Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]([C@H:38]([CH2:43][OH:44])[CH2:39][CH2:40][CH2:41][NH2:42])[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:9])[NH:42][CH2:41][CH2:40][CH2:39][C@H:38]([N:33]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([NH2:23])=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH2:34][CH:35]([CH3:36])[CH3:37])[CH2:43][OH:44])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (see example 34, step A) and amine intermediate VII. The final product was obtained in 74% yield. Rf=0.57 EtOAc 100%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH2:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23].Cl>CN(C=O)C>[CH2:25]([O:24][C:22]([C:21]1[CH:20]=[C:19]([CH:30]=[CH:29][CH:28]=1)[CH2:18][O:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])=[O:23])[CH:26]=[CH2:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C=CCOC(=O)c1cccc(CI)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cccc(COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (19.4 g, 60% in mineral oil, 484.4 mmol) is washed with dry hexanes (2×30 mL) to remove the mineral oil and then suspended in anhydrous DMF (330 mL). To this suspension a solution of N-(t-butoxycarbonyl)-L-serine (45.2 g, 220.2 mmol) in DMF (110 mL) at 0° C. is added dropwise with vigorous stirring. The mixture is stirred for an additional 5 minutes at 0° C., and then at room temperature for 30 minutes. The solution is cooled back to 0° C., and a solution of allyl 3-iodomethylbenzoate (66.6 g, 220.2 mmol) in DMF (110 mL) is added dropwise over 15 minutes. The mixture is then warmed to room temperature for 30 minutes. The reaction mixture is poured into ice water (2.2 L) and acidified to pH 2 with 1 N HCl (270 mL). The mixture is extracted with ether (1×600 mL, then 3×300 mL) and the combined ether extracts are then washed with water (5×200 ml) and then dried (MgSO4) and evaporated in vacuo to yield O-[3-(allyloxycarbonyl)-benzyl]-N-(t-butoxycarbonyl)-L-serine as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)[N:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C.CO>[CH:17](=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1cccc(N2CCC(N)=N2)c1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1cccc(N2CCC(N=Cc3ccccc3)=N2)c1
Reaction time: 4 h

Procedure:
3-Amino-1-(3-t-butylphenyl)-2-pyrazoline (500 mg) was reacted with benzaldehyde (500 mg) in boiling methanol (5 ml) in the presence of glacial acetic acid (1 drop). After some 4 hours, the mixture was cooled and 3-benzylideneamino-1-(3-t-butylphenyl)-2-pyrazoline separated in crystals m.p. 140°-141°, (yield 500 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([F:25])[C:23]=1[F:24]>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[C:20]([O:26][CH3:27])=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(F)c(F)c(F)c1
Product: CCSc1ncc(C(=O)c2c(OC)cc(F)c(F)c2F)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 3,4,5-trifluoroanisole (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@@H:8]1[CH2:32][C:33](=[S:35])[NH2:34])=[O:6])[CH:2]=[CH2:3].IC.[C:38](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@@H:8]1[CH2:32][C:33](=[NH:34])[S:35][CH3:38])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CC(N)=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CC(=N)SC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-thiocarbamoylmethyl-4-(triphenylmethylthio) pyrrolidine (110 mg) in acetonitrile (4 ml) were added iodomethane (497 mg) and potassium carbonate (61 mg). After stirring at room temperature for 3 hours, the solution was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel (eluent; n-hexane:ethyl acetate=3:2) to give (2R,4S)-1-allyloxycarbonyl-2-(2-imino-2-methylthioethyl)-4(triphenylmethylthio) pyrrolidine (72 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1)#[N:2].[K]>O1CCCC1>[C:13]([C:12]1[CH2:11][CH2:10][N:4]2[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:3]2[C:1]=1[NH2:2])(=[O:15])[CH3:14]
Reactant: CC(=O)CCCn1c(C#N)nc(C)c1C
Agent: [K]
Solvent: C1CCOC1
Product: CC(=O)C1=C(N)c2nc(C)c(C)n2CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
102 g of 2-cyano-4,5-dimethyl-1-N-(pentan-2-on-5-yl)imidazole from Example 5 are dissolved in tetrahydrofuran (1.2 l) under a dry N 2 atmosphere and cooled in an ice bath to T=0° C. Potassium tern butoxide solution (1.0 M in THF, 640 ml) is then added dropwise over a period of about 15 min. After a further 15 min, the ice bath is removed so that the beige reaction suspension slowly warms to RT. It is then stirred vigorously for 2 h. After completion of the reaction (TLC toluene/acetone=4:1 and CH2Cl2/MeOH=9:1), saturated NH4Cl solution (about 140 ml) is added until the cessation of the reaction and tetrahydrofuran is distilled off. The residue is then dissolved in dichloromethane and extracted twice with saturated NH4Cl solution and once with saturated NaCl solution. The organic phase is dried (MgSO4), filtered off with suction and concentrated to dryness in a high vacuum. The title compound is obtained here as a crude product in the form of an amorphous solid (86 g). The crude product is dissolved in ethanol (90 ml) at a temperature of about 85° C. The solution is then cooled in an ice bath and diethyl ether (180 ml) is added. The product phase is allowed to stand overnight at T=4° C. The precipitate of product is filtered off with suction, washed with a little cold diethyl ether and the filtercake is dried in a high vacuum. The mother liquor is concentrated to dryness, then taken up in the solvent mixture toluenelacetone=5:1 and treated with 5 times the amount of flash silica gel (Mallinckrodt-Baker, 30-60 μm). After filtration and removal of the solvent by distillation, precipitation is carried out again as described above. The title compound (55 g) is obtained as a pure substance in the form of a yellow-orange, amorphous solid, which is sensitive to photooxidation and is stored under N2. TLC (CH2Cl2/MeOH=9:1), Rf=0.59; m.p.: 204° C. (decomposition).
Reaction SMILES: C1(N2C3N=C([C@H]4[C@H](C)CNC4)NC(=O)C=3C=N2)CCCC1.C([N:29]1[CH2:33][C@@H:32]([CH2:34][CH3:35])[C@H:31]([C:36]2[NH:37][C:38](=[O:48])[C:39]3[CH:44]=[N:43][N:42]([CH:45]([CH3:47])[CH3:46])[C:40]=3[N:41]=2)[CH2:30]1)C1C=CC=CC=1>>[CH2:34]([C@@H:32]1[CH2:33][NH:29][CH2:30][C@H:31]1[C:36]1[NH:37][C:38](=[O:48])[C:39]2[CH:44]=[N:43][N:42]([CH:45]([CH3:47])[CH3:46])[C:40]=2[N:41]=1)[CH3:35]
Reactant: CC[C@@H]1CN(Cc2ccccc2)C[C@H]1c1nc2c(cnn2C(C)C)c(=O)[nH]1
Agent: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C(C)C)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one but substituting 6-[(3S,4S)-1-benzyl-4-ethylpyrrolidin-3-yl]-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one provided the title compound. 400 MHz 1H NMR (CD3OD) δ 8.02 (s, 1H), 5.10 (m, 1H), 3.78-3.60 (m, 3H), 3.32-3.28 (m, 1H), 3.10 (m, 1H), 2.62 (m, 1H), 1.65 (m, 1H), 1.58 (m, 1H), 1.49 (dd, J=6.6, 1.7 Hz, 6H), 0.97 (t, J=7.5 Hz, 3H). MS: (M+H m/z=276.1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.N[C:12](N)=[O:13]>O>[Cl:1][C:2]1[C:7]2[NH:8][C:12](=[O:13])[NH:9][C:6]=2[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)nc(Cl)c1N
Solvent: O
Product: O=c1[nH]c2cc(Cl)nc(Cl)c2[nH]1
Temperature: 165 °C
Reaction time: 4 h

Procedure:
A mixture of 2,6-dichloro-3,4-dihydropyridine-3,4-diamine (500 mg, 2.8 mmol) from Step B and urea (1.0 g, 16.8 mmol) was stirred as a melt at 165° C. for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z=204 (M+1).
Reaction SMILES: COCCOC[O:7][CH:8]([C:11]1[CH:12]=[C:13]([S:20]([NH2:23])(=[O:22])=[O:21])[S:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:9][CH3:10].S(=O)(=O)(O)O.[OH-].[Na+].CO.C(Cl)(Cl)Cl>CO.O>[OH:7][CH:8]([C:11]1[CH:12]=[C:13]([S:20]([NH2:23])(=[O:22])=[O:21])[S:14][C:15]=1[S:16]([CH3:19])(=[O:17])=[O:18])[CH2:9][CH3:10]
Reactant: CCC(OCOCCOC)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(O)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a stirred solution of 4-[1-(methoxyethoxymethoxy)propyl]-5-methylsulfonylthiophene-2-sulfonamide (8.0 g, 0.02 mol) in methanol (20 ml) was added a cold solution of concentrated sulfuric acid (20 ml) in water (20 ml). The mixture was stirred at room temperature for 1 hour and the solution was basified with a slight excess of 40% NaOH and the suspension was filtered to remove precipitated salts. The filtrate was washed with ether and acidified with HCl. The acidified mixture was extracted with ethyl acetate (4×25 ml). The combined extracts were washed with saturated NaCl solution and dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo at room temperature to give a viscous yellow oil which was a mixture of five components. Chromatography on 300 g of silica gel eluting with 5% methanol/CHCl3 gave 3.0 g of a pure colorless oil. Trituration of the oil in n-butyl chloride gave a white solid (2.8 g) (45%). The product was recrystallized from 1,2-dichloroethane; m.p. 125.5-126.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:4]([NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(N)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(N)cc1-c1ccccc1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To a dried flask was added 3-bromo-4-methyl-phenylamine (1 g, 5.37 mmol), phenyl boronic acid (2.62 g, 21.5 mmol), aqueous Na2CO3 (2M, 21.5 mL, 43 mmol), ethanol (21.5 mL), and toluene (43 mL). The flask was sparged with Ar, and Pd(PPh3)4 (1.55 g, 1.34 mmol) was added. The reaction mixture was stirred and heated at 80° for 18 hrs, then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4. The solvent was removed in vacuo and the residue was purified via column chromatography (SiO2, 5% DCM/hexane) to afford a yellow oil (463 mg, 47%). This was directly used in the next step.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Ni]>[CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccn2cc(C3CCCC3)cc2c1
Agent: [Ni]
Solvent: CO
Product: c1c(C2CCCC2)cn2c1CCCC2
Yield: 93.9 %

Procedure:
2-Cyclopentyl-indolizine (0.25 g, 1.35 mmol) was dissolved in methanol (5 mL) and hydrogenated over Raney nickel (50 mg) under balloon pressure at room temperature for 1 h. The reaction mixture was filtered through celite, washing with methanol. Concentration of the filtrate afforded 2-cyclopentyl-5,6,7,8-tetrahydro-indolizine (0.24 g, 94%) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[CH:39][CH:38]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cn1ccnc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccnc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.105 g, 0.26 mmol, 1 eq) in EtOH (6 mL) and DMF (0.9 mL), 4-(morpholinomethyl)-benzaldehyde (0.060 g, 0.29 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.78 mL, 0.78 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.027 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 2.34-2.42 (m, 4H), 2.56-2.64 (m, 4H), 3.53 (s, 2H, morpholine N(CH2)2), 3.56-3.68 (m, 10H), 3.72 (s, 3H, imidazole Me), 6.78 (d, J=1.5 Hz, 1H, imidazole 4-H), 7.11 (d, J=1.5 Hz, 1H, imidazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.13 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.23 min—551/553 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 551.1884, calculated for C26H32BrN8O (M+H)+: 551.1882.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of 4-fluoro-benzenesulfonyl chloride (9.68 g, 0.497 mol), glycine (4.48 g, 0.0598 mol), and sodium carbonate (16.99 g, 0.160 mol) in water (60 mL) was stirred at room temperature for 42 hours. The mixture was carefully acidified to pH 8 to 9 with concentrated hydrochloric acid, and washed 2 times with dichloromethane. The aqueous layer was acidified further to pH 2, and the resulting white suspension was extracted two times with ethyl acetate. The extracts were combined, washed with saturated sodium chloride solution, and dried over magnesium sulfate. The dried solution was rotary evaporated to give a white solid, which was dried in vacuo; yield 4.7 g (41%), mp=154.0-155.5° C.
Reaction SMILES: ClC1C=CC=C(Cl)C=1N1C=C2C(NC3C=C(C)N=C(N)N=3)=NC=CC2=N1.C(OC(=O)[NH:33][C:34]1[CH:39]=[C:38]([NH:40][C:41]2[C:46]3=[CH:47][N:48]([C:50]4[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=4[Cl:57])[N:49]=[C:45]3[CH:44]=[CH:43][N:42]=2)[N:37]=[CH:36][N:35]=1)(C)(C)C>>[Cl:56][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]([Cl:57])[C:50]=1[N:48]1[CH:47]=[C:46]2[C:41]([NH:40][C:38]3[CH:39]=[C:34]([NH2:33])[N:35]=[CH:36][N:37]=3)=[N:42][CH:43]=[CH:44][C:45]2=[N:49]1
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Agent: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(N)n1
Product: Nc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 50 %

Procedure:
Following the procedure described for N4-[2-(2,6-dichloro-phenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-6-methyl-pyrimidine-2,4-diamine, {6-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-carbamic acid tert-butyl ester was reacted to afford the title compound as a white solid (148 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.02 (br s, 1H), 9.15 (s, 1H), 8.14 (s, 1H), 7.92 (d, J=6.4 Hz, 1H), 7.84-7.79 (m, 2H), 7.72-7.71 (m, 2H), 7.15 (d, J=6.4 Hz, 1H), 6.71 (br s, 2H). LCMS (Method B): RT=2.85 min, m/z: 372 [M+H+].
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:8](=[O:20])[CH2:7][CH2:6]1)=O.[NH3:21]>CO>[O:20]=[C:8]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]([C:3]([NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCC(=O)N1CC#CCN1CCCCC1
Reactant: N
Solvent: CO
Product: NC(=O)C1CCC(=O)N1CC#CCN1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-[4-(1-piperidinyl)-2-butynyl]-2-pyrrolidinone (5.44 g) in sieve dried methanol (175 ml) was treaed with anhydrous ammonia for fifteen minutes and was allowed to stand at ambient temperature overnight. The solution was concentrated to a brown solid (5.00 g). The solid was recrystallized from toluene (125 mL) to give 3.85 g of slightly brown crystals, mp 143°-145° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])/[NH:7]1.C(N(CC)CC)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:30]1([CH2:36][C:37]([CH:2]([NH2:1])[CH2:3][CH2:4][CH2:5][C@H:6]2[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]3[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=3)=[O:13])/[NH:7]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCC(N)C(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(4-amino-butyl)-imidazolidin-(2E)-ylidene]-amide (Intermediate T) (0.032 g, 0.098 mmol) in DMF (1 ml) is added triethylamine (0.014 ml, 0.098 mmol) followed by phenylacetyl chloride (0.013 ml, 0.098 mmol). The suspension is stirred at room temperature for 90 minutes before a further 0.5 equivalents of phenylacetyl chloride (0.006 ml, 0.049 mmol) is added. The reaction is left to stir at room temperature for a further 18 hours. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) followed by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH affords the title compound as an off-white solid; [M+H]+ 445.1
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4].C1COCC1.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][CH3:42])[CH:32]=1)=[O:30]>O.CN(C=O)C>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][C:33]=3[O:41][CH3:42])(=[O:39])=[O:38])[C:11](=[O:19])[N:12]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCOCC3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(C1CCOCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
0.18 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 1 g of 5- ethoxy-1,3-dihydro-3-(tetrahydropyran-4-yl)-2H-benzimidazol-2-one, 30 ml of THF and 20 ml of DMF and the mixture is stirred for 30 minutes at RT. 1.2 g of 4- methoxycarbonyl-2-methoxybenzenesulfonyl chloride are then added and the mixture is stirred for 3 hours at RT. The reaction mixture is poured into 200 ml of water and the precipitate formed is filtered off and washed with iso ether to give 1.13 g of the expected product after drying. M.p.=165° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([CH3:23])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.O>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Si:1]([O:18][CH2:19][C@H:20]([CH3:23])[CH:21]=[O:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: C[C@H](C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
Under argon atmosphere, (R)-3-(t-butyldiphenylsilyloxy)-2-methylpropanol (48) (725 mg, 2.2 mmol) was dissolved in 40 ml of dry dichloromethane. MS-4A (30 mg), NMO (862 mg, 11.1 mmol) and TPAP (catalytic amount) were added to the resultant solution at 0° C., and the mixture was stirred for 15 min. The reaction mixture was further stirred overnight after the temperature was returned to room temperature. Subsequently, H2O was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated. The obtained crude product was purified by column chromatography (21 g, 4% AcOEt-hexane) to obtain a colorless oily product (49) (700 mg, 97%).