Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.FC(F)(F)S([O-])(=O)=O.[CH3:23][C:24]1[N:25]([S:30](N2C=CN=C2C)(=[O:32])=[O:31])[CH:26]=[CH:27][N+:28]=1C.C(#N)C.C(N(CC)CC)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([S:30]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])(=[O:32])=[O:31])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1nccn1S(=O)(=O)n1cc[n+](C)c1C
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nccn1S(=O)(=O)N1CC=C(c2ccc(F)cc2)CC1
Yield: 52 %

Procedure:
A solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (150 mg, 700 μmol), 2,3-dimethyl-1-[(2-methyl-1H-imidazol-1-yl)sulfonyl]-1H-imidazol-3-ium trifluoromethanesulfonate (410 mg, 1.05 mmol), acetonitrile (5 mL) and triethylamine (98 μL, 700 μmol) was stirred at 25° C. for 24 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (117 mg, 52%). MF=C15H16FN3O2S; LCMS found for C15H17FN3O2S(M+H)+: m/z=322.
Reaction SMILES: [C:1]([S:4][C@H:5]1[O:52][C@H:51]([CH2:53][O:54]C(=O)CCCCCCCCCCC)[C@H:36]([O:37]C(=O)CCCCCCCCCCC)[C@H:21]([O:22]C(=O)CCCCCCCCCCC)[C@H:6]1[O:7]C(=O)CCCCCCCCCCC)(=O)[CH3:2].[C:68]1(=[O:75])[CH2:74]CC[CH2:71][CH:70]=[CH:69]1>>[S:4]([CH:1]1[CH2:2][CH2:71][CH2:70][CH2:69][CH:68]([OH:75])[CH2:74]1)[C@H:5]1[O:52][C@H:51]([CH2:53][OH:54])[C@H:36]([OH:37])[C@H:21]([OH:22])[C@H:6]1[OH:7]
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](SC(C)=O)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reactant: O=C1C=CCCCC1
Product: OC[C@H]1O[C@H](SC2CCCCC(O)C2)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
The title compound was prepared according to procedures D, E and I above using 1-S-acetyl-2,3,4,6-tetra-O-lauroyl-1-thio-α-D-galactopyranose (from Example C' above) and cyclohept-en-1-one as the electrophile. Mass spectra data was as follows: M (calcd.): 308.40; M (found): 331.3 (M+Na+). Selected nmr data was as follows: 1H-nmr (CD3OD): δ 5.44 (d, J 5.8 Hz, H-1) and 5.45 (d, J 5.8 Hz, H-1).
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=[O:13].S(=O)(=O)(O)O.[Br:20]Br>>[Br:20][C:6]1[C:7]2[C:12]3[C:3]([C:2](=[O:13])[C:1](=[O:14])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: O=C1C(=O)c2cccc3cccc1c23
Agent: O=S(=O)(O)O
Product: O=C1C(=O)c2ccc(Br)c3cccc1c23

Procedure:
In the second route, the raw material acenaphthenequinone and the solvent concentrated sulfuric acid are added into liquid bromine and refluxed for 2 hours to obtain 5-bromoacenaphthylene-1,2-dione. The resulting bromoacenaphthene reacts with alcohol, thioalcohol, phenol, thiophenol, ester or amide to obtain the corresponding substituted acenaphthenequinone iv, as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1>CC(N(C)C)=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: CSc1nccc(Cl)n1
Reactant: Nc1cc(O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSc1nccc(Oc2ccc(F)c(N)c2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
In DMA (10 mL) was placed 3-amino-4-fluorophenol (500 mg, 3.93 mmol), potassium t-butoxide (441 mg, 3.93 mmol) and 4-chloro-2-(methylthio)pyrimidine (632 mg, 3.93 mmol). The mixture was warmed to 50° C. and stirred overnight. The mixture was cooled to RT and diluted with water (30 mL), extracted with ethyl acetate (2×25 mL) and the combined organic phases washed with brine, dried (Na2SO4) and concentrated to yield a dark oil. The oil was purified by column chromatography to yield 2-fluoro-5-(2-(methylthio)pyrimidin-4-yloxy)benzenamine (841 mg, 85% yield) as an oil which was used without further purification. MS (ESI) m/z: 252.0 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl>C(OC(C)(C)C)(=O)C>[NH2:1][C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([C:4]([CH3:9])([CH3:5])[CH3:3])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 108 h
Yield: 89.2 %

Procedure:
To a solution of Tyr-OMe.HCl (500 g, 2.16 mol) in tert-butyl acetate (4500 ml), 70% HCl4 (278 ml, 3.24 mol) was added and stirred for 4.5 days at room temperature. The reaction mixture was evaporated under reduced pressure; the thus obtained residue was dissolved in ethyl acetate, poured into a saturated aqueous NaHCO3 solution and stirred. The organic layer was collected and washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was mixed with ether (950 ml) and at room temperature, stirred overnight. The thus precipitated crystals were collected by filtration to give Tyr(3-tBu)-OMe (242 g, 45%).
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34][CH3:35])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]1[C:22](=[O:31])[NH:23][C:24]3[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15]2)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:35][O:34][CH2:33][CH2:32][NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]1[C:22](=[O:31])[NH:23][C:24]3[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15]2
Reactant: COCCN(CCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNCCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Reaction time: 18 h

Procedure:
10% Pd/C (840 mg) was added to a solution (150 mL) of 3-(5-{2-[Benzyl-(2-methoxyethyl)-amino]-ethoxy}-1H-indol-2-yl)-2(1H)-quinolinone, Compound 1-27, (840 mg, 1.8 mmol) in EtOAc (150 mL), and the resulting mixture was stirred under a hydrogen balloon for 18 h. The catalyst was removed by filtration and the filtrate concentrated to a yellow solid which was purified by chromatography on a silica column. Elution with EtOAc to 25% NH3-EtOH/EtOAc gave 3-(5-{2-[(2-methoxyethyl)amino]ethoxy}-1H-indol-2-yl)-2(1H)-quinolinone (2-1) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ11.05 (s, 1H), 9.65 (br s, 1H), 8.32 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.51 (t, 1H, J=8 Hz), 7.34 (d, 1H, J=8 Hz), 7.29 (t, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 7.09 (s, 1H), 6.96 (s, 1H), 6.90 (dd, 1H, J=8, 2 Hz), 4.15 (t, 2H, J=5 Hz), 3.55 (t, 2H, J=5 Hz), 3.38 (s, 3H), 3.07 (t, 2H, J=5 Hz), 2.91 (t, 2H, J=5 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][NH:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])([OH:18])[CH2:13]3)[C:7]=2[CH:29]=1)#[N:2].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][C@:14]4([O:18][C:35](=[O:36])[N:20]([CH2:21][C:22]([CH3:27])([CH3:28])[C:23]([O:25][CH3:26])=[O:24])[CH2:19]4)[CH2:13]3)[C:7]=2[CH:29]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C(C)(C)CNCC1(O)CCCC(Cn2cnc3ccc(C#N)cc32)C1
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CN1C[C@@]2(CCC[C@H](Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
A solution of methyl 3-[({3-[(6-cyano-1H-benzimidazol-1-yl)methyl]-1-hydroxycyclohexaneyl}methyl)amino]-2,2-dimethylpropanoate (1.048 g, 2.63 mmol) and CDI (0.853 g, 5.26 mmol) in 1,4-dioxane (15 mL) was stirred at 100° C. for 1 day. The reaction was then concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel column; solvent A=DCM; solvent B=MeOH (0.1M NH3); 0-5% B over 15 min; then 5% B over 5 min) to give methyl 3-{(5S,7S)-7-[(6-cyano-1H-benzimidazol-1-yl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-3-yl}-2,2-dimethylpropanoate as a beige solid (1.06 g, 95% yield). MS (m/z) 425.2 (M+H+).
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([O:7]C)=[O:6])(=[O:3])[CH3:2].[OH-].[K+]>ClCCl>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCCCCC(C(C)=O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCC(C(C)=O)C(=O)O

Procedure:
Analogously to Example 15A, 900 mg (5.23 mmol) of methyl 2-acetylheptanoate (Example 16A) are reacted with 2.5 ml of a 3.5 M potassium hydroxide solution to give 2-acetylheptanoic acid in dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH:47]12[NH:53][CH:50]([CH2:51][CH2:52]1)[CH2:49][CH2:48]2>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:24])([CH3:25])[C:21]([N:53]3[CH:47]4[CH2:52][CH2:51][CH:50]3[CH2:49][CH2:48]4)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC2CCC1N2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (856 mg in 8.0 mL methylene chloride) at 0° C. was added 310 mg of 1-hydroxybenzotriazole (HOBt)followed by 400 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture stirred at low temperature for 90 minutes. At this time, a solution of 7-aza-bicyclo[2.2.1]heptane hydrochloride (632 mg in a mixture of 2.0 mL methylene chloride and 0.66 mL triethylamine) was added and the mixture warmed to room temperature. The reaction was quenched after 24 hours by dilution with methylene chloride and washing with half-saturated brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (hexane:ethyl acetate, 70:30; then 60:40; then 50:50; then 40:60) to give the title compound (736 mg).
Reaction SMILES: [CH3:1][C:2]1NC(C)=C(C(OC(C)C)=O)[CH:4]([C:15]2[C:20]3=[N:21][O:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:24]([O:26][CH3:27])=[O:25].N1[O:29]N=C2C(C=O)=CC=CC=12.C(OC)(=O)CC(C)=O.N1CCCCC1>C(OC(C)C)(C)C.C(O)(=O)C>[CH3:27][O:26][C:24](=[O:25])[C:3]([C:2](=[O:29])[CH3:1])=[CH:4][C:15]1[C:20]2=[N:21][O:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12
Reactant: O=Cc1cccc2nonc12
Agent: COC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: COC(=O)C(=Cc1cccc2nonc12)C(C)=O

Procedure:
To achieve the afore-mentioned objects, the present invention provides for a process for the manufacture of the Isradipine which, involves two steps. In the first step 2,1,3-benzoxadiazole-4-carboxaldehyde is reacted with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether. The product 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is isolated and purified to get substantially high purity product with less than 0.3% 2,1,3-benzoxadiazole-4-carboxaldehyde content present in the purified product. In the second step the purified intermediate 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is reacted with isopropyl-β-aminocrotonate in ethanol at 25 to 35° C. The crude Isradipine is crystallised from ethanol to get pure Isradipine having substantially higher purity and containing lower amount of the symmetrical ester isomers (III) and (IV).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Cu].C(O)(=O)CC>[Cl:12][C:9]1[CH:8]=[C:3]([CH:2]=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Cl
Agent: [Cu]
Solvent: CCC(=O)O
Product: COC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with methyl 2,5-dichlorobenzoate (5.0 g, 24 mmol) and copper powder (3.04 g, 48 mmol). Propionic acid (10 mL) and xylenes (15 mL) were added, and the resulting mixture was heated to 130°-135° C. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (3 hours). The reaction mixture was cooled to room temperature and filtered; the solids were washed with xylenes. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting yellow organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum, yielding 3.93 g of methyl 3-chlorobenzoate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=O)[C@@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CSC.B>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C@@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=1
Reactant: O=C(c1cccs1)N1CCC[C@@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: B
Solvent: CSC
Product: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3cccs3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1

Procedure:
The compound of Example 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was recrystallised from ether and hexane to give the product as a white crystalline solid. 1H NMR (250 MHz, CDCl3) d 1.44-1.64 (2H, m, CH2), 1.9-2.2 (2H, m, CH2), 2.24 (1H, d, J=7 Hz, CHN), 3.14 (1H, d, J=7 Hz, CHN), 3.4 (1H, s, CHO), 3.56 (1H, s, NCHPh), 3.6 (1H, s, CH-thiophene), 4.88 (1H, d, J=10 Hz, CH-thiophene), 4.0 (1H, d, J=10 Hz, CHAr), 4.24 (1H, d, J=10 Hz, CHAr), 6.7 (1H, d, J=1 Hz, thiophene-H), 6.9 (H, dd, J=2 Hz, 3 Hz, thiophene-H), 7.2 (1H, d, J=3 Hz, thiophene-H), 7.28 (4H, m, Ar--H), 7.5 (3 H, m, Ar--H), 7.68 (1H, s, Ar--H). MS m/z 500 (M+, 100%).
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>C(#N)C>[N:20]([CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2](=[O:1])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC(=O)C1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
To as solution of (Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2.0 g, 9.5 mmol) in acetonitrile (3 mL), was added trimethylsilyl azide (3.76 mL, 28.4 mmol) followed by AMBERLITE® IRA 900F resin (loading: 2-3 mmolg-1, 2.4 g) and the resulting mixture was heated at 60° C. behind a blast shield for 16 hr. After cooling to room temperature, the solution was filtered washing the resin with acetonitrile and the filtrate was concentrated under reduced pressure (temperature of bath<40° C.) to give tert-butyl 5-azido-3-oxoazepane-1-carboxylate as a yellow liquid (2.21 g). To a solution of the azide (2.2 g, 8.70 mmol) in THF/water (1/1, 40 mL), was added portionwise NaBH4 (0.82 mg, 21.8 mmol) and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 5-azido-3-hydroxyazepane-1-carboxylate as an oil (2.01 g). To a solution of this oil (2.0 g, 7.8 mmol) in MeOH (20 mL), was added HCl (4 M in 1,4-dioxane, 43 mL, 173 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and passed through an SCX column, washing with MeOH and eluting with 7 N ammonia in MeOH to give 5-azidoazepan-3-ol as a yellow oil. To this oil in dry DMSO (20 mL) was added potassium fluoride (1.68 g, 28.9 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.17 g, 7.2 mmol) and the mixture heated at 65° C. for 16 hr. The mixture was diluted with water (300 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (3×20 mL), separated, dried over MgSO4 and the solvents removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol as a viscous yellow oil (1.9 g, 72% over four steps). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.02 (2s, 1H), 4.15-3.97 (m, 2H), 3.95-3.83 (m, 4H), 3.58-3.46 (m, 1H), 3.39-3.16 (m, 3H), 2.29-1.91 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2c(Br)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100-mL of flask was charged with (±)-tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (500 mg, 1.1 mmol) dissolved in 20% TFA in CH2Cl2 solution (15 mL) at 0° C. The mixture was stirred for 0.5 h at 0° C. Then the mixture was concentrated to give crude (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([S:14](=[O:35])(=[O:34])[NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([S:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=3[F:33])[N:17]=2)[CH2:10][CH2:9]1)C>CO>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][S:24][C:18]1[N:17]=[C:16]([NH:15][S:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:13][CH2:12]2)(=[O:34])=[O:35])[CH:21]=[C:20]([O:22][CH3:23])[N:19]=1
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NS(=O)(=O)N2CCN(CC(=O)O)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared by adding 1M NaOH (1 mL) to a solution of {4-[2-(2,3-Difluoro-benzylsulfanyl)-6-methoxy-pyrimidin-4-ylsulfamoyl]-piperazin-1-yl}-acetic acid ethyl ester (the product from step i) (0.31 g) in MeOH (1 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with Toluene, DCM followed by Et2O to give the title compound as a white solid. Yield: 85 mg
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:24]=[CH:23][C:19]([CH2:20][OH:21])=[C:18]([F:25])[CH:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)O)c(F)c3)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(CO)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
7.8 g of 4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-2-fluorobenzoic acid are added to a suspension of 4.5 g of lithium aluminium hydride in 150 ml of dry ether and the mixture is stirred under reflux for 23 hrs. The suspension is cooled to 0° C., treated cautiously with 40 ml of water and then with 150 ml of 3N sulfuric acid, extracted with ether and the organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated. Chromatography of the residue on silica gel with methylene chloride/acetone (95:5) gives 4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-2-fluorobenzyl alcohol.
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[N:5]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]([OH:25])[C:15]=3[CH:26]=2)[CH:9]=[CH:8][N:7]=[CH:6]1>CO>[N:5]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]([O:25][CH3:1])[C:15]=3[CH:26]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: C[O-]
Reactant: On1c(-c2ccccc2)nc2ccc(Cn3ccnc3)cc21
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COn1c(-c2ccccc2)nc2ccc(Cn3ccnc3)cc21
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred sodium methoxide solution previously prepared starting from 0.46 parts of sodium and 32 parts of methanol were added 6.16 parts of 6-(1H-imidazol-1-ylmethyl)-2-phenyl-1H-benzimidazol-1-ol. After stirring for a while, the whole was concentrated and 2 portions of 18 parts of methylbenzene were added. After evaporation, there were added successively 27 parts of N,N-dimethylformamide and a solution of 2.84 parts of iodomethane in 9 parts of N,N-dimethylformamide. The whole was stirred first for 10 minutes at room temperature and then for 30 minutes at 60° C. The reaction mixture was evaporated and 50 parts of water were added to the residue. The precipitated product was filtered off, washed with water and purified by filtration over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybisproprane. The product was filtered off and dried, yielding 5.4 parts (88.7%) of 6-(1H-imidazol-1-ylmethyl)-1-methoxy-2-phenyl-1H-benzimidazole; mp. 142.1° C. (compound 227).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1c(Cl)cc(N)cc1Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1c(Cl)cc(N2CCNCC2)cc1Cl
Yield: 29.8 %

Procedure:
A mixture of 3,5-dichloro-4-methoxyaniline (16.0g) and bis-(2-chloroethyl)amine hydrochloride (14.77g) in n-butanol (100 ml) was stirred under reflux for 48 hr. Anhydrous potassium carbonate (11.45g) was added and the resulting mixture was stirred under reflux for a further 24 hr., then filtered hot. The solid which precipitated on cooling was crystallised from ethanol-ether to give 1-(3,5-dichloro-4-methoxyphenyl)piperazine hydrochloride (3.7g) m.p. 252°-255°.