Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:64][O:65][NH:66][CH3:67].Cl>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:25]([C:26](=[O:27])[N:66]([O:65][CH3:64])[CH3:67])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
DIPEA (28.2 ml, 20.9 g, 162 mmol) was added to a stirred solution of (RS)-3-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (20.0 g, 53.9 mmol), BOP (25.00 g, 56.5 mmol) and MeONHMe.HCl (5.52 g, 56.6 mmol) in DMF (300 mL). After stirring 2 hr, the DMF was evaporated and the residue was dissolved in EtOAc and washed with water, 5% aq. HCl, saturated aq. NaHCO3 and brine, then dried with Na2SO4 and evaporated to afford (RS)-[2-(4-Benzyloxy-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (22.39 g, 100%), mp 107.1-108.7° C. 1H NMR (CDCl3) δ 0.40 (s, 9H), 2.83 (dd, J=6.2, 14.2 Hz, 1H), 3.00 (dd, J=6.1, 13.6 Hz, 1H), 3.17 (s, 3H), 3.65 (s, 3H), 4.91 (br s, 1H), 5.04 (s, 2H), 5.15 (br d, J=7.1 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.32-7.44 (m, 5H). 13C NMR (CDCl3) δ 172.3, 157.7, 155.2, 137.1, 130.4, 128.9, 128.5, 127.9, 127.4, 114.7, 79.6, 70.0, 61.5, 51.6, 38.0, 32.1, 28.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([CH2:9][N:10]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:11]1(=[O:13])=[O:12])=[O:8].ClC1C=CC=C(C(OO)=[O:30])C=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[S:7]([CH2:9][N:10]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:11]1(=[O:13])=[O:12])(=[O:30])=[O:8]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CS(=O)c1ncccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C1c2ccccc2S(=O)(=O)N1CS(=O)(=O)c1ncccn1

Procedure:
Following a procedure similar to that described in Example 32A, 0.75 g (0.0023 mol) of 2-(2-pyrimidinylsulfinylmethyl)saccharin was oxidized with 0.4 g (0.0023 mol) of 3-chloroperbenzoic acid in 50 ml of MDC and the product recrystallized from 75:25 acetonitrile:ethanol to give 2-(2-pyrimidinylsulfonylmethyl)saccharin, mp 225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:27]Cl)[C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]2[C:21]1[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=1.[NH3:29]>C(O)C>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)=[C:6]([CH2:27][NH2:29])[CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: Cc1cc(-c2ccnn2C)c2cccc(OCc3c(Cl)cncc3CCl)c2n1
Solvent: CCO
Product: Cc1cc(-c2ccnn2C)c2cccc(OCc3c(Cl)cncc3CN)c2n1

Procedure:
Conversion of {5-chloro-4-[2-methyl-4-(2-methyl-2H-pyrazol-3-yl)-quinolin-8-yloxymethyl]-pyridin-3-yl}-methanol into the corresponding chloride according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine yielded the benzylchloride which was used in the following step without further purification. A solution of 8-(3-chloro-5-chloromethyl-pyridin-4-ylmethoxy)-2-methyl-4-(2-methyl-2H-pyrazol-3-yl)-quinoline (6.2 mg, 0.015 mmol) in a 2 M NH3 in ethanol (0.3 mL) was stirred at 45° C. for 2 h. Solvents were evaporated to dryness and the residue was used in the following step without further purification. MS (m/z): 394.1 [M+H+].
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:23])=[C:17]([CH2:20][CH2:21]Cl)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]2[C:44]3[CH:45]=[CH:46][C:47]([OH:49])=[CH:48][C:43]=3[O:42][N:41]=2)[CH2:36][CH2:35]1>CO>[Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:23])=[C:17]([CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][CH:37]([C:40]4[C:44]5[CH:45]=[CH:46][C:47]([OH:49])=[CH:48][C:43]=5[O:42][N:41]=4)[CH2:38][CH2:39]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Oc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-((tert-butyldimethylsilyl)oxy)-3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (0.5 g, 1.40 mmol) in methanol (25 mL) and diisopropylethylamine (732.83 μL, 4.20 mmol) was treated with 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol hydrochloride salt (374.62 mg, 1.47 mmol), and the reaction mixture was stirred for 17 h at 60° C. under argon. Diisopropylethylamine (732.83 μL, 4.20 mmol) was added and the mixture was stirred additionally for 4 h at 60° C. The reaction mixture was evaporated under vacuum and the residue was taken up in water (25 mL), extracted with chloroform (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by silica gel chromatography (elution with dichloromethane/methanol (98/2) to give the title compound (ESI-MS (M+1) 539).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]C(C)(C)C.[Cl-:17].[Zn+2:18].[Cl-]>C1COCC1>[Cl-:17].[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Zn+:18])(=[O:4])=[O:5]
Reactant: [Zn+2]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Zn+]

Procedure:
N-dimethylsulfamoyl-imidaz-2-yl zinc chloride was prepared in situ by lithiation of N-dimethylsulfamoylimidazole (0.97 g, 5.5 mmol) in THF (20 mL) with t-BuLi (1.7M, 6.7 mL), followed by quenching with zinc chloride (1.87 g, 13.75 mmol).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH2:38][CH3:39])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[C:27]([CH3:40])=[CH:26]2)[CH2:24][CH2:23]1.Cl.Cl.[O:43]=[C:44]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[N:61][CH:62]=[C:63]([CH:68]=3)[C:64]([O:66]C)=[O:65])[CH:57]=2)[O:52][C:46]2([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45]1>CN(C=O)C>[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH2:38][CH3:39])[CH:30]=[C:31]([C:34]([N:49]4[CH2:50][CH2:51][C:46]5([CH2:45][C:44](=[O:43])[C:58]6[C:53](=[CH:54][CH:55]=[C:56]([C:59]7[CH:60]=[N:61][CH:62]=[C:63]([CH:68]=7)[C:64]([OH:66])=[O:65])[CH:57]=6)[O:52]5)[CH2:47][CH2:48]4)=[O:36])[CH:32]=3)[C:27]([CH3:40])=[CH:26]2)[CH2:23][CH2:24]1
Reactant: COC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1c(C)cn2C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
TEA (162 mg) was added to a mixture of EDCI (92 mg), HOBT (73.5 mg), 1-cyclopropyl-4-ethoxy-3-methyl-1H-indole-6-carboxylic acid (104 mg), and methyl 5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)nicotinate dihydrochloride (170 mg) and DMF (3 ml), and the mixture was stirred at r.t. for 5 hours. The mixture was evaporated and purified through SiO2 column chromatography (eluted with Hex-EtOAc, then MeOH—CHCl3) to give methyl ester of the title compound as a pale yellow solid. 1 ml of 1N NaOHaq was added to its solution in 3 ml of MeOH and 3 ml of THF, and the mixture was stirred at r.t. for 4 h. Then the mixture was neutralized with 1N HClaq and diluted with CHCl3-MeOH. The mixture was dried over Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc-n-hexane to give the title compound as a slightly yellowish powder. 1H-NMR (400 MHz, DMSO-d6) δ: 13.57 (1H, s), 9.08 (1H, d, J=2.0 Hz), 9.03 (1H, d, J=2.0 Hz), 8.41 (1H, dd, J=2.0, 2.0 Hz), 8.08-8.02 (2H, m), 7.26 (1H, dd, J=7.8, 1.0 Hz), 7.12 (1H, d, J=1.0 Hz), 7.00 (1H, d, J=1.0 Hz), 6.48 (1H, s), 4.36-4.14 (1H, br m), 4.08 (2H, q, J=7.0 Hz), 3.78-3.20 (4H, br m), 2.96 (2H, s), 2.33 (3H, d, J=1.0 Hz), 2.09-1.73 (4H, m), 1.37 (3H, t, J=7.0 Hz), 1.03-0.98 (2H, m), 0.89-0.85 (2H, m); MS [M+H]+=580.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH3:37])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH3:37])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(C)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.8 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL), was added potassium carbonate (102 mg, 0.745 mmol) and 3-bromomethyl-3-methyl-oxetane (122 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 20%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:4]=[N:3]1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]3[CH:28]=[C:29]([CH2:33]O)[CH:30]=[CH:31][CH:32]=3)=[N:25][CH:26]=2)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[N:25][C:24]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH2:33][N:11]3[C:10](=[O:13])[CH:9]=[CH:8][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:12]3)=[N:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: Cn1cc(-c2ccc(=O)[nH]n2)cn1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cnn(C)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
71 mg (0.40 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one and 163 mg (0.40 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol are suspended in 3 ml of THF and 1 ml of DMF with 200 mg (0.60 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and shaken at room temperature for 30 min. 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 1 h. A further 200 mg (0.6 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and 139 mg (0.60 mmol) of di-tert-butyl azodicarboxylate are added, and the reaction mixture is shaken at room temperature for 2 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by means of preparative HPLC; yield: 18 mg of “A286”; HPLC: Rt=2.08 min (method C); LC-MS: 443 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:34][C:6]=3[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 21, a solution of 8-fluoro-6-phenyl-1-(2-phthalimidoethyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in ethanol is heated with hydrazine hydrate to give 1-(2-aminoethyl)-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[CH3:14][N:15]1[C:23]2[N:22]=[C:21]([Br:24])[N:20]([CH2:25][C:26]#[C:27][CH3:28])[C:19]=2[C:18](=[O:29])[NH:17][C:16]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][N:17]1[C:18](=[O:29])[C:19]2[N:20]([CH2:25][C:26]#[C:27][CH3:28])[C:21]([Br:24])=[N:22][C:23]=2[N:15]([CH3:14])[C:16]1=[O:30]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(CC(O)COc1ccccc1)c(=O)n2C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
556 mg of 2-phenoxymethyl-oxirane and 110 mg of potassium iodide are added to a mixture of 1.00 g 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine and 677 mg of potassium carbonate in 25 ml of N,N-dimethylformamide. The reaction mixture is stirred for approx. eight hours at 120° C. For working up it is diluted with water and extracted with ethyl acetate. The combined extracts are dried over magnesium sulphate, evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (4:1 to 1:1) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9](=[CH:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>CCCCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[N:24]=[C:25]3[NH:26][N:27]=[C:28]([CH3:30])[C:29]3=[C:15]([C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=Cc1ccc(C)o1)C(=O)c1ccc(OC)cc1
Reactant: Cc1cc(N)n[nH]1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCO
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(C)c2c1-c1ccc(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 0.76 g (2.41 mmol) of ethyl 2-(4-methoxybenzoyl)-3-(5-methylfuran-2-yl)acrylate and of 0.23 g (2.41 mmol) of 3-amino-5-methyl-pyrazole is heated to 140° C. in 6 ml of n-BuOH for 24 h. The mixture is then cooled to room temperature and 0.55 g (2.4 mmol) of DDQ in 6 ml of THF is added. The mixture is stirred at room temperature for 1 h. The mixture is then poured onto a saturated solution of NaHCO3 then extracted with ethyl acetate. The organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The mixture is then purified using reverse-phase HPLC to yield 146 mg (15%) of ethyl 6-(4-methoxyphenyl)-3-methyl-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]12([C:33](O)=[O:34])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33]([C:23]23[CH2:32][CH:27]4[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]4)[CH2:30]2)[CH2:24]3)=[O:34])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C45CC6CC(CC(C6)C4)C5)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) and commercially available adamantanecarboxylic acid (110 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (107 mg) was added, and the admixture was stirred at room temperature for 15 hours. The reaction mixture was purified in the same manner as described in Example 51 to obtain 13 mg of the title compound (yield: 17%).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:23]([NH:26][C@@H:27]1[C@H:32]([O:33][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=[C:30]([C:51]([O:53]C)=[O:52])[O:29][C@H:28]1[C:55]([O-:57])=O)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.[CH2:67]([CH2:75][CH2:76][CH2:77][NH2:78])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C)C=O>[C:23]([NH:26][C@H:27]1[C@H:28]([C:55](=[O:57])[NH:78][CH2:77][CH2:76][CH2:75][CH2:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:29][C:30]([C:51]([OH:53])=[O:52])=[CH:31][C@H:32]1[OH:33])(=[O:25])[CH3:24]
Reactant: NCCCCCc1ccccc1
Reactant: COC(=O)C1=C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](NC(C)=O)[C@H](C(=O)[O-])O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1[C@H](O)C=C(C(=O)O)O[C@H]1C(=O)NCCCCCc1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.42 g) was added to a solution of (2R,3S,4R)-3-acetylamino-4-(tert-butyldiphenylsilanyloxy)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid, 6-methyl ester (2 g) and N,N-diisopropylethylamine (1.4 ml) in dimethylformamide (5 ml), under nitrogen. To this was added N-phenethylpropylamine (722 mg) and the reaction was stirred at 23° C. for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo to give a fawn foam. The foam was chromatographed over silica (Merck 9385, 45 g) using medium pressure (ca 4 psi) and ethyl acetate/cyclohexane (1:2 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam (1.1 g). 1H NMR (250 MHz, CDCl3, rotamers) 7.6--7.1 (15H, m), 6.0+5.95 (1H, 2×m), 5.9--5.8 (1H, 2×d, J=6Hz), 5.2 (1H, 2×d, J=5Hz), 4.6 (1H, 2×d, J=3Hz), 4.0--3.7 (1H, m), 3.8 (3H, 2×s), 3.5--2.9 (4H, m), 2.8+2.5 (2H, 2×m), 2.0 (3H, 2×s), 1.5 --1.2 (2H, m), 1.1 (9H, s), 0.9+0.7 (3H, 2×t, J=7Hz).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]=[O:55].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 6n (1.21 g, 1.63 mmol) was dissolved in 12 mL 1,4-dioxane, followed by addition of 2.65 mL 37% formaldehyde solution and dropwise addition of 4.89 mL 1 M sodium hydroxide. The reaction mixture was stirred for 16 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure and was partitioned after 30 mL of saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydro-pyran-2-carbaldehyde 6p (1.27 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH2:7]N)[C:3]([OH:5])=[O:4].[CH2:9]([O:16][C:17]([NH:19][C:20]([N:32]1C=CC=N1)=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]([N:19]([CH2:7][CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])[C:20]([NH2:32])=[N:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Reactant: NCC[C@H](O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid: MS: m/z (M+H)+ calcd. 430.15, found 430.1.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[N:25]2[C:33](=[O:34])[CH:28]3[CH2:29][NH:30][CH2:31][CH2:32][N:27]3[C:26]2=[O:35])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:30]1[CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:33](=[O:34])[CH:28]2[CH2:29]1)=[O:9]
Reactant: O=C1C2CNCCN2C(=O)N1[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1-c1ccccc1)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
[1,1′-Biphenyl]-2-yl-isocyanate (1.1 eq) was added to a stirred solution of A5 and DIPEA (3.0 eq) in DCM (0.09 M), and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 10-80% EtOAc/petroleum ether to give the title compound in 76% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.36 (1H, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, m), 4.19 (1H, m), 3.93 (1H, m), 3.85-3.77 (2H, m), 2.86 (1H, m), 2.74 (2H, d, J=9.3 Hz), 2.67 (1H, m), 2.40-2.30 (1H, m), 1.58-1.48 (1H, m), 1.43-1.37 (1H, m). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+H)+.