Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[CH2:32]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:32][N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:27][CH2:28]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Reactant: COCCN1CCNCC1
Reactant: C=O
Solvent: CCO
Product: COCCN1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.051 g, 0.19 mmol) obtained in Example A1, Step 1 in ethanol (2.0 mL) was added with 1-(2-methoxyethyl)piperazine (0.036 g, 0.25 mmol), and 37% aqueous formaldehyde (0.021 g, 0.25 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-{[4-(2-methoxyethyl)piperazin-1-yl]methyl}benzofuran-3(2H)-one (0.027 g, 33%).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Br[CH:27]([CH3:31])[C:28](Cl)=[O:29].[N-:32]=[N+]=[N-].[Na+]>>[O:25]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:28](=[O:29])[C@H:27]([CH3:31])[NH2:32])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Reactant: CC(Br)C(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)[C@H](C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 40-2 in Scheme 18 by using 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine, 2-bromopropionyl chloride and sodium azide. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.07-7.85 (m, 3 H), 7.64-7.51 (m, 2 H), 7.46-7.35 (m, 2 H), 5.22-5.08 (m, 2 H), 4.51-4.42 (m, 1 H), 3.65-3.53 (m, 2 H), 3.37 (s, 3 H), 2.51-2.40 (m, 3 H), 1.73 (d, J=7.07 Hz, 1 H), 1.30 (d, J=2.78 Hz, 2 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:13])[CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+].CCOC(C)=O>CCO.O>[CH3:12][C:11]1[S:13][C:8]2[CH:9]=[C:4]([O:3][C:2]([F:14])([F:1])[F:15])[CH:5]=[CH:6][C:7]=2[N:10]=1
Reactant: CC(=S)Nc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
N-(4-(trifluoromethoxy)phenyl)ethanethioamide (38 g, 0.162 mol) was dissolved in EtOH (70 ml), water solution of NaOH (52.5 g, in 175 ml water) was added and the solution was diluted with 350 ml water. This solution was then added drop wise, within 30 min., into a solution of K2Fe(CN)6 (210 g) in 520 ml water at 85-95° C. The reaction mixture was then stirred at 85-95° C. for 1 hr and cooled. TLC (7:3-hexane:EtOAc) was performed. The product was extracted with DCM, the organic phase was dried over Na2SO4, filtered and evaporated and the residue was purified by flash column chromatography (5% EtOAc in hexane) to give 16.8 g (44.5%) of 2-methyl-6-(trifluoromethoxy)benzo[d]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](=O)[CH3:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]=[C:20]([C:26]2S[CH:28]=[CH:29][CH:30]=2)S[C:22]=1[C:23](=O)[CH3:24].[NH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:8][C:5]4[C:4](=[CH:28][CH:29]=[C:30]([CH2:26][CH2:20][N:19]5[CH2:24][CH2:23][CH2:22][C@H:18]5[CH3:17])[CH:6]=4)[N:31]=3)=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Reactant: N
Product: Cc1onc(-c2ccc(Cl)cc2)c1-c1ccc2cc(CCN3CCC[C@H]3C)ccc2n1

Procedure:
The title compound was prepared using the procedure described in Example 1G-substituting 1-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-yl]-ethanone (CAS # 169814-48-6, Maybridge Chemical Company Ltd., catalog number SPB 04957) for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.14 (d, J=5.76 Hz, 3H), 1.47 (m, 1H), 1.78 (m, 2H), 1.96 (m, 1H), 2.25 (q, J=8.70 Hz, 1H), 2.40 (m, 2H), 2.68 (s, 3H), 3.03 (m, 2H), 3.15 (m, 1H), 3.30 (td, J=8.39, 2.54 Hz, 1H), 7.08 (d, J=8.48 Hz, 1H), 7.32 (ddd, J=8.65, 2.20, 2.03 Hz, 2H), 7.45 (ddd, J=8.65, 2.37, 2.20 Hz, 2H), 7.65 (m, 2H), 8.01 (d, J=8.48 Hz, 1H), 8.03 (d, J=8.82 Hz, 1H); MS (DCI-NH3) [M+H]+ at 432.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(F)cc(F)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,5-difluoroaniline to yield 2-[(3,5-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Solvent: ClCCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CCl)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′B)-one from Step A (203 mg, 0.64 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (761 mg, 6.40 mmol) and the resulting mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted further with CH2Cl2 (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=336 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:6]([O:8]C)=[O:7])#[N:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(F)c(F)c(C#N)c1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Yield: 81.3 %

Procedure:
A solution of 156 g of methyl 3-cyano-2,4,5-trifluoro-benzoate in 960 ml of glacial acetic acid, 140 ml of water and 69 ml of concentrated sulphuric acid is heated to reflux for 8 hours. The acetic acid is then largely removed by distillation in vacuo and the residue is treated with water. The precipitated solid is filtered off with suction, washed with water and dried. 118.6 g of 3-cyano-2,4,5-trifluoro-benzoic acid are obtained as a white solid of melting point 187-190° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1.[CH3:33][NH:34][CH3:35]>CCO>[CH3:33][N:34]([CH3:35])[CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCCl)nc1C
Reactant: CNC
Solvent: CCO
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCN(C)C)nc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Into a vessel with condensor, was placed a solution of 4-(1-(3-(2-(2-chloroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 24.1, 26 mg, 0.06 mmol, 1.00 equiv) in EtOH (10 mL). Dimethylamine (1 M in THF, 0.3 mL, 0.3 mmol) was added and the mixture was sealed under a nitrogen balloon. The resulting solution was stirred overnight with a 100° C. oil bath. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,) (Bridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, WATER WITH 0.03% NH3H2O and CH3CN (31% CH3CN up to 43% in 7 min, up to 100% in 0.5 min, down to 31% in 3.5 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield 6.3 mg (24%) of the title compound as a white solid. m/z (ES+) 456 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH:39]2[CH2:45][CH:44]3[CH:42]([CH2:43]3)[CH2:41][CH:40]2[C:46](O)=[O:47])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[C:4]([CH2:3][NH:2][C:46]([CH:40]1[CH:39]([CH2:38][S:37][C:34]2[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=2)[CH2:45][CH:44]2[CH:42]([CH2:43]2)[CH2:41]1)=[O:47])#[N:5]
Reactant: N#CCN
Reactant: CSc1ccc(SCC2CC3CC3CC2C(=O)O)cc1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ccc(SCC2CC3CC3CC2C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of aminoacetonitrile hydrochloride (153 mg, 1.65 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (800 mg, 1.54 mmol) was added 1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]sulfanyl}methyl)bicyclo[4.1.0]-heptane-3-carboxylic acid and dimethylformamide (4 mL). After adding triethylamine (0.52 mL, 3.7 mmol) the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The product was extracted into ethyl acetate and the combined organic phases were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were removed and the residue was chromatographed on a silica gel with methanol:dichloromethane (1.5:98.5) as eluent to give crude product which was purified in 1.4 mg portions by preparative RP HPLC (Waters, RCM, C18, μBondapak, 1×24 mm) by gradient elution with acetonitrile:water (containing 25 mM ammonium acetate)/30:70 to 50:50, 6.0 mL/min flowrate, UV detector set at 300 nM to give the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.83 (1H, br s), 7.28 (2H, d), 7.19 (2H, d), 4.20 (2H, m), 3.12 (1H, dd), 2.62 (1H, dd), 2.46 (3H, s), 2.26 (1H, m), 2.21 (1H, m), 2.10 (1H, m), 1.67 (1H, m), 1.58 (1H, m), 1.52 (1H, m), 0.99 (1H, m), 0.90 (1H, m), 0.57 (1H, m), −0.06 (1H, m). MS [ESI, (M−H)] m/z=345.2 amu.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.CC(C)=O>C(O)C.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12]/[CH:13]=[CH:14]\[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCN(CC#Cc1cccnc1)CC2
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1nc2c(s1)CCN(C/C=C\c1cccnc1)CC2
Yield: 42 %

Procedure:
Prepared by catalytic hydrogenation of 2-amino-6 -(3-(3-pyridyl)-2-propyn-1-yl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine with palladium/barium sulphate (5%) in ethanol. Yield: 42% of theory, Melting point: 125°-126° C. (acetone).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1Br.[Mg].II.[CH:14](=[O:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:14]([C:15]1[O:19][CH:18]=[CH:17][CH:16]=1)[OH:20]
Reactant: O=Cc1ccco1
Reactant: Cc1cc(C)c(Br)c(C)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)c2ccco2)c(C)c1
Reaction time: 0.42 h

Procedure:
A solution of 2,4,6-trimethyl-1-bromobenzene (30.9 g, 155 mmol) in tetrahydrofuran (100 ml) is added slowly to magnesium turnings (3.77 g, 155 mmol), until the magnesium is just covered. A small quantity of iodine is added and the mixture is allowed to stand at room temperature for 25 minutes and then heated and stirred until the brown colour is lost. The remainder of the aryl bromide solution is added dropwise over a 20 minute period, with occasional heating to maintain the formation of the Grignard reagent solution. The reaction is stirred at room temperature for 1 hour. A solution of furfural (12.8 ml, 155 mmol) in tetrahydrofuran (70 ml) is added dropwise, and once the addition is complete, the reaction is stirred at room temperature for 2 hours. The reaction is quenched by cautious addition of excess saturated ammonium chloride solution, then extracted into ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel affords (2,4,6-trimethylphenyl)furan-2-ylmethanol.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-n2ccc(Oc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 60 °C
Yield: 14 %

Procedure:
To a solution of N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.20 g, 0.58 mmol) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.19 g, 0.64 mmol) in anhydrous acetonitrile (10 mL) was added cesium fluoride (0.22 g, 1.46 mmol). The reaction mixture was heated at 60° C. for 16 hours, followed by the addition of ethyl acetate (30 mL). The mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/1) and further purified by recrystallization in ether to afford the title compound as a colorless solid in 14% yield (0.032 g): mp 67-70° C. (ether); 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=8.1 Hz, 1H), 7.45-7.25 (m, 8H), 7.11-7.08 (m, 2H), 6.35 (dd, J=8.1, 2.7 Hz, 1H), 6.05 (t, J=5.6 Hz, 1H), 5.81 (d, J=2.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.1, 161.8, 153.3, 152.8, 152.1, 137.7, 132.2, 130.3, 128.8, 127.9, 127.7, 126.4, 122.5, 121.1, 103.4, 100.2, 44.1, 17.3; MS (ES+) m/z 418.2 (M+1).
Reaction SMILES: Br[C:2](Br)([F:4])[F:3].C(N(P(N(CC)CC)N(CC)CC)CC)C.[F:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[CH:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1>C1COCC1>[F:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:30][CH2:31][CH:32]([CH:35]3[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)[CH:26]=[CH:25][C:24]=1[CH:46]1[CH2:47][CH2:48][C:49](=[C:2]([F:4])[F:3])[CH2:50][CH2:51]1
Reactant: CCCCCC1CCC(C2CCC(c3ccc(C4CCC(=O)CC4)c(F)c3)CC2)CC1
Reactant: FC(F)(Br)Br
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(c3ccc(C4CCC(=C(F)F)CC4)c(F)c3)CC2)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Dibromodifluoromethane (16.2 g) and THF (30 ml) were put into a vessel under a nitrogen atmosphere and cooled to 10° C. Trisdiethylaminophosphine (38.2 g) in THF (50.0 ml) solution was added dropwise thereto and the stirring was continued for another 60 minutes. The compound (T-8) (16.5 g) in THF (400 ml) solution was then added dropwise in the temperature range of 20° C. to 35° C., and allowed to react overnight while the reaction mixture was coming to room temperature. The reaction mixture obtained was poured into ice-water (400 ml) and mixed. Organic and aqueous layers were separated by adding toluene (300 ml) and the aqueous layer was extracted with toluene. The organic layers combined were washed sequentially with water, 3N-hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and purified by means of column chromatography (silica gel; heptane/ethyl acetate), giving 4-[2-fluoro-4-(4′-pentyl-1,1′-bicyclohexane-4-yl)phenyl]difluoromethylenecyclohexane (T-9) (15.1 g). The yield based on the compound (T-8) was 85%.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:13](=[O:15])[CH3:14])[O:11][CH:12]=1)=[O:7])[CH3:4].COC([O:21][CH3:22])OC.[C:23]([O-])([O-])=O.[Na+].[Na+]>C(O)CO>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:13]2([CH3:14])[O:21][CH2:22][CH2:23][O:15]2)[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1coc(C(C)=O)n1
Reactant: COC(OC)OC
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CCOC(=O)c1coc(C2(C)OCCO2)n1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-acetyl-oxazole-4-carboxylic acid ethyl ester (7.0 g, 38.0 mmol) in ethylene glycol (42.7 mL) was treated with trimethylorthoformate (10.5 mL, 96.0 mmol) followed by LiBF4 (0.73 g, 8.0 mmol). The reaction mixture was heated at 95° C. until completion of the reaction. Aq. 0.5 M Na2CO3 was added and the mixture was extracted with Et2O. The org. layer was washed with aq. 0.5 M Na2CO3 (2×), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.76 min; [M+H]+=227.99.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CCOCCC(=O)O
Product: C#CCOCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6,7-trioxabicyclo[2.2,2]octane was prepared from 3-(prop-2-ynyloxy)propionic acid and 3-t-butyl-3hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C(O)C.[C-:16]#[N:17].[Na+]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH2:2][C:16]#[N:17])=[O:4])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 25.0 g. portion of α-bromo-p-methoxyacetophenone is suspended in 125 ml. of ethanol. A solution of 16.0 g. of sodium cyanide in 75 ml. of water is added, using an ice-water bath to keep the temperature at 25°-30° C. The mixture is stirred for 45 minutes at room temperature. A total of 1.2 liters of water is added in 200 ml. increments with filtration through celite until no more precipitate forms. The filtrate is acidified to pH 5 with acetic acid. The solid is collected, washed with water, dried and recrystallized from benzene giving p-methoxybenzoylacetonitrile.
Reaction SMILES: [OH-].[Li+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([O:15]C)=[O:14]>O.CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of lithium hydroxide (20.0 mg, 0.84 mmol) in water (1 mL), methyl quinoline-2-carboxylate (20.0 mg, 0.11 mmol) in methanol (3 mL) was added. The solution was left to stir at room temperature for 2 h. The solution was then concentrated in vacuo. The yellow solid residue was dissolved in water and made acidic with concentrated hydrochloric acid. The organic material was extracted with ethyl acetate. The organic layers were dried with anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield quinoline-2-carboxylic acid as a white solid.
Reaction SMILES: [Na+].[Br:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[N:8]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]([CH:13]([CH3:15])[CH3:14])[C:10](=[O:12])[O:11]2)=[CH:16][CH:17]=1
Reactant: CC(C)C(N=Cc1ccc(Br)cc1)C(=O)[O-]
Reactant: CCCCC(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)N1C(c2ccc(Br)cc2)OC(=O)C1C(C)C
Temperature: 40 °C
Yield: 34 %

Procedure:
12.6 g of 2-[(4-bromobenzylidene)amino]-3-methylbutyric acid sodium salt (41.1 mmoles) are suspended in 80 ml of dry dichloromethane. The mixture is refluxed (40° C.), under slight nitrogen stream. 7.9 g of valeryl chloride (65.5 mmoles) are added. After 2 hours under reflux, the mixture is cooled to 25° C. The organic phase is washed three times with 50 ml of water and concentrated under reduced pressure, at 25-30° C., to obtain an oily residue. 50 ml of ethyl acetate are added and the organic phase is washed with a weakly basic NaOH solution and/or with water to neutrality. The organic phase is washed with a sodium bisulfite solution. The organic phase is washed with water and dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue is taken up with ethanol from which the product crystallizes as a white solid. 2-(4-Bromophenyl)-4-isopropyl-3-pentanoyl-oxazolidin-5-one is obtained (5.2 g; 14.1 mmoles; molar yield: 34%).