Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCC1>CO>[Cl:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:1]/[C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(Cl)cc2)s1
Yield: 67 %

Procedure:
A solution (1.74 M) of methyl 5-methyl-4-nitrothiophene-2-carboxylate (prepared as described in example 1, step 1) in MeOH, was treated with 4-chlorobenzaldehyde (1.5 eq.). The reaction mixture was heated to reflux and when it became a clear solution, a catalytic amount of pyrrolidine (0.10 eq.) was added. The reaction mixture was heated to reflux overnight. After cooling down, evaporation of the solvent gave a residue that was triturated with petroleum ether/Et2O and filtered to afford the title compound title compound (67%) as a solid.
Reaction SMILES: [Br:1][C:2]([CH3:12])([CH3:11])[C:3]([NH:5][C:6]([N:8]([CH3:10])C)=[O:7])=[O:4].Br[C:14](C)(C)C(Br)=O.CNC(NC)=O>CS(C)=O>[Br:1][C:2]([CH3:11])([CH3:12])[C:3]([N:5]([CH3:14])[C:6]([NH:8][CH3:10])=[O:7])=[O:4]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CN(C)C(=O)NC(=O)C(C)(C)Br
Agent: CNC(=O)NC
Solvent: CS(C)=O
Product: CNC(=O)N(C)C(=O)C(C)(C)Br
Yield: 38 %

Procedure:
This compound was prepared similarly to 1-(2-bromo-2-methylpropionyl)-3,3-dimethylurea in Example 7a from 2-bromo-2-methylpropionyl bromide and 1,3-dimethylurea. It was obtained in 38% yield as a yellow oil, νmax (Nujol) 3330 (NH), 1730, 1700 cm-1 (CON. CON). τ(DMSO d6) 6.44 (NMe) 7.13 (d,J 5; NHMe), 7.95 (CMe2).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)C=Cc1cccnc1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CLVII was prepared from 6-bromo-1H-indole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [C:1]([C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:13].[Br:14]C1C=C(C)C=CN=1>>[BrH:14].[Br:13][CH2:2][C:1]([C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CCc1ccnc(C(C)=O)c1Cl
Reactant: Cc1ccnc(Br)c1
Agent: Br
Product: CCc1ccnc(C(=O)CBr)c1Cl

Procedure:
The title compound was prepared from 2-acetyl-3-chloro-4-ethylpyridine according to the procedure for preparing 2-bromo-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:13]([C:17]([F:20])([F:19])[F:18])[O:14]3)=[CH:9][C:8]=2[Cl:26])=[C:4]([F:29])[CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:21]([OH:23])=[O:22])[CH:13]([C:17]([F:20])([F:18])[F:19])[O:14]3)=[CH:9][C:8]=2[Cl:26])=[C:4]([F:29])[CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(N)cc3F)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
The ester from Step 2 (0.10 g, 0.23 mmole) was dissolved in 0.5 mL methanol and 0.5 mL THF. Sodium hydroxide (2.5 N) (0.2 mL, 0.46 mmole) was added to above solution and stirred at room temperature for overnight. The reaction mixture was acidified with 0.5 N HCl. The compound was extracted out with EtOAc. The organic layer was washed with water and dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo to afford the title compound as a yellow solid (0.07 g, 75%): LCMS m/z 402.85 (M+H). 1H NMR (acetone-d6/400 MHz) 7.89 (s, 1H), 7.73 (s, 1H), 7.67 (dd, 1H, J=10.8, 2.4 Hz), 7.53 (dd, 1H, J=10, 1.6 Hz), 7.47 (m, 1H), 5.81 (q, 1H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.O1CCCC1.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g), tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5 mL) of thionyl chloride (1.5 mL) in toluene under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals (4.50 g, 94%) of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole. melting point: 100-101° C.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH3:24])[N:23]=2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:19]([O:18][C:16]([N:15]1[C:14]2[CH:13]=[CH:12][N:11]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:10]3[C:9]=2[CH:32]=[C:31]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Nc1ccn2cc(C)nc2c1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c(-c2ccccc2)cc2c1ccn1cc(C)nc21
Reaction time: 0.08 h
Yield: 10.8 %

Procedure:
To a mixture of Et3N (10 mL), DMF (75 μL), carbamate 19 (215 mg, 0.72 mmol), PdCl2(PPh3)2 (10 mg, 2 mol %) and phenylacetylene (89 mg, 0.87 mmol) stirred 5 min beforehand, CuI (5 mg, 4 mol %) was added and stirring was continued for another 2 min before flushing with Ar. After stirring for 2 days at 60° C., the mixture was concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with CH2Cl2 (3×30 mL). The organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography using cyclohexane/EtOAc (4/1, v/v) as eluent to afford compound 20 as an oil (24.8 mg, yield: 11%); 1H NMR (400 MHz, CDCl3) δ 1.06 (t, 3H, J=7.1 Hz), 2.48 (s, 3H), 4.25 (q, 2H, J=7.1 Hz), 7.09 (s, 1H), 7.32 (s, 1H), 7.40 (m, 5H), 7.69 (d, 1H, J=7.3 Hz), 7.87 (d, 1H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 13.5, 14.2, 63.6, 103.0, 108.1, 109.5, 115.8, 121.5, 127.8, 127.9, 129.0, 132.3, 133.7, 139.7, 140.4, 141.7, 151.3. Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 72.03; H, 5.42; N, 13.25. Further elution afforded starting material 19 (124 mg, 58%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[C:5]([O:19][CH3:20])[CH:4]=2)=[CH:24][CH:23]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1
Product: COc1cc(CNCCc2ccc(F)cc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 94.7 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 4-fluorophenethylamine (0.0256 g, 0.184 mmol) gives the title compound (0.0689 g. 94.9%): TOF MS ES+ 396.2 (M+H)+, HRMS calcd for C22H23N3O3F 396.1723 (M+H)+found 396.1714, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.1 min, 100% purity.
Reaction SMILES: [CH2:1]([C@H:7]([CH:11]([OH:32])[CH2:12][CH:13](OC1CCCCO1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:8](O)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([C@@H:7]1[CH:11]([OH:32])[CH2:12][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:33][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O
Reactant: CCCCCCCCCCCC(CC(O)[C@@H](CCCCCC)C(=O)O)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCCCCCCCCC1CC(O)[C@@H](CCCCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.4 g of a diastereomer mixture of 2-hexyl-3-hydroxy-(R)-5 [(tetrahydro-2H -pyran-2-yl)oxy]hexadecanoic acid are dissolved in 160 ml of ethanol and 800 mg of toluene-4-sulphonic acid monohydrate are added. The reaction mixture is heated to 55°-60° C. until the reaction has finished. The solvent is removed in vacuo and the residue is dissolved in 160 ml of dichloromethane. The solution is stirred at room temperature for 1 hour. The reaction mixture is evaporated. The material obtained is chromatographed on silica gel. There is obtained tetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2H-pyran-2-one, m.p. 95°-96° C.
Reaction SMILES: CS([O: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][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O.[CH2:28]([OH:40])[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]O.C(O[K])(C)(C)C>C(OCC)(=O)C>[CH2:6]([O:5][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][OH:40])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: OCCOCCOCCOCCO
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCCCOCCOCCOCCOCCO
Temperature: 110 °C
Reaction time: 3 h

Procedure:
80.4 g of 1-docosanyl methanesulfonate was added to 207 mL of tetraethylene glycol, and the mixture was heated at 110° C. 40.0 g of t-butoxypotassium was gradually added over 2 hours. The mixture was further stirred for 3 hours, and after cooling, the reaction mixture was poured into 3 L of ice water, to which was then added 2 L of ethyl acetate, the mixture was stirred, and 22.2 g of an insoluble matter was filtered. An ethyl acetate phase was extracted and separated from the filtrate, after concentration under reduced pressure, 0.5 L of acetonitrile was added, and the mixture was stirred under ice cooling for one hour. The reaction mixture was filtered under reduced pressure and washed with 0.2 L of cold acetonitrile to obtain 81.6 g of a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[Br:14]Br>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][Br:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-acetyl-benzoic acid methyl ester (8.4 mmol) in acetic acid (20 mL) was added bromine (8.4 mmol). The reaction was stirred at RT for 2 h over which time the red colour disappeared and an off white precipitate formed. The product was collected by filtration and washed with cold methanol/water (200 mL 1:1) to yield a white powder (55%). 1H NMR (400 MHz, CDCl3) 3.98 (3H, s), 4.20 (2H, s), 8.02 (2H, d, J=8 Hz), 8.18 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:14])=O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(C(C)=O)C(=O)Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Dimethylformamide (2 drops) is added to a solution, at 20° C., of 2-methoxyimino-3-oxo-butyric acid, syn isomer (4.08 g) in diethyl ether (50 cc), after which oxalyl chloride (2 cc) dissolved in diethyl ether (5 cc) is added dropwise in the course of 15 minutes. The mixture is stirred for 1 hour at 20° C., dimethylformamide (1 drop) is added again and the reaction is continued for 15 minutes. The mixture is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in petroleum ether (2×30 cc), the solvent being evaporated each time at 20° C. under 20 mm Hg (2.7 kPa). The 2-methoxyimino-3-oxo-butanoyl chloride, syn isomer, thus obtained is dissolved in methylene chloride (50 cc) and a 5.4 N solution of hydrogen chloride in ether (0.2 cc), and bromine (1.14 cc), are added to this solution at 20° C. The mixture is stirred for 20 hours at 20° C. and then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), and a brown oil (5.42 g) consisting principally of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride, syn isomer, is obtained.
Reaction SMILES: N1(C(N)=O)CC[O:4]CC1.[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:20])=S)[CH:16]=1>C(O)(=O)C.Cl.O>[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:4])=[O:20])[CH:16]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(O)=S
Reactant: NC(=O)N1CCOCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O

Procedure:
A solution of 11.07 g (30 mmole) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylthioacetic acid morpholinamide in 120 ml of glacial acetic acid and 30 ml of concentrated hydrochloric acid is boiled under reflux for 22 hours. The reaction mixture is cooled, diluted with water and extracted with methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and concentrated by evaporation in a vacuum rotary evaporator. Chromatography over silica gel with chloroform/methanol (19:1) yields 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid which after recrystallisation with methylene chloride/hexane melts at 120°-122°.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:55]1[N:60]=[C:59]([NH:61][CH2:62][CH2:63][NH:64][C:65]2[CH:70]=[CH:69]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:66]=2)[CH:58]=[CH:57][C:56]=1[N+:84]([O-:86])=[O:85]>CC#N>[N+:84]([C:56]1[CH:57]=[CH:58][C:59]([NH:61][CH2:62][CH2:63][NH:64][C:65]2[N:66]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:69][CH:70]=2)=[N:60][CH:55]=1)([O-:86])=[O:85]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccccc1

Procedure:
ethyl 6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)-2-phenylpyridine-3-carboxylate was prepared from ethyl 3-oxo-3-phenylpropanoate as the starting material and DDQ in the oxidation step. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in CH3CN and Hüing's base at 80° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 3-(2,4-difluorophenyl)-3-oxopropionate (9 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.4 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.43 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced-pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(2,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.6 g, 77%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>C1COCC1>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:10]1([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of N-Boc-3-azetidinone (0.45 g, 2.64 mmol) in THF (5 mL) was slowly added a 0.5 M solution of 2-tert-butoxy-2-oxoethyl-zinc chloride in Et2O (10 mL, 5.0 mmol), and the reaction mixture was stirred for 5 h. The reaction was then quenched with sat. aq. NH4Cl (10 mL), and the aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with 5% aq. NaHCO3 (2×10 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness to yield tert-butyl-2-(N-Boc-3-hydroxy-azetidin-3-yl)-acetate (MS m/e [M+H]+ calcd 288.2. found 287.7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7]C)=[O:6].Cl.CCOC(C)=O>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6]
Reactant: CCCOc1ccc(C(=O)OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)O)cc1Cl
Yield: 67.7 %

Procedure:
A solution of methyl 3-chloro-4-(propyloxy)benzoate (D99) (12.22 g, 0.053 mol) in ethanol (40 ml) and 2M NaOH aq. (40 ml) was heated at 60° C. for 3 hours. The reaction was allowed to cool and then left at room temperature over the weekend. The reaction mixture was poured into a mixture of dilute aq. HCl and EtOAc. The organic layer was separated, dried and evaporated to give a solid which was triturated with ether to give the title compound as a white solid (7.7 g). δH (400 MHz, d6-DMSO) 1.00 (3H, t), 1.67-1.87 (2H, m) 4.10 (2H, t), 7.24 (1H, d), 7.84-8.06 (2H, m), 12.97 (1H, br s). MS (ES) C10H1135ClO3 requires 214; found 213 (M−H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=O.OC(C(F)(F)F)=O.[NH2:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33].C[O-].[Na+]>CCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])=[O:2]
Reactant: COC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 47.4 %

Procedure:
A mixture of 4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.22 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (200 mg, 0.86 mmol) and NaOMe (93 mg, 1.72 mmol) in EtOH (2.2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 38 mg of the title compound. MS: (+) m/z 365.11 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=2)[C:12]#[N:13])[S:5][CH:6]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CCO>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=2)[C:12](=[N:20][OH:21])[NH2:13])[S:5][CH:6]=1
Reactant: N#Cc1c(F)ccc(OCc2nc(Br)cs2)c1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1c(F)ccc(OCc2nc(Br)cs2)c1F

Procedure:
To a solution of 3-((4-bromothiazol-2-yl)methoxy)-2,6-difluorobenzonitrile (0.10 g, 0.30 mmol) in EtOH (5 ml) was added hydroxylamine hydrochloride (0.103 g, 1.50 mmol) and NaOH (0.060 g, 1.50 mmol). The resulting reaction mixture was refluxed for 3 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vaccuo and used as such for the next step (crude yield 0.07 g, 63%). MS: 363.93 (M+H)+.
Reaction SMILES: [CH3:1][CH:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][Sb-:20]([F:25])([F:24])([F:23])([F:22])[F:21].[Na+]>CO>[F:19][Sb-:20]([F:25])([F:24])([F:23])([F:22])[F:21].[CH3:1][CH:2]([N+:11]([CH3:18])([CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: CC(Cl)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccc1)[N+](C)(C)c1ccccc1

Procedure:
4.218 g (0.03 mol) of α-methylbenzyl chloride and 3.638 g (0.03 mol) of N,N-dimethylaniline were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporated in vacuo and ether-water was added to the residue to extract unreacted reactants in the etherial layer. To the aqueous layer was added 7.77 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the title compound.