Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20]Br.O>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(CC#N)c1Cl
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCC2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A solution (15 mL) of methyl 2-chloro-3-(cyanomethyl)benzoate (1.50, 7.16 mmol) produced in Example C61(iii) in dimethylsulfoxide was cooled at which the solution did not solidify, sodium hydride (60%, 869 mg, 21.7 mmol) was slowly added, and the mixture was stirred at room temperature for 30 min. To the suspension was added dropwise 1,3-dibromopropane (1.45 mL, 14.3 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was slowly added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→50/50) to give the title compound (714 mg, 40%) as a white powder.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](OCC)=O.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:24]([CH2:23][C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1cccs1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccs3)nc(=O)c1-2
Temperature: 25 °C
Yield: 40.3 %

Procedure:
Sodium (414 mg) was dissolved in ethanol (45 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2 g, 9 mmol), followed by ethyl 2-thienylacetate (3.1 g, 18 mmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature and the ethanol was stripped. Water, followed by 2N HCl were added to the residue and the product was collected by filtration, and washed with water. The product was recrystallized from ethyl acetate and dried at 90° C. and 0.2 mm Hg to afford 1.19 g of 1-cyclopentyl-3-ethyl-6-(2-thienylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 173°-174° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[C:24](=[O:25])[CH:23]=[C:22](I)[CH:21]=[N:20]1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.[CH3:27][S:28][C:29]1[N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1>CN1C(=O)CCC1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:31]3[CH:32]=[CH:33][N:34]=[C:29]([S:28][CH3:27])[N:30]=3)[CH:21]=[N:20]2)[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ncc(I)cc1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1nccc(-c2cnn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A solution of (S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-iodopyridazin-3(2H)-one (0.402 g, 0.790 mmol), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.361 g, 0.869 mmol), copper(I) iodide (0.0150 g, 0.0790 mmol) and PdCl2(PPh3)2 (0.0555 g, 0.0790 mmol) in NMP (4 mL) was heated to 120° C. under Ar for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The organics were washed with brine (3×50 mL), dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (1:1) to give (S)-2-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-(methylthio)pyrimidin-4-yl)pyridazin-3(2H)-one (0.25 g, 79%). m/z (APCI-pos) M+1=393.0, 395.0.
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([S:18][C:19]#[N:20])[C:13](OCC)=[O:14])=[CH:7][CH:6]=1.[OH2:28]>C(O)C.Cl>[CH3:21][C:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]2[S:18][C:19](=[O:28])[NH:20][C:13]2=[O:14])=[CH:7][CH:6]=1
Reactant: O
Reactant: CCOC(=O)C(Cc1ccc(OCC(C)(C)c2ccccc2)cc1)SC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(COc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1

Procedure:
1.9 g Of ethyl 3-[4-(2-methyl-2-phenylpropyloxy)phenyl]-2-thiocyanatopropionate is dissolved in 20 ml of ethanol and to the solution 20 ml of 6 N-hydrochloric acid is added. The mixture is refluxed for 24 hours. After cooling, water is added to the mixture. The mixture is subjected to extraction with ether. The extract is washed with water and then dried. After distilling off ether, the residue is crystallized from ether-n-hexane, whereby 730 mg of 5-[4-(2-methyl-2-phenylpropyloxy)benzyl]thiazolidine-2,4-dione is obtained.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[S:19]2(=[O:29])=[O:28])[CH2:11]1)=[O:7])(C)(C)C.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[S:19]3(=[O:28])=[O:29])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN2C(=O)c3ccccc3S2(=O)=O)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3S2(=O)=O)C1

Procedure:
3-tert-Butoxycarbonylaminomethyl-1-(3-(1,1,3-trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl)propyl)pyrrolidine (0.28 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.13 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(1,1,3-trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:19](Cl)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:19]([NH:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)C=Cc1ccccc1)C(C)=O
Reaction time: 0.33 h

Procedure:
Triethylamine (8.3 ml) was added dropwise to a solution of ethyl 2-aminoacetoacetate hydrochloride (5.43 g) and cinnamoyl chloride (5.0 g) in chloroform (90 ml) with ice-cooling and stirring. After 20 minutes, the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was treated with isopropyl ether to give ethyl 2-cinnamoylaminoacetoacetate as crystals; yield 6.1 g (73.9%). Recrystallization from ethanol gave colorless needles melting at 113°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[N:7]=[C:6]([CH3:13])[C:5]=1[OH:14].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[N:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)c1cc(C2CC2)nc(C)c1O
Product: COC(=O)c1cc(C2CC2)nc(C)c1OCc1cccc(C#N)c1
Yield: 64.2 %

Procedure:
The coupling of 6-cyclopropyl-3-hydroxy-2-methyl-isonicotinic acid methyl ester (182) (614 mg, 2.9 mmol) and α-bromo-m-tolunitrile (638 mg, 3.26 mmol), as described in Example 1, gave 3-(3-cyano-benzyloxy)-6-cyclopropyl-2-methyl-isonicotinic acid methyl ester (188) (600 mg, 63% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17]I>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])[N:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:5])[CH3:2]
Reactant: FC(F)(F)CCI
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1CCC(F)(F)F
Yield: 31 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and 1,1,1-trifluoro-3-iodo-propane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 68 mg (15%) of the desired regioisomer and 141 mg (31%) of 4-nitro-2-(3,3,3-trifluoropropyl)-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:19](=[O:20])[CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: CN1CCN(CCC(=O)O)CC1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(CCC(=O)NNc2ccc(F)cn2)CC1
Reaction time: 18 h
Yield: 70.3 %

Procedure:
5-fluoro-2-hydrazinopyridine (295 mg, 2.32 mmol) and 3-(4-methyl-1-piperazinyl)propionic acid (400 mg, 2.32 mmol) were dissolved in DCM (15 mL). EDC (536 mg, 2.79 mmol) and HOBt (31.0 mg, 0.23 mmol) were added and the reaction stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, which was washed with MeOH product eluted with 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM, afforded the title compound (458 mg, 1.63 mmol, 73%). 1H NMR (400 MHz, CDCl3): 2.32 (3H, s), 2.48-2.54 (2H, t, J 6.0), 2.54-2.70 (8H, br s), 2.69-2.75 (2H, t, J 6.0), 6.60-6.65 (1H, dd, J 8.9, 3.3), 6.75-6.78 (1H, d, J 4.4), 7.25-7.34 (1H, m), 8.02-8.05 (1H, d, J 3.0), 10.50 (1H, s).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: NCCCCOc1cccnc1
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCC(=O)NCCCCOc2cccnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 4-(3-pyridinyloxy)butyl amine according to procedure A and the product was purified by HPLC to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyloxy)butyl]hexanamide, the title compound, mp 50°-53° (from ethyl acetate) in 73% yield.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:11]1[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH2:17]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2.9 g) and dichloromethane (29 ml) were mixed, and TFA (7.3 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The aqueous layer was concentrated under reduced pressure, and CHCl3 was added to the residue, followed by stirring and filtrating. The filtrate was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain {2-fluoro-3-[3-(piperidin-4-yl)azetidin-1-yl]phenyl}methanol (1.25 g).
Reaction SMILES: [O:1]([CH3:21])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][CH:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH2:11]3)[N:6]([CH3:7])[CH2:5]1)=[O:3].B(F)(F)F.CCOCC.S(Cl)([Cl:34])(=O)=O>C(Cl)Cl>[Cl:34][CH:11]1[NH:12][C:13]2[C:20]3[CH:10]1[CH2:9][C@@H:8]1[C:18]([C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:19][C@@H:4]([C:2](=[O:3])[O:1][CH3:21])[CH2:5][N:6]1[CH3:7]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4c3C(CN4)C[C@H]2N(C)C1
Reactant: O=S(=O)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H]1C=C2c3cccc4c3C(C[C@H]2N(C)C1)C(Cl)N4

Procedure:
885 mg. of methyl dihydrolysergate were dissolved in 50 ml. of methylene dichloride. 0.95 ml. of boron trifluoride etherate were added and the reaction mixture cooled to a temperature in the range 0°-5° C. A solution of 0.27 ml. sulfuryl chloride in 20 ml. of methylene dichloride was added in dropwise fashion. The reaction mixture was stirred and cooled for about 15 minutes and then quenched by pouring into an ice-dilute ammonium hydroxide mixture. D-2-chloro-6-methyl-8-carboxyergoline, methyl ester or methyl 2-chlorodihydrolysergate formed in the above reaction was isolated and purified by the procedure of Example 1. Chromatography over fluorosil using 2 percent methanol in chloroform yielded 730 mg. (74 percent yield) of crystalline material melting at 206°-8° C. with decomposition.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([F:44])[CH:38]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][C:20]2=[O:31])[CH:13]([C:32]([O:34]C)=[O:33])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+]>O>[C:3]([O:7][C:8]([N:10]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([F:44])[CH:38]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][C:20]2=[O:31])[CH:13]([C:32]([OH:34])=[O:33])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)C1CC(N(Cc2ccc(C)c(F)c2)C(=O)OC(C)(C)C)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc(C)c(F)c4)C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Reaction time: 2.5 h
Yield: 39.7 %

Procedure:
To 5 mL of a methanol solution containing 80 mg of methyl 4-((tert-butoxycarbonyl) (3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate, 0.2 mL of 2 mol/L aqueous sodium hydroxide solution was added at room temperature, and stirred for 2.5 hours. Further, 0.2 mL of 2 mol/L aqueous sodium hydroxide solution and 0.5 mL of water were added, stirred at the sane temperature for 4 hour and 40 min, and allowed to stand overnight. The solvent was removed under reduced pressure, and the reaction mixture was adjusted to pH 7.0 with 2 mol/L hydrochloric acid. To the mixture, water and ethyl acetate were added, the organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 31 mg of 4-((tert-butoxycarbonyl) (3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid as a yellow solid. (2) To 5 mL of an ethyl acetate solution containing 31 mg of 4-((tert-butoxycarbonyl)(3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid, 0.1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 6 hours and 40 min, further, 0.1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 3.5 hours. The resulting solid was filtered to give 30 mg of 4-((3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid hydrochloride as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (0.11 g), 1-bromo-6-phthalimidohexane (0.47 g) and potassium carbonate (0.42 g) in N,N-dimethylformamide (5 ml) was stirred overnight at room temperature. The mixture was taken up in ethyl acetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-{(2S,3R)-2-hydroxy-5-[2-(6-phthalimidohexyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide (6-1) (219 mg).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:25]#[CH:26].C(N(C(C)C)CC)(C)C>O1CCCC1.[Cu]I>[CH2:24]([C:25]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C#CCc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Reaction time: 8 h

Procedure:
To a stirred solution of propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate (1 eq) (Synthesis described in WO07019675 A1) and prop-2-yn-1-ylbenzene (2 eq) in tetrahydrofuran (THF) (0.1M) at room temperature was added diisopropyl ethylamine (DIPEA) (5 eq) and CuI (5 eq). The reaction mixture was stirred overnight then quenched with NH4Cl sat and extracted with ethyl acetate (EA), washed with brine, dried over Na2SO4 and evaporated. Purification by combi-flash EA/Hex 0-100% afforded the desired compound which was used directly for next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)=[C:12]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([C:13]2[C:12]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)=[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: CCCCCCOc1cc(-c2cccc([N+](=O)[O-])c2)c(OCCCCCC)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCOc1cc(-c2cccc(N)c2)c(OCCCCCC)cc1-c1cccc(N)c1
Yield: 87.8 %

Procedure:
Into a 500 ml three-necked flask equipped with a stirrer, 1,4-bis(3-nitrophenyl)-3,6-di-hexyloxybenzene 9.0 g (17.3 mmol) and 10 wt % palladium activated carbon (Pd/C) 2 g were introduced and dissolved in 200 ml of THF, and then the resulting mixture was reacted for 24 hours at room temperature while filling hydrogen gas therein. After the reaction was completed, the reaction mixture was dried with anhydrous magnesium sulfate, and then solvent was removed to give white crystal. The crystal was dried in a vacuum oven at 40° C. to give 7.0 g of desired product (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[N:9]2)=[C:4]([C:19]([N:21]2[C@H:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]2)=[C:4]([C:19]([N:21]2[C@H:30]([CH2:31][OH:32])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)nn1-c1ccc(Br)cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-ethyl 1-(4-bromo-2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-methyl-1H-pyrazole-3-carboxylate (50.0 g, 100.6 mmol) in THF (80 mL) and water (20 mL) was added lithium hydroxide monohydrate (21.1 g, 503.0 mmol) followed by stirring at RT for 12 h. The reaction mixture was concentrated invacuo, diluted with water (80 mL) and extracted with diethyl ether (100 mL). The aq. layer was cooled to 0° C., acidified up to pH ˜4 using 3N HCl and extracted with EtOAc (200 mL×2), twice. The combined organic layers were washed with water (200 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a pale yellow solid, 40 g (crude). Rf=0.10 (30% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 12.80-11.80 (m, 1H), 8.15-7.40 (m, 3H), 7.30-6.90 (m, 4H), 6.70-6.30 (m, 1H), 5.10-3.70 (m, 5H), 3.50-2.40 (m, 3H), 2.38-2.10 (m, 3H); ES-MS: m/z 470.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([NH:8][C:9]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]([NH:18][C:19]2[NH:23][C:22]3[C:24]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[O:17])=[O:10])[CH:7]=1.[C:36](#N)C.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([NH:8][C:9]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]([NH:18][C:19]2[NH:23][C:22]3[C:24]([O:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]4)=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[O:17])=[O:10])[CH:7]=1
Reactant: CC#N
Reactant: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cccc(OC3CCNCC3)c2[nH]1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cccc(OC3CCN(C)CC3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N4-(5-Bromo-2-methylphenyl)-N5-(7-(piperidin-4-yloxy)-1H-benzo[d]imidazol-2-yl)-1H-imidazole-4,5-dicarboxamide (0.1 mmol) was weighted out into a round bottomed flask and acetonitrile (5 mL) was added and the resulting solution was stirred at 25° C. Formaldehyde (1.0 mmol) and sodium cyanoborohydride (0.32 mmol) was added. The reaction mixture was kept neutral by the addition of acetic acid. After 2 hours, the reaction mixture was concentrated under reduced pressure. The crude product was purified via reverse phase HPLC (aqueous ammonium acetate/acetonitrile) to give N4-(5-bromo-2-methylphenyl)-N5-{7-[(1-methylpiperidin-4-yl)oxy]-1H-benzimidazol-2-yl}-1H-imidazole-4,5-dicarboxamide as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.97 (s, 1H), 7.35 (m, 1H), 7.28 (d, 1H), 7.12 (dd, 1H), 6.99 (m, 1H), 6.67 (m, 1H), 4.67 (m, 1H), 2.32 (m, 4H), 2.19 (s, 3H), 1.89 (m, 5H), MS (EI): 553.3 (MH+).