Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.Cl>O1CCOCC1.O>[CH2:18]([O:17][P:12]([CH2:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][C:4]([OH:20])=[O:3])([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOP(=O)(CC(CC(=O)O)CC(C)C)OCC
Yield: 61.8 %

Procedure:
Lactam 6 (0.64 g, 3.87 mmol) was dissolved in 1,4-dioxane (4 mL) and hydrochloric acid (16 mL of a 6N solution), and the mixture was refluxed for 6 hours. After cooling, the mixture was diluted with water (20 mL) and washed with dichloromethane (2×15 mL). The aqueous layer was evaporated under reduced pressure to give acid 7 (0.67 g, 79%) as a white solid. Recrystallization using ethyl acetate/methanol gave Example 41 exclusively (0.26 g);δH (400 MHz; d6-DMSO) 7.98 (2H, br s, NH2), 3.13 (2H, s, CH2NH2), 2.70 (2H, s), 2.17–2.14 (4H, m), 1.85 (2H, dd, J 13.3, 8.0), 1.63 (2H, m), 1.55 (2H, dd, J 12.9, 5.1); m/z (ES+) 184 (M+H, 100%); LCMS (Prodigy C18, 50 mm×4.6 mmid column, 5–50% Acetonitrile/water) Retention Time=2.40 minutes, 98% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH:16]1[CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:15][CH:16]1[CH2:18][O:17]1
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCC1CO1)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 5.0 g, 0.028 mole), 2-chloromethyl-oxirane (4.4 mL, 0.056 mole), and potassium carbonate (11.6 g, 0.084 mole) was stirred in 50 mL of DMF at 70° C. overnight under Argon. The reaction was then diluted with 200 mL of ethyl acetate and washed 3 times with water. The ethyl acetate solution was dried over sodium sulfate and the solvent removed in vacuo to yield the title compound (Intermediate M). MS m/z 236 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.[NH:14]=[C:15]=[NH:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[O:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]([NH2:16])=[NH:14])=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1
Reactant: N=C=N
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1ccc(-c2cnco2)cc1
Yield: 110.9 %

Procedure:
Hydrochloric acid (4.04 mL, 24.35 mmol) was added to a solution of 4-(oxazol-5-yl)aniline (5 g, 31.22 mmol) and carbodiimide (1.444 g, 34.34 mmol) in ethanol (50 mL). The resulting mixture was heated to reflux for 5 h. The reaction mixture was concentrated under reduced pressure and potassium carbonate (2.59 g, 18.73 mmol) in water (50.00 mL) was added. The formed crystals were filtered off, washed with several portions of potassium carbonate (aq) and dried over night under reduced pressure. The crude solid was slurried in DCM and filtered to give 1-(4-(oxazol-5-yl)phenyl)guanidine (7.00 g, 86%). No further purification. MS (ESI+)/(ESI−) m/z 203/201
Reaction SMILES: Cl.[CH2:2]1[CH:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:6]2[CH2:5][CH2:4][NH:3]1.[Na].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[CH2:2]1[CH:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:6]2[CH2:5][CH2:4][N:3]1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)OC1CNCCC21
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2c3ccccc3OC2C1

Procedure:
To a mixture of 3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine hydrochloride (3.2 g, 15.1 mmol) and sodium hydrogenocarbonate (14 g) in chloroform (40 mL), was slowly added a solution of acetyl chloride (1.5 mL, 21 mmol) in chloroform (5 mL). After stirring for 2 h another portion of acetyl chloride was added. After 5 h the solvent was evaporated. Purification using silica gel chromatography (78 g SiO2) eluting with ethyl acetate yielded 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Br)cc21
Yield: 92.4 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (328 mg, 773 μmol) was stirred in TFA (2 mL, 26.9 mmol) at room temperature for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as an off-white solid (263 mg). MS (m/e)=368.1 (M+H)+. Calculated for C15H14BrNO5 367.01.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[CH:7]=1.[OH-].[Li+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.5 g) in a mixture of THF (10 ml) and water (10 ml) was added aqueous lithium hydroxide (381 mg), and the resulting mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuo, and partitioned between EtOAc and water. The organic layer was neutralized with 2 M HCl. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo to give the title compound (1 g) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>O>[N+:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2cccn3ccnc23)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cccn3ccnc23)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Add 20 g (0.10 mole) of the product from Example 4 slowly to 150 ml of concentrated sulfuric acid at -15° C. Add 7 ml of concentrated nitric acid slowly, maintaining the temperature -10° C. Stir at -10° C. for 30 minutes. Pour onto 500 g of ice. Add 2 L of water and neutralize with potassium carbonate. Extract with three 500 ml portions of methylene chloride. Combine the extracts, dry over magnesium sulfate, treat with charcoal and remove the solvent in vacuo. The residue is crystallized from ether to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[C:12]([CH3:22])[C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[C:12]([CH3:22])[C:11](=[O:23])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2nc(C)c(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2nc(C)c(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 69.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-3-methylquinoxalin-2(1H)-one (Intermediate 159, 75 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol), and sodium triacetoxy borohydride (150 mg, 0.72 mmol) were reacted as described according to Example 69 to give 80 mg (73% yield) of the free base of the product.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:20]([NH:30][C@H:31]([C:35]([CH:7]([OH:8])[C@H:6]1[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3][C@@H:2]1[F:1])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)C(O)[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Reaction time: 72 h

Procedure:
To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (810 mg, 3 mmole) and 4-dimethylaminopyridine (73 mg, 0.6 mmole), N-CBz-L-valine (1.5 g, 6 mmole) and 1-hydroxybenzotriazole (810 mg, 6 mmole) in DMF (20 ml) was added DCC (1.36 g, 6.6 mmole). After 72 h, the reaction mixture was filtered and concentrated in vacuo. 5′-(N-CBz-L-valyl)-2′,3′-dideoxy-3′-fluoroguanosine was isolated by silica gel column chromatography (1.15 g).
Reaction SMILES: [H-].[Na+].CS([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1)(=O)=O.[CH2:25]([CH:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][OH:29])[CH3:26]>[Cl-].[Na+]>[CH2:25]([CH:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][O:29][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1)[CH3:26]
Reactant: CCCCC(CC)CO
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CCCCC(CC)COc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Sodium hydride (60% content, oil dispersion, 0.80 g) was added to a mixture of 4'-methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol) and 2-ethyl-1-hexanol (1.30 g, 0.010 mol) over a period of about 10 minutes. After stirring for 30 minutes at room temperature, the reaction mixture was refluxed and further reacted for 4 hours. After cooling to room temperature, the reaction mixture was poured into an aqueous 4M sodium chloride solution (0.3 liter). The crystal that precipitated was taken out by filtration under suction and then washed with water and hexane. The crystal was dried under reduced pressure (0.1 mm Hg) and then recrysallized from hexane to obtain 3.07 g of the above-entitled product (T-4) as a white crystal. Yield: 85%. m.p. 58.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.ClC[CH:15]([O:18]C(CCl)CCl)CCl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:15]=[O:18])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(O)ccc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
6-Bromo-2-naphthol (25.33 g) was suspended in dichloromethane (300 ml) and titanium tetrachloride (25.0 ml) was slowly added dropwise under cooling in an ice bath. 1,1-Dichloromethylmethyl ether (10.5 ml) was added dropwise to the reaction mixture and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into iced water and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed successively with IN hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated to give the title compound (28.17 g) as brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[C:4]([F:25])[CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2F)C2CCCC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1F)C1CCCC1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-2-fluoro-phenyl)-3-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a light yellow foam, MS (ESI+): m/z=392.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:39]([NH2:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][NH:45][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28]
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NCc1ccco1)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 83.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 51 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]+.
Reaction SMILES: C(OC([NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:23]([F:27])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:23]([F:27])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)N)cc1
Reaction time: 72 h
Yield: 88.5 %

Procedure:
Methyl 4′-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-3-fluoro-1,1′-biphenyl-2-carboxylate (0.25 g, 0.59 mmol) was dissolved in 6.0 mL of anhydrous ethanol. Pd/C (90 mg) was then added and the nitrogen atmosphere was exchanged for hydrogen. The reaction mixture was allowed to stir for 72 hours. After filtration though celite, the ethanol was removed under reduced pressure to yield 0.15 grams of methyl 4′-(1-amino-1-methylethyl)-3-fluoro-1,1′-biphenyl-2-carboxylate which was of sufficient purity to use directly in the next reaction.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]([CH3:26])[C:17]([C:19]1[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].O>CN(C)C=O>[CH3:15][N:16]([CH3:26])[C:17]([C:19]1[C:20]([S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CN(C)C(=O)c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
A solution of 25.0 g (223 mmol) of potassium t-butoxide in 100 ml of dimethylformamide was cooled to 0° C. and 22 ml (186 mmol) of benzyl mercaptan added dropwise at 0° C. After addition was complete, the reaction mixture was allowed to warm to 25° C. and stirred at this temperature for 15 minutes. The reaction mixture was then re-cooled to O° C. and 34.0 g (186 mmol) of N,N-dimethyl-2-(chloro)-3-pyridinecarboxamide added in one portion. After an exotherm to 50° C., the mixture was heated at 80° C. for 1.5 hour. The mixture was cooled, poured into 100 ml of water and extracted with ether. The combined organic extracts were washed twice with water, then brine and dried over sodium sulfate. Concentration gave 19.2 g of a viscous yellow oil. IR (Nujol) 1640 (CONMe2) cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(O)C.S(=O)(=O)(O)O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]2[CH2:23][C:24]3[C:3]4[C:4](=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[NH:9][C:25]=3[CH2:26][CH2:27]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NNc1cc(F)cc(F)c1
Reactant: O=C1CCC(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=S(=O)(NC1CCc2[nH]c3cc(F)cc(F)c3c2C1)c1ccc(Cl)cc1

Procedure:
14.0 g (97 mmol) of the compound of Example I and 27.95 g (97 mmol) of 4-chloro-N-(4-oxo-cyclohexyl)benzenesulphonamide are refluxed for 5 hours in 190 ml of ethanol and 36 ml of concentrated sulphuric acid, then the mixture is cooled and diluted with 300 ml of water. The mixture is extracted 4 times using 250 ml of ethyl acetate each time, and the organic phase is dried using sodium sulphate, filtered with suction over kieselguhr and evaporated. The residue is stirred with methylene chloride and dried in a high vacuum.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4][C:3]([CH2:2][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:6]=2[CH:8]=1
Reactant: Fc1ccc2sc(CBr)nc2c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2sc(CN3CCNCC3)nc2c1

Procedure:
A mixture of 2-(bromomethyl)-5-fluoro-1,3-benzothiazole (150 mg, 0.61 mmol), potassium carbonate (253 mg, 1.83 mmol) and piperazine (263 mg, 3.05 mmol) in acetonitrile (30 ml) was heated at reflux for 4.5 hours with stirring and was then concentrated under vacuum. The residue was dissolved in dichloromethane (100 ml), washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole as a yellow crude solid (130 mg). (ES, m/z): [M+H]+ 252.1; 1H NMR (400 MHz, CDCl3): δ 7.81 (dd, J=8.8, 5.2 Hz, 1H), 7.70 (dd, J=9.6, 2.4 Hz, 1H), 7.16-7.11 (m, 1H), 3.93 (s, 2H), 2.97-2.93 (m, 4H), 2.64-2.63 (m, 4H), 1.98 (s, 1H).
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:41])[CH2:13][N:14]([C@@H](C3C=CC=CC=3)CO)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.O>C(O)C.[OH-].[OH-].[Pd+2]>[OH:3][CH2:4][C:5]1[CH:11]=[C:10]([C@@H:12]([OH:41])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:9]=[CH:8][C:6]=1[OH:7]
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)[C@H](CO)c3ccccc3)ccc2O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1cc([C@@H](O)CNCCCCCCOCCCCc2ccccc2)ccc1O
Yield: 86.9 %

Procedure:
A solution of (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}ethanol (110 mg), in ethanol (75 ml), was hydrogenated over Pearlman's catalyst [Pd(OH)2, 60% H2O, 55 mg) for 18 h. The catalyst was removed by filtration and the residue washed with methanol. The combined filtrate and washings were concentrated and then applied to a 10 g SCX ion exchange cartridge. The cartridge was eluted with methanol (4 column volumes) and then with 10% aqueous 880 NH3 in methanol (3 column volumes). The ammoniacal eluent was concentrated under reduced pressure to give the title compound (69 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:63]>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21][Cl:63])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: ClCC/C(=C(/c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1

Procedure:
4-[4-(2-benzyloxyethoxy)-phenyl]-4-(4-benzyloxyphenyl)-3-phenylbut-3-en-1-ol (1.9 g, 3.45 mmol), triphenyl phosphine (1.8 g, 6.9 mmol), carbon tetrachloride (2.6 g, 17.25 mmol) and acetonitrile (10 ml) were stirred at room temperature for an hour. The product was separated by the same method as Z-1-[4-(2-benzyloxyethoxy)-phenyl]-4-chloro-1,2-diphenyl-but-1-ene described in example 2 and purified by flash chromatography (toluene: methanol, 9.75:0.25). Yield 1.2 g.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH2:25][CH:26]([CH2:43][F:44])[O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH:26]([CH2:25][F:24])[CH2:43][F:44])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(OC(CF)CF)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC(CF)CF)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-1-fluoromethyl-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 182.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=465 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.40-8.37 (m, 1H), 8.36-8.33 (m, 1H), 8.16-8.10 (m, 2H), 8.02-7.97 (m, 1H), 7.59-7.54 (m, 2H), 5.24-5.08 (m, 1H), 4.91-4.65 (m, 4H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].O>C(O)(=O)C>[CH3:6][C:5]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([F:8])[CH:10]=1)=[O:7]
Reactant: Nc1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(F)c1

Procedure:
A solution of acetic anhydride (30.30 g, 0.297 mol) in glacial acetic acid (30 ml) is added to stirred 3-fluoroaniline (30.0 g, 0.27 mol). The resulting stirred mixture is heated under reflux for 20 minutes and poured into cold water (500 ml). the product is extracted into ether (×2) and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is recrystallized from aqueous acetic acid to yield colourless crystals with a yield of 28.90 g (70%).