Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([CH3:13])[N:6]=1.CO.O>ClCCl>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([F:12])=[C:7]([CH3:13])[N:6]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)nc(Cl)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1nc(Cl)nc(C)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Sodium methoxide (446.53 mg, 8.27 mmol) is added portion wise to a stirred solution of 2,4-dichloro-5-fluoro-6-methyl-pyrimidine (1.7 g, 7.51 mmol) in methanol (8 mL, 197.66 mmol) at 0° C. The mixture is then stirred at room temperature for 1 hour. Water (20 mL) is added to the reaction mixture followed by dichloromethane. The layers are separated and the aqueous layer is re-extracted with dichloromethane. The combined organic extracts are dried over magnesium sulfate and the solvents are evaporated under reduced pressure to give an 8:1 of mixture of product to starting material. The crude material is purified by silica gel chromatography using a 0-99% gradient of dichloromethane in iso-hexanes to give the title compound (1.16 g, 87%). 1H NMR (CDCl3) δ 4.09 (s, 3H), 2.45 (d, 3H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:27]1[C:23]([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)=[CH:24][CH:25]=[N:26]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)O)cs1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-3-thiophenecarboxylic acid (414 mg, 2 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (828 mg, 6 mmol), tetrakistriphenylphosphine Pd(0) (116 mg, 0.1 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (428 mg, 2.2 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜100 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[Br-:13].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-n2ccnc2)cc1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccc(Cl)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 5.60 mmol (1.00 g) 1-(4-chlorophenyl)imidazole and 6.7 mmol (0.830 g, 0.61 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 18.5 h to 90° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Reactant: CO
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (8.21 g, 50 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (250 mL). The mixture was stirred for 10 min. Quinidine (17.84 g, 55 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (6.08 mL, 150 mmol) was added. The mixture was stirred at −55° C. for 18 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a thick oil. The oil was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (300 mL). After shaking, the layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (9.15 g, 46.6 mmol, 94%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (1H, d, J=8.4 Hz), 1.33 (1H, d, J=8.4 Hz), 3.00 (1H, s), 3.03 (1H, s), 3.21-3.29 (2H, m), 3.45 (3H, s), 6.02-6.04 (1H, m), 6.14-6.16 (1H, m), 11.86 (1H, s).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])([S:7]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:20][C:5]([S:7]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=1)(=[O:8])=[O:9])([CH3:6])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a solution of 7.67 g (23.6 mmol) of 2-methyl-2-(6-trifluoromethyl-pyridine-3-sulfonyl)-propionic acid ethyl ester in THF/water (1/1, 200 mL) were added 1.97 g (46.9 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The organic solvent was removed under reduced pressure and the aqueous layer washed with diethyl ether (200 mL). The basic aqueous layer was cooled in an ice bath and acidified with 2M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with ethyl acetate (4×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 6.34 g of 2-methyl-2-(6-trifluoromethyl-pyridine-3-sulfonyl)-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH2:30][CH3:31])=[CH:24][CH:23]=1>>[ClH:1].[CH2:30]([N:29]([CH2:28][C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:31]
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)c(CC(=O)O)n2c1
Reactant: CCNCc1ccncc1
Product: CCN(Cc1ccncc1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccc(C)cn12
Product: Cl
Yield: 32.9 %

Procedure:
According to the method of Example 14, 2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(4-pyridinylmethyl)ethylamine were used as raw materials for synthesis, to obtain white solid powder, yield 32.9%. m.p. 229-231° C., ESI-MS m/z: 420[M+H]+, 1H NMR(DMSO-d6, 400 MHz)δ: 1.11(t, 0.6H, J=7.00 Hz), 1.25(t, 2.4H, J=7.00 Hz), 2.47(s, 2.4H), 2.49(s, 0.6H), 3.42(q, 0.4H, J=7.00 Hz), 3.63(q, 1.6H, J=7.00 Hz), 4.25(s, 0.4H), 4.56(s, 1.6H), 4.78(s, 1.6H), 5.01(s, 0.4H), 7.55-7.58(m, 1H), 7.65-7.76(m, 4H), 7.84-7.86(m, 2H), 7.90-7.92(m, 1H), 8.71(s, 1H), 8.80-8.84(m, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and N-(4-amino-phenyl)-methanesulfonamide [Tetrahedron, 42, 5739. (1986)] according to the method described in Example 2. Melting Point: 221-225° C. (water)
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].CCN(CC)CC.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([NH:20][C@H:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C=NCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.360 g, 1 mmol) and Et3N (0.42 mL, 3 mmol) in 10 mL CH2Cl2 is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.425 g (96% yield) of the desired product which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([OH:23])[CH2:22][CH2:21][C:16]3([O:20]CCO3)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16](=[O:20])[CH2:21][CH2:22]3)[O:23][C:25]2=[O:27])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCCO2)c1ccc(Br)cc1
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Yield: 6 %

Procedure:
The title compounds are prepared from 8-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-1,4-dioxa-spiro[4.5]decan-8-ol and triphosgene following a procedure analogous to that described in step 3 of Intermediate 1. The ketal group is partially cleaved under these conditions to give a mixture of the title compounds that is separated by chromatography on silica gel (cyclohexane/ethyl acetate 9:1→1:1). 11-[(S)-1-(4-bromo-phenyl)-ethyl]-1,4,9-trioxa-11-aza-dispiro[4.2.5.2]pentadecan-10-one: Yield: 6% of theory; LC (method 1): tR=3.65 min; Mass spectrum (ESI+): m/z=410/412 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[CH3:22].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH:30][C:11]([C:4]1[C:3]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[CH3:22])=[C:2]([F:1])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1)=[O:13]
Reactant: NOC1CCCCO1
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOC2CCCCO2)cc2nc[nH]c2c1F

Procedure:
A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 equiv.), and a diisopropylethylamine (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]([NH2:6])=[NH:5].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:16][CH:17]([CH3:26])[C:18](=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]2[N:5]=[C:4]([NH:3][CH3:2])[NH:6][CH:18]([CH:17]([CH3:26])[CH3:16])[C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNC(=N)N
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccc(F)cc2)N=C(NC)NC1C(C)C
Temperature: 70 °C
Yield: 63 %

Procedure:
1-Methylguanidine hydrochloride (8.25 g), 4-Fluorobenzaldehyde (4.2 g), ethyl 4-methyl-3-oxo-pentanoate (5.0 g) and DMF (100 ml) were charged to a vessel equipped with a condenser and connected to a nitrogen line. The resultant mixture stirred until a clear solution is obtained. Sodium carbonate (4.0 g) was charged and the mixture heated to 70° C. for 2 hours. The reaction mixture was cooled to ambient temperature, filtered, and the solvents removed by evaporation under reduced pressure. The resultant oil was triturated in water at 50° C. and cooled to give a slurry that was filtered and dried to give ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methylamino-1,6-dihydropyrimidine-5-carboxylate in 63% yield.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+].[C:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[C:23][CH2:24][CH3:25]>CO.CN(C=O)C>[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([S:6][CH2:13][CH2:14][OH:15])([CH3:5])[CH3:4])(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CCC#COc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)(C)SCCO)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of D-penicillamine (0.5 g, 3.35 mmol) in methanol (5 mL) was cooled to 0° C. and crushed sodium hydroxide (0.28 g, 6.87 mmol) was added to give a clear solution. 2-Bromoethanol (0.26 mL, 3.71 mmol) was added and stirred at 0° C. for 1 h and at room temperature for an additional 1.5 h. The reaction was concentrated, and the oily residue was dissolved in 3 mL water and 6 mL DMF and stirred with sodium carbonate (0.82 g 7.2 mmol) and 4-butynyloxy-benzenesufonyl chloride (0.78 g, 3.18 mmol) at room temperature overnight. The reaction was concentrated and the residue was extracted with ethyl acetate and water. The aqueous layer was acidified to pH˜3 with concentrated HCl and extracted with ethyl acetate. The second ethyl acetate extract was washed with water and brine, dried over sodium sulfate, filtered and concentrated to obtain 1.2 g of N-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-[(2 hydroxyethyl)sulfanyl]valine as an oil. Yield 89.6%. Electrospray Mass Spec 400.1 (M−H)−.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:28])=[CH:19][N:20]=[C:21]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:16][CH:15]=1)=[O:13])(C)(C)C.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[Cl:28][C:18]1[C:17]2[C:22](=[CH:23][C:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][CH:7]3[C:6]([OH:29])=[O:5])=[O:13])=[CH:15][CH:16]=2)[C:21]([NH:24][C:25]([NH2:27])=[NH:26])=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)N3CCCC3C(=O)O)cc12

Procedure:
A solution of N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline t-butyl ester (175 mg, 0.42 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline trifluoroacetate (156 mg, 0.33 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH3:28])[CH2:18]1
Reactant: CCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodoethane.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.[BH4-].[Na+]>C(O)C>[Cl:1][CH:2]([CH:8]([OH:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cl)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 2-chloro-3-oxo-3-phenylpropionate (CI, 100 g, 0.44 mol) and glacial acetic acid (25 ml, 0.44 mol) in ethanol (1 l) is cooled to -5 ° and sirred for 10 min. Sodium borohydride pellets (12.54 g, 0.33 mol, diam. 11 mm) are aided in portions (4.2 g×3) with vigorous stirring. The reaction temperature is maintained at -5 to 0°. After the addition, the reaction mixture is stirred continuously at 0° for 5 hr and is then poured slowly into ice-water with stirring. The mixture is extracted with ethyl acetate (1 l). The organic phase is washed three times with water (100 ml) and saline (100 ml), dried over magnesium sulfate, and the solvent is removed under reduced pressure to give the title compound as a 1:4 mixture of the anti and syn isomers as determined by NMR, MS (m/z, CI+NH3) 246 (M+ +17), 228 (M+), 210, 194; "Anti" NMR (500 MHz, CDCl3) 7.60-7.50, 5.33, 4.64, 4.33, 1.33 δ; CMR (300 MHz, CDCl3) 167.9, 138.2, 128.7, 128.5, 126.7, 74.6, 62.9, 62.2 and 13.7 δ; "Syn" NMR (500 MHz, CDCl3) 7.60-7.50, 5.24, 4.58, 4.44 and 1.46 δ; CMR (300 MHz, CDCl3) 168.9, 138.8, 126.7, 126.5, 126.9, 75.2, 62.3, 59.2 and 13.8 δ.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5]([S-:15])=[N:6][S:7][C:8]=1[NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:3].I[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:13]([O:12][C:10](=[O:11])[NH:9][C:8]1[S:7][N:6]=[C:5]([S:15][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=1[C:2]#[N:3])[CH3:14]
Reactant: CCOC(=O)Nc1snc([S-])c1C#N
Reactant: CCCCCI
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
A mixture of sodium, 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0 g, 20 mmol), 1-iodopentane (4.0 g, 20 mmol) and tetrahydrofuran (20 mL) was stirred at ambient temperature for 16 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel using 1:1 ethyl acetate-hexane as eluent. The filtrated was concentrated and the residue was recrystallized from cold aqueous methanol, affording 2.5 g (42%) (4-cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester as a colorless solid. An additional 0.5 g (8.4%) was obtained by concentration of the mother liquor and purification by radial chromatography (4 mm plate, 4:1 hexane-ethyl acetate). 1H NMR (400 MHz, acetone-d6) δ 11.1 (bs, 1 H), 4.32 (q, 2H, J=7.2 Hz), 3.21 (t, 2H, J=7.2 Hz), 1.73 (p, 2H, J=6.8 Hz), 1.44-1.28 (m, 7H), 0.90 (t, 3H, J=7.6 Hz) ppm; MS (APCl, m/z): 312 [M+Na]30 .
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+]>C(Cl)(Cl)Cl.CO.CN1CCCC1=O>[CH:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
4-Chloro-2-fluoronitrobenzene (300 mg, 1.71 mmol), Pb2(dba)3 (236 mg, 0.228 mmol), tributyl (vinyl) tin (333 mg, 1.14 mmol), tri-2-furylphosphine (212 mg, 0.912 mmol) and lithium chloride (193 mg, 4.56 mmol) were added to methylpyrrolidinone (5 ml), and the mixture was stirred in a sealed tube at 120° C. for one hour. The mixture was diluted with chloroform-methanol, and filtered through a Celite Pad. After concentrating the filtrate, the concentrate was dissolved in ethyl acetate and washed with aqueous potassium fluoride. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified by thin-layer silica gel chromatography (hexane-ethyl acetate, 5:1) to give the title compound (146 mg) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[C:5]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[C:5]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c(-c2ccc(C)cc2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(O)ccc2C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
To a solution of 1-{4-[4-methoxy-2-(4-methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (380 mg) in dichloromethane (15 ml) at -78° C. was added a solution of 1.0M boron tribromide in dichloromethane (2.4 ml). The resulting solution was allowed to warm to ambient temperature where it was maintained for 12 hours. The mixture was cooled to 0° C., and added water. The organic layer was washed with saturated sodium bicarbonate aqueous solution and filtered through a bed of celite, and concentrated. The residue was triturated with diethyl ether to give 1-{4-[4-hydroxy-2-(4-methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (30 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([C:10](=[CH:16]N(C)C)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:23]([NH2:31])(=[NH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:31]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:30]=2)=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])cc1
Yield: 86.5 %

Procedure:
A mixture of ethyl 2-(4-nitrobenzoyl)-3-dimethylaminopropenoate (3 g), benzamidine hydrochloride (1.93 g) and triethylamine (2 ml) in n-butyl alcohol (30 ml) was refluxed for 30 min. The reaction mixture was poured into water (300 ml) and the precipitate was collected by filtration. The residue was recrystallized with diethyl ether to afford ethyl 4-(4-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (3.1 g).