Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46]>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46].[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:48]([NH:47][C:45](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([F:37])([F:51])[F:50])=[S:49])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 85%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].CS(C)=O.Br[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A mixture of 4-hydroxyindole (0.100 g, 0.75 mmol, 1.0 eq), powdered potassium hydroxide (0.042 g, 0.75 mmol, 1.0 eq), and DMSO (3 mL) was stirred at room temperature for 1 hour before 1-bromo-3-chloropropane (0.118 g, 0.75 mmol, 1.0 eq) was added. The above mixture was then stirred at room temperature for another 0.5 hour and then 15 mL of water was added to it. The resultant mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford 4-(3-chloropropoxy)-1H-indole (0.130 g, yield: 83%).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1([CH3:12])[CH3:11])=[O:3].[CH3:13][CH2:14]O>>[CH3:12][C:5]1([CH3:11])[CH2:6][CH2:7][CH2:8][C@@H:9]([CH3:10])[C@@H:4]1[C:2](=[O:3])[CH:1]=[CH:13][CH3:14]
Reactant: CC(=O)[C@H]1[C@H](C)CCCC1(C)C
Reactant: CCO
Product: CC=CC(=O)[C@H]1[C@H](C)CCCC1(C)C

Procedure:
The reaction was carried out in exactly the same manner as Reference Example 6 using 37 g of the (1S,6R)-2,2,6-trimethylcyclohexyl methyl ketone (1a) synthesized in Example 2 to obtain 29 g of (1S,6R)-1-(2,2,6-trimethylcyclohexyl)-2-buten-1-one (10a) (b.p.: 73-75° C./19.95 Pa (0.15 torr), [α]D=+15.52° (c 1.00, EtOH, 24° C.).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].F[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].Cl>CN(C=O)C.O>[NH2:8][C:6](=[O:7])[CH:5]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21])[C:3]#[N:4]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
NaH (3.41 g, 85 mmol) was added portionwise to a cold solution of 2-cyanoacetamide (7.18 g, 85 mmol) in DMF (53 mL). After 30 minutes at room temperature, a solution of methyl 4-fluoro-3-nitrobenzoate (8.5 g, 42.7 mmol) in 15 mL of DMF was added dropwise. After 3 hours a mixture of ice, water and 12 mL HCl (10%) were added. The resulting solid was filtered, rinsed with water and dried under high vacuum overnight to give 9.1 g of methyl 4-(2-amino-1-cyano-2-oxoethyl)-3-nitrobenzoate: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H) 5.78 (s, 1H) 7.77 (s, 1H) 7.91 (d, J=7.83 Hz, 1H) 8.04 (s, 1H) 8.39 (dd, J=8.02, 1.76 Hz, 1H) 8.56 (d, J=1.56 Hz, 1H).
Reaction SMILES: [Na].[Cl-:2].[CH2:3]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])[CH3:4].[CH2:15](O)[CH2:16]CC>>[Cl-:2].[CH2:3]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][NH+:11]([CH3:12])[CH3:13])[CH2:4][CH2:15][CH3:16]
Reactant: CCOC(=O)NCCC[NH+](C)C
Reactant: CCCCO
Agent: [Cl-]
Agent: [Na]
Product: CCCCOC(=O)NCCC[NH+](C)C

Procedure:
4.6 g (0.2 g-atom) of sodium are dissolved in 200 ml of n-butanol. To this add 21.0 g (0.1 mole) of N-(3-dimethylammoniopropyl)-carbamic acid ethyl ester chloride and boil the mixture for 6 hours with reflux. Concentrate, admix with water, ether out, dry the ether phase over MgSO4, introduce dry HCl gas while stirring and cooling, decant the ether solution, and drag the remaining oil in vacuum. One obtains 13.1 g of nD20 = 1.4735.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:19]([NH2:20])=[N:18][C:12]3[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: COc1cccc(-c2cc3cnc(N)nc3nc2N)c1
Product: COc1cccc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1

Procedure:
The title compound was prepared from 0.50 g of 6-(3-methoxy-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 102 and 0.23 mL tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1) to EtOAc; mp 275°-280° C.; MS(CI).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH:15]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH:15]1([NH:21][C:22](=[O:23])[O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(CSc1cccc(O)c1)OC
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(CSc1cccc(OC(=O)NC2CCCCC2)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Cyclohexyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethylthio) phenyl] N-cyclohexylcarbamate as the residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CN1CCOCC1.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:25])[CH:28]([CH3:30])[CH3:29]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)OC(=O)c1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
With the exclusion of air, 6.0 g (30 mmol) of 4-(pyridin-2-yl)-benzoic acid are suspended at -20° C. in 90 ml of THF, and 9.90 ml (90 mmol) of N-methyl-morpholine and 4.32 ml (33 mmol) of isobutyl chloroformate are added. After 30 min, the mixture is filtered, washed with a small amount of cold THF, and the filtrate is partially concentrated by evaporation; the residue is diluted with methylene chloride, washed with ice-water and cold brine, dried (Na2SO4) and concentrated by evaporation to form the title compound: 1H-NMR (CDCl3) i.a. 8.75 (m, 1H), 8.16 (AB, J=8, 4H), 7.81 (m, 2H), 7.32 (4-line system, J=5, 1 H), 4.16 (d, J=7, 2H), 2.10 (9-line system, J=7, 1 H), 1.02 (d, J=7, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Br:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Br)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.79 mmol) in methylene chloride (25 mL) was added dropwise 4bromobenzoyl chloride (122 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (51%) of the title compound as white crystals: mp 200-201° C.; [α]21D -32° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 427 and 429 (3, M+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: Oc1ccc(O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(O)cc1

Procedure:
Ethyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate is prepared by the reaction hydroquinone and ethyl 4-bromo-3-methoxy-2-pentenoate in the presence of base in acetone or the like under reflux.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:34]=[CH:33][C:17]([C:18]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[NH:7][CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].Cl>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[O:19])=[CH:33][CH:34]=3)=[CH:11][CH:12]=2)[N:7]([C:46]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:47])[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2NC[C@@H]1C
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCNCC4)cc3)cc2N(C(=O)Oc2ccccc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A reaction vial was charged with (S)-tert-butyl 4-(4-(1-acetyl-2-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)benzoyl)piperazine-1-carboxylate (0.2 M in 1,2-dichloroethane, 100 μL, 0.02 mmol), N,N-diisopropylethyl amine (25 μL, 0.14 mmol), and phenyl chloroformate (6.23 mg, 0.04 mmol), and the mixture was shaken at 50° C. for 2 h. Methanol (50 μL) was added and the mixture was shaken at 50° C. for 10 min. HCl (4 M in dioxane, 0.075 mL, 0.30 mmol) was added and the reaction was shaken at 50° C. for 2 h. The mixture was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford phenyl (S)-4-acetyl-3-methyl-7-(4-(piperazine-1-carbonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 499.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][CH:22]=[O:23])[C:3]=1[CH3:24].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.COCCOC>C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][CH:22]=[O:23])[C:3]([CH3:24])=[C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: Cc1c(Br)c2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: CCOC(C)=O
Product: Cc1c(NC=O)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1

Procedure:
A mixture of (7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 59 (1.0 g, 2.58 mmol), phenylboronic acid (345 mg, 2.83 mmol) and tetrakis(triphenylphosphine)palladium (99 mg, 0.086 mmol) in 2 N sodium carbonate aqueous solution (30 mL)-1,2-dimethoxyethane (15 mL) was heated under reflux under nitrogen atmosphere for 16 hours. The reaction solution was diluted with ethyl acetate, the insolubles were taken by filtration, and the filtrate was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the crude product of (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)formamide. This compound was dissolved in methanol (18 mL), to which concentrated hydrochloric acid (6 mL) was added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was neutralized with a 12 N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 642 mg (yield 70%) of the title compound. Melting point: 101-102° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=C[C:14]([C:17]3[C:18](C(OC(C)(C)C)=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].F[C:42](F)(F)[C:43]([OH:45])=[O:44]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[C:42]([C:43]([OH:45])=[O:44])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2)c(C(=O)O)c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].C(N(CC)CC)C.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.49 g, 1.60 mmol) and triethylamine (0.17 g, 1.64 mmol) were added to thioacetic acid (3 mL) at 0° C. The mixture was stirred at room temperature for 6 h. The mixture was poured onto ice-water and extracted with CH2Cl2. The organic phase was washed with saturated NaHCO3 and dried. The crude product was purified by flash chromatography (MeOH/CH2Cl2, 2.5:100) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propionic acid ethyl ester (0.36 g, 61%).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:9]=1.[CH2:18]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[ClH:2].[Cl:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH2:3][N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH2:18][CH3:19])[CH:9]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: CCc1ncc[nH]1
Agent: Cl
Product: CCc1nccn1Cc1cncc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=332.2 (M+H+) was obtained as an orange solid (49% yield) by the reaction of 3-chloromethyl-5-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) with 2-ethylimidazole, using sodium hydride and triethylamine as base followed by formation of the hydrochloride salt.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CC(C)c2ccccc2)[nH]n1
Yield: 6.9 %

Procedure:
Hydrazine hydrate (0.134 mL, 2.76 mmol) was added to a stirring room temperature solution of 56 0.7230 g, 2.76 mmol) in EtOH (2.8 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (50 min): The reaction was concentrated and purified by preparative reverse phase HPLC with the following conditions: 0 to 24 min, 55:45 H2O:CH3CN; 24-25 min, 55:45 to 0:100H2O:CH3CN; 20 mL/min.; λ=214 nM; 100 mg/mL, 0.2 mL/injection. 0.0489 g of 57 was obtained. 1H (CDCl3, 300 MHz): δ 10.77 (1H, broad s), 7.36-7.14 (5H, m), 6.49 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.16-2.86 (3H, m), 1.33 (3H, t, J=7.0 Hz), 1.27 (3H, d, J=5.9 Hz) ppm. 13C (CDCl3, 75 MHz): δ 162.01, 145.94, 145.75, 141.50, 128.43, 126.76, 126.32, 106.98, 60.87, 39.94, 34.64, 21.34, 14.12 ppm. DEPT (CDCl3, 75 MHz): CH3 carbons: 21.34, 14.12; CH2 carbons: 60.87, 34.64; CH carbons: 128.43, 126.77, 126.32, 106.98, 39.94 ppm. HPLC: 10.052 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([CH2:14][O:15][C:16]1[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=1)#N>>[F:26][C:17]1[C:16]([O:15][CH2:14][C:9]2[S:10][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=3[N:8]=2)=[CH:21][CH:20]=[C:19]([F:22])[C:18]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1cccc2sc(N)nc12
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Product: Cc1cccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc12
Yield: 36 %

Procedure:
Synthesised from 4-methyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 36% (second step), mp 201-202° C., HPLC-MS (method 1): m/z 335 [M+H]+, Rt=3.79 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[O:18]1CCCC1>C(O)(=O)C.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:17]=[O:18])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)O)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a mixture of 7 g 4-(2-carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL each of tetrahydrofuran (THF), acetic acid (AcOH) and water at −10° C. was added 70 g of ceric ammonium nitrate in portion over 20 minutes, the reaction temperature being maintained at about 5° C. The resulting mixture was them cooled to 0° C., stirred for another 2 hr and then diluted with 250 mL of brine. The mixture was then extracted with 2×300 mL 10% MeOH in dichloromethane (DCM). The organic extracts were combined and dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The residue was purified on silica gel column with hexanes(hex)/ethyl acetate (EtOAc)/AcOH (6:4:0.05) followed by crystallization in EtOAc to give 1.5 g of 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[NH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Reactant: CC(C)(CN)CO
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethyl-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.70 (1H, s), 10.37 (1H, t, J=6 Hz), 8.47 (1H, d, J=1.5 Hz), 7.67 (1H, dd, J=9.3, 2.4 Hz), 7.59-7.51 (2H, m), 7.30 (1H, s), 4.72 (1H, t, J=5 Hz), 4.30 (2H, s), 3.23 (2H, d, J=6 Hz), 3.16 (2H, d, J=5 Hz), 0.83 (6H, s); HRMS calcd for C22H21F4N3O4+H+: 468.1546. Found: 468.1558.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(N(C(C)C)C(C)C)C.C1N=CN([S:26](N2C=NC=C2)(=[O:28])=[O:27])C=1>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][S:26](=[O:28])(=[O:27])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-nitrophenol (7.7 g, 50 mmol) in acetonitrile (300 ml) is treated with N-ethyldiisopropylamine (18.7 ml, 110 mmol) and N,N′-sulfuryldiimidazole (10.8 g, 55 mmol) and boiled at reflux for 18 h. After cooling to RT, the solvent is distilled off under reduced pressure, the residue is taken up in 1 N HCl and the product is extracted with ethyl acetate. The product is then purified by flash chromatography (17:2:1, EtOAc/MeOH/H2O).