Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][C:6](=[O:8])[N:16]([C:14]2[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[CH3:19])[C:17]1=[S:18])[CH:2]=[CH2:3]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: C=CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 15.6 %

Procedure:
A mixture of N-allyl glycine (17.4 g), 5-chloro-2-methylphenyl-isothiocyanate (20.1 g), triethylamine (20.2 g), and methylene chloride (150 mL) was heated at reflux for 2 hours. The reaction mixture was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Recrystallization from Hexane-EtOAc afford the title compound (4.8 g) as yellow solid, m.p. 106°-109° C. Anal. Calcd. for. C13H13N2O Cl S: C, 55.61; H, 4.67; N, 9.98. Found: C, 55.45; H, 4.56; N, 9.72. Mass spectrum (EI, M.+) m/z 280.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]([OH:21])=[O:20])[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[OH:15].[C:22](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:22][O:20][C:19](=[O:21])[CH2:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[C:14]([OH:15])=[C:9]([Br:8])[CH:10]=1
Reactant: CC(=O)O
Reactant: COc1cc(CC(=O)O)cc(Br)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.409 mL, 0.818 mmol) was added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid (150 mg, 0.575 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (158 mg, 99%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:22]([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN>ClCCl>[CH3:22][NH:24][C:19](=[O:21])[CH2:18][C:17]1[C:9]2[O:8][C:7]([C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)=[CH:12][C:11](=[O:13])[C:10]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CCN(CC)CC
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CNC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (568 mg) and triethylamine (0.34 ml) were added to dichloromethane (6 ml) and to the mixture was added dropwise diphenylphosphoryl azide (0.52 ml) with stirring at room temperature. After stirring for 30 minutes, 30% aqueous methylamine solution (5 ml) was added and stirring was continued for additional 2 hours. The solvent was distilled off under reduced pressure and n-hexane was added to the residue. Crystals deposited were filtered. The crude crystals were recrystallized from methanol to obtain the title compound as prisms, yield 380 mg (64%), m.p. 213°-214° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([NH2:28])[CH:22]=1>CCO>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([NH:28][CH2:2][C:3]([C:5]2[CH:6]=[N:7][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[CH2:10][CH3:11])=[O:4])[CH:22]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: CCc1c(C(=O)CBr)cnn1-c1ccccc1
Solvent: CCO
Product: CCc1c(C(=O)CNc2cc(C(=O)OC)ccc2C)cnn1-c1ccccc1
Reaction time: 6 h
Yield: 40.4 %

Procedure:
A solution of 7.20 g (24.6 mmol) of 2-bromo-1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone and 8.52 g (51.6 mmol) of 3-amino-4-methyl benzoic acid methyl ester in EtOH (30 mL) was heated to 75° C. for 16 h. The solution was cooled and allowed to stand at rt for 6 h. The solids were filtered off and washed with cold EtOH to provide 3-[2-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-4-methyl-benzoic acid methyl ester as a white powder (3.75 g). ESI MS m/z 378 [C22H23N3O3+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]1[S:15][C:14]([CH2:16][NH:17][CH:18]=O)=[N:13][CH:12]=1)(=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([O:9][CH2:10][C:11]1[S:15][C:14]2=[CH:16][N:17]=[CH:18][N:13]2[CH:12]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCc1cnc(CNC=O)s1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1cn2cncc2s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 61116.2 %

Procedure:
A 3.8 ml potion of phosphorus oxychloride was added to 8.7 ml of a toluene solution containing 1.74 g of 5-acetoxymethyl-2-(N-formylamino)methylthiazole, followed by stirring at 100° C. for 2 hours. Then, the solvent was evaporated under reduced pressure, and to the residue, 70 ml of chloroform and 52 ml of an aqueous saturated sodium bicarbonate solution were then added. After stirring, the organic layer was separated. The aqueous layer was extracted with chloroform (26 ml×2). The combined organic layer was combined, and then washed once with the aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 974 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:10][C:11]1[C:12]([O:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: C[C@H]1CC[C@H](CO)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Temperature: 70 °C

Procedure:
To a solution of trans-(4-methylcyclohexyl)methanol (3.00 g, 23.4 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (6.43 g, 25.90 mmol) in anhydrous dimethylsulfoxide (40 mL) was added cesium carbonate (16.11 g, 49.44 mmol). The mixture was heated at 70° C. for 96 hours, and then cooled to ambient temperature; diluted with water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes gradient) to give the title compound (6.48 g 78%): 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.7 Hz, 1H), 6.61 (d, J=12.3 Hz, 1H), 3.82 (d, J=6.2 Hz, 2H), 1.91-1.73 (m, 8H), 1.56 (s, 9H), 1.17-0.96 (m, 5H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:40])[C:7]([CH2:30][CH:31]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH3:32])=[CH:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]1[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:40])[CH:7]([CH2:30][CH:31]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH3:32])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC(C)OC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC(=O)C(CC(C)OC1CCCCO1)C[C@H](O)[C@@H](N)CC(C)C
Reaction time: 4 h
Yield: 102.4 %

Procedure:
254 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)propyl]-2-propenoic acid isobutylamide was dissolved in 3 ml of ethanol. Then, a palladium black catalyst was added thereto, and hydrogen was continuously blown into the solution under atmospheric pressure for 4 hours. Then, the catalyst was filtered off, and a fresh palladium black catalyst was added. Then, hydrogen was continuously brown into the solution for further 4 hours. The catalyst was filtered off, and the reaction solution was concentrated and dried under reduced pressure to obtain 180 mg of (2RS,4S,5S)-5-amino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)propyl]-7-methyl-octanoic acid isobutylamide as a solid substance.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.Cl.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH:36]1[CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44].C(=O)([O-])[O-].[K+].[K+]>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([N:11]1[CH2:10][CH2:9][N:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[C@@H:7]([CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH:36]2[CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:12]1)(=[O:14])=[O:15]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CS(=O)(=O)NCC1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CNS(C)(=O)=O)cc1)C(F)(F)F

Procedure:
This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and N-(3-morpholinylmethyl)methanesulfonamide hydrochloride (published PCT patent application no. WO 2009/016410) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered N-((4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide as a mixture of four isomers.
Reaction SMILES: [CH2:1]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>O>[CH2:1]([C:13]1[CH:22]=[C:21]([N+:28]([O-:30])=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCc1ccc2ccccc2c1O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCc1cc([N+](=O)[O-])c2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 parts of 2-n-dodecyl-1-naphthol in 500 parts of glacial acetic acid was added 28 parts of nitric acid (specific gravity 1.4). The solution was stirred at ambient temperature for 1 hour and then poured into 2000 parts of water. The resulting mixture was extracted with 1400 parts of ether. The ether layer was separated; washed once with water (2000 parts), twice with 10% aqueous sodium bicarbonate solution (2000 parts), and finally with water (2000 parts). The ether solution was dried with anhydrous magnesium sulfate and evaporated to afford 56 parts of 2-n-dodecyl-4-nitro-1-naphthol as a viscous yellow oil, nD25 = 1.5454, which slowly crystallized to a waxy yellow solid on standing.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[F:15])#[CH:2].[N:16]([CH:19]1[CH2:25][CH2:24][C:23]2[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:20]1=[O:36])=[N+:17]=[N-:18]>>[F:30][C:26]1[C:23]2[CH2:24][CH2:25][CH:19]([N:16]3[CH:2]=[C:1]([C:3]4[CH:8]=[CH:7][C:6]([C:9]5[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=5)=[CH:5][C:4]=4[F:15])[N:18]=[N:17]3)[C:20](=[O:36])[N:21]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:22]=2[CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(-c2ccncc2)cc1F
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2N(CC(F)(F)F)C1=O
Product: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Yield: 43.6 %

Procedure:
Following GP 3, the title compound (32 mg) was prepared using 4-(4-ethynyl-3-fluorophenyl)pyridine (29 mg) and 3-azido-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (58 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C)(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to afford an off-white solid. HPLC (Condition 4) tR=4.75 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=460.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 3H) 2.68 (s, 3H) 3.58 (s, 4H) 5.47 (s, 1H) 7.26-7.40 (m, 2H) 7.77-7.92 (m, 2H) 8.04 (d, J=2.35 Hz, 1H) 8.67-8.82 (m, 3H) 10.19 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([NH:34][C@@H:32]([C:29]3[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=3)[CH3:33])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(tetrahydrofuran-3-yloxy)biphenyl-3-carboxylic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=O>C(Cl)Cl>[CH2:12]([C@@H:7]([C:8]1[C:9](=[O:11])[O:10][C:8]2[CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:15]=2[C:14]=1[OH:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC[C@@H](CC(=O)O)c1ccccc1
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)c1c(O)c2c(oc1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3[S]-Phenylvaleric acid of formula WW-3 (400 mg) is added to methylene chloride (5 mL) followed by oxalyl chloride (0.21 mL). That mixture is heated at reflux for 3 hours. The methylene chloride is removed and 1,3,5-trimethylbenzene (10 mL) is added. The solution of the acid chloride is then heated to reflux temperatures and WW-2 (same as VV-2) (210 mg) and triethylamine (210 mg) (both in 1.5 mL of 1,3,5-trimethylbenzene) are added dropwise. After complete addition the reaction is heated for an additional 7 hours. The reaction is cooled to room temperature and the solid removed by filtration. The filtrate is evaporated and the resulting residue is diluted with methanol (35 mL) and 0.5N NaOH (4 mL) and that mixtured stirred at room temperature overnight. The methanol is removed and water (35 mL) added. The aqueous is extracted with ether/hexane (2×35 mL) and the aqueous is acidified with 1.6N HCl at 0° C. to pH 3. That aqueous is extracted with ethyl acetate, dried and solvent removed in vacuo to yield 287.0 mg of the title product. Chromatography over silica gel (EtOAc/methylene chloride 1:8) affords 199.4 mg of the title product WW-5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[N:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Br)(Br)[Br:20].O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Br:20])=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Br
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A suspension of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately room temperature—may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][NH2:11].[BH4-].[Na+]>C1COCC1>[CH3:10][NH:11][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: CN
Reactant: O=Cc1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1ccccc1Br
Reaction time: 8 h
Yield: 58 %

Procedure:
29.4 g of o-Bromobenzaldehyde and 81 ml of aqueous, 40% methylamine solution are combined with 238 ml of THF and at RT 19 g of NaBH4 are added in batches within 25 minutes. The mixture is left to stand overnight at RT, concentrated using a rotary evaporator, and the residue is stirred into ice water. The aqueous phase is extracted twice with ether and the combined ether phases are evaporated down under reduced pressure. After chromatography on silica gel with ethyl acetate or ethyl acetate/methanol (4:1) as eluant, 18.5 g of N-methyl-2-bromobenzylamine (a) are obtained in the form of a yellowish liquid. Yield: 58%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1>>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])=[N:25]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccn(C)n1
Yield: 62.5 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmol) and 1-methyl-1H-pyrazol-3-amine (421 mg, 4.33 mmol) following the experimental procedure described in Preparation 27a. 680 mg (36% yield) of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([S:10]([NH:14][C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])(=[O:12])=[O:11])=[CH:4][C:5]=1[F:9]
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1cc(F)c(Br)cc1F
Yield: 72.5 %

Procedure:
Prepared from 2,5-difluoro-4-bromobenzenesulfonyl chloride (2 g, 6.9 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (858 mg, 6.9 mmol) in pyridine (30 ml) according to the method of intermediate 1, to give the title compound as a pale yellow solid (1.9 g, 5.0 mmol, 73%). δH (D-6 DMSO, 300K) 9.77 (1H, s), 8.12 (1H, dd, J=5.5 Hz 9.0 Hz), 7.55 (1H, dd J 6.Hz 7.5 Hz), 3.58 (3H, s), 1.92 (3H, s), 1.74 (3H, s). m/z (ES+, 70V) 380.0 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CO>[CH3:14][N:15]([CH3:17])[CH:16]=[N:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(C(N)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CSc1cccc(C(=O)N=CN(C)C)c1

Procedure:
8.5 g of 3-methylsulfanylbenzamide and 18 ml of dimethylformamide dimethyl acetal were heated at 120° C. while the formed methanol was eliminated by distillation. After heating for 3 h, the volatiles were removed in vacuo. The crude product was purified by flash chromatography (300 g silica gel; DCM/MOH, gradient from 100:0 to 95:5). 8 g of the title compound were obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:24])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:24])([CH3:25])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (9.80 g) in tetrahydrofuran (6 mL) is added dropwise to an ice cooled solution of methyl magnesium bromide (1.4 M in toluene/tetrahydrofuran 75:25, 74 mL). The reaction mixture is stirred for 30 min in the cooling bath and then at room temperature for 1 h. The mixture is poured into aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. Since the residue still contains a considerable amount of starting material, it is azeotropically dried using toluene and resubmitted to the procedure described above. The crude product is purified by preparative HPLC (column: Waters X-Bridge C18; mobile phase: water+0.125% NH4OH/methanol 90:10→100:0) to give the title compound. LC (method 4): tR=1.33 min; Mass spectrum (ESI+): m/z=433, 435 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[CH3:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:19]2[N:13]([CH3:12])[C:14](=[O:15])[NH:16][C:17]2=[O:18])[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: CN1CC(=O)NC1=O
Product: CN1C(=O)NC(=O)C1=Cc1cc(Br)c(O)c(Br)c1
Yield: 72.7 %

Procedure:
Prepared according to the procedure described in Example 99 using 3,5-dibromo-4-hydroxybenzaldehyde (8.4 g, 30 mmoles) and 1-methyl hydantoin (3.5 g, 30 mmoles) to afford the pure product (8.2 g), mp 271°-277° C.