Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]([N:30]=[CH:31][N:32](C)C)=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:38]N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]3[NH:38][N:32]=[CH:31][N:30]=3)=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=NC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ncn[nH]3)cc2)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A mixture of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamide (7.0 mg, 0.014 mmol) and hydrazine hydrate (5 mg, 0.1 mmol) in acetic acid (200 μL) is stirred at 90° C. for 1 h and cooled down to room temperature. The solvent is removed under vacuum and residue is treated with saturated aqueous NaHCO3 solution (1 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated. The residue is purified by preparative thin layer chromatography (silica gel, 2% MeOH/CH2Cl2) to provide the titled compound 5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (4.8 mg, 73%). 1H NMR (CDCl3) δ(ppm) 8.40(s, 1H), 8.34(s, 1H), 8.15(d, 2H), 8.03(d, 2H), 7.51(t, 2H), −7.45 (d, 2H), 7.34 (t, 1H), 7.31(d, 2H), 7.11(d, 2H); HPLC-MS calculated for C25H16ClN7O (M+H+): 466.1. Found: 466.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[CH:7]([NH:12][C:21]([C:18]1([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]1)=[O:22])[CH2:6][CH2:5]2
Reactant: NC1CCc2cc(Br)cc(F)c21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: O=C(NC1(C(=O)NC2CCc3cc(Br)cc(F)c32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-5-bromo-7-fluoro-indan-1-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-5-bromo-7-fluoro-indan-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light yellow amorphous solid. MS: 455.2 (M−H−).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].[NH2:21][C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][N:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[C@H:27]([OH:33])[CH2:26]1.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:21]([C@H:22]([CH2:34][OH:35])[CH2:23][CH2:24][N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([OH:33])[CH2:26]2)[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Temperature: 40 °C
Yield: 58.1 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 27C, 2.35 g, 8.42 mmol) in dichloromethane (15 mL) was added at room temperature to a suspension of (S)-6-((S)-3-amino-4-hydroxy-butyl)-6-aza-spiro[2.5]octan-4-ol (1.81 g, 8.42 mmol), sodium triacetoxyborohyride (2.21 g, 1.01 mmol) and acetic acid (1.01 g, 16.8 mmol) in dichloromethane (15 mL). The reaction mixture was heated at 40° C. for 72 h, then partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (2.18 g, 58%). White foam, MS (ISP)=446.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To 44 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid in 100 mL of methanol and 300 mL of chloroform at 0° C. was added 200 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform The product was then recrystallized from hexanes to give 32.6 g (73%) of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester: melting point 104 105° C. (decomposed); mass spectrum (m/e): M+H 270.9.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.Cl[C:11]([C:13]1[CH:17]=[CH:16][N:15]([C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)[CH:14]=1)=[O:12]>CO.O1CCCC1.ClCCl>[NH:4]([C:11]([C:13]1[CH:17]=[CH:16][N:15]([C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]3)[CH:14]=1)=[O:12])[C:3]([NH2:5])=[NH:2]
Reactant: O=C(Cl)c1ccn(-c2cccc3ncccc23)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: N=C(N)NC(=O)c1ccn(-c2cccc3ncccc23)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
0.9 g (9.42 mmol) of guanidine hydrochloride is added to a solution of 0.51 g (9.44 mmol) of sodium methoxide in 15 mL of methanol at a temperature in the region of 22° C. under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 2 hours, the solvent is evaporated off under reduced pressure (2.7 kPa). The residue, placed under an argon atmosphere, is taken up in 20 mL of a tetrahydrofuran/dichloromethane (1/1 by volume) mixture and then 0.55 g (1.88 mmol) of 3-chlorocarbonyl-1-(quinol-5-yl)-1H-pyrrole hydrochloride, dissolved in 5 mL of the same tetrahydrofuran/dichloromethane mixture, is added thereto. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated with water, filtered and taken up under hot conditions in 7 mL of ethanol. The insoluble material is then filtered off and discarded, and the filtrate is cooled to a temperature in the region of 22° C. The crystals formed are filtered off and dried under vacuum (2.7 kPa), to give 0.165 g of 3-guanidinocarbonyl-1-(quinol-5-yl)-1H-pyrrole in the form of a white solid melting at 260° C. Mass spectrum (EI): m/e 279 (M+.), m/e 221.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[N:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[N:14]=[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[N:12]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCCCCCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NCCCCCCCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a suspension of methyl 4-(4-(8-aminooctylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate (0.073 g) in water (6.00 mL). The mixture was heated to reflux overnight. After cooling to r.t., the reaction solution was acidified with 1N HCl to pH=3. All solvents were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(8-aminooctylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (38 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:14])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
11.1 g 1-chloro-3,5-dinitrobenzene are dissolved in 100 ml of methanol and combined with 3 g sodium methoxide. Then the mixture is refluxed for 48 hours, cooled to ambient temperature and the solid is suction filtered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:30][CH3:31])=[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[N:18]3[C:19]=2[CH:20]=[C:21]4[C:26]([O:28]C)=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClCCl>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:30][CH3:31])=[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[N:18]3[C:19]=2[CH:20]=[C:21]4[C:26]([OH:28])=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)OC)c3cccc1n32
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)O)c3cccc1n32
Temperature: 25 °C
Yield: 26.2 %

Procedure:
Methyl 3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylate (2.92 g, 7.13 mmol) was dissolved in 200 ml of methanol and 20 ml of water. Potassium hydroxide (6.40 g, 114 mmol) was added and the mixture was heated to reflux for 3 days. The reaction mixture was allowed to cool to room temperature and the methanol was evaporated. The orange solid was partitioned between 200 ml of dichloromethane and 200 ml of 1M hydrochloric acid and acidified with concentrated hydrochloric acid until pH=1. This resulted in the formation of a suspension. A further 800 ml of dichloromethane and 200 ml of water was added and the suspension was filtered to give 0.74 g (26%) of 3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylic acid as a yellow solid. The organic solution was washed with brine, dried over magnesium sulfate and evaporated to give a orange solid. This solid was recrystallised from acetone to afford 1.23 g (43%) of 3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylic acid as a yellow solid. M.p. 223-224° C. MS(SP): m/z 395 (M+). 1H-NMR (DMSO-d6, 200 MHz) δ: 1.41 (t, 3H); 3.02 (q, 2H); 5.22 (s, 2H); 7.24 (d, 2H); 7.31-7.56 (m, 5H); 7.81 (d, 2H); 7.95 (t, 1H); 8.03 (s, 1H); 8.20 (d, 1H); 8.32 (d, 1H); 12.46 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([Cl:19])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Product: COc1cc(CC(=O)Cl)cc(OC)c1OC

Procedure:
In a manner similar to Preparation 15, react 3,4,5-trimethoxybenzeneacetic acid with thionyl chloride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.C(O)C.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Yield: 95.6 %

Procedure:
To a mixture of methyl 4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoate (1.31 g) synthesized above, ethanol (20 mL) and tetrahydrofuran (20 mL) was added 1N lithium hydroxide aqueous solution (20 mL), and the mixture was stirred with heating under reflux for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration and the obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (1.21 g, 96%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4]1)[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>O.[OH-].[Na+]>[CH2:1]([N:3]1[C:7]([O:8][CH3:9])=[C:6]([N+:19]([O-:21])=[O:20])[C:5]([C:10]([F:11])([F:13])[F:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(F)(F)F)cc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1nc(C(F)(F)F)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 66050.8 %

Procedure:
1-Ethyl-5-methoxy-3-(trifluoromethyl)pyrazole (15.2 g, 0.0785 mmol) was added dropwise with stirring and cooling at about 0° C. to 150 mL of concentrated sulfuric acid and then 10.5 mL of 70 percent nitric acid (0.235 mmol) was added, also dropwise with stirring at about 0° C. The mixture was then allowed to warm to ambient temperature and stir overnight. An aliquot was removed, neutralized to a pH of about 11, extracted with dichloromethane, and analyzed by gas chromatography. Since there was still some starting material present another about 0.8 mmol of concentrated nitric acid was added with stirring and the mixture was allowed to react for 5 hours. Analysis of an aliquot as before did not reveal any remaining starting material so the mixture was poured slowly into 500 g of ice. The mixture was stirred for 15 min and was then extracted with dichloromethane (4×200 mL). The extracts were combined to obtain an acidic blue-green organic mixture. This was diluted with 100 mL of water and neutralized with 50 percent aqueous sodium hydroxide. The mixture, which turned yellow-orange, was separated into phases and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 12.4 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1cccc(I)c1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2cccc(C(C)(C)C)c2)c(=O)c1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (0.025 g, 0.097 mmol), 1-iodo-3-tertbutyl benzene (0.20 g, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (0.005 g, 0.049 mmol), Copper Iodide (0.004 g, 0.020 mmol), and Potassium Phosphate (0.041 g, 0.194 mmol) in 0.5 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (17 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with 3×'s with EtOAc (˜5 mL) and 2×'s with NaHCO3 (˜10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using an 0-100% EtOAc gradient/100-0% Hexane gradient mixture. After concentrating the appropriate fractions, the pure product was collected as an off white solid (5 mg, 19%). 1H NMR (DMSO) δ: 7.94 (s, 1H), 7.46-7.55 (m, 2H), 7.47 (m, 1H), 7.28-7.36 (m, 2H), 6.32 (s, 2H), 6.21 (m, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.25 (s, 3H), 2.09 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OCC)(=[O:22])[C:20]#[CH:21]>C(O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:19](=[O:22])[CH:20]=[CH:21][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(OC[C@@H]2Cn3ccc(=O)nc3O2)cc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a solution of (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (4.53 g, 18.3 mmol) in ethanol (35 mL) was added ethyl propiolate (2.32 g, 23.7 mmol). The reaction mixture was stirred at reflux for 6 hours. The mixture was stirred at 30° C. for a few minutes and subsequently cooled to room temperature. The resulting crystals were collected and washed twice with hexane. The solid was dried under high vacuum at 65° C. for 18 hours to afford 2.8 g (50%) of (S)-2-(4-tert-butyl-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −54.04 (c 0.503, CHCl3).
Reaction SMILES: [N+:1](=C)=[N-].[CH2:4]([N:11]1[C:23]2[C:22]([S:24][CH3:25])=[C:21]([CH2:26][C:27]([OH:29])=O)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>C(OCC)C>[CH2:4]([N:11]1[C:23]2[C:22]([S:24][CH3:25])=[C:21]([CH2:26][C:27]([NH2:1])=[O:29])[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: CSc1c(CC(=O)O)ccc2c3ccccc3n(Cc3ccccc3)c12
Solvent: CCOCC
Solvent: CC(=O)O
Product: CSc1c(CC(N)=O)ccc2c3ccccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An excess of a solution of diazomethane in diethyl ether was added to a solution of 150 mg of 9-benzyl-1-methylthiocarbazol-2-acetic acid, as obtained in Example 5, in 3 ml of diethyl ether. The resulting reaction mixture was stirred for 10 minutes at room temperature and then glacial acetic acid was added. The reaction mixture was next concentrated by evaporation under reduced pressure. 10 ml of saturated methanolic ammonia was added to a solution of the resulting residue in 5 ml of methanol, and the reaction mixture was stirred for 7 days at room temperature. After this time, the reaction mixture was concentrated by evaporation under reduced pressure and the resulting residue was subjected to column chromatography using 400 mg of silica gel using, as eluent, a 4:1 by volume mixture of hexane and ethyl acetate to yield 131 mg of the title compound as an amorphous solid.
Reaction SMILES: Cl.NO.[OH-].[K+].CC1[N:8]([C:13]2[CH:14]=[C:15]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)C(C)=CC=1>C(O)C.O>[NH2:8][C:13]1[CH:14]=[C:15]([C:19]([OH:22])([CH3:20])[CH3:21])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(C)n1-c1cccc(C(C)(C)O)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(O)c1cccc(N)c1
Temperature: 120 °C
Yield: 99.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (7.42 g, 107 mmol) and potassium hydroxide (5.41 g, 82.0 mmol) in ethanol (65 mL) and water (30 mL) was added 2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]propan-2-ol (0.840 g, 3.66 mmol). The heterogeneous mixture was heated at 120° C. overnight and then concentrated. The residue was purified by column chromatography to give the desired product (0.55 g, 65%). 1H NMR (400 MHz, CDCl3) δ: 7.11-7.15 (m, 1H), 6.85-6.87 (m, 1H), 6.84 (ddd, 1H), 6.58 (ddd, 1H), and 1.55 (s, 6H). LCMS: (FA) ES+ 152.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18](OCC)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([CH2:18][OH:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nccc(-n2nc(CO)c3ccc(Br)cc32)n1
Reaction time: 0.17 h

Procedure:
To a solution ethyl 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazole-3-carboxylate (500 mg, 0.88 mmol) in dry THF (4 mL) at 0° C. under an atmosphere of nitrogen was introduced lithium aluminium hydride (3.5 mL of a 1M solution in THF, 3.50 mmol). After 10 minutes at this temperature, the reaction mixture was quenched by carefully transferring into a rapidly stirred saturated aqueous solution of Rochelle's salt (5 mL). The suspension was extracted with DCM (10 mL) and the organic extract filtered through a pad of Celite®. The filtrate was washed with water (5 mL) and brine (5 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo to furnish the crude title compound as a colorless solid: 1H NMR (250 MHz, DMSO) delta 4.84 (2H, d, J=5.48 Hz), 5.61 (1H, t, J=5.71 Hz), 7.04 (3H, s), 7.51 (1H, dd, J=8.45, 1.75 Hz), 7.92 (1H, d, J=8.53 Hz), 8.28 (1H, d, J=5.48 Hz), 9.11 (1H, d, J=1.22 Hz); LC-MS: m/z=+319.90/321.80 (M+H)+. This compound, with LC-MS purity=76% UV, was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([N:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].CC1C=CC(NCC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([NH:7][CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NCc2cc(OC)c(OC)c(OC)c2)cc1
Yield: 93 %

Procedure:
From 108c (10.8 g, 35.8 mmol) and NaBH4 (6.8 g, 179 mmol), a similar procedure as described for 109a gave 109c (10.1 g, 93.5%) as pale purple crystals. 1H NMR (200 MHz, CDCl3) δ6.79 (d, J=8 Hz, 2H), 6.62 (d, J=8 Hz, 2H), 6.61 (s, 2H), 4.21 (s, 2H), 3.84 (s, 9H), 3.74 (s, 3H). CIMS (isobutane) m/e 304 (MH+, 20).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CCO[CH2:12][CH3:13]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:12]=1[CH:13]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Nc1ccccc1O
Reactant: CCOCC
Solvent: ClCCl
Product: Oc1ccccc1N=Cc1ccccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Aminophenol (1.09 g, 10 mmol) was dissolved in ether (20 mL) and DCM (5 mL). 2-pyridinecaroxaldehyde (0.95 mL, 10 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 17 h; precipitate was formed. The light yellow solid (1.52 g, 77%) was filtered and dried. 1H (CDCl3) δ 8.85 (s, 1H), 8.72 (d, J=3 Hz, 1H), 8.21 (d, J=9 Hz, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.31 (bs, 1H), 7.25 (t, J=9 Hz, 1H), 7.04 (d, J=6 Hz, 1H), 6.94 (t, J=7.5 Hz, 1H), MS (M+H) 199.