Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Cl[C:31]1[CH:32]=[N:33][C:34]2[C:35](=[O:44])[NH:36][CH:37]([O:42][CH3:43])[CH:38]([F:41])[C:39]=2[CH:40]=1.[CH3:45][N:46](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:41][CH:38]1[CH:37]([O:42][CH3:43])[NH:36][C:35](=[O:44])[C:34]2[N:33]=[CH:32][C:31]([C:45]#[N:46])=[CH:40][C:39]1=2
Reactant: CN(C)C=O
Reactant: COC1NC(=O)c2ncc(Cl)cc2C1F
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC1NC(=O)c2ncc(C#N)cc2C1F
Temperature: 110 °C
Yield: 72.8 %

Procedure:
A pressure bottle was charged with Pd(dba)3 (Strem, 1.032 g, 1.127 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Strem 1.157 g, 2.82 mmol), zinc cyanide (Alfa Aesar, 2.482 g, 21.14 mmol), 3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (step 1, 3.25 g, 14.09 mmol) and DMF (70 ml). The bottle was purged with Argon and the reaction mixture was heated to 110° C. for 1 h. The crude reaction mixture was filtered through a pad of Celite and the filtercake was washed with MeOH. The combined filtrates were concentrated under reduced pressure. The residue was triturated with DCM. The solid was filtered off and washed with DCM. The title compound (2.27 g, 10.26 mmol, 72.8% yield) was obtained as an off white solid. MS m/z=222 [M+H]+. Calculated for C10H8FN3O2: 221.1
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([N:17](CC)CC)[CH3:16].C(N)C>C1COCC1.O>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(CC)CC
Agent: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 15.0 g (64.0 mmol) of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate and 195 mL (1.39 mol) of triethylamine in 226 mL of THF are added 14.6 mL of aqueous 70% ethylamine solution. The mixture is stirred at room temperature for 2 hours. After diluting in water, the resulting mixture is extracted with ethyl acetate and the organic phase is dried over MgSO4. The product is purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc mixture (8/15). 13.7 g of expected product are obtained in the form of a colourless oil. Yield=89%.
Reaction SMILES: [OH:1][C:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6].Cl.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[OH:1][C@:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Yield: 72.7 %

Procedure:
44.7 g (0.131 mol) of the ammonium salt of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid was dissolved in 500 ml of water at 25° C. The resulting aqueous solution was adjusted to pH 2, using 25.5 g of 36% hydrochloric acid. The acidic solution was extracted in 1300 ml of ethyl acetate. The ethyl acetate solution was rinsed with 200 ml of aqueous saturated sodium chloride. 500 ml of aqueous sodium carbonate solution (13.9 g (0.131 mol) of sodium carbonate) was added to the resulting ethyl acetate solution, for agitation to separate the aqueous alkaline solution from ethyl acetate. 23.1 g of 36% hydrochloric acid was added to the resulting aqueous alkaline solution to adjust the solution to pH 2. (R)-(+)-1-phenylethylamine of 6.99 g (57.6 mmol) is dropwise added to the resulting acidic solution, for agitation at 25° C. for one hour. The resulting crystal was filtered and dried under reduced pressure, to obtain the (R)-(+)-1-phenylethylaine salt (21.8 g; 47.8 mmol) of (4S)-4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid (at a yield of 72.7% and optical purity of 87.4%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[CH:22]=1)([OH:20])=[O:19]>>[F:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(C(F)(F)F)nc2c1
Yield: 19 %

Procedure:
Followed the coupling procedure described in Step 1 of Compound VIII-2 (Example 65), where the starting materials were 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and 4-carboxy-2-fluorobenzeneboronic acid. After H2O quench, the aqueous layer was acidified with 0.1 M HCl to pH=1, followed by EtOAc/aqueous workup and column purification to give 3-fluoro-4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid (50 mg, yield 19%).
Reaction SMILES: [N:1]([CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[H][H]>C(O)C>[NH2:1][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Reactant: [H][H]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Yield: 57.5 %

Procedure:
5-Azido-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.63 g) is dissolved in ethanol and thereto is added 10% Pd--C (0.1 g). The mixture is subjected to catalytic hydrogenation at room temperature under 1 atm. of hydrogen. Pd--C is removed by filtration and the filtrate is evaporated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.34 g) as white powder, m.p. 198.5°-199.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH:9]=O)[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH:9][N:7]([CH3:6])[CH3:8])[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (92 g) was added dropwise to stirred DMF (78 ml) between 10°-15° C. To the resulting slurry was added 4-chlorophenylacetic acid (34.12 g). The resulting mixture was stirred at room temperature for one half hour and then heated to 70°-80° C. during 5.5 hours, during which time the mixture became effervescent. The reaction mixture was cooled and poured slowly onto cracked ice. The resulting suspension was brought to pH 10 with solid potassium carbonate. Ice was added intermittently during this addition to maintain the temperature below 15° C. Toluene (150 ml) was added and the resulting mixture heated at 100° C. for one hour. The mixture was cooled and allowed to stand overnight. The two resulting layers were separated and the aqueous layer extracted with toluene (2×100 ml). The combined organic layers were washed with water (5×200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the resulting yellow solid was triturated with hexane to yield 26 g of 2-(4-chlorophenyl)-3-dimethylaminopropenal as a tan solid mp. 120°-125° C.
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+](=[CH2:20])=[N-].CO.CCOCC>C(O)(=O)C>[CH2:10]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:20][C:8](=[O:9])[CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=[N+]=[N-]
Reactant: CCCCCCCC1CCC2C1C(=O)C2(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCC1CCC2CC(=O)CC12
Temperature: 70 °C

Procedure:
The procedure followed is the same as that described in Example 29 substituting the starting material from Example 34, 6,6-dichloro-2-(hept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-heptylbicyclo[3.2.0]heptan-6-one} and isomers (14.2 g, 0.051 moles), an etheral diazomethane solution (175 ml), methanol (5 ml), and acetic acid (15 ml). After the acetic acid is added the solvent is removed under vacuum leaving a clear yellow oil. The crude product is then dissolved in acetic acid (100 ml) and stirred while zine powder (29 g) is slowly added. The reaction is heated in a 70° C. water bath for 1 hour, after which time ether (500 ml) is added and the solution filtered. The filtrate is washed with brine (100 ml) and then with a solution of saturated bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (4.3 g, 0.015 moles).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>[Pt].C(N(CC)CC)C>[F:1][C:2]([F:11])([F:12])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 95.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.5 g of 1% Pt/C, 0.05% load) and triethylamine (0.2 g, 0.4% load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of ethyl 4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].Cl>[OH-].[Na+]>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:4]
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNC(=O)CCl
Reaction time: 0.5 h

Procedure:
18 ml (221 mMol) chloracetylchloride was added dropwise to 20 g (153 mmol) 6-aminohexanoic acid dissolved in 80 ml cold NaOH solution (2N) at room temperature (RT). The reaction mixture was stirred for 30 minutes while the pH of the solution was kept between 10-11 with occasional addition of NaOH solution (6N). The pH of the reaction mixture was then altered to pH 5 with HCl (2N) and the residue was filtered. The residue was then washed with water until the pH of the water was neutral. The product, dried over phosphorus pentoxide, was re-dissolved in 300 ml chloroform and filtered to remove the undissolved residue. Heptane was added to the filtrate and a syrup was obtained by stirring under cooling. The product was filtered, dried and was then crystallized from water.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[NH:24])[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C(O)(=O)C.O>[O:13]=[C:11]1[NH:25][C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[N:24][CH:4]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(C)COc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O

Procedure:
Diethyl ethoxymethylenemalonate (6.42 g., 0.03 mole) was added to a stirred mixture of 2-isobutoxybenzamidine (5.76 g., 0.03 mole) and potassium carbonate (4.14 g., 0.03 mole) in ethanol (70 ml.). The mixture was heated under reflux for 4 hours. The cooled mixture was added to water (100 ml.) which was then acidified to pH 8 with 6N hydrochloric acid and then to pH 5 with glacial acetic acid. The title compound was collected by filtration, washed with water, and dried. The product (6.76 g., 71%) had m.p. 88°-90°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:20])=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc2cccc(O)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a solution of 8-hydroxyquinoline (1.45 g, 10 mmol) in dichloromethane (50 ml) was added 3-chloroperbenzoic acid (MCPBA) (1.24 g, 13 mmol). The mixture was stirred at room temperature for 10 min, poured into 1.0N sodium bicarbonate (100 ml), and then extracted with dichloromethane (3×50 ml). The extract was washed with water, dried over magnesium sulfate, and evaporated to give a brown solid which was crystallized from dichloromethane and diethyl ether affording 8-Hydroxyquinoline 1-oxide (5a) (1.34 g, 83%) as yellow needle crystals. mp: 132°-133° C.; 1H-NMR (CDCl3): δ7.04-8.28 (m, 6H, Ar--H), 15.02 (br s, 1H, OH).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of 48.5 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene are added 36 g of sodium carbonate. Subsequently, 3.9 g of 2,2-azoisobutyronitrile (AIBN) are added at 60° C., and, within 4 hours, 24 g of chlorine gas are introduced and a further 6 g of AIBN are added. After the gas introduction has ended, the reaction solution is stirred for a further 30 minutes. The solid is filtered off and washed with a little chlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 74%.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OOC1(C(C)(C)C)CCCCC1)(=O)OC1(C(C)(C)C)CCCCC1.[Cl:42]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:42])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: ClCl
Agent: CC(C)(C)C1(OOC(=O)OC2(C(C)(C)C)CCCCC2)CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 40 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene are added 36.5 g of sodium carbonate. Subsequently, 1.2 g of bis(tert-butylcyclohexyl) peroxycarbonate are added at 20° C. and the mixture is heated to 40° C. Within 4 hours, 24 g of chlorine gas are introduced. After the gas introduction has ended, the reaction solution is stirred at 40° C. for a further 30 minutes. The solid is filtered off and washed with a little chlorobenzene. After removal of the solvent, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 68%.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([OH:17])=O)[CH:6]=1>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([Cl:3])=[O:17])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2ccccc2c1
Product: O=C(Cl)c1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A 300 ml eggplant-shaped flask was equipped with a Dimroth condenser, a calcium chloride tube and a dropping funnel, and in the flask, 0.6 mol of thionyl chloride was slowly dropped to 0.1 mol of 3-quinolylcarboxylic acid with stirring at room temperature. After completion of the dropping, the resulting mixture was stirred continuously for about 1 hour on an oil bath at an oil bath temperature of 65° C. Thereafter, the excess thionyl chloride was removed under a reduced pressure to obtain 3-quinolylcarboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](SC)[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28].CO>>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[NH:28])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSC(=Nc1cccc(F)c1)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Reactant: N
Solvent: CO
Product: CC(C)C(c1ccc(NC(=N)Nc2cccc(F)c2)cc1)n1ccnc1
Temperature: 40 °C
Yield: 46 %

Procedure:
A solution of methyl N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]carbamimidothioate (0.0094 mol) in NH3/CH3OH (60 ml) was stirred and heated in autoclave at 40° C. for 3 days. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.2 to 90.10/0.5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone and (C2H5)2O and filtered off, yielding 0.89 g (46%) N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]guanidine (compound 744).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C=O.[C:30](=O)([O-])[O-:31].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH2:30][OH:31])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: C=O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCO
Yield: 93.3 %

Procedure:
In a solution of 7.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 in 70 mL of 1,4-dioxane, 1.82 g of 37% formalin, 7.00 g of potassium carbonate and 15 mL of water were added at room temperature with stirring, and stirred at the same temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted by adding 200 mL of ethyl acetate, washed with water (50 mL×1), and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, filtered through silica gel, and the solvent was distilled off under reduced pressure to obtain 7.00 g of the crude product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].C(N(CC)CC)C.C([SiH](CC)CC)C>C(Cl)Cl.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of benzyl (3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}4-ethoxypyrrolidine-1-carboxylate (8.60 g, 15.8 mmole) in CH2Cl2 (0.1M, 158 ml) under N2 was added Palladium chloride (279 mg, 1.58 mmole) and triethyl amine (3.29 ml, 1.5 eq.). Triethylsilane (3.78 ml, 1.5 eq.) was added dropwise over 15 min. After one hour an additional 8.74 ml of triethylsilane was added dropwise. After 2 additional hours, the reaction mixture was filtered through celite. Trifluoroacetic acid (8 ml) was added and the reaction mixture was stirred for 30 min. Quenched to pH 10 with 2N NaOH and extracted 3×300 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Vacuum chromatography was run on a 1 L frit funnel with 5–15% MeOH/CH2Cl2 with 0.5% NH4OH to give 5.95 g (92%) of an oil. 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.33–7.26, 5.38, 4.54, 4.07, 3.68, 3.52, 3.22, 2.95, 2.71, 2.46, 1.29, 1.15; HRMS (FAB) calcd for C20H26Cl2N4O+H 409.1562. found 409.1567. Anal. Calcd for C20H26Cl2N4O: C, 58.68; H, 6.40; N, 13.69. Found: C, 58.42; H, 6.43; N, 13.50.
Reaction SMILES: [C:1]1([CH3:19])[C:2]([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.OS(O)(=O)=O>O1CCOCC1.C(Cl)(Cl)Cl>[C:1]([O:17][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][S:7]([C:2]1[C:1]([CH3:19])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])=[O:18])([CH3:19])([CH3:2])[CH3:6]
Reactant: Cc1ccccc1S(=O)(=O)Nc1ccsc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1ccsc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 146.8 %

Procedure:
To a cold (−40° C.) mixture of 3-(Toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (1.5 g, 5.05 mmol) in 1,4-dioxane/CHCl3 (1:2, 12 mL) was bubbled 2-methyl-2-propene gas (15 mL) in a sealed tube. To this was added Conc. H2SO4 (0.070 mL, 1.3 mmol) and slowly warmed up to room temperature. The resultant reaction mixture was heated at 70° C. for 2.5 days in a sealed tube, cooled to −40° C., stopper was removed. The reaction mixture was slowly brought up to room temperature and stirred until the excess gas is released. The mixture was extracted with EtOAc, washed with aq. NaHCO3 solution, brine and dried. Evaporation of the solvent and purification of the residue on silica gel using EtOAc/hexane (1:10) as an eluent furnished 3-(Toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (1.31 g 73.5% based on 90% conversion). 1H NMR (CDCl3, 300 MHz) 9.89 (s, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.43 (dt, J=7.5 Hz, 1.5 Hz, 1H), 7.3-7.25 (m, 3H), 7.2 (d, J=5.4 Hz, 1H), 2.69 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.Cl.C(O)(C)C>[Fe].O>[NH2:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COC(=O)Cc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Iron powder (8.1 g) was added to a solution of methyl 4-fluoro-3-nitrophenylacetate (27.24 g, 0.128 mol) in a mixture of concentrated hydrochloric acid (1.5 ml), isopropanol (265 ml) and water (26.5 ml) and the mixture was stirred at room temperature for 1 hour. A second portion of iron powder (8.1 g) was added and the mixture was heated to reflux for 1 hour. A further quantity of concentrated hydrochloric acid was added and the mixture was refluxed for a further 1 hour. The mixture was cooled to room temperature, filtered through a plug of Hyflo® diatomaceous earth and the filtrate was evaporated in vacuo to give methyl 3-amino-4-fluorophenylacetate (22.98 g) which was used without further purification in the next step.