Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.I[CH3:15].O>C1COCC1>[CH3:15][O:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([CH2:5][CH2:4][Br:3])=[CH:7][CH:8]=1
Reactant: CI
Reactant: OCc1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a suspension of 60% NaH in paraffin (13.9 mmol; 0.56 g) in THF (20 ml) cooled to 0° C. was first added, dropwise, a solution of 4-(2-bromoethyl)benzyl alcohol (9.25 mmol; 1.99 g) in THF (20 ml) in an ice bath, followed by iodomethane (13.9 mmol; 1.972 g; 0.86 ml). The mixture was stirred at room temperature for 1 hour 30 minutes, after which it was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCl solution (3×20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on a column of alumina, eluting with ethyl acetate, to give 1.38 g of product as an oil (65%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.4 g, 97%): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 6.81-6.51 (m, 8H), 6.41 (s, 1H), 5.70-5.44 (m, 1H), 3.20-2.82 (m, 2H); ESIMS m/z 518 ([M+H]+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[O:14][C:15]3[CH:21]=[C:20]([CH:22]([CH3:28])[C:23](OCC)=[O:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.Cl>CCOCC>[C:7]1([C:13]2[O:14][C:15]3[CH:21]=[C:20]([CH:22]([CH3:28])[CH2:23][OH:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(CO)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
A solution of lithium aluminium hydride (~ 2 gm) in ether (50 ml) was slowly added to a solution of ethyl 2-(2-phenyl-6-benzoxazolyl)-propionate (5 g) in ether (40 ml). The mixture was heated under reflux for 1 hr., then ethyl acetate was slowly added until effervescence ceased. 6-N-Aqueous hydrochloric acid was then added and the ether layer was separated off and dried. Chromatography over silica gel yield pure 2-(2-phenyl-6-benzoxazolyl)-propanol, m.p. 98° C.
Reaction SMILES: C(OCCO)C.[BH4-].[Na+].[O:9](C)[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:10]([OH:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOCCO
Product: CCCCCCCCCCO
Temperature: 25 °C
Yield: 90 %

Procedure:
7.5 g (0.083 mole) of ethylene glycol monoethyl ether was added dropwise to a mixture consisting of 1.6 g (0.042 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.027 mole) of methyl caprate at 90° C. over two hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for 2.5 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, n-decanol was obtained in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13](Cl)(=O)[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(OCC)(=O)C.C1(C)C(C)=CC=CC=1>[CH:14]([C:16]1[O:12][C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[N:1]=1)([CH3:15])[CH3:13]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2oc(C(C)C)nc2c1
Temperature: 25 °C
Yield: 104 %

Procedure:
A solution of methyl 3-amino-4-hydroxybenzoate (5.00 g, 29.9 mmol), isobutyryl chloride (3.51 g, 32.9 mmol), triethylamine (3.33 g, 32.9 mmol), pyridinium p-toluenesulfonate (2.5 g, 10 mmol) and xylene (100 mL) was heated to reflux overnight and then cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and washed with water (2×50 mL), dried with magnesium sulfate, filtered and concentrated to give the title compound (6.82 g, quantitative yield) as a brown oil. Also prepared by this method were:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Cl.Cl>CO>[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: Fc1ccccc1CCl
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@@H](CCC(=O)N[C@@H](CSCc1ccccc1F)C(=O)NCC(=O)O)C(=O)O
Temperature: 50 °C

Procedure:
A mixture of 3.07 g of glutathione, 2.8 cc of triethylamine and 100 cc of methanol is brought to a boil. Then a solution of 1.45 g of o-fluorobenzyl chloride in 20 cc of methanol is added. After this addition, the resulting mixture is heated for 3 hours at 50°C, then allowed to cool and, by addition of dilute hydrochloric acid, 3.35 g of a white product are precipitated which can then be crystallized in water. Thus a product having a melting point of around 200°C (with decomposition) is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=1)#[N:2].[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][N: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>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22]([NH:34][C@@H:32]([C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[N:31][CH:30]=2)[CH3:33])=[O:23])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)c(C#N)c1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (30 mg, 0.089 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (30 mg, 0.22 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford a brown solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]=2[CH2:9][N:8]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:7]1=[O:29].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39].[NH:19]1[CH2:18][CH2:17][CH:16]([N:8]2[CH2:9][C:10]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:6][C:7]2=[O:29])[CH2:21][CH2:20]1
Reactant: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3ncccc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cccnc2CN1C1CCNCC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (0.10 g, 0.21 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight. The reaction was concentrated to afford the bis-TFA salt of the title compound (0.048 g). MS 233.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:27]([C:28]2[CH2:32][CH2:31][O:30][N:29]=2)=[C:26]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:25]=[CH:24][C:13]=1[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=1[OH:21])=[O:15]>O1CCOCC1>[CH2:3]([O:21][C:20]1[N:19]([CH2:22][CH3:23])[N:18]=[CH:17][C:16]=1[C:14](=[O:15])[C:13]1[CH:24]=[CH:25][C:26]([S:33]([CH3:36])(=[O:35])=[O:34])=[C:27]([C:28]2[CH2:32][CH2:31][O:30][N:29]=2)[C:12]=1[Cl:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1OCc1ccccc1
Yield: 20.5 %

Procedure:
1.44 g (60 mmol) of sodium hydride and 10.40 g (60 mmol) of benzyl bromide were added a little at a time to a solution of 6.00 g (15 mmol) of 4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-1-ethyl-5-hydroxy-1H-pyrazole in 300 ml of dry dioxane. The mixture was stirred under reflux for 24 hours, the solvent was removed under reduced pressure and the residue was taken up in dichloromethane and washed three times with water. The organic phase was dried and concentrated and the residue was chromatographed over silica gel (eluent: N-pentane/ethyl acetate). 1.5 g (20% of theory) of 5-benzyloxy-4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-1-ethyl-1H-pyrazole were obtained (mp.: 70-75° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.CC1C=CC(S([CH2:23][N+:24]#[C-])(=O)=O)=CC=1.C(O[K])(C)(C)C>COCCOC.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[CH:7]([C:23]#[N:24])[CH2:6][CH2:5]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c21
Agent: CC(C)(C)O[K]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,7-dichloro-1-indanone (2.24 mmol) and TosMIC (6.71 mmol) in 25 mL 1,2-dimethoxyethan and 1 mL EtOH was added tBuOK (6.71 mmol) at 5° C. The cooling bath was removed and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (7/3) gives the desired compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[BH4-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(CN2CCOCC2)c1
Reaction time: 0.33 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzaldehyde (266 mg, 1.05 mmol) and morpholine (0.10 mL, 1.2 mmol) were dissolved in DCM (2 mL), stirred for 20 minutes, and then treated with NaBH4 (79 mg, 2.1 mmol). The reaction was stirred overnight at rt, after which time, the reaction was quenched by the slow addition of water (10 mL). The aqueous layer was further extracted with DCM (3×10 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.67 (d, J=8.3, 1H), 7.37 (d, J=8.3, 1H), 3.80-3.69 (m, 4H), 3.63 (d, J=1.7, 2H), 2.59-2.49 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[NH:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:22]1[NH:21][CH:25]=[CH:24][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: c1cc[nH]c1
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc[nH]1

Procedure:
A solution of 14.5 g. (0.05 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 10 ml. of redistilled pyrrole in 75 ml. of toluene was slowly distilled with replacement of fresh toluene to maintain the volume at 50-75 ml. After 30 minutes the reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in hexane and chromatographed on alumina (Woelm, activity II) with hexane-benzene followed by benzene to give the title compound.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([Cl:17])[CH:11]=[CH:10]2.[I:18]I.C1COCC1.O>C1COCC1.CCCCCC.C(OCC)C.O>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([Cl:17])[C:11]([I:18])=[CH:10]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1nc2ccc(Br)cc2cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of THF (50 mL) and DIPA (1.8 mL, 12.37 mmol) at −70° C. was added n-BuLi (7.7 mL, 12.4 mmol). The mixture was allowed to stir at 0° C. for 1 h. Slow addition of 6-bromo-2-chloroquinoline (3.0 g, 12.4 mmol) in THF (50 mL) was achieved at −75° C. and the mixture was stirred at this temperature for 2 h. Iodine (3.1 g, 12.4 mmol) in 10 ml of THF was then slowly added and the reaction mixture was allowed to stir at −75° C. for 2 h before hydrolysis by THF/water (20% v/v). Water and diethyl ether were added at −10° C. and the reaction mixture was extracted with ether. The organic layer was washed with sodium thiosulfate and water, dried over MgSO4 and concentrated in vacuo to give a yellow solid which was slurried with hexane and filtered to give 6-bromo-2-chloro-3-iodoquinoline as a tan solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:38]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[O:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:39]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 23.1 %

Procedure:
To a solution of Intermediate A (104 mg, 0.640 mmol) in DMF (2 mL) was added NaH (60% in oil, 70 mg, 1.74 mmol) and the mixture stirred at RT for 20 min, before Intermediate 26b (220 mg, 0.582 mmol) was added. This mixture was stirred thermally at 60° C. for 4 h, then at 60° C. in the microwave for 3 h. The cooled reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM gave the title compound as a yellow gum (70 mg, 23%). LCMS (Method 1): Rt 2.89, m/z 522 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1OC(C)C
Temperature: 25 °C

Procedure:
A solution of 4-(benzyloxy)-2-isopropoxybenzaldehyde (698) (480 mg, 1.776 mmol) and (carbethoxymethylene)triphenylphosphorane (1.1 eq.) in toluene was heated at 100° C. overnight. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford (E)-ethyl 3-(4-(benzyloxy)-2-isopropoxyphenyl)acrylate (699)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.O.CN(C)[CH:31]=[O:32]>>[C:22]1([CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:14]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:31]3=[O:32])[CH2:16][CH2:17]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)C=O
Reactant: Nc1ccccc1-c1ccccc1NC1CCN(Cc2ccccc2)CC1
Solvent: O
Product: O=C1Nc2ccccc2-c2ccccc2N1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 36.0 g (0.101 mol) of 2-amino-2′-[[1-(phenylmethyl)-4-piperidinyl]amino]-biphenyl in 200 mL of dimethylformamide were added 40.5 g (0.250 mol) of N,N′-carbonyldiimidazole, then the mixture was stirred for 2 hours at 100° C., after which the solvent was eliminated in vacuo. The residue was stirred with water, then extracted exhaustively with dichloromethane. The combined organic extracts were dried over sodium sulfate, clarified with active charcoal and evaporated down. The residue (60 g) was purified by chromatography on aluminium oxide of activity stage 3 using PE/EE 2/1 (v/v). The desired compound was obtained from the corresponding fractions in a yield of 6.2 g (16% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([Cl:24])=[CH:16][C:15]1=[O:25]>>[Cl:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([CH2:13][CH:9]=[O:8])[C:15](=[O:25])[CH:16]=1
Reactant: O=c1cc(Cl)c2ccccc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)cc(Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 3 mL of a 90% aqueous trifluoroacetic acid solution, 156 mg of 1-(1,3-dioxolan-2-ylmethyl)-4-chloroquinolin-2(1H)-one was dissolved, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the reaction mixture was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 192 mg of a pale yellow oily substance, (4-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:30]\[OH:31])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-benzoic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow solid, MS (ESI+): m/z=409.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH:9]=[C:10](Br)Br.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]1[NH:15][CH2:14][CH2:13][N:16]=1
Reactant: NCCN
Reactant: Clc1cccc(I)c1C=C(Br)Br
Product: Clc1cccc(I)c1CC1=NCCN1

Procedure:
2-(2-Chloro-6-iodo-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1-chloro-2-(2,2-dibromo-vinyl)-3-iodo-benzene and ethylenediamine in analogy to Example 1e): light yellow crystals; MS (ISP): 323.1 ([M+H]+, 35%), 321.4 ([M+H]+, 100%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:26][CH2:27][CH2:28][CH2:29][CH:30]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C:31]([NH:33][NH2:34])=[O:32].[CH3:44][O:45][C:46]1[CH:47]=[C:48](/[CH:58]=[CH:59]/[C:60](O)=[O:61])[CH:49]=[N:50][C:51]=1[N:52]1[CH:56]=[C:55]([CH3:57])[N:54]=[CH:53]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:44][O:45][C:46]1[CH:47]=[C:48](/[CH:58]=[CH:59]/[C:60]([NH:34][NH:33][C:31](=[O:32])[CH:30]([C:35]2[CH:36]=[C:37]([F:43])[C:38]([F:42])=[C:39]([F:41])[CH:40]=2)[CH2:29][CH2:28][CH2:27][Cl:26])=[O:61])[CH:49]=[N:50][C:51]=1[N:52]1[CH:56]=[C:55]([CH3:57])[N:54]=[CH:53]1
Reactant: COc1cc(/C=C/C(=O)O)cnc1-n1cnc(C)c1
Reactant: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)cnc1-n1cnc(C)c1

Procedure:
IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride (83 mg) and (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid (CAS No. 870837-77-7, 68 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for 18 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 112 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cc1ncc(Br)n1C
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ncc(C(=O)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 5-bromo-1,2-dimethyl-1H-imidazole (10.0 g, 57.1 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 19.0 mL, 57.0 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-Methoxy-N-methyl-benzamide (8.70 mL, 57.1 mmol) was added dropwise. The mixture was stirred for 7.5 h at room temperature. The mixture was worked-up by addition of water (100 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (2×75 mL), the organic layers were washed with water (2×100 mL) then dried over MgSO4 and concentrated in vacuo. Purification of the residue on silica gel afforded (1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methanone [8.41 g, yield 44%; HPLC/MS: m/z=201 (M+H); log P(HCOOH)=0.56].