Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)=[CH:15][C:14]([NH2:30])=[CH:13][N:12]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:44]([NH:30][C:14]3[CH:13]=[N:12][C:11]([CH3:10])=[C:16]([NH:17][C:18]4[N:23]=[C:22]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=[CH:20][N:19]=4)[CH:15]=3)=[O:45])=[CH:47][CH:48]=2)[CH2:35][CH2:34]1)[CH3:32]
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cnc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (47 μL, 0.27 mmol) was added into a solution of 2-Methyl-N3-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (15 mg, 0.054 mmol), 4-((4-ethylpiperazin-1-yl)methyl)benzoic acid (16.1 mg, 0.61 mmol), BOP (33.4 mg, 0.76 mmol) in DMF (1.5 mL). The reaction mixture is stirred at rt under argon atmosphere overnight. The reaction mixture was then purified by Waters semi-preparative HPLC to the final product. MS (ESI+) m/z 509.1 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ncccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a suspension of 3-hydroxy-2-hydroxymethylpyridine hydrochloride (7.0 g, 12.4 mmol) in ethanol (37.5 ml) was added a solution of KOH pellets (85% 1.6 g, 24.7 mmol) in ethanol (25 ml). The reaction was stirred for 5 minutes at ambient temperature and then benzyl bromide was added (2.11 g, 12.36 mmol). The reaction mixture was stirred at ambient temperature for 48 hours, filtered and evaporated. The residue was purified by chromatography (EtOAc, CH2Cl2) to give 3-benzyloxy-2-hydroxymethylpyridine as a colourless solid (1.55 g, 58%) [J. Med. Chem., 15, (1972) 615] m.p. 78.7°-79.2° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH3:21])[C:12]=2[CH3:22])[CH:5]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:23])=[O:2])=[C:12]([CH3:22])[N:13]2[CH3:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(C)c3cc(Cl)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-1,2-dimethyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.079 g, 0.23 mmol) was dissolved in MeOH:THF (1:1, 5 mL) and LiOH (2.30 mL, 1M aq., 2.3 mmol) was added. The reaction was stirred at room temperature overnight then submitted to aqueous workup procedure. Purification by preparatory HPLC (10-100% ACN in H2O) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH2:35].O1CCCC1>>[CH3:9][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH:35][CH3:34])=[O:24])[CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Yield: 64 %

Procedure:
Using 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (150 mg) and 2 mol/L methylamine-tetrahydrofuran solution (5 mL), a procedure as in Reference Example 284 was performed to give the title compound as a colorless oil (yield 99 mg, 64%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]1[O:16][C@@H:15]1[CH2:17]Cl>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:17][C@H:15]3[CH2:14][O:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: ClC[C@@H]1CO1
Product: c1cc(C2CCCCC2)ccc1OC[C@H]1CO1

Procedure:
The title compound was prepared from 4-cyclohexyl-phenol and S-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:39]#[N:40]>C1COCC1>[C:39]([C:38]1[CH:37]=[C:36]([NH:35][C:15]([C@@:11]2([CH:18]([CH3:19])[CH3:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10]2)=[O:16])[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=1)#[N:40]
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.091 mmol) and methanesulfonyl chloride (9 μL, 0.12 mmol) in THF (0.9 mL) at 0° C. was added diisopropylethylamine (0.047 mL, 0.27 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-amino-5-(trifluoromethyl)benzonitrile (34 mg, 0.18 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC, which failed to provide the desired product in sufficient purity. To a solution of the crude mixture (14 mg) in 2 mL THF was added aqueous NaOH (3 mL, 1.0 M) and the solution was stirred at 50° C. overnight. The following day, the solution was quenched with 10% HCl, partitioned with ethyl acetate, and the organic layer was separated. The organics were subsequently dried with sodium sulfate, concentrated in vacuo, and purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 10.28 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.04-7.17 (m, 3H), 3.99 (d, J=11.2 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 3.05 (d, J=17.2 Hz, 1H), 2.70 (d, J=17.2 Hz, 1H), 2.38 (septet, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 0.98 (t, J=6.8 Hz, 6H). LC-MS Rt (retention time): 2.81 min; MS: (ES) m/z 444 (M+H+).
Reaction SMILES: CO[C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=2)[O:8][N:7]=1.[CH3:31][NH2:32].O>O1CCOCC1>[CH3:31][NH:32][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH:16]=2)[O:8][N:7]=1
Reactant: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Reactant: CN
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Temperature: 120 °C
Yield: 66 %

Procedure:
To a solution of 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionic acid methyl ester (330 mg, 0.79 mmol) in 1,4-dioxane (4 mL) was added 40 wt % solution of methylamine in H2O (2.7 mL, 31.6 mmol). The mixture was heated at 120° C. for 12 h, cooled, and concentrated. The residue was dissolved in water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 with EtOAc/hexane 2:1 to give N-methyl-3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionamide (217 mg, 66%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:52])[C@@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)/[CH:26]=[CH:27]/[CH2:28][C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:53](Br)[CH:54]=[CH2:55]>C1COCC1>[CH2:55]([C@@H:28](/[CH:27]=[CH:26]/[C@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)[C:24]([N:19]1[C@@H:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:52])[C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[CH:54]=[CH2:53]
Reactant: O=C(C/C=C/[C@H](Cc1cccc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](/C=C/[C@H](Cc1cccc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 25.2 %

Procedure:
A solution of NaHMDS (1.0 M in THF, 0.313 mL, 0.313 mmol) was slowly added dropwise over 5 min to a −78° C. solution of (S,E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(3-fluorobenzyl)hex-3-ene-1,6-dione (170 mg, 0.298 mmol) in THF (1.6 mL). After addition the reaction mixture was allowed to stir for another 25 min at −78° C. and then allyl bromide (108 mg, 0.894 mmol) was added dropwise. The reaction temperature was then slowly raised to 0° C. over 20 min and then stirred at 0° C. for an additional 1 hr. The reaction was quenched by addition of saturated NH4Cl. The mixture was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2S,5S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-(3-fluorobenzyl)hex-3-ene-1,6-dione (46 mg, 0.075 mmol, 25% yield) as a foam. Anal. Calcd. for C36H35FN2O6 m/z 610.2. found: 611.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:12]([OH:14])=O.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]>>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:4]2[C:3]=1[C:12](=[O:14])[N:16]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:5]2=[O:7]
Reactant: Nc1c(O)ccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Product: Nc1c(O)ccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 3-amino-4-hydroxyphthalic acid with 3-aminopiperidine-2,6-dione hydrochloride, or an enantiomer or a mixture of enantiomers thereof; to form 4-amino-2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione.
Reaction SMILES: CO[C:3]([C:5]1([NH:8][C:9](=[O:25])[O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH2:6]1)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:33]1[CH2:37]OC[CH2:34]1>>[OH:4][CH2:3][C:5]1([NH:8][C:9](=[O:25])[O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH2:6][CH2:37][CH2:33][CH2:34]1
Reactant: C1CCOC1
Reactant: COC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: O=C(NC1(CO)CCCCC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 1-(methoxycarbonyl)-cyclopropylcarbamate (15 g, 44.5 mmol) in THF (100 mL) at −5° C. was added LiAlH4 (1.0 g, 26.3 mmol) in portions. After stirring at room temperature for 3 h, water (10 mL) was added to quench the reaction. The mixture was filtered and the filtrate was extracted with EtOAc (3×100 mL). The organic extract was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (12.3 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FS([C:26]([F:31])([F:30])C(O)=O)(=O)=O>C(#N)C.[Cu]I>[F:30][CH:26]([F:31])[O:21][C@H:10]1[C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](O)C1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](OC(F)F)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
Dissolve trans-tert-butyl-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate (0.9 g, 3.1 mmol) and copper(I) iodide (116 mg, 609 mmol) in ACN (7.6 mL) and heat to 50° C. Add fluorosulfonyldifluoroacetic acid (336.7 mg, 1.83 mmol) dropwise over 15 minutes. Stir the solution for 2 hours at 50° C. and then cool to ambient temperature. Quench with a 50% solution of sodium bicarbonate; separate layers; and extract the aqueous layer twice with EtOAc. Combine the organic extracts; dry over sodium sulfate; filter; collect the filtrate; and concentrate under vacuum. Purify the crude material with silica gel flash column chromatography, with a gradient of 0-20% EtOAc in hexane to give the title compound (0.18 g, 17%). 1H-NMR (d6-DMSO) δ 0.74 (s, 1H), 1.42 (s, 9H), 1.5-1.79 (m, 2H), 2.6-2.85 (m, 2H), 3.59-4.82 (m, 4H), 6.4 (dd, J=76.8 Hz, 77.9 Hz, 1H), 7.0-7.1 (m, 2H), 7.27-7.33 (m, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[N:13]=[C:12]([NH2:14])[S:11][N:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:15](O)=[O:16]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[N:13]=[C:12]([NH:14][CH:15]=[O:16])[S:11][N:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=CO
Reactant: CON=C(C(=O)OC)c1nsc(N)n1
Product: CON=C(C(=O)OC)c1nsc(NC=O)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 67.6 %

Procedure:
Methyl 2-methoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (10 g, 0.046 mol) in 99% formic acid (50 g) was heated under stirring at 70° C. for 6 hrs. It was cooled to below 10° C. to separate crystals, which were collected by filtration, washed with methanol and dried to give methyl 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (7.6 g, yield: 85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A solution of methyl 1H-indazole-5-carboxylate (825 mg, 4.68 mmol) in tetrahydrofuran (20 ml) was added to a solution of lithium aluminum hydride (580 mg, 14.1 mmol) in tetrahydrofuran (16 ml) at 0° C. and stirred at 0° C. for 1 hour. A mixture of tetrahydrofuran (10 ml) and water (10 ml) was added to the reaction solution and the resulting mixture was filtered. The filtrate was concentrated and the resulting residue was diluted with chloroform and washed with a 1N-aqueous sodium hydroxide solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby 1H-indazole-5-ylmethanol (260 mg, 38%) was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:24])[C@H:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:16])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[C@@H:15]([NH:16][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:12]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OCC
Yield: 72 %

Procedure:
Target compounds AAG154353, AAG154360 and AAG154484 were synthesized as shown in Scheme 1. Commercially available pent-4-ynoic acid 1a or hex-5-ynoic acid 1b or hept-6-ynoic acid 1c (Scheme 1) was converted to the acid chlorides 2a-c and immediately reacted with diazomethane followed by 48% HBr to give the desired α-bromomethylketones 4a-c. Condensation of 2,4-diamino-6-hydroxypyrimidine with 4a-c at room temperature for 3 days afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 5a-c (51-74% yield). Compounds 6a-c were obtained by a Sonogashira coupling of 5a-c with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester 9. Hydrogenation and saponification of 6a-c afforded AAG154353, AAG154360 and AAG154484, respectively. Compound 9 (Scheme 1) was synthesized by coupling the commercially available 5-bromo-2-thiophene-carboxylic acid 8 and L-glutamate diethyl ester hydrochloride in 72% yield.
Reaction SMILES: [CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:25])[CH3:24]>CC(C)=O>[CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:25])[CH3:24])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(SCSC2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(SCSC2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
In 300 g of acetone was dissolved 26 g of the cyclohexylthio(4-hydroxyphenylthio)methane crude product in Synthesis Example 10. To this were added 21 g (0.15 mol) of potassium carbonate and 8.7 g (0.11 mol) of acetyl chloride. While heating in an oil bath at 70° C., the solution was ripened for 4 hours. At the end of ripening, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, and the residue was dissolved in 300 g of dichloromethane and washed with 50 g of water. The organic layer was concentrated in vacuum again, obtaining 30 g of an oily product, which was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)=[C:12]2[O:11][N:10]=1.C(OO)(=[O:26])C.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([C:18]3[C:23]([OH:26])=[N:22][CH:21]=[N:20][CH:19]=3)=[C:12]2[O:11][N:10]=1
Reactant: CC(=O)OO
Reactant: Fc1ccc(-c2noc3c(-c4cncnc4)ccnc23)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3Cl)noc12
Temperature: 25 °C

Procedure:
To a vial charged with 3-(2-chloro-4-fluorophenyl)-7-(pyrimidin-5-yl) isoxazolo[4,5-b]pyridine (4.8 mg, 0.015 mmol) in acetone (Volume: 100 μl) were added peroxyacetic acid (6.18 μl, 0.029 mmol) and sulfuric acid (1.632 μl, 0.029 mmol). The reaction mixture was refluxed for 75 min, and then allowed to cool to room temperature. The reaction mixture was neutralized with 4 M NaOH and extracted with CH2Cl2 (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a yellow residue (5.0 mg, 99%). ESI MS (M+H)+=343.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:11](=[O:15])[C:12](=[O:13])[NH:8]2)=[C:3]([CH3:10])[CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(Cl)cc(N)c1N
Agent: Cl
Solvent: O
Product: Cc1cc(Cl)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
123 g (0.79 mol) of 2,3-diamino-5-chlorotoluene and 106.2 g (1.18 mol) of oxalic acid are heated at reflux for 5 hours in 800 ml of 4N hydrochloric acid. The reaction mixture is allowed to cool, and is diluted with water, filtered off on a suction filter and washed with water. The product is then stirred in hot ethanol, filtered off on a suction filter and the suction filter material is dried in vacuo at 60°. The title compound is obtained as slightly grayish crystals of m.p.>250°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.Cl>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C:20]=1[CH3:22])=[O:16])[CH3:19]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(Br)cn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Yield: 73.3 %

Procedure:
Next, 5-bromopyridin-2-ylhydrazine (25.3 g) and ethyl 2-ethoxymethyleneacetoacetate (25.1 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added to a mixed solvent of 1N hydrochloric acid aqueous solution (320 ml) and ethanol (370 ml), stirred at reflux temperature for 4.5 hours and the solvent was evaporated in vacuo. Water was added to the residue, the precipitated solid was washed with water and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (30.6 g) as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:18])[N:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[F:1][CH:2]([F:18])[N:3]1[CH:7]=[C:6]([C:8](=[S:28])[NH2:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cn(C(F)F)nc1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cn(C(F)F)nc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of the mixture (1.15 g, 4.51 mmol) obtained in step 3 in THF (18.8 mL) was added Lawesson's reagent (1.46 g, 3.61 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hr. After cooling to room temperature, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 7% ethyl acetate/hexane) to give a mixture (0.840 g, 68%, 1:1.92 mol/mol) of 1-(difluoromethyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide and 1-(difluoromethyl)-5-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide as a pale-green powder.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:6])[CH:4]=[CH2:5].[F:7][CH2:8][CH:9]([NH2:12])[CH2:10][F:11].[N-]=C=O>ClCCCl.CO>[F:7][CH2:8][CH:9]([N:12]1[CH2:5][CH2:4][C:3](=[O:6])[CH2:2][CH2:1]1)[CH2:10][F:11]
Reactant: NC(CF)CF
Reactant: C=CC(O)C=C
Agent: [N-]=C=O
Solvent: CO
Solvent: ClCCCl
Product: O=C1CCN(C(CF)CF)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
1,4-Pentadien-3-ol (200 mg, 2.38 mmol) and IBX (999 mg, 3.57 mmol) were dissolved in DCE (15 mL) and heated at 70° C. for 3 h. The reaction mixture was filtered, diluted with MeOH (10 mL) and 2-fluoro-1-fluoromethyl-ethylamine (226 mg, 2.38 mmol) was added. The reaction mixture was stirred at 70° C. for 3 h. Isocyanate resin was added and the reaction mixture stirred at room temperature for 6 h, filtered and concentrated in vacuo to give the crude title compound (160 mg, 38%) as an orange gum. LCMS (ES+): 178.1 [MH]+.