Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[N:6]=1)=[N+]=[N-]>CO.[Pd].NCCN>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN=[N+]=[N-])n1
Agent: [Pd]
Solvent: NCCN
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A suspension of 2-azidomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (2) (0.83 g, 2.98 mmol) and 5% Pd/C(en) (83.0 mg, 10 wt %) in MeOH (20 mL) was vigorously stirred for 5 hours at a room temperature under a hydrogen atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, the catalyst was removed by suction filtration with a kiriyama funnel. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=30:1 to 10:1) to give 2-aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (3) (603 mg, 80%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A mixture of 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (16.2 mg, 0.050 mmol), 4(trifluoromethylthio)benzyl bromide (20.3 mg, 0.075 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.50 mL) was stirred at 60° C. for 15 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-{4-(trifluoromethylthio)benzyl}piperidine (Compound No. 1616) (21.9 mg, 85%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545.2 (M++H, C23H26ClF3N4O2S).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH3:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][C:28]2[CH:29]=[C:30]([CH3:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) at RT for 4 days. tR: 1.22 min (LC-MS 2); ESI-MS: 509 [M+H]+ (LC-MS 2); Rf=0.32 (5% MeOH/CH2Cl2).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:10][CH3:11])=[N:5][O:6][C:7]=1[CH2:8][CH3:9].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([C:4]1[C:3]([CH2:2][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[C:7]([CH2:8][CH3:9])[O:6][N:5]=1)[CH3:11]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1noc(CC)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1noc(CC)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-diethyl-1,2-oxazole (4.6 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (440 mg, 3.3 mmol), and triethylamine (1.3 mL, 9.3 mmol) in absolute ethanol (35 mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was treated with water (50 mL). The solid material was removed by filtration. The solid was washed with diethyl ether (3×25 mL). The filtrate was recovered, extracted with water (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording the title compound (220 mg, 30% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.18 (m, 6H), 2.21 (s, 3H), 2.65 (m, 2H), 2.83 (m, 2H), 4.22 (s, 2H), 6.02 (s, 1H); M+280.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40][O:41][C:42]1[C:43]([CH:48]=O)=[N:44][CH:45]=[CH:46][CH:47]=1>C1COCC1.CC(O)(C)C>[CH3:2][N:3]([CH3:25])[CH2:4]/[CH:5]=[CH:48]\[C:43]1[C:42]([O:41][CH2:40][CH2:39][O:38][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][O:32]2)=[CH:47][CH:46]=[CH:45][N:44]=1
Reactant: O=Cc1ncccc1OCCOC1CCCCO1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CN(C)C/C=C\c1ncccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a suspension of [2-(dimethylamino)ethyl](triphenyl)phosphonium bromide (32.1 g, 77.4 mmol) in dry THF (150 mL) was added a solution of potassium tert-butoxide (9.4 g, 83.7 mmol) in dry t-BuOH (100 mL). The suspension was sonicated for 15 minutes whereafter a solution of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine-2-carbaldehyde (from Step 1; 18.3 g, 72.8 mmol) in THF (30 mL) was added to the yellow suspension and stirred at room temperature for one hour and then for a further hour at 60° C. The solvent was removed under reduced pressure and the residue was mixed with water (0.8 L) and the pH was adjusted to 3–4 with HOAc (˜10 mL) and then extracted twice with CHCl3. The aqueous phase was made basic and extracted with CHCl3 (×3), the combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product, consisting of the cis and trans* isomers were separated with preparative HPLC on an YMC ODS-AQ column (30×250 mm) with different gradients of 0.1% TFA in water/CH3CN. The cis isomer was isolated as a light yellow oil (2.33 g, 10%). HRMS m/z calcd for C17H26N2O3 (M)+ 306.1943. found 306.1942. *The corresponding trans isomer is described in Example 21, Step 1.
Reaction SMILES: [OH-:1].[Ba+2].[OH-:3].O1CCN([C:10](=S)[CH2:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][NH:19]3)=[CH:14][CH:13]=2)CC1>C(O)C>[NH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([CH2:11][C:10]([OH:3])=[O:1])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: [OH-]
Reactant: S=C(Cc1ccc2c(c1)NCCC2)N1CCOCC1
Agent: [Ba+2]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)NCCC2
Temperature: 80 °C

Procedure:
110 ml of a 20% barium hydroxide solution were added dropwise to a solution of 1-morpholino-2-(1,2,3,4-tetrahydroquinolin-7-yl)-ethanethione (11 g; 1 equiv.) in 55 ml of ethanol, and the resulting reaction mixture was heated for 10 hours at reflux. When the conversion was complete, the solvent was removed under reduced pressure and the residue was taken up in 100 ml of water and heated to 80° C. The reaction mixture was then neutralised carefully with dry ice, filtered over Celite and concentrated under reduced pressure. The resulting crude product (14 g) was used in the next stage without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)CN2CCOCC2)cc1

Procedure:
A suspension of 17.6 (0.07 mole) of Compound II and 1.76 g. of 10% palladium on carbon in 175 ml of ethanol was reduced using a Parr Hydrogenator until hydrogen uptake ceased. The catalyst was removed by filtration and the ethanol solution evaporated. The solid thus obtained was recrystallized twice from water and once from toluene whereby 5.1 g. of yellow needles of the Compound I were obtained, m.p. 107°-110° C., U.V.λmax (Am): 318(21,000), 232(6,800).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([C:14]1[O:18][C:17]([C:19]2[C:20]([NH2:37])=[N:21][CH:22]=[C:23]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:26]=3)[N:24]=2)=[N:16][N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[NH2:37][C:20]1[N:21]=[CH:22][C:23]([C:25]2[N:29]([CH3:30])[N:28]=[C:27]([CH:31]3[CH2:36][CH2:35][N:34]([C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:33][CH2:32]3)[N:26]=2)=[N:24][C:19]=1[C:17]1[O:18][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[N:15][N:16]=1
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
Ethyl 3-chloro-3-oxopropanoate (0.037 mL, 0.29 mmol) was added dropwise to a stirred solution of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and triethylamine (0.047 mL, 0.34 mmol) dissolved in CH2Cl2 (1.5 mL) over a period of 2 minutes at 0° C. under nitrogen. The mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature and stirred for 1 hour. The mixture was evaporated, dissolved in DMF; a white solid was filtered off and the filtrate was purified by preparative HPLC using a Waters X-Terra reverse-phase column eluting with a mixture of water (containing 0.2% ammonium carbonate) and acetonitrile to afford ethyl 3-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (80 mg, 61.7%) as a yellow solid. This material was suspended in THF (2 mL). 2N Sodium hydroxide (0.235 mL, 0.47 mmol) and water (0.5 ml) were added. The mixture was stirred at room temperature overnight. 2N Hydrochloric acid (230 μL) was added to the mixture. The solvents were evaporated. The residue was diluted with CH2Cl2 (30 mL) and water (5 mL). The organic phase was washed with brine and dried over MgSO4. The solvents were evaporated. The resulting foam was triturated in ether. The resulting yellow solid was filtered, dried, triturated in acetonitrile (3 mL). The yellow solid was collected by filtration, dried at 40° C. to afford the title compound (50 mg, 68%) as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2CC3)cn1
Yield: 100.1 %

Procedure:
To a solution of compound 2B (13.6 mg, 0.036 mmol) in MeOH (5 mL) was added 10% Pd/C (3 mg) and the mixture was stirred under a balloon filled with hydrogen for 1 hour. The reaction was filtered through a 0.45 micron filter membrane and concentrated in vacuo to give the title compound (13.6 mg, 100%). HPLC Rt=2.996 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA); LCMS Found: (M+H)+=378.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([O:12][C@H:9]2[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C@H:8]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:41][CH:40]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccc(Br)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6.26 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 4.76 g of 4-bromophenol and 250 ml of benzene is added dropwise, at 5° C. under nitrogen, a solution of 4.79 g of diethyl azocarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred at room temperature overnight. The reaction mixture is processed according to the procedure of Example 75 to give product as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: C1CCNC1
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Solvent: CC#N
Product: O=[N+]([O-])C=C(NCC1CCOC1)N1CCCC1
Temperature: 25 °C

Procedure:
A mixture comprising 1.2 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene, 1.5 ml of pyrrolidine and 15 ml of acetonitrile was stirred at room temperature for an hour. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/acetone=1/1) to obtain 0.92 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-(1-pyrrolidinyl)-2-nitroethylene.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][N:5]12.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:14][CH:11]2[CH2:10][N:5]3[C:6]4[C:2]([CH:3]=[C:4]3[CH2:13][CH2:12]2)=[CH:1][CH:9]=[CH:8][CH:7]=4)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NC1CCc2cc3ccccc3n2C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CCc2cc3ccccc3n2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of (+/−) 6,7,8,9-tetrahydropyrido[1,2-α]indol-7-amine from Step 9 in CH2Cl2 (0.14 M) at rt were added 4-fluorobenzenesulfonyl chloride (1.2 equiv.), triethylamine (5 equiv.) and DMAP (0.03 equiv). The reaction mixture was stirred at rt for 2 h. It was poured into aqueous NaHCO3 and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (0:100 to 50:50 for 15 min, then at 50:50 for 5 min) to give the title compound (78%) as a light yellow foam.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:10][C:11]#[N:12].Cl>O1CCCC1.[Br-].[Zn+2].[Br-]>[CH:1]([C:7]1[CH:8]=[C:9]([CH2:10][C:11]#[N:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: COc1ccc(CC#N)cc1Br
Agent: Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COc1ccc(CC#N)cc1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
An isopropylmagnesium bromide-0.63M tetrahydrofuran solution (3.2 ml, 2.0 mmol) was added dropwise to a solution of zinc bromide (473 mg, 2.1 mmol) in tetrahydrofuran (2 ml) under ice-cooling. After the mixture was stirred for 15 minutes, the reaction mixture was cooled to −78° C. After 3-bromo-4-methoxybenzyl cyanide (226 mg, 1.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (32 mg, 0.04 mmol) were added to the mixture at −78° C., the temperature of the reaction mixture was raised to room temperature and the mixture was further stirred for 5 hours. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-6/1) to give crude (3-isopropyl-4-methoxyphenyl)acetonitrile (158 mg).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[Si:14]([CH:2]([OH:1])[C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g, 135 mmol) in anhydrous DMF (70 mL) was added tert-butyldiphenylsilyl chloride (18.14 g, 66 mmol, 17.2 mL), and the solution was stirred at room temperature under a nitrogen atmosphere for 1 h. After removal of the solvent by evaporation, the residue was dissolved in CHCl3, washed with water and brine, dried (Na2SO4), filtered, and concentrated. After crystallization from hexane, the oily residue gave the title compound 4 as a white crystalline solid (20.6 g, 97%). M.P. 76° C.; 1H NMR (CDCl3) δ7.68–7.65 (m, 4H, arom.), 7.47–7.39 (m, 6H, arom.), 4.63–4.61 (m, 1H, H-5), 3.90–3.87 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.70–3.67 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.69–2.65 (m, 1H, H-3), 2.56–2.52 (m, 1H, H-3), 2.32–2.23 (m, 2H, H-4), 1.06 (s, 9H, t-Bu).
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][NH2:20]>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:20][CH3:19])[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: CN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Product: CNCc1ccc2nc(-c3c(C)n[nH]c3N)sc2c1

Procedure:
The title compound (1.6 mg) was prepared starting from 18 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess methylamine. MS (m/z, ES+): 274.1 (M+1, 100%), 243.1 (M-CH3NH, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[NH:21][C:20](=S)[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][C:10]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:26]>>[Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[N:21]=[C:20]([NH2:26])[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][C:10]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC2(CC1)OCCO2
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC2(CC1)OCCO2
Temperature: 110 °C
Yield: 118.1 %

Procedure:
6″-Bromo-5′″-methyl-3″H-trispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-indene-1″,2′″-imidazole]-4″(3′″H)-thione (Example 115 Step 4, 0.5 g, 1.19 mmol) was taken up in ammonia (7 M in MeOH, 15 mL, 105 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated in vacuo and the same procedure (addition of ammonia, heating and evaporation) was repeated 3 times. The solvent was evaporated to yield the title compound (0.568 g, quantitative yield) that was used without further purification: 1H NMR (500 MHz, CDCl3) δ ppm 1.35-1.49 (m, 2 H), 1.61 (d, 2 H), 1.69-1.81 (m, 2 H), 2.33 (s, 3 H), 3.14 (s, 2 H), 3.87-3.98 (m, 4 H), 6.88 (d, 1 H), 7.19 (d, 1 H), 7.35 (dd, 1 H); MS (ES+) m/z 404 [M+H]+.
Reaction SMILES: C([O:8][N:9]([CH2:20][CH2:21][CH2:22][P:23](=[O:30])([O:27]CC)[O:24]CC)S(C1C=CC(C)=CC=1)(=O)=O)C1C=CC=CC=1.Cl.C(O)(=O)C.C>O>[OH:8][NH:9][CH2:20][CH2:21][CH2:22][P:23](=[O:24])([OH:30])[OH:27]
Reactant: CCOP(=O)(CCCN(OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=P(O)(O)CCCNO
Reaction time: 45 h
Yield: 1831.2 %

Procedure:
A mixture of diethyl 3-(N-benzyloxy-N-tosylamino)propylphosphonate (13.2 g), conc. hydrochloric acid (130 ml) and acetic acid (130 ml) was refluxed with stirring for 45 hours. The resultant mixture was concentrated under reduced pressure to give a residue and then water and an activated charcoal was added thereto, whereafter the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resultant residual oil (8.59 g) was dissolved in water (25 ml). To the solution were added pyridine (2.08 g) and ethanol (5 ml), and then the mixture was allowed to stand overnight at 4° C. to give 3-(N-hydroxyamino)propylphosphonic acid 82.30 g) in the form of crystals. MP: 160°~166° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:24]([OH:36])[CH2:25][S:26][C:27]3[S:28][C:29]4C=CC=C[C:30]=4[N:31]=3)[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+]>O.C1COCC1>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:24]([OH:36])[CH2:25][S:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)C(CC(O)CSc1nc2ccccc2s1)NS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC(O)CSc1nccs1)NS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
2-[(4′-Trifluoromethyl[1,1′-biphenyl]-4-yl)sulfonyl]amino-4-hydroxy-5-[2-benzothiazolylthio]-pentanoic acid: To a solution of 3-[(4′-trifluoromethyl[1,1′-biphenyl]-4-yl)sulfonyl]amino-[2-oxo-5-(thiazol-2-yl)thio]methyl]-tetrahydrofuran 14c (1.13 g, 2.2 mmol) in water (5 mL) and THF (5 mL) is slowly added lithium hydroxide (0.53 g, 22 mmol). The reaction is stirred for 2 hr, then concentrated to dryness. The reaction mixture is diluted with water and then the mixture is extracted with ethyl ether (2×25 mL) The ethyl ether layer is discarded and the aqueous layer is slowly acidified with 1N HCl to pH 5, and then extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The solid is purified by prep HPLC to give the desired white solid product.