Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].F[B-](F)(F)F.N1([O:45][C:46](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH:46]=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C=O)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.248 g, 0.604 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.263 g, 0.819 mmol) and Formic acid (0.0346 mL, 0.917 mmol) were combined then added dry N,N-Dimethylformamide (2.50 mL, 32.3 mmol) followed by N,N-Diisopropylethylamine (0.583 mL, 3.35 mmol). The reaction mixture stirred for overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.23 (d, J=20.5, 1H), 8.17 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.16 (t, J=5.1, 1H), 4.64 (dd, J=18.2, 11.9, 1H), 4.41 (dd, J=73.9, 18.2, 1H), 3.91 (d, J=17.0, 1H), 3.84 (d, J=11.1, 1H), 3.76 (dd, J=15.6, 12.5, 2H), 3.70-3.61 (m, 2H), 3.59-3.36 (m, 3H), 3.18-3.05 (m, 2H), 2.85-2.58 (m, 2H), 1.91-1.65 (m, 2H), 1.06 (t, J=7.2, 3H), 0.89-0.77 (m, 3H). LC/MS-m/z+439.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=O.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9]/[C:10](/[C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=[N:31]\[OH:32]
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(2-chloro-phenyl)-3-(4-methanesulfonyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=445.2 [M+H]+.
Reaction SMILES: [NH:1]([C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:8][CH:7]=1)[NH2:2]>CC(O)=O.[Pd]>[NH:1]([C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[NH2:2]
Reactant: NNC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: NNC(=O)COc1ccc(C(=O)O)cc1
Yield: 43.2 %

Procedure:
In an Parr autoclave, a solution of benzyl 4-(2-hydrazino-2-oxoethoxy)benzoate (400 mg, 1.3 mmol) and a catalytic amount Pd/C in AcOH (25 mL) was stirred under hydrogen pressure (5 Bars) at rt for 45 min. After filtration over celite, the filtrate was evaporated off. The residue was taken up in MeOH and a beige solid precipitated out. Filtration and drying under vacuo at 50° C. overnight gave the title compound as a beige solid (118 mg) in a 42% yield.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=2)[CH:19]=[CH:20][CH:21]=[O:22])=[CH:13][CH:12]=1>O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:13][CH:12]=1
Reactant: COCCOCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(COCCOC)n1
Reaction time: 1 h

Procedure:
Ethyl acetoacetate dianion (2.1 mL of freshly prepared 1M solution as described in Example 10) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2,4-pentadienal (0.9 g, 2.0 mmoles) in 15 mL of tetrahydrofuran at -50° C. After stirring for 1 hour, another 1 mL of dianion solution was added and the mixture stirred for an additional 30 minutes. The reaction mixture was quenched with 1N HCl and then extracted with methylene chloride. The organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 0.55 g of the title compound. MS (CI): m/e=557 for (M+H)+ ;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:13]1=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(O)(O)[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1.[F-].[Cs+]>O1CCCC1.C(OCC)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH:17]=[C:16]([C:43]2[C:44]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[CH:41][CH:42]=2)[CH:15]=[C:14]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:13]1=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccccc1)n1cc(Br)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccccc1)n1cc(-c2cccc3ccccc23)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of (S)-2-[5-bromo-2-oxo-3-(4-trifluoromethylbenzoylamino)-2H-pyridin-1-yl]-3-phenylpropionic acid methyl ester from Step E (66.8 mg, 0.128 mmol), 1-naphthyleneboronic acid (44.0 mg, 0.256 mmol), cesium fluoride (97 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform complex (13.0 mg, 0.013 mmol) and bis(tri-t-butylphosphine)palladium(0) (16.0 mg, 0.031 mmol) in tetrahydrofuran (2.0 mL) was heated to reflux for 15 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (100 mL), washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated. Purification by medium pressure liquid chromatography on silica gel (1:5 ethyl acetate/hexanes) gave 59 mg (81%) of the title compound as a semisolid. MS 571.2 (M+H)+.
Reaction SMILES: [OH-].[K+].[C:3]1(C)C=CC=CC=1.[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(OC)(OC)(=O)=O>O>[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:3])=[O:25])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Reactant: Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
85% Potassium hydroxide (0.79 g, 12.0 mmol) and toluene (20 ml) were added to (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (2.70 g, 10.0 mmol) and dissolved by heating to 50° C. After 10 minutes, the solution was concentrated under reduced pressure. Toluene (20 ml) was added to the residue, and dimethyl sulfate (1.32 ml, 14.0 mmol) was added dropwise under ice-cooling and reacted at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-(2-phenoxyphenyl)-2-methoxyimino-N-methylacetamide (2.33 g, Yield: 82.1%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]2[N:10]=[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH3:13][N:12]1[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:30]=[CH:29][C:9]=2[N:10]=[C:11]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CCOC(=O)c1ccc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)O)cc21
Yield: 95.4 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (2.5 g) was prepared by following General Procedure E starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid ethyl ester (2.8 g) and 2 N NaOH (6 mL) in methanol:THF (1:1, 12 mL).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[OH:20]O>C(O)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][OH:14])=[O:20]
Reactant: CC(C)(CO)CCCCSCCCCC(C)(C)CO
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CO)CCCCS(=O)CCCCC(C)(C)CO
Temperature: 25 °C
Reaction time: 22 h
Yield: 104.4 %

Procedure:
To a solution of 6-(5,5-dimethyl-6-hydroxy-hexyl-sulfanyl)-2,2-dimethyl-hexan-1-ol 5.1 g, 17.5 mmol) in glacial acetic acid (25 ml) was added hydrogen peroxide (50 wt. % in water; 1.20 g; 17.5 mmol). The reaction mixture was stirred at rt for 22 h, then diluted with water (200 ml), and extracted with chloroform (2×150 ml). The combined organic phases were subsequently washed with saturated NaHCO3 solution (3×100 ml) and saturated NaCl solution (100 ml), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give crude product (5.60 g; 105%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppp=3.29 (AB, 2 H, J=12.2); 3.27 (AB, 2 H, J=12.2); 2.70 (m, 4 H); 2.48 (s br, 2 H); 1.76 (m, 4 H); 1.44 (m, 4 H); 1.30 (4 H); 0.87 (s, 6 H); 0.86 (s, 6H). 13C NMR (75 MHz, CDCl3) δ ppp=76.80; 71.39; 52.20; 38.08; 35.15; 24.21; 24.03; 23.66; 23.26. Calcd. for C16H35SO3 (MH+): 307.2307, found 307.2309.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[NH:16])[CH:9](OCC)OCC)=[CH:4][CH:3]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:18]=[C:17]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:7][C:8]([NH2:16])=[CH:9]2
Reactant: CCOC(OCC)C(=N)NCc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2cc(Br)ccc2cn1
Yield: 40.1 %

Procedure:
N-(4-bromobenzyl)-2,2-diethoxyacetimidamide (1.53 g, 4.85 mmol) in sulfuric acid (4 mL, 95-98%) was heated at 40 C for 14 h. The mixture was neutralized with 1 M NaOH to pH 7 and the resulting suspension was filtered. The residue was purified by silica gel chromatography with 20-55% ethyl acetate in hexanes. The desired fractions were concentrated to give a brownish yellow solid (0.434 g, 40%). LCMS: R.T.=1.62; [M+2]+=225.1.
Reaction SMILES: [F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)CC1(F)Cl
Product: CC1(C(=O)Cl)CC1(F)Cl
Yield: 95.7 %

Procedure:
In a distillation equipment, a mixture of 51 g (0.33 mol) of 2-fluoro-2-chloro-1-methylcyclopropanecarboxylic acid and 60 g (0.5 mol) of thionyl chloride is heated slowly with stirring, during which process excess thionyl chloride distils over first and the desired product later. In this manner, 54 g (97% of theory) of 2-fluoro-2-chloro-1-methylcyclopropanecarbonyl chloride are obtained in the form of a liquid of boiling point 82°-85° C./100 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[Br:15]/[C:16](=[CH:20]\[CH3:21])/[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Br:15]/[C:16](=[CH:20]\[CH3:21])/[C:17]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:18]
Reactant: C/C=C(\Br)C(=O)Cl
Reactant: Nc1cccc(F)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C/C=C(\Br)C(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a stirred solution of 4.2 grams (0.038 mole) of 3-fluoroaniline in 35 ml of chloroform was added 3.1 ml of pyridine. The reaction mixture was cooled to 0° and 7.0 grams (0.038 mole) of [Z]-2-bromo-2-butenoyl chloride (Step C product) was added dropwise at such a rate that the reaction mixture temperature did not exceed 10°. Upon completion of addition, the reaction mixture was stirred at 0° for one hour, then was allowed to warm to ambient temperature where it was stirred for 16 hours. The reaction mixture was washed with 10 ml of water, two portions of 10 ml each of aqueous 0.1N hydrochloric acid, 10 ml of water, and finally 10 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was crystallized from hexane using silica gel as a decolorant to give 6.7 grams of [Z]-2-bromo-N-(3-fluorophenyl)-2-butenamide; mp 44°-45.5°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][O:11][C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN1CCCC1=O>[CH3:10][O:11][C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[OH:1])[CH:15]=1
Reactant: NCc1ccccc1O
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(CNCc2ccccc2O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A mixture of 2-hydroxybenzylamine (407 mg) and (3-formylphenyl)acetic acid methyl ester (594 mg) in dichloromethane (10 mL) and 1-methyl-2-pyrrolidone (10 mL) was treated with acetic acid (333 mg) followed by sodium triacetoxyborohydride (1.41 g) and the whole stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was washed twice with saturated aqueous brine before being separated, dried and evaporated under reduced pressure to yield the sub-titled compound (0.81 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH:21]1[CH2:23][CH2:22]1.O>ClCCl>[CH2:10]([O:9][C:7](=[O:8])[C:6]([C:18]1[CH:17]=[CH:16][C:15]([S:20][CH:21]2[CH2:22][CH2:23]2)=[C:14]([Br:13])[CH:19]=1)=[O:12])[CH3:11]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Brc1ccccc1SC1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a suspension of aluminum chloride (40.2 g) in dichloromethane (1200 mL) was added dropwise ethyl chloro(oxo)acetate (32.3 g) at 0° C., followed by stirring at the same temperature for 1 hour. To the reaction mixture was added dropwise a solution of 1-bromo-2-(cyclopropylsulfanyl)benzene (49.3 g) in dichloromethane (280 mL) while keeping it at 5° C. or lower, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and water was added thereto to stop the reaction. The reaction mixture was extracted with ethyl acetate and the organic layer was sequentially washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The solution was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography to obtain ethyl[3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetate (29.8 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(C)(=O)=O)c1)N2
Yield: 32.7 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) in dichloromethane (3 mL) was added pyridine (79 mg, 1.01 mmol) in dichloromethane (2 mL) and methanesulfonyl chloride (96 mg, 0.84 mmol) under nitrogen. The resultant mixture was stirred for 16 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 63 mg of N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide as yellow solid (Yield: 33%). MS (ESI+APCI) M+1=345.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[N:4]=1.[H][H]>[Ni]>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8]([NH2:9])=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: COc1nc(N2CCc3ccccc3C2)nc(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1N

Procedure:
A suspension of Raney®-Nickel in a methanolic solution of 4b (0.57 g in 50 ml, 1.8 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.51 g, 1.78 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([F:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:15]([O-])=O.[Na+]>O.C(O)(=O)C>[F:14][C:9]1[CH:10]=[CH:11][C:12]2[N:13]=[N:15][NH:1][C:2]=2[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(F)ccc(N)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(F)ccc2nn[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
ethyl 2,3-diamino-6-fluorobenzoate (1.00 g, 5.04 mmole) in 50 ml of water and 10 ml acetic acid was cooled to −10° C. To this solution was added dropwise sodium nitrite (348 mg, 5.04 mmole) in 30 ml of water. After the addition the reaction was warmed to 0° C. for 30 min, then to room temperature for 1 hr, and finally 50° C. for 1 hr. The reaction was filtered after stirring over night and washed with water. The dark brownish purple solid was dissolved in ethylacetate dried over magnesium sulfate and evaporated to afford ethyl 6-fluoro-1H-1,2,3-benzotriazole-7-carboxylate (920 mg, 87% yield) 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.3 (t, J=7.1 Hz, 3H) 4.4 (q, J=7.0 Hz, 2H) 7.2 (dd, J=11.2, 9.0 Hz, 1H) 8.1 (dd, J=9.1, 4.1 Hz, 1H).
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=1)\[CH2:5][C@H:6]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:39][C:35]1[CH:34]=[C:33](/[C:4](=[N:3]/[OH:2])/[CH2:5][C@H:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=3)=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)=N/O)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(/C(C[C@H](c2ccc(C3=CCNCC3)cc2)c2ccccc2C)=N/O)ccn1
Temperature: 50 °C
Yield: 55.3 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 0.22 mL, 0.88 mmol) was added to a solution of (R,E)-tert-butyl 4-(4-(3-(hydroxyimino)-3-(2-methylpyridin-4-yl)-1-o-tolylpropyl)-phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (45 mg, 87.9 μmol) in 1,4-dioxane (4 mL). The reaction mixture was heated for 17 h at 50° C., then treated with sat. aq. sodium hydrogen-carbonate solution (4 mL) and partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The crude material was triturated with ethyl acetate to afford the title compound (20 mg, 55%). Off-white solid, MS (ESI+): m/z=412.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:40])[C:22]([OH:39])([C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[N:32]([CH3:37])[C:31]=2[CH:38]=1)[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.CC(=CC)C.Cl([O-])=[O:47].[Na+].P([O-])(O)(O)=O.[Na+].Cl>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:40])[C:22]([OH:39])([C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[N:32]([CH3:37])[C:31]=2[CH:38]=1)[C:23]([F:24])([F:26])[F:25])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:47])=[O:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a suspension of 4-{3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxy}-2-trifluoromethyl-benzaldehyde (87 mg, 0.15 mmol) in tert-butanol (0.8 ml) were added 2-methyl-2-butene (52 mg, 0.74 mmol) and a solution of sodium chlorite (17 mg, 0.19 mmol) and sodium dihydrogen phosphate dehydrate (27 mg, 0.19 mmol) in water (0.6 ml) at 2° C. The mixture was stirred for 5 min. at 2° C., 17 h at r.t. and 1.5 h at 40° C. Ice water was added and the mixture was acidified using 1 M aqueous HCl. The mixture was extracted twice with AcOEt. The organic layers were washed with brine, dried (MgSO4) and concentrated. The product was purified by column chromatography (silica gel, dichhloromethane/methanol 9:1) to give the title compound (67 mg) as a white solid. MS (m/e, ISP neg. ion)=602.3 [M−H+].
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5].[CH3:17][O-:18].[Na+].O.Cl>COCCOC>[CH3:17][O:18][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(-c2ccccc2)nc(Cl)c1C#N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(-c2ccccc2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2-chloro4-methyl-6-phenyl-nicotinonitrile (455 mg, 1.99 mmol) was dissolved in 20 mL of DME, added with 95% sodium methoxide (1.13 g, 19.90 mmol) and then stirred at room temperature for about 1 hour. The mixture was added to cool water and was adjusted to have a pH of about 6 to 7 with 10% HCl and then extracted with ethyl acetate. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the resulting residue and 370 mg (83%) of 2-methoxy-4-methyl-6-phenyl-nicotinonitrile was obtained in white solid.