Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[N:29]O)[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH2:29])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -40 °C

Procedure:
4-[2,4-Bis(tert-butyldimethylsilyloxy)phenyl]cyclohexanone oxime (120 mg) was dissolved in anhydrous methanol (10 ml) with stirring. The solution was cooled to −40° C., and nickel chloride hexahydrate (133 mg) was added. Stirring was continued for 10 min before sodium borohydride (42 mg) was added in one portion. The reaction mixture was stirred at −40° C. for 20 min and water (0.5 ml) was added. The reaction mixture was allowed to warm to room temperature with stirring. Silica gel was added and the solvent removed in vacuo. Purification via flash column chromatography (SiO2 eluting with CH2Cl2:MeOH:NH4OH, 44:50:6 v/v) afforded the desired product as a pale brown oil (83 mg, 71%) and a mixture of diastereoisomers. δH (CD3OD): 0.22 (6H, s), 0.27 (6H, s), 1.02 (9H, s), 1.08 (9H, s), 1.24-1.40 (1H, m), 1.42-1.57 (1H, m), 1.57-1.68 (1H, m), 1.71-1.90 (4H, m), 1.99-2.07 (1H, m), 2.84-2.98 (1H, m), 4.28-4.40 (1H, m), 6.34 (1H, d), 6.44 (1H, t), 7.04 (0.5H, d), 7.16 (0.5H, d); m/z (ES+) 436 (M+1)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][Cl:29])[CH:32]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Reactant: Cc1cccc(C(Cl)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1cccc(CCl)c1)Nc1c(C(C)C)cccc1C(C)C
Yield: 32.8 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-m-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of xylene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly yellow crystal. The crystal was then recrystallized from acetone to obtain 5.1 g of white powder.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#C[C@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (1R*,5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 39b; 44 g, 140 mmol), 10% palladium on charcoal (11 g, 10 mmol), ethyl acetate (200 ml) was stirred under hydrogen atmosphere (1 atm) at room temperature for 1.5 hours. The reaction mixture was treated with dichloromethane (500 ml), filtered through a pad of Celite™. The Celite™ cake was well washed with dichloromethane to dissolve solid product. The filtrate was concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnnn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
In THF (6.4 ml)/methanol (3.2 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1-methyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.32 g). To the solution was added 1N sodium hydroxide solution (3.2 ml), and the mixture was stirred at room temperature for 14 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (5/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(1-methyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.25 g).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)C.B(Br)(Br)Br>C(Cl)Cl>[CH3:26][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([NH:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:5]3[CH:4]=[C:3]([OH:1])[CH:8]=[CH:7][CH:6]=3)[N:15]=1)=[CH:25][CH:24]=2
Reactant: COc1cccc(Nc2nccc(Nc3ccc4[nH]c(C)cc4c3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(Nc3ccnc(Nc4cccc(O)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of N2-(3-methoxylphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine (0.1 mmol) in 5 ml CH2Cl2 was placed in an ice bath. To this was added BBr3(0.5 mmol). The reaction mixture was stirred overnight at room temperature, then poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to provide the desired product in a yield of 83%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:36][N:35]([CH3:37])[C:34](=[O:38])[CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:36][N:35]([CH3:37])[C:34](=[O:38])[CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CN1CC(c2cccnc2F)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1=O
Temperature: 140 °C
Yield: 60.7 %

Procedure:
To a mixture of cesium carbonate (563 mg, 1.73 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.381 g, 1.60 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.131 g, 0.675 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 140° C. for 11 h. The mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) gave 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one (0.169 g, 0.410 mmol, 61% yield) as an off-white solid. MS m/z: 413.1 (M+1). The mixture of enantiomers was separated by preparatory SFC (Chiralcel OJH (21×250 mm), 25% EtOH/0.2% diethylamine) to afford the individual enantiomers (R)-4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one and (S)-4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one. MS (ESI, pos. ion) m/z: 413.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH:1]1([CH2:4][O:5]/[N:6]=[C:7](/[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)\[CH2:8][NH2:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].O>ClCCl>[Cl:16][C:15]1[C:10](/[C:7](=[N:6]/[O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)/[CH2:8][NH:9][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[C:29]([F:28])([F:39])[F:40])=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Yield: 94.7 %

Procedure:
In a solution of 65 mg of (E)-2-amino-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanone-O-(cyclopropylmethyl)oxime and 32 mg of triethylamine in 2 ml of dichloromethane, 39 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 2 ml of water and extracted with dichloromethane (2 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 85 mg of the desired product as white crystals.
Reaction SMILES: [CH2:1]([C:5]([NH:16]C(OC(C)(C)C)=O)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH:3]=[CH2:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC(N)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2-but-3-enyl-2-(tert-butoxycarbonylamino)propanedioate 81b (14.5 g, 4.4 mmol) in DCM (30 mL) was added TFA (10 mL), The mixture was stirred at room temperature for 16 h, quenched with saturated NaHCO3 (50 mL) and then extracted with DCM (150 mL) two times, washed with saturated NaHCO3 (100 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford diethyl 2-amino-2-but-3-enyl-propanedioate as a crude product (9.5 g, 94%), which was used for next step without further purification. MS: calc'd (MH+) 230, measured (MH+) 230.
Reaction SMILES: N1(C(OC(C)(C)C)=O)CCC[C@H]1C([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[OH:42][CH:43]1[O:51][C@H:50]([CH2:52][OH:53])[C@H:48]([OH:49])[C@H:46]([OH:47])[C@H:44]1[OH:45].[NH2:54][C@H:55]([C:60]([NH2:62])=[O:61])[CH2:56][CH2:57][S:58][CH3:59].Cl>C(O)(=O)C>[NH:54]1[CH2:43][CH2:44][CH2:46][CH2:48][C@H:50]1[C:52]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:53].[OH:42][CH:43]1[O:51][C@H:50]([CH2:52][OH:53])[C@H:48]([OH:49])[C@H:46]([OH:47])[C@H:44]1[OH:45].[NH2:54][C@H:55]([C:60]([NH2:62])=[O:61])[CH2:56][CH2:57][S:58][CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Agent: CSCC[C@H](N)C(N)=O
Agent: Cl
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1

Procedure:
Condensation of BocPro-Phe-Phe-GlyOH (1.61 g.) and HGal-MetNH2 dihydrochloride salt (0.70 g.) using dicyclohexylcarbodiimide and 4-dimethylaminopyridine as catalyst gave BocPro-Phe-Phe-Gly-Gal-MetNH2 in 28% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Gal-MetNH2 (0.44 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Gal-MetNH2, which was isolated as the amorphous white solid dihydrochloride acetate salt hydrate in 35% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].B.C1COCC1.Cl.CO>C1COCC1.O1CCOCC1>[NH2:9][CH2:8][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]2[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=[C:3]2[C:2]=1[NH2:1]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: NCc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N
Temperature: 0 °C
Yield: 26.6 %

Procedure:
To a solution of 8-amino-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (112 mg, 0.29 mmol) in THF (4 mL) was added a BH3.THF complex (1.0 M solution in THF, 1.2 mL, 1.2 mmol) followed by a 4M HCl solution in dioxane (2 drops). The reaction mixture was stirred and refluxed for 3 h, then cooled to 0° C. (ice bath) and poured into MeOH. The mixture was concentrated under vacuum, the remaining residue was dissolved in a 2M HCl solution in water, and the mixture was washed with Et2O (2×). The aqueous layer was frozen and lyophilized. The remaining residue was purified by recrystallization in a mixture of MeOH/AcOEt to yield the title compound (2HCl salt, 36 mg, 0.077 mmol, 27%). MS: 392 [M+1]+; HPLC: AtRet=1.13.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][CH2:23][CH3:24])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]([Br:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=2)[CH:9]=1)([O-])=O>Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][CH2:23][CH3:24])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]([Br:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=2)[CH:9]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Agent: Cl
Product: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
The compound (4.0 g, 10 mmol) of Example 33 was suspended in concentrated hydrochloric acid and heated to be refluxed. Reduced iron powder (1.7 g, 30 mmol) was added into the reaction mixture in batch, and stirred for 1 h. The hot reaction mixture was filtered and cooled to room temperature to generate a yellowish precipitate. After filtered, the solid was dried at 60° C. to give the hydrochlorate of the title compound (3.0 g, yield: 82%). 1H NMR (DMSO-d6) δ: 12.55 (1H, br), 10.18 (2H, br), 7.72 (1H, d), 7.50 (1H, dd), 7.27 (1H, d), 4.04 (2H, t), 3.39 (1H, m), 1.73 (2H, m), 1.17 (6H, d), 0.95 (3H, t).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[CH:12]=[C:11]2[S:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[C:11]([S:20]([N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)(=[O:21])=[O:22])[NH:10]2)=[CH:14][CH:15]=1
Reactant: O=S(=O)(c1cc2ccc(Cl)cc2n1S(=O)(=O)c1ccccc1)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(c1cc2ccc(Cl)cc2[nH]1)N1CCNCC1
Temperature: 25 °C

Procedure:
The requisite 1-(6-chloroindol-2-ylsulphonyl)piperazine starting material was prepared as follows. 1-(1-Benzenesulphonyl-6-chloroindol-2-ylsulphonyl)piperazine (500 mg, 1.18 mmol) was treated with sodium hydroxide solution (4 ml of 10M), and the suspension refluxed for 2 hrs. The reaction mixture was cooled to ambient temperature and carefully treated with concentrated hydrochloric acid to pH 8; the resultant precipitate was filtered off, washed with water and dried to give 1-(6-chloroindol-2-ylsulphonyl)piperazine as a pale yellow solid which was used without further purification; 1H NMR (d6DMSO) 3.1 ppm (m, 4H), 3.2 ppm (m, 4H), 7.1 ppm (s, 1H), 7.2 ppm (dd, 1H), 7.5 ppm (s, 1H), 7.7 ppm (d, 1H); the spectrum also contained signals due to benzene sulphonic acid (ca 25 mol %); MS (M+H)+ 300/302.
Reaction SMILES: [OH:1][C@@H:2]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][S:6](=[O:15])(=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>[OH:1][C@@H:2]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:7][S:6](=[O:15])(=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C@@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@@H](c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.6 %

Procedure:
To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH2C2, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH2Cl2 (3×10 ml) washed with water, brine and dried over MgSO4 and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Proton and carbon NMR and mass spectra were consistent with the product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:49])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:37])=[O:36])=[O:33])=[C:28]([O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:27]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO.O>[CH:43]1([O:42][C:28]2[CH:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:10]([CH2:9][C@H:8]([OH:49])[C:5]4[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=4)[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[CH:21][CH:22]=3)[CH:31]=[CH:30][C:29]=2[C:32]([NH:34][S:35]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:36])=[O:37])=[O:33])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1cccnc1
Yield: 84.8 %

Procedure:
The mixture of tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-[3′-(cyclohexyloxy)-4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl]-ethyl]carbamate (145 mg), ammonium formate (128 mg) and palladium on carbon powder (50 mg) in methanol (2 ml) and water (0.2 ml) was refluxed for 50 minutes. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=94/6) to give tert-butyl [2-[3′-(cyclohexyloxy)-4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (117 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][N:4]2[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH2:23].Cl>ClCCl.CN(C)C=O.O.C(N(CC)CC)C>[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH:23][C:10]([C:8]1[CH:7]=[N:6][C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:13]=2)[CH:9]=1)=[O:12]
Reactant: CC(C)(N)CN
Reactant: Cc1cc2ncc(C(=O)O)cn2n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc2ncc(C(=O)NCC(C)(C)N)cn2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.18 g) was suspended in dichloromethane (5 ml), and N,N-dimethylformamide (1 drop) was added thereto. The mixture was cooled to 0° C., and a solution of oxalyl chloride (10 μl) in dichloromethane (3 ml) was added dropwise thereto over 10 minutes, and the mixture was stirred as such for 1 hour at 0° C. Thereafter, the mixture was stirred for 5 hours at room temperature to prepare the corresponding acid chloride. 2-Amino-2-methylpropylamine (0.11 g) was dissolved in dichloromethane, and triethylamine (0.33 ml) was added thereto and cooled to −78° C. The prepared acid chloride solution was added dropwise thereto over 30 minutes and stirred as such for 30 minutes. The temperature of the mixture was increased to room temperature, and the mixture was stirred for 1 hour at room temperature. Water was added thereto, and the aqueous phase was acidified by 2 N hydrochloric acid. After washing with chloroform, the aqueous phase was alkalinized by 5 N sodium hydroxide solution and extracted with chloroform. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give the title compound (0.14 g, Y.:56%) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Yield: 103.4 %

Procedure:
To a stirred solution of N-(5-nitro-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (3.0 g) in methanol (100 mL) was added activated nickel (0.3 g). Hydrogen was added to the reaction mixture at atmospheric pressure till the starting material disappeared. The solid was filtered off and the filtrate was concentrated to give the N-(5-amino-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (2.8 g).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH3:11])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[C:7]2[N:8]([CH3:11])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cnc2ccnc(Cl)c21
Reactant: NCc1ccccc1F
Product: Cn1cnc2ccnc(NCc3ccccc3F)c21

Procedure:
A mixture of 16.76 g of 4-chloro-3-methyl-3H-imidazo(4,5-c)pyridine and 30 g of o-fluorobenzylamine is melted at 180° for 2 hours. After customary working up, 4-o-fluorobenzylamino-3-methyl-3H-imidazo-(4,5-c)pyridine of m.p. 163°-164° is obtained.