Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH2:12])[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOc1ccccc1CCN
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCNC(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
2-(2-Ethoxyphenyl)ethanamine (0.55 g, 3.33 mmol) and 3-(4-hydroxyphenyl)propanoic acid (0.50 g, 3.00 mmol) was dissolved in dimethyl formamide (5 ml) and cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (1.18 g, 3.66 mmol) and diisopropylethylamine (0.90 g, 7.0 mmol) were added and the solution was warmed to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). The organic phase was dried (MgSO4) and EtOAc was removed by evaporation to give 0.98 gram of N-[2-(2-ethoxyphenyl)ethyl]-3-(4-hydroxyphenyl)propanamide (yield 93.9%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CCC.IC1C=NNC=1>>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]=1[CH3:7]
Reactant: CCCCCCCCBr
Reactant: Cc1n[nH]c(C)c1Br
Agent: Ic1cn[nH]c1
Product: CCCCCn1nc(C)c(Br)c1C

Procedure:
The desired product was prepared by substituting 5-iodopentane and 4-bromo-3,5-dimethylpyrazole for 1-bromooctane and 4-iodopyrazole, respectively, in Example 198A. MS (ESI(+)) m/e 245, 247 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:32](OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH3:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)OC(C)C
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Product: CC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 312, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde. Crystals (diisopropyl ether).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([C:51]1[S:52][CH:53]=[C:54](/[CH:56]=[CH:57]/[C:58](O)=[O:59])[N:55]=1)[CH:43]=[CH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.N>C(Cl)Cl.CO>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:17][C:58](=[O:59])/[CH:57]=[CH:56]/[C:54]1[N:55]=[C:51]([CH2:42][CH:43]=[CH:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[S:52][CH:53]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)/C=C/c1csc(CC=Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)/C=C/c1csc(CC=Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
DIPEA (0.21 g, 0.54 mmol), o-phenylene diamine (39 mg, 0.36 mmol) and HATU (89 mg, 0.23 mmol) were added to a solution of (E)-3-(2-cinnamylthiazol-4-yl)acrylic acid (50 mg, 0.18 mmol) in DCM (20 mL) and the reaction mixture was stirred overnight at room temperature under nitrogen. After completion of the reaction as indicated by HPLC, the reaction mixture was washed with saturated NaHCO3 and brine. The organic layer was then dried (Na2SO4) and evaporated to give the crude product. Repeated silica gel column chromatography using a 0-10% gradient of MeOH, containing 0.1% NH3 in DCM gave pure (E)-N-(2-aminophenyl)-3-(2-cinnamylthiazol-4-yl)acrylamide (26 mg) as a tan-colored solid. ES+ (M+H)+362. 1H NMR (CD3OD) δ: 7.66 (s, 1H), 7.60 (d, J=15.4 Hz, 1H), 7.39-7.45 (m, 2H), 7.27-7.35 (m, 2H), 7.20 (dd, J=8.0, 1.4 Hz, 1H), 7.17-7.26 (m, 1H), 7.04 (ddd, J=8.0, 7.7, 1.4 Hz, 1H), 7.05 (d, J=15.3 Hz, 1H), 6.87 (dd, J=8.0, 1.4 Hz, 1H), 6.74 (td, J=7.7, 1.4 Hz, 1H), 6.66 (dt, J=15.9, 1.1 Hz, 1H), 6.47 (dt, J=15.9, 6.9 Hz, 1H), 3.95 (dd, J=6.9, 1.1 Hz, 2H)
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH3:12][NH:13][OH:14]>>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([N:13]([OH:14])[CH3:12])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: CNO
Reactant: C=CCC1C(=O)C=CC1(C)O
Product: C=CCC1=C(C)C(N(C)O)CC1=O
Reaction time: 1 h
Yield: 91.2 %

Procedure:
2-Allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added to a 25% aqueous solution of N-methylhydroxylamine (30 g) in the same flask as used in Example 1 at a temperature of 15° to 25° C. for 1 hour. At the same temperature, the reaction mixture was kept for 2 hours. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 5 to obtain 2-allyl-3-methyl-4-(N-hydroxy-N-methylamino)-2-cyclopentenone (16.5 g). Yield, 91%. nD20 1.5102.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[S-:13][C:14]#[N:15].[K+].BrBr.O>CO.[Br-].[K+]>[CH:1]([C:4]1[C:12]([S:13][C:14]#[N:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1nn2ccccc2c1SC#N
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution of 3 g of 2-isopropylpyrazolo[1,5-a]pyridine in 56 ml of methanol was added 5.74 g of potassium thiocyanate and stirred at room temperature. 3.3 g of bromine was dissolved in 13 ml of methanol saturated with potassium bromide and added dropwise to the previous solution. Then, the mixture was stirred at room temperature for an hour, poured into 130 ml of water and resulting precipitate was filtered and dried. This crude precipitate was recrystallized from methanol to give 3.53 g (yield 87%) of the aimed compound as pale yellow prismatic crystals. mp 91°-92.5° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:33])[CH2:28][C:29](=O)[CH2:30]Br)[C:24](=[O:34])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11]>O1CCCC1.O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:33])[CH2:28][C:29]3[N:1]=[C:2]([NH2:4])[S:3][CH:30]=3)[C:24](=[O:34])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11]
Reactant: NC(N)=S
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of thiourea (0.103 g.) and sodium bicarbonate (0.11 g.) in a mixture of tetrahydrofuran (1.3 ml.) and water (1.3 ml.) was gradually added 3-carbamoyloxymethyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (0.55 g.) with stirring at room temperature, and then the resulting solution was stirred for 40 minutes at room temperature. After the reaction, the precipitated crystals were collected by filtration with suction, washed with water, tetrahydrofuran and water in turn, and then dried over phosphorus pentoxide to give 3-carbamoyloxymethyl-7-(2-aminothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (0.48 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]=O.Cl>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[CH2:15][O:13][C:12](=[O:14])[CH2:11]2
Reactant: C=O
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)OC2
Temperature: 120 °C

Procedure:
Heat at 120° C. for 1 hour a mixture of 19.6 g (100 mmol) of 3,4-dimethoxyphenyl acetic acid (VII), 7.4 g (246 mmol) of paraformaldehyde and 20 ml of concentrated HCl in 100 ml of AcOH. Evaporate to dryness. Add 100 ml of H2O, and extract three times with 200 ml of CH2Cl2. Wash the organic phases with 50 ml of 0.5 N NaHCO3 and dry on Na2SO4. Evaporate to dryness. Allow to crystallize for 2 hours in 50 ml of Et2O.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[CH:5]=[C:6]([CH:10](Cl)[CH3:11])[C:7]=1[O:8][CH3:9].[CH3:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[NH:18][N:17]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]([N:18]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([NH2:25])=[C:24]3[C:16]([CH3:15])=[N:17]2)[CH3:11])[CH:5]=[C:4]([Cl:13])[C:3]=1[CH3:14]
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 140 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg, 0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol, ACES Pharma Product List, item #47024), potassium iodide (9.0 mg, 0.05 mmol) and cesium carbonate (330 mg, 1.0 mmol) in N,N-dimethylformamide (4 mL) and was stirred at 140° C. for 1 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2, to give the desired product (103 mg, 50%). LCMS calculated for C16H18BrClN5O (M+H)+: m/z=410.0; Found: 410.2. The racemic products were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size), eluting with 5% ethanol in hexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide two enantiomers. Peak 1, retention time: 12.35 min; Peak 2, retention time: 14.98 min,
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]([CH3:18])=[CH:16][C:11]2[C:12](=[O:15])[O:13][CH2:14][C:10]=2[CH:9]=1)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH:7]([C:8]1[C:17]([CH3:18])=[CH:16][C:11]2[C:12](=[O:15])[O:13][CH2:14][C:10]=2[CH:9]=1)=[CH2:6]
Reactant: Cc1cc2c(cc1CCOS(C)(=O)=O)COC2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=Cc1cc2c(cc1C)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl methanesulfonate (2.0 g, 7.4 mmol) and TEA (5 mL) in DCM (50 mL) was added DBU (5 mL) slowly at 0° C. The mixture was stirred at r.t. overnight, and then diluted with 50 mL of DCM, washed with 2 N HCl in three times and brine. The organic layer was dried and concentrated to dryness. The residue was purified by prep-TLC to give 5-ethenyl-6-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](C(OCC)C)[N:9]=[C:10]([CH2:11][CH3:12])[C:3]=12.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.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.O>[CH2:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:20]2[CH:19]=[N:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:8][N:9]=1)[CH3:12]
Reactant: CCOC(C)n1nc(CC)c2c(Cl)ccnc21
Reactant: OB(O)c1cnc2ccccc2c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCc1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 85 °C
Reaction time: 25 h
Yield: 29 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.69 g) was added to a solution of compound (3d) (3.01 g), quinoline-3-boronic acid (2.67 g), and an aqueous sodium carbonate solution (2 M, 23 mL) in ethylene glycol dimethyl ether (30 mL) under a nitrogen atmosphere, followed by stirring at 85° C. for 25 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, 1,4-dioxane (23 mL) and 6 N hydrochloric acid (23 mL) were added to the residue, and the resulting mixture was stirred at room temperature for 90 min. The pH was adjusted to 7 with an aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (3e) (0.942 g, the second stage yield: 29%) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1
Reactant: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(CCl)ccn2)s1

Procedure:
2-(4-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.883 g, 3.80 mmol) was stirred in anhydrous CH2Cl2 (12 mL) under N2. Dimethylformamide (0.354 mL, 3.80 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.294 mL, 3.80 mmol). After 4 hours the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([O:46][CH3:47])[N:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CCl)n1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1cccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)n1
Yield: 48.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 6-chloromethyl-2-methoxypyridine (0.47 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.CC(O)=O>COCCO.[Pd]>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc(N)c3)n2)s1
Reaction time: 0.17 h

Procedure:
To a mixture of {4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-(3-nitro-phenyl)-amine (3.97 mmol, 1.3 g) in 2-methoxyethanol (15 mL) was added AcOH (1 mL). The reaction mixture was stirred under N2 for 10 min. Palladium catalyst (660 mg; 10% on activated carbon) was the added and the reaction mixture was allowed to stir under H2 for 18 h. The reaction mixture was passed through Celite 521 and the precipitates were washed several times with MeOH. The filtrate was concentrated and recrystallised from MeOH/EtOAc to afford grey crystals of N-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,3-diamine. An aliquot of this material (500 mg) in 2-methoxylethanol was cooled on an ice bath and was treated with HCl (conc. 1 mL). Cyanamide (50% aq soln., 4 mL) was added dropwise. After completion of the addition the reaction mixture was warmed to r.t. and heated at reflux for 20 h. The reaction mixture was concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic phase was evaporated and purified by chromatography, using EtOAc/MeOH (3:1, v/v) to elute the title compound. DE MALDI-TOF MS: {M+H}+=339.16 (C16H17N7S requires 339.42).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CN)C(N)=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Boc-Gly-Pro-Nleu-NH2 (3.5 g, 0.0089 mol.) was dissolved in a solution of 30% TFA in DCM (50 ml). The solution was stirred for 40 minutes. The DCM and TFA were removed under reduced pressure, and 3×50 ml benzene were added and distilled under reduced pressure to remove trace TFA. The resulting mixture was dissolved in 30 ml methanol and the solution was chilled to 0° C. HCl/dioxane (4N, 10 ml) was added to the solution to transfer the product from TFA salt to HCl salt. Ethyl ether (200 ml) was added to the solution and a precipitation formed. The ether was removed by filtration and a white solid product was obtained (2.9 g, 87%). Analytical RP-HPLC chromatogram, single peak, RT=15.7 min. (5-15% B in 30 min.). FAB-MS, observed (M+H)+ =285. 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ 8.03 (m, 3H, Gly-NH3), 7.65 (s, C-terminal NH2), 7.46 (s, C-terminal NH2), 7.34 (s, C-terminal NH2), 7.24 (d, C-terminal NH2), 7.08 (s, C-terminal NH2), 6.92 (s, C-terminal NH2), 4.94 (d, Pro-α), 4.76 (m, Pro-α), 4.59 (m, Pro-α), 4.25-3.52 (sets of bands, Nleu-α, Gly-α), 3.52-3.44 (m, Pro-δ), 3.42-2.70 (sets of bands, Gly-α, Nleu-β), 2.36-1.65 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 0.90 (m, Nleu-δ), 0.79 (m, Nleu-δ).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.Cl.[N:15]([O-])=[O:16].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:15]=[O:16]
Reactant: CC(C)Cn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 44.7 g (0.24 mol) of 6-amino-1-(2-methylpropyl)-2,4-(1H,3H)-pyrimidinedione (XIV), dissolved in 2 l hot water, was added 50 ml of 5 N HCl and 17 g of NaNO2 (0.25 mol) which were dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 44.6 g (95%) (XV), NMR.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C@@H:14]([NH:16][S@@](C(C)(C)C)=O)[CH3:15])[CH:10]=2)=[CH:5][CH:4]=1>O1CCOCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C@@H:14]([NH2:16])[CH3:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cc(-c2ccc(Cl)cc2)on1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cc(-c2ccc(Cl)cc2)on1
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A solution of hydrochloric acid (4.0 M in 1,4-dioxane, 2.1 mL, 8.2 mmol, 2 equiv) was added to a solution of (R)—N—((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.34 g, 4.1 mmol) in 1,4-dioxane at room temperature. A precipitate formed. The suspension was stirred for 1 hour and then concentrated in vacuo to give the hydrochloride salt of (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (1.1 g, light yellow solid), which was used without purification. 1H NMR (400 MHz, CD3OD) δ 7.87 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 4.72 (q, J=6.9 Hz, 1H), 1.72 (d, J=7.0 Hz, 3H). MS m/z 223.1 (M+H)+; Rt-0.59 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][N:11]1[C:15](=[O:16])[C:14]([CH2:17][Cl:18])=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:12]1>>[CH3:10][N:11]1[C:15](=[O:16])[C:14]([CH2:17][Cl:18])=[C:13]([C:19]2[CH:24]=[CH:23][C:22]([N+:1]([O-:4])=[O:2])=[CH:21][CH:20]=2)[O:12]1
Reactant: Cn1oc(-c2ccccc2)c(CCl)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1oc(-c2ccc([N+](=O)[O-])cc2)c(CCl)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
After cooling 76 ml of concentrated nitric acid (specific gravity 1.42) to 0° C., 80 ml of concentrated sulfuric acid was gradually added thereto and further 9 g of 2-methyl-4 chloromethyl-5-phenyl-3-isooxazolone was added thereto as crystals thereof while keeping the temperature thereof below 5° C. The resultant mixture was stirred for 30 minutes at 5° C. and poured into 2 liters of ice water followed by stirring for one hour to deposit crystals, which were collected by filtration and dried to provide 9.4 g of the desired product. The yield was 87%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:38](=[O:40])[CH3:39])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(C)=O)CC4)nc12
Yield: 74 %

Procedure:
To a suspension of 0.037 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.007 ml acetylchloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.028 g (74%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-ethanone as yellow solid; M.p.: 195–197° C.; MS (ISP): m/e=428 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[C:17][Si](C)(C)C)[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[CH:17])[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:14])[CH3:15])[CH3:2]
Reactant: CCc1cc(C#C[Si](C)(C)C)cc2c1C(=O)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(CC)c2c(c1)C(C)(C)CCC2=O

Procedure:
Following General Procedure F and using 8-ethyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 179, 0.66 g, 2.2 mmol), methanol (10 mL) and potassium carbonate (0.4 g, 2.9 mmol) the title compound was obtained as an orange oil (0.59 g, 100%).