Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:19](OCC)=[O:20])([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC.C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][OH:20])([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(n2cncn2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCC1(n2cncn2)CCN(Cc2ccccc2)CC1
Temperature: 15 °C
Yield: 79.9 %

Procedure:
A solution of ethyl 1-benzyl-4-(1,2,4-triazol-1-yl)-piperidin-4-ylcarboxylate (D28, 460 mg, 0.00147 mol) in ether (15 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (67 mg, 0.00175 mol) in ether (25 ml) and dry THF (8 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to 15° C. over 20 minutes, then treated with water (0.06 ml), followed by 10% sodium hydroxide solution (0.18 ml) and then water (0.06 ml). The grey precipitate was removed by filtration through a pad of Kieselguhr and the filtrate dried (Na2SO4) and concentrated in vacuo to leave a yellow oil. This was purified by passage through a short silica gel column eluting with 10% methanol/ethyl acetate to give the title compound (D29) (320 mg, 80%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[C:14]([OH:23])(=[O:22])[C@@H:15]([C@H:17]([C:19]([OH:21])=[O:20])[OH:18])[OH:16]>CO>[CH3:13][N:2]([CH3:1])[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[C:14]([O-:23])(=[O:22])[C@@H:15]([C@H:17]([C:19]([O-:21])=[O:20])[OH:18])[OH:16]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCC(CO)(c1cccs1)N(C)C
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 8 h
Yield: 66.9 %

Procedure:
2-Dimethylamino-2-(2-thienyl)-1-butanol (11.2 g) and L-(+)-tartaric acid (4.2 g) are dissolved in methanol with heating and the solution is concentrated to remove solvent. Ethanol is added to the residue and the mixture is allowed to stand overnight. The precipitates are collected by filtration and recrystallized from ethanol, whereby (+)-2- dimethylamino-2-(2-thienyl)-1-butanol·L-(+)-tartarate (6.5 g) is obtained. An aqueous potassium carbonate solution is added to the salt and the mixture is extracted with chloroform. The extract is dried and concentrated to remove solvent. The residue is crystallized with n-hexane, whereby (+)-2-dimethylamino-2-(2-thienyl)-1-butanol (2.7 g) is obtained.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13]>C(O)C>[CH3:11][CH:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][PH:2](=[O:4])[OH:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=[PH2][O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C[PH](=O)O)CC(C)(C)C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A 2 L 4-neck flask, equipped with thermocouple well, a dropping funnel, overhead stirrer and reflux condenser is charged with 199 grams (1.88 moles) of sodium hypophosphite monohydrate and 500 mL of 2B ethanol. Into the resultant stirred suspension is added via the dropping funnel, 52 mL (1.87 moles) of concentrated sulfuric acid. During the addition the reaction mixture temperature rises from 21° C. to 27° C. After approximately 15 minutes, 100 mL (0.624 moles) of 2,4,4-trimethyl-1-pentene is added, followed by 10.24 g (0.062 moles) of AlBN powder. The reaction mixture is heated at reflux under a nitrogen atmosphere for 20 hours. An additional 6.84 g (0.042 moles) of AlBN powder is added and the mixture is refluxed under nitrogen for another 20 hours. Solvent is removed under vacuum and the residue is partitioned between 400 mL heptane and 1 L of water. The heptane layer is concentrated under vacuum to give 98 grams (88% of theory) of 2,4,4-trimethylpentyl phosphinic acid as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:28]([BH3-])#N.[Na+].C=O.O.C(OCC)C>C(#N)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:20][CH2:19][N:18]([CH3:28])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2cn[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Br)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension (±)-5-bromo-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (33 mg, 0.076 mmol) and sodium cyanoborohydride (9.6 mg, 0.15 mmol) in acetonitrile (1 mL) was added formalin (50 μl) and one drop of acetic acid. The reaction was stirred at room temperature for 1 h, poured into water/diethyl ether, washed with 1M sodium hydroxide, then water, and concentrated. The crude residue was loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. 1H-NMR (CDCl3, 500 MHz) δ 9.78 (bs, 1H), 7.89 (s, 1H), 7.73 (d, J=1.5, 1H), 7.25 (m, 2H), 7.10 (d, J=1.2, 1H), 7.05 (m, 2H), 4.49 (q, J=6.7, 1H), 3.39 (d, J=9.2, 1H), 3.25 (d, J=9.2, 1H), 2.60 (m, 1H), 2.53 (m, 1H), 1.95-2.32 (m, 5H), 2.21 (s, 3H), 1.92 (m, 1H), 1.41 (d, J=6.7, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 162.5, 160.6, 135.9, 133.7, 128.7 (d, J=7.7), 128.0, 126.5, 125.5, 122.2, 115.6, 115.4, 113.5, 78.2, 51.9, 51.7, 46.2, 40.3, 32.8, 32.5, 22.2. Mass spec.: 445.93 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5]2.[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32](O)=O)=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C.CCCCCC.C(OCC)(=O)C>[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32]3[O:13][C:12](=[O:14])[C:11]4[C:2](=[C:3]([CH3:19])[C:4]5[C:9]([CH:10]=4)=[N:8][C:7]([C:15]([F:18])([F:16])[F:17])=[CH:6][CH:5]=5)[N:1]=3)=[CH:30][C:29]([C:35]([F:38])([F:36])[F:37])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1c(N)c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: Cc1c2ccc(C(F)(F)F)nc2cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Yield: 85.7 %

Procedure:
A solution of 6-amino-5-methyl-2-trifluoromethyl-quinoline-7-carboxylic acid (0.60 g), 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (0.65 g, example 2, step 2) and pyridine (0.79 g) in acetonitrile (30 mL) is cooled to 0-5° C. and treated drop wise with methane sulfonyl chloride (0.89 g) dissolved in 2 mL acetonitrile. TLC analysis (hexane/ethyl acetate 4:1) after 2 h shows reaction completion. The reaction mixture is concentrated to ⅔ of the original volume in vacuum and poured onto 75 mL of ice/water. The resultant crystals are filtered off, washed with water and dried in vacuum to give 1.0 g of the title compound of the formula
Reaction SMILES: [OH:1][C:2]1[C:12]([O:13]C(=O)C)=[CH:11][C:5]2[C:6](=[O:10])[N:7]([CH3:9])[S:8][C:4]=2[C:3]=1[N+:17]([O-:19])=[O:18]>Cl.CO>[OH:13][C:12]1[C:2]([OH:1])=[C:3]([N+:17]([O-:19])=[O:18])[C:4]2[S:8][N:7]([CH3:9])[C:6](=[O:10])[C:5]=2[CH:11]=1
Reactant: CC(=O)Oc1cc2c(=O)n(C)sc2c([N+](=O)[O-])c1O
Agent: Cl
Solvent: CO
Product: Cn1sc2c([N+](=O)[O-])c(O)c(O)cc2c1=O

Procedure:
Acetic acid 6-hydroxy-2-methyl-7-nitro-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl ester (0.046 g) in methanol-HCl (14:1, 7 ml) was heated at 60° C. for 3 hours. The mixture was evaporated to dryness. The crude product was purified by flash chromatography using ethyl acetate as an eluent and followed by crystallization from isopropanol-methanol.
Reaction SMILES: C(OC(N1C2C(=CC3OC(F)(F)OC=3C=2)[C@@H](N)CCC1)=O)(C)(C)C.C(O[BH-](O[C:35](=[O:37])[CH3:36])OC(=O)C)(=O)C.[Na+].[C:39]([O:43][C:44]([N:46]1[C:59]2[C:51](=[CH:52][C:53]3[O:54][C:55]([F:61])([F:60])[O:56][C:57]=3[CH:58]=2)[C@@H:50]([NH:62][CH2:63][C:64]2[CH:69]=[C:68]([C:70]([F:73])([F:72])[F:71])[CH:67]=[C:66]([C:74]([F:77])([F:76])[F:75])[CH:65]=2)[CH2:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].N1C=CC=CC=1.C(Cl)(=O)C>ClCCCl.C(Cl)Cl.C(O)(=O)C>[C:39]([O:43][C:44]([N:46]1[C:59]2[C:51](=[CH:52][C:53]3[O:54][C:55]([F:60])([F:61])[O:56][C:57]=3[CH:58]=2)[C@@H:50]([N:62]([C:35](=[O:37])[CH3:36])[CH2:63][C:64]2[CH:65]=[C:66]([C:74]([F:75])([F:77])[F:76])[CH:67]=[C:68]([C:70]([F:72])([F:73])[F:71])[CH:69]=2)[CH2:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)OC(F)(F)O3
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)c2cc3c(cc21)OC(F)(F)O3
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc3c(cc21)OC(F)(F)O3
Reaction time: 14 h

Procedure:
To a solution of (S)-9-Amino-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.8 mmol) in DCE (20 mL), add 3,5-bis(trifluoromethyl)benzylaldehyde (2.8 mmol), acetic acid (cat.), and Sodium triacetoxyborohydride (5.7 mmol). After stirring for 14 h, dilute with DCM (100 mL) and quench with concentrated sodium carbonate (50 mL). Separate the organics, dry over sodium sulfate, and remove solvent under vacuum. Chromatograph using ethyl acetate/hexane (5-25%) to elute. This provides (S)-9-(3,5-Bis-trifluoromethyl-benzylamino)-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester as an oil. MS (ES+): 569 (M+H). To a solution of (S)-9-(3,5-Bis-trifluoromethyl-benzylamino)-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (0.35 mmol) in DCM (5 mL), add pyridine (1.06 mmol) and acetyl chloride (1.06 mmol). After stirring for 1.5 h remove solvent under vacuum and chromatograph using ethyl acetate/hexane (5-25%) to elute. This provides the title compound as a foam. MS (ES+): 609 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH:18]([OH:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CN(C)CCNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCNc1c2c(nc3ccccc13)CCCC2O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 4.4 g of 3,4-dihydro-9-[2-(dimethylamino)ethylamino]acridin-1(2H)-one in 80 ml of tetrahydrofuran was added 8 ml of 1 molar solution of lithium aluminum hydride in THF. This was stirred for 1/2 hour and then quenched with 6 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate. The combined organics were then dried over anhydrous magnesium sulfate and concentrated to give a solid. This was twice recrystallized from acetone/hexane to give 1.4 g of an analytically pure powder, mp 135°-138° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][CH2:10][CH2:9][C:7](=O)[C:5]=2[CH:6]=1.O1C2C(=CC=CC=2)CCC1O>>[O:11]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:9][CH2:10]1
Reactant: O=C1CCOc2ccccc21
Agent: OC1CCc2ccccc2O1
Product: C1=Cc2ccccc2OC1

Procedure:
In the same manner as described in Example 32, the formed chromanone compound was converted to a chromanol compound, and the dehydration reaction, separation and purification were carried out to obtain 6.58 g of a chromene compound represented by the following formula: ##STR167##
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:6]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[CH2:42]([O:49][NH:50][C:11]([C:10]1[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:6][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:8]([F:14])[CH:9]=1)=[O:13])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(N2CCCC2)nc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of 2-cyclopropylamino-5-fluoro-6-pyrrolidinyl-3-pyridinecarboxylic acid (Example G-2, 215 mg, 0.80 mmol) and 1-hydroxybenzotriazole (HOBT) (119 mg, 0.88 mmol) in chloroform (10 mL) was added 1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide (EDCI) (169 mg, 0.88 mmol). After being stirred at room temperature for 30 minutes, O-benzylhydroxylamine hydrochloride (141 mg, 0.88 mmol) and triethylamine (0.122 mL, 0.88 mmol) were added. The reaction mixture was heated to reflux for 4 hours, diluted with dichloromethane, washed with water, and dried on sodium sulfate. The residue was purified by flash chromatography on a silica gel column with dichloromethane as eluent giving 155 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]2[C:12]3[N:13]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:15]([CH3:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([C:11]2[C:12]3[N:13]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:15]([CH3:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1ccc(C(=O)O)c(Br)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
To a solution of 2-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (50.0 mg) in tetrahydrofuran (1 mL) was added a solution of 1 M borane-tetrahydrofuran complex (0.348 mL) in an ice bath. After stirring for 2 hours at room temperature, additional solution of the borane-tetrahydrofuran complex (0.348 mL) was added. The mixture was stirred for 15 hours at room temperature. The mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (54.2 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCC(O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCC(C)O
Product: COc1cc2nccc(Nc3ccc([N+](=O)[O-])cc3)c2cc1OC
Temperature: 25 °C
Yield: 73 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.40 g, 1.79 mmol, p-nitroaniline (0.414 g, 2.68 mmol) and p-toluenesulfonic acid (0.154 g, 0.894 mmol) in 1-methoxy-2-propanol (5 mL) were heated to 120° C. for 8 h. The mixture was cooled to rt, triturated with ether and filtered to yield (6,7-dimethoxyquinolin-4-yl)-(4-nitrophenyl)amine (0.43 g, 73%). LCMS m/z=326 (M+1); 1H NMR (DMSO) δ: 14.37 (s, 1H), 10.72 (s, 1H), 8.54 (d, 1H, J=6.80 Hz), 8.39 (d, 2H, J=9.08 Hz), 8.05 (s, 1H), 7.74 (d, 2H, J=9.09 Hz), 7.47 (d, 1H, 8.13 Hz), 7.43 (s, 1H), 7.19 (d, 1H, J=6.85), 7.10 (d, 1H, J=7.84), 4.02 (d, 7H, J=5.48), 2.28, (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:9]=2[CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)cccc2-c2ccc(Cl)cc2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 199A (1.5 g) in N,N-dimethylformamide (20 ml) was added 60% sodium hydride (0.596 g). The mixture was stirred at room temperature for 30 minutes and dimethylaminoethyl chloride hydrochloride salt (1.073 g) was added. After the resulting mixture was stirred overnight, additional 60% sodium hydride (0.596 g) and dimethylaminoethyl chloride hydrochloride salt (1.073 g) were added. The reaction mixture was further stirred overnight, diluted with ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc2nccnc2c1

Procedure:
Following the general method as outlined in Example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and rhodanine, the title compound was obtained.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O.S1C2C=CC=CC=2N=C1.Cl>CN(C=O)C.[Cl-].[Na+].O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[CH:2][S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.5 %

Procedure:
2-Amino-6-methoxybenzothiazole (9.0 g) in dry DMF (10 ml) was added dropwise over 35 minutes to a stirred solution of t-butyl nitrite (9.9 ml) in DMF (40 ml) at 65° C. The temperature of the mixture was kept <73° C. during the addition. On complete addition of the solution of benzothiazole, the dark red solution was stirred for an additional 15 minutes, cooled to ambient temperature then poured into dilute hydrochloric acid (200 ml) and diluted with brine. The dark red suspension was extracted with diethyl ether and the solid filtered then washed with further water and diethyl ether. The diethyl ether extracts were combined and the aqueous fraction re-extracted with ethyl acetate. The organic fractions were combined, washed with water and dried over magnesium sulphate then evaporated to give a brown solid. The solid was purified by flash column chromatography on silica gel (40-60 mesh) eluting with hexane/ethyl acetate (4:1 by volume) to give 6-methoxybenzothiazole as a colourless solid (2.1 g).
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([I:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[CH2:22]([Mg]Br)[CH3:23].C(OC(N1CCC2C3C(C4CC4)(O)CCC=3C=CC=2CC1)=O)C>>[CH2:22]([CH:12]1[C:11]2[C:10]3[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[C:16]([I:18])[C:15]=2[CH2:14][CH2:13]1)[CH3:23]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CC3
Reactant: CC[Mg]Br
Agent: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(C1CC1)CC3
Product: CCC1CCc2c(I)cc3c(c21)CCNCC3

Procedure:
Example 7 was prepared in a similar fashion to Example 4, except Intermediate 1 was used as the starting material and ethylmagnesium bromide (3M in diethyl ether) was used for instead of cyclopropylmagnesium bromide (Example 4, step (a)). 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 1H); 3.28-3.21 (m, 1H); 2.97-2.73 (8H); 2.62-2.60 (br s, 1H); 2.22-1.90 (m, 3H); 1.45-1.30 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); MS: ESI (positive): 342, (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>O.C(#N)C>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-n2ccnc2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CCc1cc(-n2ccnc2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
To a mixture of 3-ethyl-5-imidazol-1-yl-2-methoxy-6-methyl-pyridine (76 mg, 0.350 mmol) and sodium iodide (158 mg, 1.05 mmol) under a N2 atmosphere is added anhydrous acetonitrile (4 mL) followed by drop-wise addition of chlorotrimethylsilane (132 μL, 1.05 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 17 h. LC/MS shows the reaction is incomplete. Further sodium iodide (158 mg) and chlorotrimethylsilane (132 μL) are added and the heating is continued for 2 h. Further sodium iodide (158 mg) and chlorotrimethylsilane (132 μL) are added and heating is continued for 45 min. LC/MS indicates the reaction is complete. The reaction mixture is allowed to cool, diluted with water, treated with solid sodium bicarbonate and the resulting mixture is extracted with 10 portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is triturated with ether/acetonitrile, then the solid is suspended in dichloromethane:ethyl acetate (1:1) and filtered. The filtrate is evaporated and the residue is triturated with ether to give 3-ethyl-5-imidazol-1-yl-6-methyl-1H-pyridin-2-one (52 mg, 73% yield) as a light orange powder. This material (38 mg) is suspended in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0M, 0.38 mL). The heterogeneous mixture is stirred for 1.5 h, evaporated and the residue is triturated with ether to give 3-ethyl-5-(imidazol-1-yl)-6-methyl-1H-pyridin-2-one hydrochloride (29 mg) as an orange solid. LC/MS: RT: 0.45 min, MS: m/e=204 (M+H); 1H NMR (δ ppm): 12.09 (1H, s), 9.36 (1H, d), 7.91 (1H, t), 7.88 (1H, d), 7.40 (1H, s), 2.40 (2H, q), 2.06 (3H, s), 1.10 (3H, t).
Reaction SMILES: S(F)([O:4][C:5](F)(F)[C:6]([I:9])([F:8])[F:7])(=O)=O.[F-].[K+].[CH2:15]([OH:17])[CH3:16]>>[I:9][C:6]([F:8])([F:7])[C:5]([O:17][CH2:15][CH3:16])=[O:4]
Reactant: O=S(=O)(F)OC(F)(F)C(F)(F)I
Reactant: CCO
Agent: [F-]
Agent: [K+]
Product: CCOC(=O)C(F)(F)I
Yield: 74 %

Procedure:
Ethyl iododifluoroacetate (73.4 g, 74% yield) could also be prepared from 2-iodo-1,1,2,2-tetrafluoroethyl fluorosulfate (130.4 g, 0.4 mol), potassium fluoride (23.2 g, 0.4 mol) and ethanol (150 mL) according to the procedure described in Experiment (3a).