Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[Cl:23][S:24](O)(=[O:26])=[O:25]>O>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:24]([Cl:23])(=[O:26])=[O:25])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCC(Cc2ccccc2)CC1)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To the mixture of 1-(trifluoroacetyl)-4-benzylpiperidine (29.2 g, 108 mmol) and methylene chloride (10 ml) was dropwise added chlorosulfonic acid (36 ml, 539 mmol) at −10° C. for an hour. The mixture was stirred at 0° C. for an hour and then stirred at room temperature for an hour. The reaction mixture was poured into ice-cooled water (500 ml) and extracted with methylene chloride (200 ml×2). The extract was washed with an aqueous solution of 5% sodium bicarbonate (500 ml) and saturated brine (500 ml) successively. The organic phase was dried over magnesium sulfate (anhydrous), then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 100 g, ethyl acetate/hexane=1/20→1/5) to give the title compound as a colorless powdery crystal (16.5 g, 41%).
Reaction SMILES: Br[C:2]1[N:18]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:19][C:20]1[O:24][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)=[N:22][N:21]=1>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:31][CH:28]3[CH2:29][CH2:30][N:25]([C:23]4[O:24][C:20]([CH3:19])=[N:21][N:22]=4)[CH2:26][CH2:27]3)[N:18]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc(Oc2cccn3nc(Br)nc23)c1
Reactant: Cc1nnc(N2CCC(N)CC2)o1
Product: Cc1nnc(N2CCC(Nc3nc4c(Oc5cccc(Cl)c5)cccn4n3)CC2)o1

Procedure:
Prepared in analogy to example 66f employing 2-bromo-8-(3-chlorophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (see example 152a) and 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-ylamine (see example 40b). The title compound was obtained as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[CH:11])([CH3:4])([CH3:3])[CH3:2].I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC#Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
But-3-ynylcarbamic acid tert-butyl ester (3.66 g, 22 mmol) was added dropwise to an ice cooled, stirring, argon purged mixture of 4-iodobenzonitrile (4.5 g, 19.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.69 g, 0.98 mmol), copper (1) iodide (0.19 g, 0.98 mmol), triethylamine (11 mL, 78.4 mmol), and THF (24 mL). After stirring for 10 min, the ice bath was removed, and the reaction was allowed to stir for an additional 2 h. The reaction mixture was passed through a pad of silica gel with methylene chloride/ethyl acetate (5:1) as eluant. After evaporating the solvent, the crude product was chromatographed with methylene chloride/ethyl acetate (20:1) as eluant. Evaporation of the solvent, followed by placement under vacuum for 1 h, afforded the pure product 56 (5.2 g, 99%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 2.64 (t, 2H), 3.37 (m, 2H), 4.85 (br s, 1H), 7.47 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:30])([F:31])[F:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccccc1C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
5.6 g of manganese dioxide were added to a solution of 560 mg (1.3 mmol) of N-[2-t-butyl-5-(hydroxymethyl)phenyl]-3-(2-trifluoromethyl-phenyl)octanamide (prepared as described in Preparation 19) in 20 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then filtered using a Celite (trade mark) filter aid, and the manganese dioxide used was washed several times with methylene chloride. The filtrate was combined with the washings and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 511 mg (yield 91%) of the title compound.
Reaction SMILES: C(=O)C.[CH3:4][C:5]1[N:9]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[S:20][CH:21]=[C:22]([C:24](=[N:26][O:27]CCCCC4C=CC=CC=4)[CH3:25])[N:23]=3)[CH2:15][CH2:14]2)=[O:12])[N:8]=[C:7]([C:38]([F:41])([F:40])[F:39])[CH:6]=1.Cl.NO>CO>[OH:27][N:26]=[C:24]([C:22]1[N:23]=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][N:9]3[C:5]([CH3:4])=[CH:6][C:7]([C:38]([F:41])([F:40])[F:39])=[N:8]3)[CH2:14][CH2:15]2)[S:20][CH:21]=1)[CH3:25]
Reactant: CC(=NOCCCCc1ccccc1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: CC=O
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(=NO)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
A mixture of 1-[4-(4-acetyl-2-thiazolyl)-1-piperidinyl]-2-[5-methyl-3-trifluoromethyl)-1H-pyrazol-1-yl)ethanone (i.e. the product of Example 1, Step D) (4.5 g, 11.25 mmol) and hydroxylamine hydrochloride (0.945 g, 13.5 mmol) in methanol (60 mL) was heated at reflux for 6 h. The reaction mixture was concentrated under reduced pressure and partitioned between saturated sodium bicarbonate and dichloromethane. The organic phase was separated and the aqueous phase was extracted two additional times with dichloromethane. The organic phases were combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to provide 4.2 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10]C(C)C(Br)=O>CCOCC>[BrH:10].[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)Br
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3,4-dichlorobenzylchloride (49.2 g, 0.254 mole) in dry ether (125 ml) was added dropwise during one hour to magnesium (6.08 g, 0.250 mole) in a three-necked flask equipped with stirrer and reflux condenser. Refluxing was continued until all the magnesium was dissolved and the solution was then cooled. Acetone (15.0 g, 0.258 mole) was added dropwise and the solution heated to reflux for three hours. After cooling the reaction mixture was poured out on ice (125 ml) and a concentrated hydrochloric acid (23 ml). The phases were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was distilled affording 1-(3,4-dichlorophenyl)-2-methyl-2-propanol (bp. 81°-83° C./0.2 mm Hg; 31.3 g, 57% yield). After several recrystallizations from petroleum ether the compound melted at 40°-41° C. The substituted propanol above (21.9 g, 0.100 mole) was mixed with dimethylaniline (12.4 g, 0.102 mole) and ether (50 ml). The solution was cooled and α-bromopropionyl bromide (21.4 g, 0.099 mole) was added dropwise during 40 minutes. Stirring at room temperature for 48 hours gave a crystalline precipitate of dimethylaniline hydrobromide, which was filtered off and washed with ether. The etheral solutions were combined and evaporated in vacuo. The residual oil was distilled affording 2-bromopropanoic acid 1-(3,4-dichlorophenyl)-2-methyl-2-propolyester (bp. 135°-143° C./0.2 mm Hg; 19.2 g, 55% yield).
Reaction SMILES: [C:1]1([C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:31]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[N:10]=[CH:9]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C(#CCCC1CCCCC1)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C(=C\CCC1CCCCC1)\CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.6 %

Procedure:
1-[1-Triphenylmethyl-1H-imidazol-4-yl]-6-cyclohexyl-3-hexyne (6.8 g, 0.014 mol) was dissolved in dry ethyl acetate (100 ml). Lindlar catalyst (5%, 1.8 g Pd on CaCO3 poisoned with lead) and 15 mgs of quinoline were added. H2 was added to the reaction flask via a balloon. The reaction flask was evacuated and then refilled with H2 gas from the balloon 3 times. The reaction was left to stir at room temperature under the presence of H2 (1 atm) for 48 hours. The H2 gas was removed and the reaction mixture filtered through a pad of celite with ethyl acetate, the ethyl acetate was removed in vacuo to afford 6.75 g of 1-[1-triphenylmethyl-1H-imidazol-4-yl]-6-cyclohexyl-cis-3-hexene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][CH2:23][C@@:24]([CH3:29])([CH:26]1[CH2:28][CH2:27]1)[OH:25]>>[CH:26]1([C@:24]([OH:25])([CH3:29])[CH2:23][NH:22][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Reactant: C[C@](O)(CN)C1CC1
Product: C[C@](O)(CNC(=O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-fluoro-phenyl)-6-cyclopropylmethoxy-nicotinic acid and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 385.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[NH:34][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 5-[3-fluoro-4-(methylsulfanyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (127 mg) in acetic acid (2 mL) was added ammonium acetate (377% mg), and the mixture was stirred at 110° C. for 2 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (98.8 mg, yield 81%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH3:24]>>[NH2:24][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: N
Product: CCCOc1ccccc1-c1nc2nc(N)ncc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.55 g) was heated in ethanolic ammonia (50 ml) in a pressure vessel for 8 hours at 90° C. and then for 8 hours at 145° C. After cooling a grey solid (0.64 g) was collected and was recrystallized from ethanol (with charcoal) to yield a crude product (0.47 g) which was recrystallized from ethanol to yield the title compound, 0.29 g, m.p. 261-262° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1>O>[CH3:1][O:2][C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCN(c3cccc(C)c3)CC2)nn1
Yield: 50 %

Procedure:
To a stirred sodium methoxide solution, previously prepared starting from 1.6 parts of sodium in 24 parts of methanol, were added 4 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole was stirred and refluxed for 40 hours. After cooling 25 parts of water were added. The product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (50%) of 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 137.1° C. (compound 258).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28](O)[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH3:29])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: CC(O)c1ccccn1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(C)(C)O2)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.28 mmol) and 1-pyridin-2-yl-ethanol (81a) (48 mg, 0.39 mmol) in 4 mL of THF was added PPh3 (110 mg, 0.42 mmol) at 0° C., followed by DIAD (0.082 mL, 0.42 mmol) drop-wise. The mixture was stirred at room temperature overnight, concentrated, and purified by reverse phase HPLC to give a white solid (30 mg, 27% yield). 1H NMR (400 MHz, CDCl3) δ 9.61 (br. s., 1 H) 8.79 (d, J=4.55 Hz, 1H) 7.94-8.06 (m, 1 H) 7.69 (d, J=8.08 Hz, 1 H) 7.45-7.53 (m, 1 H) 7.27-7.31 (m, 1 H) 6.94-7.00 (m, 2H) 6.81-6.86 (m, 1 H) 5.84 (q, J=6.40 Hz, 1 H) 3.80 (s, 3 H) 3.09 (s, 2 H) 1.70-1.77 (m, 3 H) 1.48 (d, J=4.80 Hz, 6 H); LCMS for C22H24N4O3 m/z 393.20 (M+H+).
Reaction SMILES: Br[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][CH:9]=1.II.[Mg].Cl[P:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([P:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[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][CH:9]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Brc1ccccc1-c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 2-bromobiphenyl (5.38 g, 23.1 mmol) and a few iodine crystals in 40 mL of THF with magnesium turnings (617 mg, 25.4 mmol) was heated to a reflux for 2 h. Heat was temporarily removed for the addition of cuprous chloride (2.40 g, 24.2 mmol) followed by chlorodi-tert-butylphosphine. Heating was resumed for 8 h. The reaction mixture was then removed from heat and allowed to cool to rt. The reaction mixture was poured onto 200 mL of 1:1 hexane/ether. The suspension was filtered and the filtercake was washed with 60 mL of hexane. The solid was partitioned between 150 mL of 1:1 hexane/ethyl acetate and 60 mL of concentrated ammonium hydroxide with 100 mL of water. The organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The white solid was recrystallized from 30 mL of MeOH to give white crystals of 2-(di-tert-butylphosphino)biphenyl (4.01 g, 58%). A second crop (464 mg, 67%) was obtained by recrystallization from 50 mL of MeOH and 25 mL of water.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([F:30])[CH:17]=1>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[CH:17][C:18]=1[F:30])#[N:29]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1F
Reactant: CCCCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(F)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.8 %

Procedure:
A solution of methyl 3-oxoheptanoate (7 g) in tetrahydrofuran (30 mL) was added to a mixture of sodium hydride (1.2 g) and tetrahydrofuran (80 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. And then, 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile (5.3 g) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, the residue was extracted with 5% aqueous potassium hydrogensulfate solution and then with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (7.3 g, 90%).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].C([OH:24])C>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:24])([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1C#N
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(F)c1

Procedure:
A 5.5 g. portion of ethyl 5-cyano-1-(3-fluorophenyl)-4-pyrazolecarboxylate and 4.7 g. of potassium hydroxide were dissolved in 100 ml. of ethanol at the reflux temperature and the mixture was stirred at that temperature for2 hours. The mixture was then diluted to 350 ml. with cold water, and was heated slightly to obtain a solution which was made acid with concentratedhydrochloric acid. The product was precipitated by adding small amounts of ice, and the precipitated product was then collected by filtration and crystallized from ethanol-water to obtain 3.6 g. of the desired product, m.p. 215°-216°, having the following elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N+:12]([O-])([OH:14])=[O:13]>>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)ccc2o1
Reactant: O=[N+]([O-])O
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 300 ml concentrated nitric acid, at room temperature, was added portionwise 73.2 g (0.48 mole) of 5-fluorobenzoxazolin-2-one. The reaction mixture was warmed to 50° C., and was stirred for 4 hours. After cooling, the reaction mixture was poured onto ice. The precipitate which formed was collected, washed with water, and dried to give 72.8 g of the title compound as a brown powder: m.p. 207°-209° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[CH3:1])=[N:20][CH:19]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (1.56 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure and ice water was added to the residue. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (1.53 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 78–79° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[S:18][C:12]=3[C:11]2=[O:26])=[CH:6][C:5]=1[O:27][CH3:28].[OH-].[Na+]>CO.O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[S:18][C:12]3[C:11](=[O:26])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([O:27][CH3:28])[CH:6]=4)[CH2:15][CH2:14][C:13]=3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1C(=O)O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
Suspend 4-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-benzoic acid methyl ester (0.4 g, 0.94 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) and add 1 N NaOH (1.13 mL, 1.13 mmol). Heat the mixture at reflux for 16 h, cool to RT, and concentrate in vacuo. Suspend the residue in water (25 mL) and acidify with 10% sodium bisulfate. Extract the mixture with ethyl acetate (4×20 mL) to give a suspension in the organic portion. Filter the solid and dry in vacuo to give 0.19 g (49%) of the title compound. Concentrate the filtrate in vacuo to give 0.09 g (23%) more of the title compound. MS/ES m/z (35Cl) 414.0 [M+H]+.