Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:28][C@@H:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][N:24]=2)[CH3:27])=[O:10])=[CH:5][CH:6]=1
Reactant: COc1ccc([C@@H](C)N)nc1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
To a mixture of 4-biphenylacetic acid (2.00 g, 9.42 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethanamine hydrochloride (1.96 g, 10.36 mmol), 1-hydroxy-7-azabenzotriazole (1.70 g, 12.49 mmol) and diisopropyl-ethyl amine (5.20 ml, 31.46 mmol) in DMF (55 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.40 g, 12.52 mmol) at room temperature. The reaction was stirred for 18 hours and then washed with saturated sodium bicarbonate solution and brine. Organics were extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (0-80% EtOAc/Hex) afforded 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H); 7.58 (m, 4H); 7.44 (m, 2H); 7.34 (m, 3H); 7.14 (m, 2H); 6.78 (d, J=6.80 Hz, 1H); 5.10 (m, 1H); 3.83 (s, 3H); 3.63 (s, 2H); 1.41 (d, J=6.80 Hz, 3H). MS (Electrospray): m/z 347.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]([F:15])=[C:12]([F:14])[F:13].[OH-].[K+].CN(C)C=O>O.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([O:8][C:12]([F:14])([F:13])[CH:11]([F:15])[Cl:10])[N:7]=1
Reactant: Cc1cc(O)nc(N)n1
Reactant: FC(F)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OC(F)(F)C(F)Cl)nc(N)n1
Yield: 18 %

Procedure:
25 g of 2-amino-4-hydroxy-6-methyl-pyrimidine, 25.6 g of chlorotrifluoroethylene, 13.8 g of potassium hydroxide and 200 ml of dimethylformamide are stirred together at 60° in an autoclave for 8 hours. The mixture is diluted with water and extracted with ethyl acetate and the extract is evaporated to give a dark oil. A little methylene chloride is added and the crystalline precipitate formed is separated off to give 8.7 g of 2-amino-4-methyl-6-(1,1,2-trifluoro-2-chloro-ethoxy)-pyrimidine of melting point 73°-74° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@@H:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:18]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])=[CH:35][CH:34]=2)[C@@H:17]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]3[O:57][CH2:56][CH2:55][N:54]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])[C:53]=3[CH:63]=2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1CCCN(C)C1=O.COC(C)(C)C>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@H:17]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]3[O:57][CH2:56][CH2:55][N:54]([CH2:58][CH2:59][CH2:60][O:61][CH3:62])[C:53]=3[CH:63]=2)[C@@H:18]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])=[CH:35][CH:34]=2)[C@H:19]([CH2:21][N:1]=[N+:2]=[N-:3])[CH2:20]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN=[N+]=[N-])[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
31.265 mmol of sodium azide are added to a solution of 6.253 mmol of (3R,4R,5S)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl) -piperidine-1-carboxylic acid benzyl ester in 50 ml of 1,3-dimethyl-tetrahydro -pyrimidin-2-one (DMPU) under argon at 45° C. After 5 hours, the reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulfate and evaporated. The crude title compound is obtained as a yellow oil. Rf=0.58 (EtOAc-heptane 2:1); Rt=5.96 (gradient I).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.[C:28]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH3:31])=[O:29]>CO>[CH3:31][O:30][C:28]([CH:32]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)=[O:29]
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.2 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.77 g) is dissolved in methanol (100 ml) and thereto is added carbomethoxymethylenetriphenylphosphorane (5.3 g) and the mixture is stirred at room temperature for 1 hour. The solvent is concentrated and the residue is purified roughly by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give a mixture (8 g) of 1-{1-[4-(2-methoxycarbonylvinyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril and triphenylphosphineoxide.
Reaction SMILES: C([N:3](CC)CC)C.C(O[CH:11]=[C:12]([C:24](=[O:26])[CH3:25])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])=[O:14])C.Cl.NO>C(#N)C>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[CH:11]=[N:3][O:26][C:24]=1[CH3:25])=[O:14])([O-:23])=[O:22]
Reactant: CCOC=C(C(C)=O)C(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CC#N
Product: Cc1oncc1C(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Triethylamine (1.9 g) was added to a mixture of 2-ethoxymethylene-1-(2-nitrophenyl)-butan-1,3-dione (4.9 g) and hydroxylamine hydrochloride (1.3 g) in acetonitrile (100 ml) with stirring. The mixture was stirred for 2 hours and left to stand overnight. The mixture was evaporated almost to dryness and water (100 ml) was added. The mixture was extracted with ethyl acetate (2×75 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4(2-nitrobenzoyl)-5-methylisoxazole (compound 2, 2.4 g) as a brown solid, mp 104.5°-105.5° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=O.[N-:11]=[N+]=[N-].[Na+].[OH-:15].[Na+]>S(=O)(=O)(O)O.O>[O:15]=[C:4]1[NH:11][CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1
Reactant: O=C1CC2CCN1CC2
Reactant: [N-]=[N+]=[N-]
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1CN2CCC(CC2)N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
Quinuclidone HCl (200 g, 1.24 moles) was dissolved in concentrated sulfuric acid (500 ml) and chilled to 0°-5° C. in a very large ice-water bath. NaN3 (200 g, 3.07 moles) was added in small portions over 2 hours. The resulting mixture was stirred at 0° C. for 4 hours. The reaction mixture was then slowly and carefully diluted with 1 liter of water and slowly quenched with a solution of sodium hydroxide (900 g, 22.5 moles) in 1.5 liters of water. After the quench, the pH of the reaction mixture was approximately 13.5. The resulting sodium sulfate was filtered and then washed with 2 liters of chloroform. The aqueous supernatant was extracted with three times 2 l of chloroform. The combined extracts were dried with magnesium sulfate and concentrated to give 94.9 g of a solid residue. This residue was chromatographed (2.0 kg SiO2 ; 9:1 chloroform:methanol) to give 13.59 g of the title compound as white crystals, m.p. 210°-211° C., yield 7.8%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:31][CH2:30]2)[S:27][CH:28]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 35.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (212 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 101 mg (35.2%) of the desired product as a solid. mp 215-216° C.
Reaction SMILES: [Mg].[CH3:2][O:3][CH2:4]Cl.[CH2:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1>O1CCCC1>[CH3:2][O:3][CH2:4][C:14]1([OH:15])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: COCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: COCC1(O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of chloromethyl methyl ether (40.2 g, 0.5 mole, freshly distilled) in dry tetrahydrofuran (80 ml) is prepared, and about 5 ml of that solution are added to a stirred mixture of magnesium turnings (12.0 g, 0.5 g - atom) and mercuric chloride (500 mg) in tetrahydrofuran (20 ml) until an exothermic reaction ensues. The flask is cooled to 0° ± 10° and the remainder of the chloromethyl methyl ether solution is added dropwise with thorough agitation. After completion of addition a solution of 10,11-dihydro-5H- dibenzo[a,b]cyclohepten-5-one (56.1 g 0.25 mole) in tetrahydrofuran is added dropwise. The reaction mixture is stirred overnight at room temperature and the complex is hydrolyzed with ice-cold ammonium chloride solution. The aqueous layer is extracted with ether (3 × 100 ml) and the combined extracts are washed with sodium chloride solution, dried and evaporated under reduced pressure to give 10,11-dihydro-5-methoxymethyl-5H-dibenzo[a,d]cyclohepten- 5-ol as an oil with b.p. 143° -144° C/0.05 mm, γmaxfilm : 3500 cm-1, 2820 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[NH:20]([C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1)[NH2:21]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)C(F)(F)F
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1C(F)(F)C(F)(F)F
Yield: 95 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-pentafluoroethylpyrimidine-5-carboxylate (0.30 g, 0.99 mmol) and hydrazine (0.16 g, 5.0 mmol) in THF (20 mL) resulting in a 95% yield (0.28 g); 1HNMR (CDCl3) δ 8.86 (bs, 1H), 7.12 (bs, 1H), 4.37 (q, 2H), 1.72 (bs, 2H), 1.38 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][CH:32]=2)=[CH:21][CH:20]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Li+].Cl.C(#N)C>O1CCCC1.O>[CH2:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:39])=[O:2])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:31][CH:32]=2)=[CH:21][CH:20]=1)=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@H](COCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](COCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)C(=O)O)OCc1ccccc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of crude N-benzyloxycarbonyl-O-(4-(2-(2-phenyloxazol-4-yl)ethoxy)phenyl)methyl-L-serine methyl ester (13.32 g, 25.1 mmol) in 133 mL of tetrahydrofuran at 2° C. was added 44 mL of deionized water. A solution of lithium hydroxide (1.2 g, 50.2 mmol) in 40 mL of deionized water was added slowly over 25 minutes keeping the temperature of the reaction below 4° C. After the addition was complete the reaction was allowed to stir at 2° C. for 1 hour. The pH of the mixture was adjusted to about 1 with 6N hydrochloric acid (8.3 mL). Water (130 mL) was added and the reaction was extracted with ethyl acetate (2×260 mL). The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed to give an oil that was solvent exchanged into 125 mL of acetonitrile. The product crystallized and the slurry was stirred for about 1 hour at about 2° C. The precipitate was filtered using filtrete and rinsed with cold acetonitrile to give 7.65 g of the title compound.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[C:14]([Cl:35])=[CH:15][C:16](F)=[C:17]([S:19]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH3:33])([CH3:32])[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:18]=1>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:16]1[CH:15]=[C:14]([Cl:35])[C:13]([Br:12])=[CH:18][C:17]=1[S:19]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH3:33])([CH3:32])[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:1]([O:8][CH3:9])=[O:7]
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(Cl)c(Br)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a dry DMF (10 mL) solution containing dimethyl malonate (0.79 mL, 6.9 mmol), was added NaH (276 mg, 6.9 mmol) slowly at 0° C. under N2. The slurry was stirred for 10 min, then 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (1.0 g, 2.3 mmol) in dry DMF (5 mL) was added dropwise. The mixture was heated at 80° C. for 24 hrs, cooled to rt, carefully quenched with 1N HCl (10 mL), and extracted with ethyl acetate. The organic layer was washed with saturated aq. NaHCO3 solution and water, then was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with hexane/ethyl acetate (100/15) to yield 2-[4-bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-malonic acid dimethyl ester (0.75 g). MS: 545.9 (M+H)+; tR=2.64 min (method 1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C(#N)C>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCNCC3)ccc2S(C)(=O)=O)c1OC
Temperature: 67 °C
Yield: 22 %

Procedure:
[1-(5-Chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (100 g, 0.26 mol), piperazine (444 g, 5.16 mol), Hunig's base (0.45 L, 2.6 mol) and ACN (0.75 L) were heated at 80° C. for 13.5 hours (a solution formed upon heating to 67° C.). Upon cooling, a large amount of solids precipitated. Filtration, washing of the filter cake with ACN, and concentration afforded a solid which was treated with 1 L EtOAc. The EtOAc layers were combined and washed with 3×1 L water, dried over sodium sulfate, and concentrated to give 26 g of product. The solid collected by filtration was suspended in 0.5 L DCM and washed with 0.5 L water. The water was back-extracted with 0.25 L DCM. The DCM layers were combined, washed with 7×0.5 L water, dried over sodium sulfate and concentrated. 65 g of the resulting white solid were suspended in TBME and left o/n. The mixture was filtered, re-triturated in 210 mL TBME, filtered, washed with 70 mL TBME and air-dried to afford 59.4 g (50.7%) of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][CH2:11][P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O:28]C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:10][CH2:11][P:12](=[O:28])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OC(C)C
Reactant: O=Cc1ccccc1Cl
Reactant: NCP(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O=P(CN=Cc1ccccc1Cl)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
2.18 g. (0.015 mol) o-chlorobenzaldehyde is added dropwise to a solution of 3.5 g. (0.015 mol) aminomethyldiphenylphosphine in 150 ml. ethanol at ambient temperature. After evaporation of the solvent by heating to 50° C. under a slight vacuum, a clear yellow oil is obtained which is taken up hot in 50 ml. of a mixture of diisopropyl ether and ethanol (25/1 v/v). After cooling to 10° C., filtering and drying at 40° C. in vacuo, there are obtained 4.9 g. of crystals of the desired product; m.p. 89° C.
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[F:24])[C:11]=2[C:25](=[O:27])[NH2:26])C=CC=CC=1.[CH:29]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:31])[CH3:30]>>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:25]([NH2:26])=[O:27])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH:29]([CH3:31])[CH3:30])=[O:28])[S:14][N:13]=1
Reactant: CC(C)NCCCCCN
Reactant: Cc1ccc(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1ccc(COc2nsc(NC(=O)NCCCCCNC(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-isopropyl-pentane-1,5-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 452 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[C:12](=[O:13])[CH:11]([Br:14])[CH2:10][CH2:9][C:7]=2[N:8]=1)(=[NH:3])[NH2:2].C(NC(N)=S)(=N)N>>[BrH:14].[C:1]([C:4]1[S:5][C:6]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1nc2c(s1)C(=O)C(Br)CC2
Agent: N=C(N)NC(N)=S
Product: Br
Product: N=C(N)c1nc2c(s1)C(=O)CCC2

Procedure:
2-Bromo-1,3-cyclohexadione prepared in Example 1, Route 1 (A) was reacted with amidinothiourea in the similar manner to that of Example 1, Route 1(B) to give 2-amidino-4,5-dihydrobenzothiazole-7(6H)-one hydrobromide. The hydrobromide (3.4 g) was dissolved into conc. hydrobromic acid (20 ml), and one equivalent of bromine was added dropwise at a temperature of 85° C. The mixture was stirred at a temperature of 80° C. to 90° C. for 30 minutes, cooled and filtered. The solids were neutralized with sodium carbonate to give the titled compound (3.17 g, 67%).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.O.C(Cl)(Cl)Cl>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Yield: 76 %

Procedure:
To 4 mL of chloroform was added 4-[4-benzhydryloxy]piperidino]-1-butanol obtained from step 2 (0.11 g), 4-nitrobenzoic acid (0.1 g), 4-dimethylaminopyridine (DMAP, 0.12 g), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.1 g). The resulting mixture was allowed to react at room temperature for 3 hrs. before adding water to end the reaction. The resulting solution was acidified with 1N hydrochloric acid, and extracted by using chloroform. An organic solution layer was washed with 1N sodium hydroxide, dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (0. 12 g, 76% yield) of the title.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N:18]([CH2:19][CH3:20])[C:17]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:16]=3[N:15]=2)=[O:13])=[C:4]([N:26]2[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]2=[O:36])[CH:3]=1.[NH2:37][NH2:38]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:16]2[N:15]=[C:14]([S:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][C:4]=3[NH:26][C:27]([C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[C:30]([NH:37][NH2:38])=[O:31])=[O:36])=[O:13])[N:18]([CH2:19][CH3:20])[C:17]=2[CH:21]=1
Reactant: CCn1c(S(=O)Cc2c(N3C(=O)c4ccccc4C3=O)cc(C)c(OC)c2C)nc2ccc(Cl)cc21
Reactant: NN
Product: CCn1c(S(=O)Cc2c(NC(=O)c3ccccc3C(=O)NN)cc(C)c(OC)c2C)nc2ccc(Cl)cc21

Procedure:
The title compound of Example 122 (65 mg, 0.12 mmol) was treated with hydrazine according to the general procedure of Example 39 to give 48 mg (100%) of the partially deprotected amine title compound. 1H NMR (CDCl3) δ1.31 (t, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 3.65 (s, 3H), 4.16 (s, 1H), 4.32 (m, 2H), 4.48 (q, 2H), 7.19 (s, 1H), 7.31 (m, 1H), 7.49 (s, 1H), 7.59 (m, 2H), 7.70 (m, 1H), 7.80 (m, 2H).