Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: Fc1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(4-fluorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].O>C1(C)C=CC=CC=1>[CH3:4][CH:3]=[CH:2][CH:1]([OH:5])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: C/C=C/C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC=CC(O)CCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
31.5 g of crotonaldehyde are added dropwise, at -20° C. in the course of 75 minutes, to 32 g of butyllithium, dissolved in 145.8 g of toluene. After the reaction has proceeded for two hours, the temperature increasing slowly to 0° C., 250 ml of water are carefully added dropwise. The aqueous phase is separated off and washed once with 100 ml of toluene. The combined organic phases are washed neutral with water, dried over sodium sulphate and distilled. 46 g of oct-2-en-4-ol of boiling point 68°-72° C./13 mb are obtained. According to the gas chromatogram, the purity is 96%. The NMR spectrum confirms the expected structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]([C:7](=[O:9])[C:4]3[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=3)[C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1
Reactant: NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=C(O)c1cc(Cl)cs1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2ccc(Cl)cc21
Yield: 53 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 463 mg (2.85 mmole) portion of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem., 13, 393 (1976)) was transformed into the acyl imidazole by reaction with 500 mg (3.09 mmole) of 1,1'-carbonyldiimidazole. The intermediate 4-chloro-2-thiophene-(1-imidazo)carboxamide coupled directly with 500 mg (2.37 mmole) of 6-chloro-2-oxindole-1-carboxamide in the presence of 783 mg (6.41 mmole) of 4-(N,N-dimethylamino)pyridine to give 665 mg of crude greenish-yellow solid. Recrystallization gave 450 mg (1.27 mmole, 53% yield) of pure title compound as a yellow solid, m.p. 231°-3° C. (acetic acid).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(Cc2cccc(Br)n2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5cccc(F)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-fluoro-benzyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3CC[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4NC(=O)C)[CH2:13]3)[C:6]=2[N:7]=1.C(Cl)Cl.[CH3:35][OH:36]>>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:36][CH3:35])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: CO
Reactant: CC(=O)Nc1cccc2c1CCN(c1ncnc3c(N4CCOCC4)nc(Cl)nc13)C2
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1

Procedure:
2-chloro-8-(5-acetylamino-1,2,3,4 -tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido [5,4-d]pyrimidine Rf value: 0.55 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)O)=[CH:4][CH:3]=1.[N:26]1[CH:31]=CC=C[CH:27]=1.CS(Cl)(=O)=O.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[N:26]([CH3:31])[CH3:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Reactant: c1ccncc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a mixture of (4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol (141 mg, 0.382 mmol) (synthesized in an analogous way as described in Example 3) in methylene chloride (2.8 mL) was added pyridine (6.0 mL, 74 mmol) and methanesulfonyl chloride (0.148 mL, 1.91 mmol) at 0° C. After the addition, the mixture was warmed to rt and stirred for 30 min and then heated at 60° C. for 20 min. The mixture was cooled in an ice bath and dimethylamine (0.553 mL, 11.5 mmol) in THF was added to the mixture. After the addition, the ice bath was removed and the mixture was stirred at rt for 30 min and then heated at 55° C. for 2 h. The mixture was cooled, concentrated, and the residue was purified by HPLC to afford 1-(4-chlorophenyl)-N,N-dimethyl-1-[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanamine as white powder (115 mg, 76%). LCMS: (AA) ES+ 396.3, 398.1; 1H NMR (400 MHz, d6-DMSO) δ: 14.48-14.27 (m, 1H), 8.71 (s, 1H), 8.57 (dd, J=4.55, 1.62 Hz, 2H), 7.95 (s, 1H), 7.73-7.63 (m, 4H), 7.39-7.30 (m, 2H), 5.53 (s, 1H), 2.13 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:34][NH2:35]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:35][CH3:34])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(N)ccc3Cl)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2cc(-c3cc(N)ccc3Cl)c(=O)n(C)c2n1
Yield: 79.8 %

Procedure:
6-(5-amino-2-chlorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.500 g, 1.5 mmol), mCPBA (0.481 g, 1.953 mmol) and methylamine (0.76 mL. 2.0 M in THF, 1.52 mmol) were combined by analogy to Example A1 to provide 6-(5-amino-2-chlorophenyl)-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.378 g, 80% yield). MS (ESI) m/z: 316.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(N)C#N
Product: CC(C)C(C)(N)C(N)=O

Procedure:
In a similar way, hydrolysis of the (±)-2-amino-2,3-dimethylbutyronitrile with sulfuric acid yields (±)-2-amino-2,3-dimethylbutyramide, mp 74.5°-76° C.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>C(O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:6]3[CH2:5][CH2:4][NH:3][CH2:8][C:7]=3[C:15]=2[CH:14]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CNCC3

Procedure:
A suspension of 4-piperidone monohydrate hydrochloride (1.0 g, 6.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (1.14 g, 6.5 mmol) in ethanol (17 ml) is kept stirring at reflux overnight. The resulting solid is filtered off and washed with diethyl ether to afford crude sub-title compound, which is used without further purification: tR (LC-1) 0.38; ESI-MS (positive ion): m/z 203.19 [M+H]+ (calcd 202.25 for C12H14N2O).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:23][Si](C=[N+]=[N-])(C)C>C(Cl)Cl>[CH3:23][O:14][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([Cl:20])[C:18]([F:19])=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 4.5 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (4.00 g, 13.2 mmol) in CH2Cl2 (100 mL) were added MeOH (6.94 mL, 171 mmol) and subsequently trimethylsilyldiazomethane (8.56 mL, 17.1 mmol) in a dropwise manner over 15 min. Stirring was continued at RT for 4.5 h. Volatiles were then evaporated under reduced pressure to afford the title compound as a colorless oil, which was used directly in the next step without further purification. TLC Rf (c-hexane/EtOAc 6:1)=0.40; tR (HPLC conditions c): 5.56 min.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=1)=[O:19]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)C=Cc1cccc(F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(3-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (18 g) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:2]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3c[nH]c4ccccc34)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(1H-indol-3-yl)-cyclohexanone (prepared following the procedure described in EP 345808 A119891213) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: NCc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Oc1ccc2nc(NCc3ccccc3Cl)oc2c1

Procedure:
2-Chloro-benzooxazol-6-ol (1 eq) and 2-chloro-benzylamine (2 eq) was dissolved in NMP. Using a Personal Chemistry microwave system, the mixture was reacted at 180° C. for six minutes. The crude reaction mixture was diluted with ethyl acetate and washed once with brine and once with 1N HCl, or washed twice with brine, depending on the amine used. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. This material was purified by silica gel column using hexane and ethyl acetate. MH+=275.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.NO.Cl.CCN=C=NCCCN(C)C.C1C=CC2[N:63]([OH:64])N=NC=2C=1.CCN(CC)CC>CN(C)C=O>[OH:64][NH:63][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:32][CH:33]=1)=[O:36]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)NO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To a solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid prepared in Example 232 (50 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added. NH2OH.HCl (18 mg, 0.26 mmol), EDCI (33 mg, 0.17 mmol), HOBT (21 mg, 0.15 mmol) and NEt3 (0.036 mL, 0.26 mmol). The reaction mixture was heated at 80° C. for 48 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by prep-HPLC to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxycarbamoyl-phenyl)-amide as a white solid (24 mg, 47%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[CH:15][CH:14]=1>C(#N)C.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:23])[CH2:21][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
Add potassium carbonate (2.1 g, 15.5 mmol) and pyrrolidine (9.65 mL, 116 mmol) to a solution of N-(4-bromophenyl)-2-chloroacetamide (2.0 g, 7.7 mmol) in acetonitrile (78 mL) at RT. Heat the mixture at 80° C. for 4 h. Cool the mixture to RT, dilute with CH2Cl2, and wash with brine and water. Dry the organic layer over Na2SO4, filter, and concentrate to give 2.17 g (99%) of the title compound. LC-ES/MS m/z (79Br) 283.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[O-:9][CH2:10][CH3:11].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:9][CH2:10][CH3:11])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(Br)n1
Temperature: 25 °C

Procedure:
A mixture of 2,6-dibromopyridine (1.5 g) in ethanol (6 mL) was treated with sodium ethoxide (3.55 mL) solution dropwise and resulting mixture was refluxed for 18 hours. The mixture was allowed to cool to room temperature and poured into a beaker containing 5% sodium bicarbonate, extracted with diethyl ether. The combined organics were washed with brine, dried, evaporated in vacuo and purified by column chromatography on silica gel (1-3% methanol in dichloromethane) to obtain the title compound (0.840 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([CH:4]([C:3]([O:2][CH3:1])=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 12.3 g (66.0 mmol) of BOC-piperazine. The reaction mixture was refluxed for 3.5 hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography using chloroform as eluent and was concentrated to dryness to yield 7.73 g (100%) of the desired mixture of isomers as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([OH:18])[C:16]=2[N:17]=1)[C@@H:4]1[O:10][C@H:7]([CH2:8][OH:9])[CH2:6][CH2:5]1.[CH2:19](N)[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][C@@:4]1([N:3]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([OH:18])[C:16]=3[N:17]=[CH:2]2)[O:10][C@H:7]([CH2:8][OH:9])[CH2:6][CH2:5]1
Reactant: OC[C@@H]1CC[C@H](n2c(Br)nc3c(O)ncnc32)O1
Reactant: NCCN
Product: NCC[C@]1(n2cnc3c(O)ncnc32)CC[C@@H](CO)O1

Procedure:
The product from step 1 can then be reacted with ethylenediamine to give 8-(2-aminoethyl -2',3'-dideoxyinosine (8-AE-ddI) (Reaction B).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]([OH:18])[C:15]([S:19](=[O:26])(=[O:25])[N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[CH2:27]([O:7][C:8]1[CH:17]=[C:16]([O:18][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:8]=2)[C:15]([S:19](=[O:26])(=[O:25])[N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)OC)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2.7 71.25 g of potassium carbonate are added to a solution of 75 g of methyl 2,4-dihydroxy-5-(N-methyl-N-propylsulfamoyl)benzoate in 800 ml of acetonitrile. 60 ml of benzyl bromide are subsequently added dropwise. The mixture is refluxed for 3 hours, cooled and subjected to conventional work-up. HPLC gives 113 g of methyl 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:19])=[C:13]([CH:18]=1)[C:14]([O:16]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]1COCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:20])[C:12]([Br:19])=[C:13]([CH2:14][OH:16])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1Br
Product: Cc1cc(OCc2ccccc2)cc(CO)c1Br
Temperature: -78 °C
Reaction time: 21 h

Procedure:
A solution of methyl 5-(benzyloxy)-2-bromobenzoate (1.08 g, 3.36 mmol) in anhydrous THF (7 mL) was made before cooling the reaction mixture in a −78° C. bath. Reaction mixture was then treated, dropwise, with LiAlD4 (1 M solution in THF; 3.7 mL, 3.7 mmol) and allowed to stir for 21 h. before the reaction mixture was warmed to room temperature and quenched with 1N HCl to adjust pH 7 before addition of 10 mL of EtOAc. The organic layer was separated and the aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give (5-(benzyloxy)-2-bromo-3-methylphenyl)methanol −d2 (2.00 g, 86%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]I>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:22]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccccn1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(=O)n(-c3ccccn3)n2)cc1
Yield: 3.6 %

Procedure:
In a 50 mL round bottom flask, 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one (250 mg, 0.71 mmol), 2-bromopyridine (105 μL, 1.07 mmol), copper(I)iodide (13.6 mg, 0.07 mmol), and potassium carbonate (296 mg, 2.14 mmol) in dimethylformamide (10 mL) was heated to reflux 14 h. The reaction was cooled and water (20 mL) was added. The sticky solids were filtered off and then partitioned between methylene chloride and water, separated, and dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 10 mg (2.4%) oil. MS m/z 391 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[N+:1]([O-:4])=[O:2])(=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 64 %

Procedure:
A mixed acid was prepared by adding fuming nitric acid (1 mL), which was added 3 times as divided portions, to concentrated sulfuric acid (6 mL) under ice cooling, and added portionwise with 4-acetamidobenzaldehyde (1.91 g, 11.7 mmol). After the addition, the reaction mixture was immediately poured onto ice, and the solids were collected by filtration. The solids were sufficiently washed with cold water, dried, purified by silica gel column chromatography (developing solvent: CH2Cl2), and then recrystallized from water to obtain the target compound as pale yellow needlelike solid (1.57 g, yield: 64%).