Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25](O)[CH2:26][S:27][C@H:22]12)=[O:19]>O1CCCC1>[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:19]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 67.9 %

Procedure:
Trifluoroacetic anhydride (1 ml.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1 g.) in tetrahydrofuran (3 ml.) and the mixture was treated in a similar manner to that of Example 18 to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 0.65 g.).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.[BH4-].[Na+].Cl>C(OCC)(=O)C=C>[OH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH:4]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: C=CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 4-oxo-1-(phenylmethyl)-3-piperidinecarboxylate hydrochloride (56.2 g, 190 mmol) in methanol (11) was added triethylamine (31.8 mL, 230 mmol) and the mixture stirred at room temperature for 10 min. Sodium borohydride (24.0 g, 630 mmol) was then added portionwise with ice cooling, and the reaction was then stirred at room temperature for 4.5 h. 5N HCl solution (200 mL) was added and the mixture was evaporated. The aqueous residue was basified with aqueous sodium bicarbonate and the extracted several times with a 9:1 dichloromethane:methanol mixture. The extracts were dried and evaporated to give the product (44.3 g, 89%) as a mixture of cis and trans isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[O:9][CH2:8][CH2:7][C:6]2(O[Si](C)(C)C)[C:14]#[N:15].C[Si](Cl)(C)C.[I-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]#[N:15]
Reactant: COc1cc2c(cc1C)OCCC2(C#N)O[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1C)OCCC2C#N

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 2, by 1) the reaction of 0.9 gram (0.0046 mole) of 6-methoxy-7-methylchroman-4-one (ii) with 1.40 grams (0.0138 mole) of trimethylsilyl cyanide, in the presence of 0.1 gram (catalyst) of aluminum chloride in 30 mL of toluene, affording an intermediate product, namely: 6-methoxy-7-methyl-4-(1,1-dimethyl-1-silaethoxy)chromane-4-carbonitrile (cyano-silyl intermediate), then 2) the reaction of the I-silaethoxy intermediate with 2.35 mL (0.0184 mole) of trimethylsilyl chloride, 2.8 grams (0.0184 mole) of sodium iodide, and 0.12 mL of water in 30 mL of acetonitirile, yielding 0.6 gram of subject compound. Contrary to Step E of Example 2, the hydrogenation step was not necessary to obtain the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26](Cl)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:42]#[C:43][CH2:44][CH2:45][CH2:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([C:42]#[C:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: C#CCCCC
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(C)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCCC#Cc1nc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ncn([C@@H]3C[C@H](n4cc(C)cn4)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BB1) (0.1 g, 0.17 mmol), 1-hexyne (0.42 g, 1.70 mmol), copper (I) iodide (0.008 g, 43 μmol), dichlorobis(triphenylphosphine)palladium(II) (0.031 g, 43 μmol), triphenylphosphine (0.023 g, 86 μmol), diethylamine (1 mL) and DMF (0.5 mL) are placed in a 0.5-2.5 mL microwave vial. The reaction mixture is heated to 120° C. using microwave radiation. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is partitioned between dichloromethane (20 mL) and 2M HCl (20 mL). The organic layer is washed with sat. NaHCO3 (20 mL), water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1). MS (ES+) m/e 622 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:12][C:5]2[S:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH2:3]1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>O=S(Cl)Cl.ClCCl>[C:15]([NH:18][C:9]([C:7]1[S:6][C:5]2[CH2:12][C:2]([CH3:1])([CH3:13])[CH2:3][C:4]=2[CH:8]=1)=[O:11])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)N
Reactant: CC1(C)Cc2cc(C(=O)O)sc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2cc(C(=O)NC(C)(C)C)sc2C1
Temperature: 65 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
A suspension of 131d (12.0 g, 61.0 mmol) in SOCl2 (80 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. See FIG. 15. The residue was diluted with dichloromethane (20 mL), which was added to the solution of 2-methylpropan-2-amine (4.45 g, 61.0 mmol) and triethylamine (18.0 g, 180 mmol) in dichloromethane (180 mL). The resulting mixture was stirred for 16 h and diluted with dichloromethane (200 mL). It was washed with water (3×50 mL), dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure to afford 131e (15.0 g, 97%) as a yellow solid. MS-ESI: [M+H]+ 252.0
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.C([O:33][C:34]([C:37](Cl)=[O:38])([CH3:36])[CH3:35])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO.O>[OH:33][C:34]([CH3:36])([CH3:35])[C:37]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:38]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (240 mg, 0.87 mmol, example 9 (step 3) and DIEA (151 μL, 0.87 mmol) in DCM (3 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (125 μL, 0.87 mmol) slowly. After addition, the mixture was stirred at RT for 16 h. Then, an additional amount of 1-chlorocarbonyl-1-methylethyl acetate (60 μL) was added and the mixture was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was stirred at RT for 10 min. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×3 mL). The combined organic extracts were then dried over MgSO4 and concentrated to give a crude intermediate. Then, the crude intermediate was dissolved in MeOH (10 mL), and then potassium carbonate (239 mg, 1.7 mmol) was added. The resulting mixture was then stirred at RT for 16 h. Then, the mixture was filtered and the solid was washed with DCM (2×5 mL). The combined filtrates were concentrated and the residue was purified by silica gel flash column chromatography (0%-400% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 364 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](Br)[CH:3]=1.C([Li])CCC.[N:15]1[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]=12>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C@:19]23[CH2:20][O:21][CH2:22][CH2:23][C@H:18]2[CH2:17][O:16][NH:15]3)[CH:3]=1
Reactant: Fc1ccc(Br)cc1Br
Reactant: C1CC2CON=C2CO1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1[C@]12COCC[C@H]1CON2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a toluene-THF (10:1) mixture (15 ml). The mixture was cooled to −78° C. and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (200 mg) in toluene-THF (10:1) (5.0 ml) and a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time. After stirring at the same temperature for three hours, the reaction was terminated with an ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C1CCCN1Cc1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.68 g. (0.025 mole) of m-trifluoromethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oily residue of 1-(1-benzyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea HCl, m.p. = 164°-165° C.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5](C#N)=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.C(OCC)(=O)[CH2:15][C:16]([O:18]CC)=[O:17]>>[CH2:7]([CH:6]([CH2:5][C:4]([OH:3])=[O:13])[CH2:15][C:16]([OH:18])=[O:17])[CH:8]([CH3:9])[CH3:10]
Reactant: CCOC(=O)C(C#N)=CCC(C)C
Reactant: CCOC(=O)CC(=O)OCC
Product: CC(C)CC(CC(=O)O)CC(=O)O

Procedure:
Reacting the 2-cyano-5-methylhex-2-enoic acid ethyl ester with diethyl malonate to form 3-isobutylglutaric acid;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(NC(C)C)(C)C>O1CCOCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4.44 mL of p-fluoronitrobenzene, 6 gms. 3-(4-methyl-piperazin-1-yl)-propylamine and 6.65 mL N,N-diisopropylamine in 19 mL dioxane is heated at 105° C. for 2 days. The reaction mixture is cooled to room temperature, evaporated to dryness, and recrystallized from hot isopropanol yielding [3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in the amount of 0.1385 gms.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-amino-4-chlorobenzoic acid (10 g, 0.06 mmol), anhydrous DMF (30 mL) and anhydrous dioxane was cooled to 0° C. in 300 mL 3-necked flask fitted with magnetic stirrer and constant additional funnel. Bromoacetyl bromide was added dropwise over a 2 h period, keeping the internal temperature between 0°-2° C. After the addition was completed, the solution was allowed to warm to room temperature and the reaction mixture was stirred 20 h. The reaction mixture was cooled in an ice-bath and slowly diluted with water (300 mL). The resulting white crystalline product was filtered. Recrystallization from EtOAc/Hex afforded 9.2 g (54%) of the title compound, mp 156.4°-158° C.; 1H NMR (DMSO-d6) δ 13.99 (s, 1H, NH), 11.72 (s, 1H, COOH), 8.54 (d, 1H, J=2.0), 8.00 (d, 1H, J=8.8), 7.27 (dd, 1H, J=2.4, J=6.4), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ 168.60, 165.54, 141.12, 138.51, 133.88, 123.36, 119.23, 115.58, 30.54; MS (EI, m/z) 293 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH3:23])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:28].C(O)C>C(OCC)C>[IH:28].[CH3:23][O:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: COCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl) [1,4]diazepane (1.69 g, 5.23 mmol), aqueous hydriodic acid (10 mL, 57%), and ethanol (20 mL). Heat to reflux. After 1 hour, cool to ambient temperature and pour the reaction mixture into diethyl ether (350 mL) and stir to give a solid. After 1 hour, collect the solid and dry in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[N:6][CH:7]=1.CC[O:29]C(C)=O.CCCCCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[N+:6]([O-:29])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)cn1)C(=O)NCC#N
Solvent: CCCCCC
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)c[n+]1[O-])C(=O)NCC#N

Procedure:
Using the same procedure as described for example 40, (2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide (51 mg, 0.123 mmol) was oxidized to give the title compound after chromatography with 50% EtOAc/hexane.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH2:35])=[CH:26]1>>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH:35][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)=[CH:26]1
Reactant: NCc1csc2ccccc12
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3csc4ccccc34)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 476.3. HPLC (Condition A), Rt: 4.79 min (HPLC purity: 86.7%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Cl)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:8][C:7]1[C:2]2[N:3]([CH:18]=[C:17]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:22][CH:21]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1Br
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2cn3cccc(Br)c3n2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
2-Amino-3-bromopyridine (0.250 g, 1.45 mmol) and 4-tert-butylphenacyl chloride (0.306 g, 1.45 mmol) were dissolved in isopropanol (4.5 mL) and treated with sodium bicarbonate (0.146 g, 1.74 mmol). The mixture was stirred in a sealed tube at 80° C. for 48 h. The mixture was concentrated under reduced pressure and redissolved in ethyl acetate (30 mL). The organic mixture was washed with water and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 10% acetone/hexane to give 0.370 g (77%) of the title compound. HPLC (Method B): r.t.=10.7 min., purity 100% at 210-370 nm, 99.3% at 252 nm. HRMS: calcd for C17H17BrN2+H+, 329.06478; found (ESI, [M+H]+), 329.0662.
Reaction SMILES: C(OC(=O)N[CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:26][C:27]#[C:28][CH3:29])[C:17](=[O:25])[N:18]3[CH3:24])[CH2:9]1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:13][CH:12]1[CH2:32][CH2:8][CH2:9][N:10]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:26][C:27]#[C:28][CH3:29])[C:17](=[O:25])[N:18]3[CH3:24])[CH2:11]1
Reactant: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCNC(NC(=O)OC(C)(C)C)C3)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCCC(N)C3)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
[1-[7-(2-Butynyl)-2-chloro-9-methyl-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazin-3-yl]c arbamic acid t-butyl ester (15 mg) was dissolved in trifluoroacetic acid. This reaction solution was stirred at room temperature for five minutes, and then concentrated. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (7.23 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>>[Cl:16][S:12]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:14])=[O:13]
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Yield: 58.2 %

Procedure:
2-Methoxybenzoic acid (available from Aldrich, 5.0 g, 32.9 mmol) was warmed with chlorosulfuric acid (164 mmol, 5.0 eq., 19.1 g, 11.0 mmol) at 50° C. for 2 h. The resulting thick brown liquid was poured on crushed ice with vigorous stirring. The resulting white precipitates were filtered, washed with H2O, and dried overnight under high vacuum to give Intermediate 6 (4.8 g, 58%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[CH2:1]([C:3]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3ccccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and indole, the title compound is prepared as in example 1.89 mg (54%). LC-MS m/z 280.0 (M++1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: Clc1ncccn1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4ncccn4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-pyrimidine at 120° C.:
Reaction SMILES: [CH2:1]([CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(OCC)(=O)CC(C)=O>>[CH2:1]([CH:3]([CH:9]([OH:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)C(C)=O
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(CC)C(C)O
Yield: 60 %

Procedure:
Ethyl 2-ethyl-3-hydroxybutyrate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that ethyl 2-ethyl-3-oxo-butyrate was used to replace for ethyl acetoacetate. Yield 60%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCC=O
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1>[Pt].C(OCC)(=O)C.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
Zinc bromide (226 mg, 1 mmol) and platinum on carbon (5%, 491 mg, 2.52 mmol) were added to a solution of 5-chloro-2-methoxy-3-nitropyridine (Preparation 23a, 950 mg, 5.04 mmol) in ethyl acetate (15 mL) and the reaction mixture was stirred at ambient temperature for 5 hours under a hydrogen atmosphere. The mixture was then filtered through Celite® and the filter cake was washed with methanol. The combined filtrate and washings were concentrated to give the title compound (820 mg, 100%) as a white solid.