Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=1[NH2:10])(=[O:3])[CH3:2].[CH2:15](OC(OCCCC)N(C)C)CCC>CN(C=O)C>[OH:3][C:1]1[C:4]2[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=2[N:10]=[CH:15][CH:2]=1
Reactant: CCCCOC(OCCCC)N(C)C
Reactant: CC(=O)c1c(N)n(C)c(=O)n(C)c1=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(O)ccnc2n(C)c1=O
Temperature: 80 °C
Yield: 70.2 %

Procedure:
0.8 g of 5-acetyl-6-amino-1,3-dimethyluracil was dissolved in DMF and 4 ml of dimethylformamide dibutylacetal was added thereto. The solution was heated for 8 hr at 80° C. and distilled under reduced pressure. After purification by silica gel column chromatography, the crude product was recrystallized from ethanol to give 0.59 g of 5-hydroxy1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 14).
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[V]>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [V]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 85 °C

Procedure:
Vanadium pentoxide (V2O5) (229 g) was added to water (500 mL), to thereby yield a mixture, and an aliquot of oxalic acid (477 g) was added to the mixture with stirring at 80-90° C. so as to dissolve the vanadium compound, to thereby yield a solution of vanadium oxalate. Another aliquot of oxalic acid (963 g) was added to water (400 mL), and the resultant mixture was heated to 50-60° C. To the mixture, a solution of chromic anhydride (CrO3) (252 g) in water (200 mL) was added under sufficient stirring so as to dissolve the components, to thereby yield a solution of chromium oxalate. The thus-yielded solutions were mixed at 50-60° C., to thereby prepare a V-Cr-containing solution. To the V-Cr-containing solution were added a solution of phosphomolybdic acid (H3(PMo12O40).20H2O) (41.1 g) dissolved in water (100 mL), and a solution of potassium acetate (CH3COOK) (4.0 g) dissolved in water (100 mL). Subsequently, a 20 wt. % aqueous silica sol (containing Na2O (0.02 wt. %)) (2,500 g) was added, to thereby form a slurry.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=[O:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(CCN)=CC=1)(OC)=O.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[NH2:47])=[CH:41][CH:40]=1)([O:37][CH3:38])=[O:36]>>[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([NH:47][CH2:17][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=2)[OH:16])[CH3:48])=[CH:41][CH:40]=1)([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: O=CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared as a mixture of diastereoisomers by the process of Example 25, replacing phenyl glyoxal by 4-benzyloxy-3-nitrophenyl glyoxal and 2-(4-carbomethoxyphenyl)ethanamine by 2-(4-carbomethoxyphenyl)-1-methylethanamine. τ (CDCl3) 8.93 (3H, d, J=6 Hz), 6.70-7.80 (7H, m), 6.14 (3H, s), 5.40 (1H, m), 4.81 (2H, s), 2.30-3.10 (10H, m), 2.02 (2H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[C:33]([CH2:32][C:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:34]
Reactant: CCOC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (0.28 g, 1.00 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (1.00 mL, 1.00 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (0.69 mL, 1.00 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes), to obtain the title compound. MS (DCI+) m/z 333 (M+NH4)+.
Reaction SMILES: [CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[N:9]1)[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[N:9]1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:5]
Reactant: NOC1CCCCO1
Reactant: Cc1nn(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (129 mg, 0.38 mmol, 1 eq) in anhydrous DCM (7 mL) was added DIPEA (140 uL, 0.804 mmol, 2.1 eq), followed by HOBt (120 mg, 0.784 mmol, 2.05 eq) and the solution was stirred at RT for 30 minutes. The mixture was then treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (70 mg, 0.60 mmol, 1.6 eq) followed by EDCI (110 mg, 0.574 mmol, 1.5 eq) and the reaction was allowed to stir at RT. The reaction mixture was concentrated in vacuo to give a crude white solid. The crude mixture was purified via flash chromatography using an Analogix SF15-12 g silica column eluting with ethyl acetate in heptane (0-80%) to give (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (110 mg, 66% yield). LC-MS M+H+436.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][N:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CN1C(=O)CCC1.CO>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccncn3)cc(Cl)nn12
Solvent: CN1CCCC1=O
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccncn3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 120 °C

Procedure:
A solution of 6-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 0.033 mmol) in NMP (1 mL) was treated with (trans)-cyclohexane-1,4-diamine (37.4 mg, 0.327 mmol) and heated to 120° C. for 4 hours. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=19.202 minutes) was isolated and lyophilized to dryness to afford 6-((trans-4-aminocyclohexyl)amino)-N-4-pyridinyl-8-(4-pyrimidinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.1 mg, 8.59%). 1H NMR (500 MHz, DMSO) δ ppm 8.87 (1H, s), 8.65-8.74 (3H, m), 8.51 (1H, d, J=10.45 Hz), 8.25 (2H, d, J=6.60 Hz), 8.21 (2H, s), 7.25 (1H, d, J=6.05 Hz), 3.82-3.93 (1H, m), 3.16-3.24 (1H, m), 2.39 (2H, d, J=14.57 Hz), 2.11-2.22 (3H, m), 1.45-1.68 (4H, m). HPLC Rt=1.888 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=445.0.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][C@@H:8]([C@@H:15]1[C@@:19]2([CH3:37])[CH2:20][CH2:21][CH:22]3[C@@:27]4([CH3:36])[CH2:28][CH2:29][CH:30]([O:32][C:33](Cl)=[O:34])[CH2:31][C:26]4=[CH:25][CH2:24][CH:23]3[CH:18]2[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:33]([O:32][C@H:30]1[CH2:29][CH2:28][C@@:27]2([CH3:36])[C:26](=[CH:25][CH2:24][C@@H:23]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:37])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:8]([CH3:7])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:31]1)=[O:34]
Reactant: NCC(O)CO
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(O)CO)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3-Amino-1,2-propanediol (2.0 g, 22.0 mmoles) is coevaporated twice with dry pyridine (50 mL each) then dissolved in dry pyridine (147 mL). The solution is stirred in an ice bath, and a solution of cholesteryl chloroformate (10.4 g, 23.1 mmoles) in toluene (50 mL) is added dropwise over 30 minutes. After addition, the ice bath is removed and the reaction mixture is stirred at ambient temperature for 16 hours. The solution is then evaporated, and the residue is coevaporated twice with toluene (50 mL each). The crude product is purified on silica gel (300 mL bed volume) eluting with hexanes:acetone (90:10 [v/v], 1000 mL; then 85:15 [v/v], 1000 mL; then 70:30 [v/v], 1000 mL; then 65:35 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to syrup which is dried well in vacuo. The yield is 5.7 g (51%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: COC(=O)c1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of 2-iodo-benzoic acid methyl ester (792 mg, 3.02 mmol) in DMF (10 mL) are added trimethylsilylacetylene (854 μL, 6.04 mmol) and triethylamine (2.95 mL, 21.1 mmol). The reaction mixture is degassed for 20 minutes with a stream of nitrogen. Dichloro(bistriphenylphosphene) palladium (II) (212 mg, 0.302 mmol, 10 mol %) and copper (I) iodide (58 mg, 0.302 mmol, 10 mol %) are added and the reaction is heated to 80° C. After 3 h, the reaction is concentrated and the residue is chromatographed eluting with 0 to 5% EtOAc/Hexanes to yield the title compound (597 mg, 85%). GC/MS: 232.
Reaction SMILES: ClCCl.[C:4]([OH:8])(=[O:7])[CH2:5]O.[Cl:9][C:10]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[C:11]=1[O:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH3:26])[C:18](=[O:25])[C:19]([CH3:24])([C:21]([OH:23])=[O:22])[O:20][C:15]=2[CH:14]=1>C(N(CC)CC)C>[Cl:9][C:10]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([F:37])[C:11]=1[O:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH3:26])[C:18](=[O:25])[C:19]([CH3:24])([C:21]([O:23][CH2:5][C:4]([OH:8])=[O:7])=[O:22])[O:20][C:15]=2[CH:14]=1
Reactant: O=C(O)CO
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C)(C(=O)OCC(=O)O)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane solution (20 ml) of glycolic acid (0.3 g) and triethylamine (1.0 ml) was added an acid chloride (1.5 g) prepared as in Example 6 from 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 25), and the mixture was stirred at room temperature for one hour. The reaction mixture was then concentrated under a reduced pressure, the residue was extracted twice with ethyl acetate (20 ml), and the extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate, followed by evaporation of the solvent under a reduced pressure to obtain carboxymethyl 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate. The acid was dissolved in benzene (20 ml), thionyl chloride (0.9 g) was added thereto, and the mixture was heated under reflux for 3 hours. Then after an evaporation of the solvent under a reduced pressure, the residue was dissolved in dichloromethane (20 ml), ethylamine hydrochloride (0.6 g) and triethylamine (2 ml) were added thereto, and the mixture was stirred for one hour. The reaction mixture was then concentrated under a reduced pressure, and the residue was extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate, followed by an evaporation of the solvent under a reduced pressure. The residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.5 g of the title compound (colorless oil).
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:22]([O:27]C)([O:25][CH3:26])(=[O:24])=[O:23].[CH3:29]OS([O-])(=O)=O>>[CH3:26][O:25][S:22]([O-:27])(=[O:24])=[O:23].[C:7]([CH:6]([N+:1]1([CH3:29])[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)#[N:8]
Reactant: COS(=O)(=O)OC
Reactant: N#CC(c1cccc(Oc2ccccc2)c1)N1CCCC1
Agent: COS(=O)(=O)[O-]
Product: C[N+]1(C(C#N)c2cccc(Oc3ccccc3)c2)CCCC1

Procedure:
N-(α-Cyano-3-phenoxybenzyl)-N-methylpyrrolidinium methylsulfate (5) was prepared from α-(1-pyrrolidinyl)-3-phenoxybenzeneacetonitrile (Example 3) and dimethyl sulfate following essentially the same procedure as that described in Example 2. The product was obtained as a yellow oil. Proton magnetic resonance spectrum (CDCl3 ; ε in ppm): 2.4 (4H, m, pyrrolidine ring β-protons); 3.2 (4H, m, pyrrolidine ring α-protons); 3.2-3.8 (6H, m, N--CH3 and CH3SO4); 6.8 (1H, s, CH); 7.0-7.7 (9H, m, aromatic protons).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:14]1([NH:13][CH2:1][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
Methyl 4-formylbenzoate (1 g, 6 mmol) and aniline (837 mg, 9 mmol) were dissolved in methanol (30 mL). The mixture was heated to 50° C., and acetic acid (two or three drop) was added to the reaction mixture. The resultant mixture was stirred at 50° C. for 1 hour. After the mixture was cooled to room temperature, sodium cyanoborohydride (1.13 g, 18 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to give methyl 4-((phenylamino)methyl)benzoate (0.8 g, 55%). LRMS (M+H+) m/z: cald. 241.08. found 241. LRMS (M+H+) m/z: calcd 241.08. found 241. 1H NMR (300 MHz, CD3OD): δ 7.95 (dd, J=7.2 Hz, J=2.1 Hz, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.05 (t, J=6.0 Hz, 2H), 6.60-6.56 (m, 3H), 4.37 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[NH3:18]>>[NH2:18][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Reactant: N
Product: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5-amino-2′-deoxyuridine was prepared from 5-bromo-2′-deoxyuridine according to the procedure of Roberts and Visser, J. Am. Chem. Soc. 14:665–669 (1952). 5-bromo-2′-deoxyuridine (2 g, 6.2 mmol) dissolved in liquid ammonia (20 ml) was scaled in a glass tube and heated at 50° for 5 days. The tube was opened, and the ammonia was evaporated. 5-amino-2′-deoxyuridine was recrystallized from 5 ml water and 75 ml hot isopropyl alcohol.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11](Cl)=[O:12])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:38]=[CH:37][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[CH:30]([OH:33])[C:31]#[N:32])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH:7]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11]([O:33][CH:30]([C:31]#[N:32])[C:29]2[CH:34]=[CH:35][CH:36]=[C:27]([O:26][C:25]3[CH:37]=[CH:38][C:22]([F:21])=[CH:23][CH:24]=3)[CH:28]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: N#CC(O)c1cccc(Oc2ccc(F)cc2)c1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC(OC(=O)C(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccc(F)cc2)c1

Procedure:
With stirring, 1 g of pyridine in 3 ml of toluene and 2.3 g of α-cyclopropyl-4-chlorophenylacetyl chloride in 3 ml of toluene are added successively at 0° to 10° C. to a solution of 2.43 g of 3-(4-fluorophenoxy)-α-cyanobenzyl alcohol in 20 ml of toluene. After stirring for 10 hours at room temperature, the reaction mixture is washed with water, 2 N hydrochloric acid and 3% sodium bicarbonate solution. The organic layer is dried over sodium sulfate and the toluene is distilled off, affording the compound of the formula ##STR4## with a refractive index of nD20 =1.5880.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16]C)=[O:15])[CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=[C:2]2[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[CH3:18]
Reactant: COC(=O)c1cc(Cl)c2cccc(OC)c2n1
Reactant: Cc1ccccc1CN
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc2c(NCc3ccccc3C)cc(C(=O)O)nc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A mixture of 54 g (=215 mmol) of methyl 4-chloro-8-methoxyquinoline-2-carboxylate, 33.7 g (=278 mmol) of 2-methylbenzylamine and 243 g (=2.58 mmol) of phenol was heated at 140° C. in an autoclave for 4 hours. The cooled reaction mixture was added dropwise to 4 1 of ethyl acetate, and the resulting precipitate was filtered off with suction. The solid was dissolved in 1 1 of THF and the pH was adjusted to 10 with 10% NaOH. The mixture was stirred at 50° C. for 1 hour, maintaining the pH constant, cooled to 10° C. and adjusted to pH 5-6 with dilute HCl. This resulted in the product crystallizing. 18.85 g of 8-methoxy-4-(2-methylbenzylamino)quinoline-2-carboxylic acid of melting point 276-277° C. were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH2:7]([CH:9]1[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:13]2[CH2:12][CH2:11][N:10]1[C:19](OC1C=CC=CC=1)=[O:20])[CH3:8]>O1CCCC1>[CH2:7]([CH:9]1[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:13]2[CH2:12][CH2:11][N:10]1[C:19]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:20])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCC1c2nccnc2CCN1C(=O)Oc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1c2nccnc2CCN1C(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (11.0M in tetrahydrofuran, 0.7 mL, 0.7 mmol) was added over 3 min to a solution of phenyl 5-ethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate (91 mg, 0.32 mmol) in tetrahydrofuran (1.8 mL) cooled in a −20 to −30° C. bath. After 30 min, the bath was removed and stirring was continued for 75 min. The mixture was added to saturated aqueous sodium bicarbonate solution (10 mL) which was then extracted with two portions of ethyl acetate (35 mL and 15 mL). The organic layers were washed in succession with saturated aqueous brine (10 mL), dried over sodium sulfate, decanted, and evaporated. Purification by flash column chromatography (silica gel, 15% ethyl acetate/hexanes) gave the title compound as a colorless oil. 1H NMR (500 MHz, CD3OD) δ 8.43 (d, 1H, J=2 Hz), 8.40 (d, 1H, J=2 Hz), 5.17-5.02 (bm, 1H), 4.40-4.25 (bm, 1H), 3.37-3.20 (bm, 1H), 3.04 (ddd, 1H, J=17, 12, 6 Hz), 2.90 (dd, 1H, J=17, 4 Hz), 2.10-2.00 (m, 1H), 1.87-1.76 (m, 1H), 1.49 (s, 9H), 1.04 (bt, 3H). LC/MS 208 (M+1-56).
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([O:38]C)=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1.CO>O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([OH:38])=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(CN(C(=O)CC(C)(C)C)[C@H]2C[C@@H](C(=O)O)N(Cc3ccc4c(c3)OCO4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Lithium hydroxide monohydrate (17 mg, 0.405 mmol) was added to a solution of methyl(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (20) (100 mg, 0.20 mmol) in 66% v/v methanol in water (1.0 mL). The mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure and the residue partitioned between dichloromethane (1.0 mL) and water (1.0 ml). The aqueous phase was acidified with 1.0 M aqueous citric acid solution and the two layers were vigorously stirred for 10 min at room temperature. The layers were separated and the aqueous layer was back-extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane/ethyl acetate (1:1, v/v) and then dichloromethane/methanol (9:1, v/v) as eluents to give the title acid (21) (88 mg, 91%) as an off-white solid:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11]
Reactant: CNC(Cc1ccccc1N)c1ccsc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Br)ccc1N)c1ccsc1C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A stirred solution of 3.0 g of 2-amino-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine in 50 ml of N,N-dimethylformamide was treated with a solution of 2.6 g of N-bromosuccinimide in 50 ml of N,N-dimethylformamide and allowed to stand overnight at room temperature. Evaporation of the volatiles afforded an oil :which was purified by HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). The resultant oil was dissolved in diethyl ether, filtered and concentrated. Trituration with diethyl ether afforded 1.2 g of 2-amino-5-bromo-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine, mp 72.5°-74° C.