Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:23].Cl.Cl.NC[C@H](N1CCN(CC2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)CC1)C(O)=O>>[ClH:23].[ClH:23].[ClH:23].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:19][CH2:20]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: NC[C@@H](C(=O)O)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: CCN1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)OC)CC1
Agent: Cl
Product: COC(=O)[C@H](CN)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
In a manner similar to example 2-3, starting from 5.3 g (13.4 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate, 5.4 g (100%) of (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate trihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH:9](O)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)C(O)c1c(F)ccc(F)c1F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=Cc1c(F)ccc(F)c1F)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[Hydroxy-(2,3,6-trifluoro-phenyl)-methyl]-malonic acid dimethyl ester (13 g, 44.5 mmol) and NEt3 (9 g, 89 mmol) were dissolved in 300 mL CH2Cl2. MsCl (10.3 g, 89 mmol) was then added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 1N HCl solution (200 mL×2), brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (gradient from 0/100 to 25/75 in 40 min, 6.5 g, 53%). 1H NMR (CDCl3 400 MHz) δ 7.71 (s, 1H), 7.20 (m, 1H), 6.89 (m, 1H), 3.87 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CC(C)=O>[P:7]([N:16]=[N+:17]=[N-:18])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:8]
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure of Baldwin and Washburn, J. Org. Chem., 30, 3860 (1965), 6.99 g (0.0297 mole) of diphenylphosphinyl chloride and 2.09 g (0.032 mole) of sodium azide were stirred in 40 ml of anhydrous acetone under a nitrogen atmosphere for 48 hours. The sodium chloride and unreacted sodium azide was removed by gravity filtration and the acetone solvent removed in vacuo. The crude diphenylphosphinic azide was analyzed for Cl content and in all cases only trace quantities (less than .1%) were found. The colorless diphenylphosphinic azide was purified by distillation to yield 6.31 g (87%) boiling at 138°-140° C./0.05 mm; literature value 137°-140° C./0.05 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([NH:35][NH:34][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:37][CH:36]=3)=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)NNC(=O)c3ccc(Cl)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the crude 2-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carboxylic acid in 10 ml of DMF was added 900 mg of 4-chlorobenzoic acid hydrazide, 1.1 g of EDCI and 700 mg of HOBT. The reaction was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture was diluted with water and the resulting precipitates were collected by filtration and purified by column chromatography (DCM:MeOH=20:1) to give the title compound. LCMS ret T=1.19 min, m/z=504.1, Method 10.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:18][CH3:19])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1.Cl>O1CCOCC1>[CH3:19][O:18][C:10]1[CH:9]=[C:8]2[C:13](=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=1)[N:5]([CH2:4][CH:3]=[O:2])[N:6]=[CH:7]2
Reactant: COC(=O)c1cc(OC)cc2cnn(CC(OC)OC)c12
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)cc2cnn(CC=O)c12
Temperature: 75 °C

Procedure:
To methyl 1-(2,2-dimethoxyethyl)-5-methoxy-1H-indazole-7-carboxylate (161 mg, 0.5 mmol) from Step G above in 1,4-dioxane (3 ml) was added 2N hydrogen chloride (3 ml) and the reaction mixture was heated to 75° C. for 2 h. The solvent was concentrated in vacuo to afford methyl 5-methoxy-1-(2-oxoethyl)-1H-indazole-7-carboxylate: MS (ESI+) m/z 249 (M+H).
Reaction SMILES: CN1CCOCC1.[C:8]([NH:15][C@H:16]([C:24]([OH:26])=O)[C@H:17]([CH3:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(OC(Cl)=O)C(C)C.[N+:35](=[CH2:37])=[N-:36].CCOCC>C(Cl)Cl>[C:8]([NH:15][C@H:16]([C:24]([CH:37]=[N+:35]=[N-:36])=[O:26])[C@H:17]([CH3:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: C[C@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
N-methylmorpholine (1.7 mL, 2.2 equiv) was added to a solution of (2S, 3S)-N-Boc-O-t-butylthreonine (2.0 g, 7.0 mmol, 1.0 equiv) in anhydrous CH2Cl2 (40 mL). The resulting solution was cooled to −15° C. under an argon atmosphere. Iso-butylchloroformate (0.94 mL, 1.03 equiv) was added and the mixture was stirred for 20 min. A solution of diazomethane in Et2O (75 mL, about 67 mmol) was added over 5 min, the cold bath was removed and the reaction was allowed to warm over a 1 h period. Acetic acid was added dropwise until the bubbling stopped. The reaction solution was diluted with CH2Cl2 (150 mL) and washed sequentially with saturated sodium bicarbonate (2×100 mL), water (1×100 mL) and saturated brine (1×100 mL). The organic layer was dried over Na2SO4, decanted and concentrated in vacuo to yield (2S, 3S)-N-Boc-O-t-butyl-threonyldiazomethane as a yellow oil that was used without further purification.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:41])[C:37]([OH:40])=[CH:38][CH:39]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[OH:41][C:36]1[CH:35]=[C:34]([CH2:33][NH:32][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[CH:26]=[CH:25][CH:24]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: NCc1ccc(O)c(O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5ccc(O)c(O)c5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in dichloroethane (2 mL) was added 4-(aminomethyl)-1,2-benzenediol (12.1 mg, 0.087 mmol). The reaction solution was stirred at ambient temperature for 10 min prior to addition of NaBH(OAc)3 (58 mg, 0.261 mmol). The resulting mixture was shaken overnight at ambient temperature after which time the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (7.4 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:31]=[CH:30][C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)=[O:20])[C@@H:11]([CH3:32])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:31]=[CH:30][C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)=[O:20])[C@@H:11]([CH3:32])[CH2:10]2)[C:42](=[O:44])[CH3:43])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc2c(c1)OCCN2C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc3c(c2)OCCN3C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S,4R)-[4-(4-Chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone (540 mg, 1.25 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (0.240 mL, 1.37 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at room temperature 4 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aq. NaHCO3, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford the final product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:35])=[C:16]([NH:26][C:27](=[O:34])OCC(Cl)(Cl)Cl)[C:17]([CH3:25])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][C:37]([NH:36][C:27]([NH:26][C:16]1[C:17]([CH3:25])=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:35])=[O:34])([CH3:41])[CH3:40]
Reactant: CC(C)(N)CO
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)NC(C)(C)CO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 49 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 49%. Melting point: 181-182° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=C[CH:35]=1>>[O:31]=[S:30]1(=[O:32])[CH2:29][CH2:28][CH2:35][N:23]1[C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: c1ccncc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCCS5(=O)=O)c4)CC3)cccc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 30 mg) in pyridine (0.5 mL) was added 2-chloroethylsulfonyl chloride (13 μL). The mixture was stirred 1 h then concentrated in vacuo and partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic layer was washed (water), dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in THF (1 mL) and cooled to 0° C. with stirring. To the stirred solution was added sodium hydride (60%, 20 mg). The mixture was warmed to room temperature and left to stand for 4 days. The reaction was diluted with water and concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was washed (water), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (SiO2; EtOAc) to give the title compound (4.4 mg).
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH2:8][CH2:7]1.Cl.Cl.N[CH:31]1[CH2:36]CN(CC2CCCCCC2)C[CH2:32]1>>[CH:4]1([CH2:5][N:6]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)([OH:20])[C:15]3[S:19][CH:18]=[N:17][CH:16]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2][CH2:1][CH2:36][CH2:31][CH2:32]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2cncs2)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1cncs1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-hydroxy-2-(5-thiazolyl)acetic acid obtained in Example 57 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: O=C(O)c1occc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1occc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 3-bromofuran-2-carboxylic acid (23.5 g), iodoethane (11.8 mL) and potassium carbonate (25.6 g) in DMF (200 mL) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with diethylether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in hexane, passed through a silica gel (NH) layer, and the eluate was concentrated under reduced pressure to give the title compound (23.0 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O1CCCC1.C(OCC)C>[F:18][C:13]([F:19])([C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:23])[OH:21])=[CH:8][CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A 1.5 M solution of n-butyllithium in tetrahydrofuran (0.57 mL) was added to a solution of 1-bromo-4-pentafluoroethylbenzene (180 mg, 0.65 mmol) in diethyl ether (1.0 mL) at −78° C., and the mixture was stirred for 20 minutes. Thereafter, trimethyl borate (101 mg, 3.28 mmol) was added and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 30 minutes. 6 N aqueous hydrochloric acid (200 μL) was added to the reaction mixture, and the reaction was terminated. The mixture was then purified by silica gel column chromatography to give 4-pentafluoroethylphenylboronic acid as a white solid (111 mg, 71%).
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1)[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]=[C:1]=[S:3])[CH2:23][CH2:24]1)[CH3:5]
Reactant: CCOCCn1c(CN2CCN(CCN)CC2)nc2cccnc21
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCN=C=S)CC2)nc2cccnc21
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 18 parts of carbon disulfide, 7.22 parts of N,N'-methanetetraylbis[cyclohexanamine] and 135 parts of tetrahydrofuran was added dropwise a solution of 12.9 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineethanamine in tetrahydrofuran. Upon complete addition, the temperature was allowed to reach room temperature. After stirring for 1 hour at room temperature, the mixture was evaporated, yielding 13.1 parts (100%) of 3-(2-ethoxyethyl)-2-[[4-(2-isothiocyanatoethyl) -1-piperazinyl]methyl]-3H-imidazo[4,5-b]pyridine as a residue (compound 121)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][C:9](=[O:22])[CH2:10][C:11](=[O:21])[C:12]2([CH3:20])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]2)[CH:7]=1.CN(C)C1C=CC=CC=1.[CH2:34]([S:50](Cl)(=[O:52])=[O:51])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].Cl>O1CCCC1.O>[CH2:34]([S:50]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][C:9](=[O:22])[CH2:10][C:11](=[O:21])[C:12]2([CH3:20])[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14][CH2:13]2)[CH:7]=1)(=[O:52])=[O:51])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc(OC)c(NC(=O)CC(=O)C2(C)COC(C)(C)OC2)c1
Reaction time: 0.5 h

Procedure:
The amine product of Reaction Example 8, N-(5-amino-2-methoxyphenyl)-2,2,5-trimethyl-β-oxo-1,3-dioxane-5-propanamide, (18.5 parts) and N,N-dimethylaniline (8.5 parts) are combined in tetrahydrofuran (250 parts) and a solution of 1-hexadecylsulfonyl chloride (17.9 parts) dissolved in tetrahydrofuran (25 parts) is added dropwise with stirring, ca. 0.5 hr. The reaction is allowed to stand several hours and subsequently poured into cold water (600 parts) containing concentrated hydrochloric acid (5 parts). The crude product is extracted with ethyl ether and the ethereal layer washed once with sodium bicarbonate solution, once with water, dried over magnesium sulfate, filtered and subsequently flash evaporated in vacuo to give a light tan product in 90% of theoretical yield. Analytical samples are crystallized from ethyl alcohol, m.p. 83-85° C. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C33H56N2O6S--Calculated: C, 65.1%; H, 9.3%; N, 4.6%; S, 5.3%. Found: C, 65.6%; H, 9.1; N, 4.4%; S, 5.0%.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[C:11]([C:13]1[CH2:27][C@@H:26]([O:28][Si](C(C)(C)C)(C)C)[C@H:25](/[CH:36]=[CH:37]/[C@@H:38]([O:46][Si](C(C)(C)C)(C)C)[CH2:39][C@H:40]([CH3:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:14]=1[S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:12]>N1C=CC=CC=1>[C:11]([C:13]1[CH2:27][C@@H:26]([OH:28])[C@H:25](/[CH:36]=[CH:37]/[C@@H:38]([OH:46])[CH2:39][C@H:40]([CH3:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:14]=1[S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:12]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C#N)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C#N)C[C@H]1O
Reaction time: 15 h
Yield: 86.8 %

Procedure:
To a solution of ice-cooled acetonitrile (2 mL) and pyridine (0.2 mL) was added hydrogen fluoride-pyridine (0.2 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-cyano-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (170 mg, 0.261 mmol) in pyridine (0.2 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-cyano-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate 96 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]=O)[CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:17]/[CH2:16][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CCC1CCOCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC1CCOCC1
Yield: 35.6 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with (tetrahydro-pyran-4-yl)-acetaldehyde (Pharmacore) (0.64 g, 5 mmol) in CH2Cl2 at room temperature for 5 h to give [2-(tetrahydro-pyran-4-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.43 g, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH3:27])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19]CC4C=CC=CC=4)[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH3:27])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(O)cc12
Yield: 90.5 %

Procedure:
A mixture consisting of 6-benzyloxy-a-methyl carbazole-2-acetic acid ethyl ester (7.3 g, 0.0195 mol) and ethanol (130 mL) is subjected to hydrogenation over 10% Pd/c (0.9 g) for 18 hours at 35 psi. The reaction mixture is filtered and concentrated to give 5.0 g product as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH:21]=O)[CH:4]=1.[NH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5](/[CH:21]=[N:23]/[N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:4]=1
Reactant: NN1CCOCC1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(C=O)cc31)NCCC2
Solvent: Cc1ccccc1
Product: COCn1c(=O)c2c(c3c(OC)cc(/C=N/N4CCOCC4)cc31)NCCC2
Temperature: 25 °C
Yield: 91 %

Procedure:
The compound (95 mg, 0.31 mmol) prepared in step 1 was dissolved in toluene (10 ml), added with 4-aminomorpholine (0.031 ml, 0.31 mmol) at room temperature. The resulting mixture was then heated and allowed to reflux under dean-stark condenser for 5 hours. After cooling to room temperature, the solivent was removed under reduced pressure and the residue was purified by flash column chromatography (dichloromethane:methanol=20:1) to obtain the title compound (109 mg, yield: 89%, yellow solid).