propyl alcohol (20 ml) and a solution of 50% aqueous sodium hydroxide (0.644 g, 0.0083 mole) is added dropwise and the reaction mixture stirred for 1 hour before removing the solvent and water under vacuum at 0.2 mm overnight to afford 2.8 g of sodium 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1.[BH4-].[Na+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:31]=1
Reactant: O=C1CCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1nc2c(s1)CCCC2O

Procedure:
To the suspension of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one (7 mg, 0.01 mmol) in EtOH (1 mL) is added sodium borohydride (3 mg, 0.08 mmol). After 15 min the reaction is diluted with EtOAc and washed with 1N HCl, NaHCO3 and brine. The solution is dried (MgSO4) and concentrated to provide 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-(4-hydroxy-4,5,6,7-tetrahydro-benzothiazol-2-ylmethyl)-piperazin-2-one. 1H NMR (300 MHz, CDCl3) δ 7.88-7.82 (m, 3H), 7.46 (dd, 1H), 4.83-4.81 (m, 1H), 4.76 (s, 1H), 4.75 (s, 1H), 3.92 (s, 1H), 3.91 (s, 1H), 3.62-3.55 (m, 2H), 3.47-3.41 (m, 2H), 2.76-2.62 (m, 2H), 2.05-1.78 (m, 4H); MS (Ion Spray) 498 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:15]1([C@@H:21]2CCC[C@H:22]2[NH2:26])[CH:20]=[CH:19][CH:18]=CC=1>>[ClH:1].[C:2]1([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Agent: Cl
Product: c1ccc([C@@H]2CCC[C@H]2N=C2CCCCCN2)cc1

Procedure:
Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride the appropriate molar equivalent amount of trans-2-phenylcyclopentylamine hydrochloride, M.P. 147°-149° C., the desired product was obtained, M.P. 192°-195° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.Br[CH2:23][CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH:25]=[CH:24][CH2:23][S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SCC=Cc3ccccc3)nc1-2
Yield: 56 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 3-bromo-1-phenyl-1-propene, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 56%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[C@H:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH:7][C:8](=[O:13])[C:9]([NH2:12])([CH3:11])[CH3:10])[CH3:3].C(N(CC)CC)C.[C:30]([S:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])(=[O:32])[CH3:31].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O>[CH2:2]([O:4][C:5](=[O:22])[C@H:6]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[NH:7][C:8](=[O:13])[C:9]([NH:12][C:35](=[O:36])[C@@H:34]([S:33][C:30](=[O:32])[CH3:31])[CH:38]([CH3:40])[CH3:39])([CH3:11])[CH3:10])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)N
Reactant: CC(=O)S[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)NC(=O)[C@@H](SC(C)=O)C(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(2-amino-2-methyl-1-oxopropyl)-L-tyrosine ethyl ester monohydrochloride (1.33 g, 3.70 mmol) in dimethylformamide (50 mL) and triethylamine (0.52 mL, 3.70 mmol) is added (S)-2-acetylthio-3-methylbutanoic acid (0.65 g, 3.70 mmol). To this mixture is added 1-hydroxy-7-azabenzotriazole (0.55 g, 4.07 mmol) and 1,3-dicyclohexylcarbodiimide (0.84 g, 4.07 mmol). The mixture is stirred overnight and then water (50 mL) is added to the mixture. The solution is extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with a saturated solution of sodium bicarbonate (20 mL), brine, dried over magnesium sulfate and the solvent is removed to give a yellow foam. The foam is purified by flash chromatography (SiO2 :hexane/ethyl acetate, 6:4) to give as a white solid N-[2-(2(S)-acetylthio-3-methyl-1-oxobutylamino)-2-methyl-1-oxopropyl]-L-tyrosine ethyl ester, m.p. 137°-138° C., the compound of formula II wherein R1 is 4-hydroxyphenyl, R2 is ethyl, R3 is acetyl, R4 is isopropyl, and R6 and R7 are methyl.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.O>[I:7][C:8]1[CH:9]=[N:10][N:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of cesium carbonate (20.7 g, 63.4 mmol) and 4-iodopyrazole (10.00 g, 51.6 mmol) in DMF (100 mL) was allowed to stir for 10 min. To the mixture was added 2-(2-bromoethoxy)tetrahydro-2 h-pyran (9.98 ml, 63.4 mmol) and heated at 80° C. overnight. The mixture was diluted with water and extracted with EtOAc (3×50 mL), and subsequently washed with water (2×50 mL) and brine, dried over sodium sulfate, and filtered. The crude mixture was evaporated onto silica gel and purified via MPLC (0% to 50%; EtOAc in hexanes). Isolated 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (15.3 g, 92%) as a clear oil. MS m/z=323.0 [M+1]+. Calc'd for C10H15IN2: 322.1.
Reaction SMILES: C([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=O)=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])(C)(C)C.[ClH:25].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl.O1CCOCC1>[ClH:25].[N+:21]([C:8]1[CH:9]=[C:10]([CH2:13][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]=[CH:12][C:7]=1[C:6]([OH:24])=[O:5])([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCCCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-Nitro-4-(piperidine-1-carbonyl)-benzoic acid tert-butyl ester (1.87 mmol) was dissolved in dry THF and added drop-wise to 3.7 mL of borane tetrahydrofuran complex 1.0 M solution, at room temperature, under nitrogen, with stirring. The reaction was then refluxed for six hours, cooled to room temperature and treated carefully with 2N HCl (10 mL). After stirring for 15 minutes, solid K2CO3 was added in portions (1.75 g). The mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried over sodium sulphate and evaporated leaving an oil that by HPLC-MS analysis resulted a 4:6 mixture of the tertiary amine and the corresponding borane complex. The mixture was dissolved in DCM (1 mL) and treated with 4N HCl in dioxane (7 mL). After 4 days at room temperature, an off white was formed which was filtered, washed with dioxane (5 mL) and dried at 50° C. under vacuum. 0.40 g of title compound were obtained in 70% overall yield.