Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([O:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:34][CH:35]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc(Cl)nc2)cc1)c1ccccc1C(F)(F)F
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-chloro-5-hydroxy-pyridine, the title compound was isolated as a yellow solid in 73% yield (98% purity by HPLC).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:22].FC(F)(F)C(O)=O>>[N:17]1([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][C:8](=[O:22])[N:7]3[CH2:6][CH:2]=[O:1])=[N:12][CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=c1ccc2ncc(-n3ccnc3)cc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2ncc(-n3ccnc3)cc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 117.3 %

Procedure:
To 0.12 g of 1-((1,3-dioxolan-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthyridin-2(1H)-one, 2 mL of an 80% aqueous trifluoroacetic acid solution was added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was then distilled off under reduced pressure. The resultant residue was charged with chloroform and water and adjusted to pH 7.8 with a 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform, and then further extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.12 g of (7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:20])=[N:15][CH:16]=[C:17](Br)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([S:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH3:22].CCOC(C)=O>O>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([N:29]4[CH2:28][CH2:27][N:26]([S:23]([CH2:21][CH3:22])(=[O:24])=[O:25])[CH2:31][CH2:30]4)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2nnc(-c3nc(Br)cnc3N)[nH]2)c1
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4cccc(N)c4)[nH]3)n2)CC1
Yield: 8.4 %

Procedure:
3-[5-(3-aminophenyl)-4H-1,2,4-triazol-3-yl]-5-bromo-pyrazin-2-amine (220 mg, 0.6623 mmol) was heated in neat 1-ethanesulfonyl piperazine (590.4 mg, 3.312 mmol) in the microwave at 190° C. for 2 hours. The reaction was treated with EtOAc and H2O, the two layers separated and the organics dried and concentrated to give a yellow oil which was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (23.9 mg, 8% Yield). 1H NMR (400.0 MHz, DMSO) d 8.38 (s, 2H), 8.04 (s, 1H), 7.33 (s, 2H), 7.24 (s, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1H), 3.55 (s, 4H), 3.28 (s, 4H), 3.08 (d, J=5.7 Hz, 2H) and 1.20 (s, 3H) ppm; MS (ES+) 430.0
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[N:7]([N:12]2C(=O)C3=CC=CC=C3C2=O)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].CN>C(O)C>[NH2:12][N:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=1[Cl:1]
Reactant: Cc1ccc(C(=O)c2ccccc2Cl)n1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Product: Cc1ccc(C(=O)c2ccccc2Cl)n1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 2-(2-chlorobenzoyl)-5-methyl-1-phthalimidopyrrole (48 g, 0.13 mol) in 200 ml of 95% ethanol was treated with 80 ml of 40% aqueous solution of methylamine and stirred at room temperature for 6 hours. The reaction was quenched with 1.5 liter of H2O and extracted with three 400 ml portions of ether. The combined ether extracts were washed with H2O, dried (MgSO4), filtered, and evaporated to an oil. This oil crystallized from hexane to give 22.7 g (74%) of cubes, m.p. 84°-85°.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][O:6]1>CO>[CH2:5]1[C:10]2([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCOC2)CC1
Solvent: CO
Solvent: CC(=O)Cl
Product: C1COCC2(C1)CCNCC2
Yield: 119.3 %

Procedure:
Acetyl chloride (1 mL) was added to stirred, cooled (0° C.) methanol (10 mL) and the mixture was stirred at 0° C. for 5 minutes. 1,1-Dimethylethyl 2-oxa-9-azaspiro[5.5]undecane-9-carboxylate (Description 138, 78 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, aqueous sodium carbonate (10%, 10 mL) was added and the mixture was extracted with dichloromethane (3×10 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (50 mg, 100%). m/z (ES+) 156 (M+1).
Reaction SMILES: P(=O)(O)(O)O.N(CCO)(CCO)CCO.CO[CH:18]([O:24]C)[C:19]([CH3:23])=[CH:20][CH2:21][CH3:22].[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29]O>C(O)(=O)C>[CH3:23][C:19](=[CH:20][CH:21]([CH3:22])[CH2:29][CH:28]=[C:27]([CH3:31])[CH3:26])[CH:18]=[O:24]
Reactant: CC(C)=CCO
Reactant: CCC=C(C)C(OC)OC
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: OCCN(CCO)CCO
Product: CC(C)=CCC(C)C=C(C)C=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
The amine-H4PO3 catalyst (2.0 g, 1 w/w %) prepared by mixing orthophosphoric acid (85%) with triethanolamine (in 1:1 equivalent) was dissolved in acetic acid (4 ml, 2 ml/w %) and added to a mixture of 1,1-dimethoxy-2-methylpent-2-ene (200 g, 1.52 mol) and 3-methyl-but-2-en-1-ol (131 g, 1.52 mol). The mixture was heated to 110° C. for 2 h, then at 160° C. for further 4 h. During this period, volatile materials were collected through a 10 cm Vigreux column. The remaining oil was distilled in vacuo to give 2,4,7-trimethylocta-2,6-dienal (66%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[C:7](O)(=O)[CH2:8][CH3:9]>CCOCC>[NH2:1][N:2]1[C:7]([CH2:8][CH3:9])=[N:6][N:5]=[C:3]1[SH:4]
Reactant: CCC(=O)O
Reactant: NNC(=S)NN
Solvent: CCOCC
Product: CCc1nnc(S)n1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiocarbohydrazide, 212.2 grams, is added to 500 ml. of propionic acid and heated to its reflux temperature for approximately 90 minutes. The reaction mixture is cooled to room temperature and diluted with anhydrous ether. After standing overnight in the refrigerator, the desired 4-amino-5-ethyl-4H-1,2,4-triazole-3 -thiol is filtered, washed with anhydrous ether and air dried to yield a product having a m.p. of 143°-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]O.ClC1C=C(N)C=CC=1OCC1C=CC=CN=1>>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=1
Reactant: OCc1cccc(F)c1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 88.8 %

Procedure:
Compound 3A (1.65 g, 78%) was prepared from 4-amino-2-chloro-phenol (1.06 g, 7.38 mmol), 3-fluorobenzyl alcohol (2.4 g, 16.8 mmol) by a route analogous to that used for the preparation of 1C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:15][OH:16])[CH:5]=[C:6]2[CH:10]=[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:7]=12.C1CCCCC=1>[Pd].CCO>[OH:16][CH2:15][C:4]1[CH:5]=[C:6]2[CH:10]=[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:7]2=[CH:2][N:3]=1
Reactant: C[Si](C)(C)c1cc2cc(CO)nc(Cl)c2o1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: C[Si](C)(C)c1cc2cc(CO)ncc2o1
Yield: 90 %

Procedure:
C5 (1.05 g, 4.1 mmol) and 10% Pd/C catalyst (1.05 g) are placed in 20 mL absolute EtOH. Cyclohexene (4 mL, 40.1 mmol) is added, and the reaction is refluxed for 2.5 h, and then filtered through celite. The filter cake is washed with 1:1 EtOH/CH2Cl2, and the filtrate is concentrated to a pale yellow solid. The residue is partitioned between 40 mL saturated NaHCO3 and extracted with CH2Cl2 (4×20 mL). The combined organic layer is dried over MgSO4, filtered, and then concentrated in vacuo to a pale oil (1.04 g). The pale oil is chromatographed over 50 g silica gel (230-400 mesh) eluting with 50-70% EtOAc/hexane to afford 5-hydroxymethyl-2-trimethylsilyl-furo[2,3-c]pyridine (C14) as a white solid (90% yield). MS (EI) for C11H15NO2Si, m/z: 221(M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:32])[CH:29]([CH3:31])[CH3:30]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:32]=[C:28]([CH:29]([CH3:31])[CH3:30])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Reactant: CC(C)C(N)=NO
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCOCC3)C2)cc1C

Procedure:
100 mg (0.29 mmol) of the compound from Example 130A and 46 mg (0.43 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 107 mg (90% of theory)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[N:7]=1.[CH3:13][NH:14][CH3:15].C(O)C>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:7]=[C:8]([N:14]([CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1
Reactant: CNC
Reactant: Fc1cccc(C2OCCO2)n1
Solvent: CCO
Product: CN(C)c1cccc(C2OCCO2)n1
Temperature: 100 °C

Procedure:
0.60 g of 2-[1,3]dioxolan-2-yl-6-fluoropyridine (3.55 mmol) and 2.50 ml of dimethylamine at 33% in ethanol (17.7 mmol) are mixed and then the mixture is heated at the temperature of 100° C. for 12 hours. After evaporation under vacuum, the residue is taken up in chloroform, the mixture is washed with water, dried over magnesium sulfate, filtered and the chloroform is evaporated under vacuum. The title product is obtained in the form of a yellow oil which is used in the next stage without further purification.
Reaction SMILES: CN(C)C=O.[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>O>[C:6]1([S:12][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2ccccc2)cc1
Reaction time: 3 h
Yield: 28.2 %

Procedure:
Into a dimethylformamide (DMF) solution (30 mL) of 11.0 g (100 mmol) of benzenethiol is gradually added 14.0 g (132 mmol) of anhydrous Na2CO3 at 85° C. Then 4-chlorobenzaldehyde (11.3 g, 80.0 mol) is added during 20 min. at 85° C. The reaction solution is stirred at this temperature for 3 h. After adding H2O into the reaction mixture, the crude product is extracted with ethyl acetate. The organic layer is washed twice with H2O and with brine, dried over anhydrous MgSO4 and condensed. The residue is applied to column chromatography on silica gel with acetone-hexane (from 1:30 to 1:10) as eluent. 6.05 g of pale yellow oil are obtained (35%). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 7.24 (d, 2H), 7.42-7.44 (m, 3H), 7.53 (dd, 2H), 7.71 (d, 2H), 9.96 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([CH:32]=1)[NH2:31]>CCCCCC.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([NH:31][C:30]1[CH:32]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=1[CH3:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(C#N)cc1
Reactant: Cc1ccc(Cl)cc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(Cl)ccc1C)c1ccc(C#N)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (step H3) and 5-chloro-2-methyl-aniline as starting materials. tR: 1.35 min (LC-MS 2); ESI-MS: 515.2 [M−H]+ (LC-MS 2); Rf=0.16 (hexane/ EtOAc, 3:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:25]([O:22][CH2:21][C:20]([CH3:24])([CH3:23])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a solution of (S)-benzyl 2-(tert-butoxycarbonylamino)-4-hydroxy-3,3-dimethylbutanoate (0.3 g) in DCM (3 mL) was added DMAP (0.109 g, 0.889 mmol) and acetic anhydride (0.084 mL, 0.889 mmol). The reaction mixture was stirred at rt for 16 hrs, then diluted with EtOAc, washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-benzyl 4-acetoxy-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate (0.31 g). LC/MS (Cond. N-1): [M+Na]+ 402.22, RT=3.821 min.
Reaction SMILES: [C:1](NCCCCCCN1C2N=CN(C)C=2C(=O)N(CCCC[C@H](O)C)C1=O)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.[C:42]([O:45][C@H:46]([CH3:66])[CH2:47][CH2:48][CH2:49][CH2:50][N:51]1[C:60](=[O:61])[C:59]2[N:58]([CH3:62])[CH:57]=[N:56][C:55]=2[N:54]([CH2:63][CH2:64][NH2:65])[C:52]1=[O:53])(=[O:44])[CH3:43]>>[C:1]([NH:65][CH2:64][CH2:63][N:54]1[C:55]2[N:56]=[CH:57][N:58]([CH3:62])[C:59]=2[C:60](=[O:61])[N:51]([CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]([OH:45])[CH3:66])[C:52]1=[O:53])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.[C:42]([O:45][C@H:46]([CH3:66])[CH2:47][CH2:48][CH2:49][CH2:50][N:51]1[C:60](=[O:61])[C:59]2[N:58]([CH3:62])[CH:57]=[N:56][C:55]=2[N:54]([CH2:63][CH2:64][NH2:65])[C:52]1=[O:53])(=[O:44])[CH3:43]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)c1=O
Agent: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCN)c1=O
Product: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(CCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)c1=O

Procedure:
(R)-3-(N-Biotinyl-2-aminoethyl)-1-(5-hydroxyhexyl)-7-methylxanthine (CT13410) was prepared according to the method described above for (R)-3-(N-biotinyl-6-aminohexyl)-1-(5-hydroxyhexyl)-7-methylxanthine (CT 12460) but using (R)-1-(5-acetoxyhexyl)-3-(2-aminoethyl)-7-methylxanthine in place of (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine. The (R)-1-(5-acetoxyhexyl)-3-(2-aminoethyl)-7-methylxanthine was prepared according to the following procedure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:36].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:36]
Reactant: CCOC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Procedure:
Prepared according to Procedure H utilizing ethyl 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoate (0.50 g) and aqueous sodium hydroxide (2M, 2 mL) in THF (6 mL) to afford the title compound (0.46 9). Electrospray MS m/z 516 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)C.Cl>>[OH:5][CH:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc(NC(=O)C(C)(C)C)nc1
Agent: Cl
Solvent: CCO
Product: CCCC(O)c1ccc(NC(=O)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.2 %

Procedure:
To a solution of N-(5-butyryl-pyridin-2-yl)-2,2-dimethyl-propionamide (2.47 g, 9.95 mmol) in ethanol (20 mL) sodium borohydride (185 mg, 5.0 mmol) was added. After 40 min stirring at room temperature the mixture was acidified with 1 N hydrochloric acid to pH 2 and stirred for 10 min. After neutralisation with sodium hydrogencarbonate the mixture was extracted three times with dichloromethane. The combined organic extracts were washed twice with sodium hydrogen carbonate solution and once with brine. After drying and concentration under reduced pressure the residue was purified by flash chromatography (dichloromethane/methanol 30:1) to give N-[5-(1-hydroxy-butyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (1.025 g, 41%).
Reaction SMILES: [C:1]([C:5]1[N:14]([CH2:15][CH2:16][OH:17])[C:8]2=[CH:9][N:10]=[C:11](Cl)[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:18]>CO>[NH2:18][C:11]1[CH:12]=[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:14]([CH2:15][CH2:16][OH:17])[C:8]2=[CH:9][N:10]=1
Reactant: CC(C)(C)c1cc2cc(Cl)ncc2n1CCO
Reactant: N
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)ncc2n1CCO
Temperature: 120 °C
Yield: 16 %

Procedure:
In a 100 mL autoclave, a mixture of 2-(2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (350 mg, 1.39 mmol) and CuSO4.5H2O (35 mg, 1.4 mmol) in aqueous ammonia (14 mL) and CH3OH (7 ml) was heated to 120° C. for 14 h. The mixture was allowed to cool down to 25° C. The methanol was removed by evaporation under vacuum and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (5% CH3OH in dichloromethane as eluant) to afford 2-(5-amino-2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (50 mg, 16%). 1H-NMR (CDCl3, 300 MHz) δ 8.22 (s, 1H), 6.59 (s, 1H), 6.08 (s, 1H), 4.44 (t, J=6.9 Hz, 2H), 3.99 (t, J=6.9 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>CCO>[CH3:21][C:17]1[N:16]=[C:15]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(-c2cccc(C)n2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2nn3ccccc3c2C(=O)O)n1
Yield: 100 %

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (0.18 g, 0.6 mmol) in EtOH (10 mL) is treated with a 2N NaOH solution (3 mL) and refluxed for 3 hours. The reaction is concentrated to a yellow solid and diluted with 1N HCl (30 mL). The aqueous is extracted with CH2Cl2 (3×10 mL) and the organic solution dried over Na2SO4. The solution is filtered and the solvent removed in vacuo to afford 0.152 g (94%) of desired product as a white solid. MS ES+ m/e 254.1 (M+1). UV (95% EtOH) λmax 284 nm (ε 23625), 244 nm (ε 24036). TOF MS ES+ exact mass calculated for C14H11N3O2 (p+1): m/z=254.0930. Found: 254.0919. Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.22; H, 4.42; N, 16.25.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cccc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)pyrrolo[2,1-f][1,2,4]triazine (4.25 g, 15.5 mmol) in 40 mL of tetrahydrofuran and 60 mL of methanol at 0° C. was added zinc dust (3.04 g, 46.5 mmol, <10 micron) followed by ammonium chloride (2.49 g, 46.5 mmol). The mixture was stirred at room temperature overnight. Additional zinc dust (6.08 g, 93 mmol) and ammonium chloride (5.0 g, 93 mmol) were added and the reaction was allowed to stir at room temperature for 4 h. The heterogeneous mixture was filtered through a thin pad of Celite® with methanol and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:1) gave the title compound (3.5 g, 92%) as a yellow foam.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)(C)(C)C.CCOCC.C(OCC)(=O)C.[ClH:54]>>[ClH:54].[ClH:54].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)[C@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3.5 h

Procedure:
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.72 g of tert-butyl 3(R)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3.5 hours. Ether (10 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.50 g of 3(R)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride as a colorless powder.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[NH4+].[Cl-]>C(O)C.[Fe]>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([NH2:16])=[C:9]([S:8][C:1]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1SCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(Cl)cc1Sc1ccccc1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
To a suspension of 1.8 g of 2-benzylthio-4-chloro-nitrobenzene in 100 ml ethanol was added 2 g powdered iron and 20 mL of 0.33N NH4Cl. The mixture was heated at 70° C. for 6 hr. The mixture was cooled and filtered through a pad of Celite. The filtrate was condensed and purified by flash chromatography (hexane/ethyl acetate 4:1 as eluent) to yield 1.25 g of an oil. LC-MS showed a single peak with the expected (M+H+ of 236.