Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1.O[C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([CH3:27])[CH:15]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([O:12][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-butanol (626 mg, 2.72 mmol) and ethyl (4-hydroxy-2-methylphenoxy)acetate (539 mg, 2.56 mmol) in dry THF (51 mL) at 0° C. (ice/water bath) under nitrogen was added ADDM (1.32 g, 5.13 mmol) followed by nBu3P (1.28 mL, 4.95 mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3×75 mL), dried (Na2SO4), filtered and reduced to give a yellow oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 10:1) afforded the title compound (388 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:16]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:15])[CH:9]([CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:16]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)CCC(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)CC1Cc2cccc(Cl)c2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
101.8 g (453 mmole) 1-(2-Chloro-phenyl)-4,4-dimethyl-pentan-1-one, 133.4 g (2.1 eq.) urotropine and 124.7 g (2.7 eq.) of acetic anhydride were placed in a 1000 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 200 ml water and 200 ml 2M NaOH were added and the mixture was extracted two times with 250 ml dichloromethane each. The organic layer was washed two times with 150 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 250 ml volume and the solution was added dropwise over a period of 2.5 h to 1000 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was given to approx. 800 g of ice and extracted three times with 250 ml dichloromethane each. The organic layer was washed twice with 250 ml of a saturated sodium bicarbonate solution and once with 200 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 1:1) to yield 79.4 g (74%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.44 (t, 1H, aromatic), 7.30 (d, 1H, aromatic), 7.27 (d, 1H, aromatic), 3.38 (dd, 1H, COCH), 2.79, 2.60 (2×m, 2H, benzylic), 2.10, 1.21 (2×m, 1H, CH2-t-Bu), 0.90 (s, 9H, t-Bu) ppm.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:43][O:44][C:45](=[O:69])[C@H:46]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([N:62]([CH2:66][CH2:67][Cl:68])[CH2:63][CH2:64][Cl:65])=[CH:58][CH:57]=1)[NH:47]C(OC(C)(C)C)=O)[O:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>Cl>[C:1]([O:20][CH2:21][CH:22]([CH2:43][O:44][C:45](=[O:69])[C@H:46]([CH2:55][C:56]1[CH:57]=[CH:58][C:59]([N:62]([CH2:66][CH2:67][Cl:68])[CH2:63][CH2:64][Cl:65])=[CH:60][CH:61]=1)[NH2:47])[O:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@H](Cc1ccc(N(CCCl)CCCl)cc1)NC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC
Agent: Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](N)Cc1ccc(N(CCCl)CCCl)cc1)OC(=O)CCCCCCCCCCCCCCCCC

Procedure:
A solution of 5 mmol of the product obtained in Example 1 in 25 ml of hydrogen chloride-saturated dioxane is stirred for 20 minutes at 20° C. The whole mixture is concentrated under vacuum and the residue is washed with pentane, to give the expected product in hydrochloride form.
Reaction SMILES: C([O:8][C:9](=[O:44])[CH2:10][C@:11]1([C:34]([O:36]CC2C=CC=CC=2)=[O:35])[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23](=[O:33])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[CH:17]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].C1COCC1>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([O:22][C:18]2[CH:17]=[C:16]([C:13]3[CH2:12][C@@:11]([CH2:10][C:9]([OH:44])=[O:8])([C:34]([OH:36])=[O:35])[O:15][N:14]=3)[CH:21]=[CH:20][CH:19]=2)=[O:33])=[CH:29][CH:28]=1
Reactant: O=C(C[C@@]1(C(=O)OCc2ccccc2)CC(c2cccc(OC(=O)c3ccc([N+](=O)[O-])cc3)c2)=NO1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Oc2cccc(C3=NO[C@](CC(=O)O)(C(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of benzyl (5R)-5-(2-(benzyloxy)-2-oxoethyl)-3-(3-((4-nitrobenzoyl)oxy)phenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (77.5 g), 10% Pd/C (containing about 55% water, 7.8 g), and THF (780 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure to obtain (5R)-3-(3-((4-aminobenzoyl)oxy)phenyl)-5-(carboxymethyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid as a crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1
Reactant: COc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (825 mg, 3.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.23 mmol), potassium carbonate (1.34 g, 9.697 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) (158 mg, 0.193 mmol) in N,N-dimethylformamide (19 mL) was purged with argon. After 30 minutes, the reaction mixture was heated at 90° C. and stirred for 22 hours before cooling to room temperature and filtering through Celite™, washing with ethyl acetate. The filtrate was concentrated in vacuo to ˜quarter and partitioned between water (100 mL) and ethyl acetate (75 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL). Combined organic layers were washed with water, aqueous lithium chloride solution, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by automated flash chromatography (24 g silica gel) eluting with hexanes:ethyl acetate (gradient 1:0 to 3:1, by volume) to afford the title compound as a clear oil, 1.1 g.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:31])[CH2:30][O:29][CH2:28]1>CC#N>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:33]([NH:32][C:23]2[CH:24]=[CH:25][C:26]([C:27]3([OH:31])[CH2:30][O:29][CH2:28]3)=[C:21]([F:20])[CH:22]=2)=[O:34])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C3(O)COC3)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 76.6 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (96 mg, 0.32 mmol, 1.0 eq) in MeCN (8 mL) was added TEA (0.178 mL, 1.28 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (99 mg, 0.3 3 mmol, 1.02 eq) at RT and stirred at reflux for 16 h. The solvent was evaporated and the crude product was purified by CC (EtOAc/cyclohexane 1:1 as eluent) to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)urea (116 mg; 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([C:15]#[N:16])=[CH:6]2.[CH3:17][N:18]([CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>COCCO>[CH3:17][N:18]([CH3:26])[C:19]1[CH:20]=[C:21]([NH:25][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][C:7]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2cc(C#N)cnc2cc1OC
Reactant: CN(C)c1cccc(N)c1
Solvent: COCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(N(C)C)c3)c2cc1OC
Yield: 19 %

Procedure:
A 1.25 gram (5 mmole) portion of 4-chloro, 6,7-dimethoxy-quinoline-3-carbonitrile and a 1.05 gram (5 mmole) portion of N, N-dimethyl-1,3-phenylenediamine in 10 ml of 2-methoxyethanol were refluxed for 2 hours in an oil bath at 154 deg. Cooling gave a solid which was recrystallized from water to give 0.4 grams (19%) of 4-(3-Dimethylamino-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile which melted at 246-249° C.: mass spectrum (electrospray m/e):.(M+H)=349.2., (M+2H)'2 =174.9.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([CH3:23])([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:23][C:4]1([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH:3]=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(O)c2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(COc2ccc([N+](=O)[O-])cc2)C=Cc2ccccc2O1
Yield: 84.8 %

Procedure:
A mixture of 1 g of 4-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 2), 70 mg of p-toluenesulfonic acid monohydrate and 10 ml of benzene was heated under reflux for 45 minutes. At the end of this time, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 20:1 by volume mixture of hexane and ethyl acetate, to afford 800 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: C(OC([N:8]([C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]2[C:30]=1[CH:31]([CH3:33])[CH3:32])[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[CH:31]([C:30]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11])([CH3:33])[CH3:32]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2nc3ccccn3c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of compound 4-F (0.230 g, 0.486 mmol) in dioxane (3 mL) was added 4N HCl in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 1 day. An additional portion of 4N HCl in dioxane (5 mL) was added and the mixture stirred an additional two days at room temperature. The solvent was evaporated in vacuo, and the solid triturated in Et2O, collected by filtration, washed with Et2O and dried to afford compound 4-G as a yellow solid (0.196 g, 98%). 1H-NMR (CD3OD): δ 8.72 (d, J=6.8 Hz, 1H), 8.21 (d, J=8.6 Hz, 2H), 7.90-7.99 (m, 3H), 7.82 (d, J=9.0 Hz, 1H), 7.45-7.50 (m, 1H), 3.94 (s, 3H), 3.12-3.23 (m, 1H), 1.14 (d, J=7.1 Hz, 6H); MS: m/z 374.1 (MH+).
Reaction SMILES: [CH:1]1([C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>C(#N)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9](=[O:11])[CH2:8][C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](CC(=O)O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(=O)Nc1ccc(Cl)cc1)C1CCCCC1
Yield: 94.5 %

Procedure:
To a suspension of (3R)-3-cyclohexyl-4-methoxy-4-oxobutanoic acid (0.21 g), 4-chloroaniline (0.13 g) and HOBt (0.23 g) in acetonitrile (10 ml) were added WSC (0.29 g) and N-methylmorpholine (0.10 g), and mixed at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed sequentially with an aqueous sodium hydrogen carbonate solution, water, a 5% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale brown solid (0.30 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:30])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{3-[(trifluoromethyl)sulfonyl]benzyl}-1,3-oxazolidine-3-carboxylate (0.90 g, 1.79 mmol) in methanol (10 ml) was added a solution of 0.5N sodium hydroxide in methanol (10.8 ml, 5.40 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (0.72 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C1(C)C=CC=C([O:15][C:16](=[NH:20])[NH:17][C:18]#[N:19])C=1.[ClH:22]>C(O)(C)C>[ClH:22].[ClH:22].[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:18]([NH:17][C:16]([NH2:20])=[O:15])=[NH:19])[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: Cc1cccc(OC(=N)NC#N)c1
Agent: Cl
Solvent: CC(C)O
Product: N=C(NCCc1c[nH]cn1)NC(N)=O

Procedure:
47.5 g. histamine (0.401 mole) and 71.66 g. (0.409 mole) O-m-tolyl-N-cyanoisourea are combined in 500 ml. of isopropanol. The mixture is then heated for 10 minutes to reflux, refluxed for one hour, and the reaction mixture is stripped to an oil. The oil is taken up in 2 l. of isopropanol and 102 ml. conc. HCl, heated 25 minutes to reflux, refluxed for 35 minutes, cooled slowly, then with ice. The mixture is filtered to obtain 1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride as a crude product. This is recrystallized from MeOH/CH3CN to obtain 1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride with a m.p. of 180.5°-181.5° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=S)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[O:17]C1C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1N[C@@H](Cc2ccccc2)CS1
Reactant: CC1CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@@H](Cc2ccccc2)CS1
Reaction time: 2 h

Procedure:
To a solution (4S)-4-benzyl-1,3-thiazolidine-2-thione (38 g) in dichloromethane (350 mL), cooled to 0° C. was added propylene oxide (12.7 mL) and trifluoroacetic acid (14 mL). After stirring the reaction mixture for 2 hours, the solvents were evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (0.9 g). Mass (m/z): 194.18
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:10]([C:23](=[O:46])[C@@H:24]([NH:26][C@H:27]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:25])[C:9]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:23](=[O:46])[C@@H:24]([NH:26][C@H:27]([C:36]([OH:38])=[O:37])[CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:25])[C:9]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Yield: 83.6 %

Procedure:
5.4 g of benzyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 300 mg of palladium black are treated in the same manner as described in Example 1-(2), whereby 3.23 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 83.6%
Reaction SMILES: [C:1]([C:7]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:1]([C:7]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:8]=1[C:9](=[O:10])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N,4-bis(methyloxy)benzamide (79) (0.42 g, 1.51 mmol) was dissolved in THF (10 mL). Cooled to 0° C. in an ice bath, benzylmagnesium chloride (2 M in THF, 1.50 mL, 3.0 mmol) was added. The mixture was stirred at 0° C. for 3 h, quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 eluted with a gradient from hexanes to 15% EtOAc in hexanes to give 0.37 g (80%) of the title compound (80) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 1.55-1.65 (m, 2H), 2.46 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 4.44 (s, 2H), 6.82 (dd, J1=8.8 Hz, J2=2.7 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.20-7.34 (m, 5H), 7.65 (d, J=8.7 Hz, 1H). LCMS (ESI): m/z 307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 10.0 g. of 4-[[2,2-bis(p-chlorophenyl)ethyl]amino]benzoic acid, ethyl ester, 5.0 g. of potassium hydroxide, and 100 ml. of 95% ethanol is stirred at 80° C. for 31/2 hours, cooled, diluted with 200 ml. of water, and extracted with two 150 ml. portions of ether. The combined ether extracts are washed with 100 ml. of water. The water wash is combined with the original aqueous layer and adjusted to pH 6.5 with 37% hydrochloric acid. The resulting precipitate is collected and dried in vacuo, giving 9.0 g. of the desired product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.2 ml of 3-chloro-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 172 mg of expected product is obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1O>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: Cn1nccc(NCC(=O)N2CCC(O)CC2)c1=O
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: Cn1nccc(NCC(=O)N2CCC(Oc3cc([N+](=O)[O-])ccc3Cl)CC2)c1=O
Yield: 7 %

Procedure:
Compound 9 is prepared from intermediate 5b and from 2-chloro-5-nitro-phenol following synthesis method 3 (yield: 7%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:16]=[C:17]([CH3:24])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>CS(C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:16]=[C:17]([CH3:24])[CH:18]=[CH:19][C:20]=3[N+:21]([O-:23])=[O:22])[S:6][C:5]=2[CH:7]=1
Reactant: N#Cc1c(N)sc2cc(F)ccc12
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(Nc2sc3cc(F)ccc3c2C#N)c1
Yield: 88.1 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile (5.0 g), 3-fluoro-4-nitrotoluene (4.7 g) and dimethyl sulfoxide (55 ml), 6-fluoro-2-(5-methyl-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (7.5 g) was obtained.