Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc(Br)ccn1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3ccnc(C#N)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=330.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:15].[BH4-].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([CH2:6][OH:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=C1OCc2c(F)cc(C(F)(F)F)cc21
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cc(C(F)(F)F)cc(F)c1CO

Procedure:
Prepared in analogy to Example A16(a) from 4-Fluoro-6-trifluoromethyl-3H-isobenzofuran-1-one e and sodium borohydride. Colorless oil. MS (m/e): 225.1 ([M+H+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([Br:19])[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnn(C2CCNCC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.515 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). The reaction was stirred at room temperature until LCMS indicated completion of the reaction. The solvents were removed in vacuo, and the residue was dissolved in MeOH (15 mL). The pH of the solution was adjusted to 9 with hydroxide resin to afford 4-(4-bromo-pyrazol-1-yl)-piperidine.
Reaction SMILES: [N+]([CH2:3][C:4](OCC)=O)#[C-].[C-]#N.[Na+].N#[C-].[CH2:14]([O:16][C:17]([C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH3:24])=[O:18])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH2:24][CH2:3][CH3:4])=[O:18])[CH3:15]
Reactant: CCOC(=O)c1ncsc1C
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCCc1scnc1C(=O)OCC
Reaction time: 0.08 h

Procedure:
A solution of 2.25 g. (0.02 m) of ethyl isocyanoacetate and 2.08 g. (0.02 m) 0-ethyl thioacetate in 10 ml. absolute ethanol is added dropwise to a suspension of 0.25 g. sodium cyanide in 10 ml. absolute ethanol. After 5 minutes a mild exotherm occurs and the temperature rises to from 22° to 32° C. remaining there for about 1/2 hour. The reaction mixture is then heated at 50° C. for 8 hours at which time the smell of isonitrile is gone. The reaction mixture is then evaporated to dryness in vacuo leaving a dark oil which is extracted several times with hot hexane. The hexane is evaporated affording 2.8 g. (82%) of a tan solid which is the desired 4-ethoxycarbonyl-5-methylthiazole. This solid is recrystallized from ether/hexane affording a pure product with a m.p. 89°-90° C. Following the foregoing procedures employing 0-ethyl thiobutyrate in place of 0-ethyl thioacetate, there is obtained 4-ethoxycarbonyl-5-(n-propyl) thiazole with a boiling point of 85°-87° C. at 0.15 mm of Hg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[Br:13]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:13][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)c1cnccn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1cnccn1
Temperature: 25 °C

Procedure:
A carbon tetrachloride (150 mL) solution containing the intermediate from Step B (18 g, 108 mmol), N-bromosuccinimide (26.6 g, 150 mmol) and AIBN (0.5 g) was heated at reflux overnight. The solution was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. m/z=245.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1
Reactant: CO
Reactant: Nc1ccnc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccn1

Procedure:
Prepared analogously to example 366a from 4-aminopicolinic acid and sulfuric acid in methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1([F:17])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15]O)=[CH:14][C:8]=2[O:7]1>ClCCl>[Cl:3][CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:6]([F:17])([F:5])[O:7][C:8]=2[CH:14]=1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) in dichloromethane (200 mL) at 0° C. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was partitioned between an aqueous solution of saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 mL) and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) which was used directly in the next step.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[Cl:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[C:28]1[C:29]([C:34]([OH:36])=O)=[CH:30][CH:31]=[CH:32][CH:33]=1>O>[Cl:20][C:21]1[C:22]2[C:28]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34](=[O:36])[C:23]=2[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a mixture of phosphorus pentoxide (150 g) and methanesulfonic acid (1500 ml) was added 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid (153 g), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to 0° C. While keeping the temperature of the reaction mixture at 90° C. or below, water (1500 ml) was added dropwise, and the mixture was further stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with water (1000 ml). The solid was suspended in 50 v/v % ethanol-water (1500 ml), and the slurry was stirred at room temperature for 2 hr, and filtered. The obtained solid was air-dried for 1 hr and dried under reduced pressure at 80° C. to give the title compound (140.12 g, 99%).
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4](N1C(C2C=CC=CC=2)COC1=O)=[O:5].[O:28]1CCCC1.OO.[OH-].[Li+]>O>[OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4]([OH:5])=[O:28]
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC1c1ccccc1)[C@H](O)c1ccccc1
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of 65.0 g (179 mmol) of 4S)-3-{(2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoyl}-4-phenyl-1,3-oxazolidin-2-one from Step B above in 1050 mL of a 20 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 77.0 mL (894 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 395 mL (395 mmol) of a 1.0 M aqueous lithium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 5° C. All volatiles were removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3×200 mL). The aqueous phase was then cooled to 0° C. and acidified with a 6 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×300 mL) and the combined organics were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient to afford the title compound as a colorless gum (32.0 g, 82.0%). 1H NMR (500 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.85 (d, J=8.2, 1H), 3.03-2.97 (m, 1H), 2.29-2.15 (m, 2H), 1.97 (t, J=2.5 Hz, 1H), 1.93-1.82 (m, 1H), 1.62-1.55 (m, 1H). LC-MS: m/z (ES) 201.0 (MH—H2O)+.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]2([CH2:36][OH:37])[CH2:35][O:34][CH2:33]2)[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (103.5 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (135.7 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 28.8%).
Reaction SMILES: [Na].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([CH2:15][CH2:14][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC(=O)C(CCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Sodium (2.3 g; 0.10 mol) was allowed to react with dry ethanol (50 ml) under nitrogen. The resulting clear solution was cooled (ice bath) and t-butyl acetoacetate (15.8 g; 0.10 mol) was added during 10 minutes with stirring. After 10 minutes, 2-(bromoethyl)benzene (18.5 g; 0.10 mol) was added during 30 minutes. The resulting solution was heated at reflux for 4 hours, then cooled and filtered. After concentration, the residue was partitioned between water and ether, and the ether layer was dried (MgSO4) and concentrated. Distillation of the residue gave 21.0 g (0.080 mol; 80%) of the title product; bp 110°-120° (0.3 mm). NMR (CDCL3); 1.45 (9H,s), 2.17 (3H,s), 1.8-2.4 (2H,m), 2.5-2.7 (2H,m); 3.28 (1H,J=7); 7.2-7.4 (5H, broad s). MS (m/e); 262 (M+).
Reaction SMILES: [OH:1][CH:2]([CH2:29][OH:30])[CH2:3][O:4][NH:5][C:6]([C:8]1[N:16]([CH:17]2[CH2:19][CH2:18]2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:7].CC1(C)O[C@@H](CON)CO1>>[OH:1][C@H:2]([CH2:29][OH:30])[CH2:3][O:4][NH:5][C:6]([C:8]1[N:16]([CH:17]2[CH2:18][CH2:19]2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:7]
Reactant: O=C(NOCC(O)CO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: CC1(C)OC[C@H](CON)O1
Product: O=C(NOC[C@H](O)CO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1

Procedure:
The title compound was prepared in an analogous fashion to 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2,3-dihydroxy-propoxy)-amide, replacing O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine with O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine. 1H-NMR (500 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 8.53 (s, 1H), 8.32 (d, J=5.86 Hz, 1H), 7.57 (d, J=5.69 Hz, 1H), 7.53-7.48 (m, 2H), 7.20 (d, J=8.06 Hz, 1H), 6.26 (t, J=8.81 Hz, 1H), 4.87 (d, J=4.05 Hz, 1H), 4.60 (t, J=5.43 Hz, 1H), 3.94 (dd, J=9.88, 2.80 Hz, 1H), 3.76 (t, J=8.0 Hz, 1H), 3.70 (broad s, 1H), 3.56-3.45 (m, 1H), 3.40-3.34 (m, 2H), 1.15-1.08 (m, 2H), 0.88-0.83 (m, 2H); LC-MS (method E): [M+H]+=527.1, RT=7.31 min.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]([C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1)([CH3:28])([CH3:27])[CH3:26].C1C=CC=CC=1.C[O-].[Na+]>[I-].[K+].CO>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:30]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 48.9 %

Procedure:
To a mixture of 8.27 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate, 3.75 g of m-tert.-butylphenol, 10 ml of benzene and 40 ml of methanol is added 1.19 g of sodium methoxide and 50 mg of potassium iodide. The mixture is refluxed for 24 hours and the solvent removed under reduced pressure. To the residue is added acetone and hexane and the mixture is filtered. The filtrate is dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil is chromatographed over silica gel with dichloromethane as eluent to give 4.72 g of product as a colorless viscous oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC#Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC#Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Phenyl-prop-2-yn-1-ol 37 (3.0 g, 22.7 mmol) is dissolved in DCM (50 mL). The solution is cooled to 0° C., then methanesulfonyl chloride (4.5 mL, 34.1 mmol) and triethyl amine (4.7 mL, 34.1 mmol) is added. The mixture is allowed to warm to room temperature and stirred overnight at room temperature. The mixture is washed with H2O (2×30 mL). The organic layer is dried (MgSO4), filtered, and concentrated to afford crude methanesulfonic acid 3-phenyl-prop-2-ynyl ester 38 as a clear oil: 1H-NMR (400 MHz, CDCl3) δ=7.47-7.32 (m, 5H), 4.38 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([CH:17]([OH:21])[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH:23]([CH3:25])[CH3:24])[CH:12]=1)[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH:23]([CH3:25])[CH3:24])[CH:12]=1)[CH3:2]
Reactant: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OC(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Product: CCCC(=O)c1cnc(-c2c(CC)cccc2CC)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[6-(2,6-diethyl-phenyl)-4-isopropoxy-pyridin-3-yl]-butan-1-ol (482 mg, 1.41 mmol, prepared analogously to Example 16) and pyridinium dichromate (1.0 g, 2.82 mmol) in CH2CH2 (50 mL) is stirred at room temperature overnight. The mixture is washed with brine, dried and concentrated. The residue is chromatographed on silica gel to give 360 mg of 1-[6-(2,6-diethyl-phenyl)-4-isopropoxy-pyridin-3-yl]-butan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C:23]([F:26])([F:25])[F:24])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1cc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)COc1cc(Cl)ncc1Cl
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a solution of 2,5-dichloropyridin-4-ol (CAN 847664-65-7, 1.5 g, 9.15 mmol) in DMF (15 ml) in a microwave vial were added cesium carbonate (4.47 g, 13.7 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.18 g, 13.7 mmol). The vial was sealed and heated at 90° C. overnight. The reaction mixture was diluted with ethylacetate and extracted with water. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. Organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with a heptane/ethylacetate gradient on silica to yield the titled compound as a colorless oil (1.33 g, 59%). MS (ESI, m/z): 246.2 (M+H+).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][C@@H:41]1[CH2:46][OH:47])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:30])([F:32])[F:31])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:42][C@@H:41]1[CH2:46][OH:47])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(OC)cc3C(F)(F)F)c2)S1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C(=O)OC(C)(C)C)[C@@H](CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(2R)2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](Cl)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)CC(C)C)oc2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)oc2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a mixture of 5-chloro-2-(1-chloro-3-methylbutyl)-3-methyl-1-benzofuran (668 mg) synthesized above, methyl 4-aminobenzoate (410 mg), sodium iodide (737 mg) and N,N-dimethylformamide (10 mL) was added sodium carbonate (521 mg) and the mixture was stirred at 80° C. for 8 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred with heating under reflux for 8 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (394 mg, 43%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>CN(C=O)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])=[O:37]
Reactant: O=C=Nc1ccccc1F
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)Nc3ccccc3F)cc2s1
Yield: 26 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 2-fluorophenyl isocyanate in DMF was reacted to give the desired compound 0.022 g (26%). LC/MS 430.01 (M+1); LC retention time 2.89 min.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:21]#[N:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[N:5]=[C:6]([C:21]#[N:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CC(=O)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 3-acetyl-4-(3-fluorophenyl)isoquinoline-1-carbonitrile (4 mg, 0.01 mmol) and ammonium acetate (10.6 mg, 0.138 mmol) in methanol (0.078 mL) and acetonitrile (0.078 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (1.7 mg, 0.028 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C18H15FN3 (M+H)+: m/z=292.1; Found: 292.1.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClC1C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:4]2[C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[S:7][C:3]=2[N:2]([CH3:12])[CH3:1])=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: CN(C)c1cc2ccccc2s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Clc1ccccc1
Product: CN(C)c1sc2ccccc2c1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
A mixture of 5.00 g (28.2 mmol) of 2-dimethylaminobenzo[b]thiophene (Vesterager et al., Tetrahedron, 1973, 29, 321-329) and 6.3 g (33.9 mmol) of 4-nitrobenzoyl chloride in 100 mL of chlorobenzene was heated at 105° C. for 6 h. The reaction was cooled and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2; 5% then 10% then 25% EtOAc in hexanes) afforded 7.51 g (23.0 mmol; 82%) of the title compound as burgundy flakes.