Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3]/[C:4](/[O-:8])=[CH:5]/[N+]#N.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:8]
Reactant: CCO/C([O-])=C/[N+]#N
Reactant: C1CCOC1
Product: CCOC(=O)CC1CCCO1

Procedure:
Following the procedure of Preparative Example 14, 2.0 g (17.5 mmol) of ethyl diazo acetate was reacted with tetrahydrofuran to give 1.7 g of the product as a colorless oil, bp 84°-86° C. at 20 mm Hg.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=O)[CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:2].[CH3:14][CH:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:16]([C:18]1C=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH3:17]>>[CH2:1]([CH:3]1[C:7]2[C:21]3[C:22]([OH:23])=[CH:24][C:18]([CH:16]([CH:15]([CH3:14])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:17])=[CH:13][C:12]=3[O:11][C:9](=[O:10])[C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1CCC(CC)C1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CCC3CC

Procedure:
5-Ethyl-2-carboethoxycyclopentanone is reacted with 5-(3-methyl-2-octyl)-resorcinol to produce 1-ethyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [l]benzopyran.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=O)=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][OH:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]([O:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:42]
Reactant: OCc1cccc(Cl)c1
Reactant: O=C(Oc1cccnc1)N1CCN(C(=O)c2ccc(O)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccc(CN2CCN(C(=O)Oc3cccnc3)CC2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
A THF (5 ml) solution containing 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (300 mg) and diethyl azodicarboxylate (0.62 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-chlorobenzyl alcohol (200 mg) and triphenylphosphine (360 mg), at 0° C., followed by stirring at room temperature for 3 days. The reaction solution was diluted with chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzoyl)oxy]benzyl}-1-piperazinecarboxylate (260 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23](=[O:25])[CH3:24].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:24]/[C:23]([C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][CH3:13])=[O:25])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (1 g, 6.1 mmol) and 2′,5′-dimethoxyacetophenone (1.1 g, 6.1 mmol) in methanol (15 ml) was added 50% w/v solution of aqueous sodium hydroxide (9.7 ml, 0.122 mol). The reaction mixture was stirred at room temperature for 18 h. A precipitate was isolated by filtration and subsequently recrystallised from ethanol to afford 0.97 g (49%) of pale yellow crystals. 1H-NMR (CDCl3) δ 1.0 (t, 3H), 1.8 (m, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 3.9 (t, 2H), 6.9 (m, 3H), 6.9 (d, 1H) 7.15 (d, 1H), 7.25 (d, 1H), 7.5 (m, 3H), 13C-NMR (CDCl3) δ 192.59, 160.86,161.11, 153.59, 152.34, 130.07, 127.56, 22.47. Mass Spectrum m/e (M+1) 327. Anal. Calcd. for C20H2O4: C, 73.62; H, 6.75. Found C, 73.55; H, 6.88.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccccc2O)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol gives “A73”; method 1: HPLC/MS: 1.16 min, [M+H]=307;
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cn2c(n1)CCCC2
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CCCC2
Yield: 70.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (2.58 mmol, 428 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.717 mmol, 479 mg). DMF (10 ml) was used as the solvent. The reaction mixture was diluted with water and extracted three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated. The crude product was purified by flash chromatography. 515 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 1.78-1.94 (m, 4H), 2.76 (t, 2H), 3.95 (t, 2H), 4.24-4.31 (m, 1H), 4.33-4.46 (m, 2H), 7.01 (d, 1H), 7.43 (s, 1H), 7.84 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.08 (d, 1H).
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([C:3](=[CH:12][NH:23][NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: NNc1ccccc1
Product: CCOC(=O)NC(=O)C(C#N)=CNNc1ccccc1

Procedure:
Following the procedure of Example 1, α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is reacted with phenylhydrazine to give α-cyano-β-phenylhydrazino-N-ethoxycarbonylacrylamide, which in turn is cyclized by heating in tetralin, yielding 5-cyano-1-anilino-2,4-pyrimidinedione. The foregoing compound has been reported by G. Shaw, J. Chem. Soc., 1955, 1834-1840.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.CC([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:39]2[CH2:40][CH2:41][CH:37]([C:34]3[CH:35]=[CH:36][C:31]([CH2:30][NH2:26])=[CH:32][CH:33]=3)[CH2:38]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Product: NCc1ccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)cc1

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.95 g, 3.2 mmol) and 1,1 dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (0.75 g) as a yellow solid, mp 225°-227° C.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[CH3:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[OH:26].[OH-].[Na+]>C(#N)C.O.[Cl-].[Na+].O>[CH2:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][C@@H:6]([O:26][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[CH3:18])[C@H:1]([OH:7])[CH2:2]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(O)c1C
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (21.0 g, 92.0 mmol) was added to a stirred solution of 2,3-dimethylphenol (23.0 g, 188 mmol) and aqueous sodium hydroxide (100 ml, 2N, 200 mmol) in acetonitrile (400 ml). The reaction mixture was heated at reflux for 14 h. On cooling to room temperature, the reaction mixture was concentrated in vacuo before dilution with water (500 ml). Extraction with dichloromethane (4×100 ml) was followed by washing of the combined organics with aqueous sodium hydroxide (100 ml, 3N, 300 mmol), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish a crude product. Purification was carried out by silica gel chromatography using a gradient eluent system of iso-hexanes and ethyl acetate (100% iso-hexanes to 80:20 iso-hexanes:ethyl acetate) to furnish trans-benzyl-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (16.8 g, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].[CH2:11]([O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:16]=1)[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:31])[C:15]1[CH:16]=[C:17]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:18]=[C:19]([O:21][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:20]=1)[CH3:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2cccc(C#N)c2)cc(Oc2ccc(C#N)cc2)c1
Reaction time: 8 h
Yield: 81 %

Procedure:
Potassium carbonate K2CO3 0.44 g (3.18 mmol) followed by 3-cyano benzylbromide 0.31 g (1.58 mmol) in 2 ml of DMF were added to a solution of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester 0.45 g (1.58 mmol) in 7 ml of DMF at 20° C. The reaction mixture was allowed to attain RT and stirred overnight. The reaction mixture was quenched with ice cold water, extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated to afford 0.51 g of a thick oily liquid. 1H NMR (CDCl3): δ 1.3 (3H, t), 4.3 (2H, q), 5.25 (2H, s), 6.88 (1H, s), 7.02 (2H, d), 7.34 (1H, s), 7.5 (2H, m), 7.66 (4H, m), 7.78 (1H, s).
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].I[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: ICCn1cnc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCn1cnc(-c2ccccc2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of Ethyl 2-(methylsulfonyl)propanoate (377 mg, 2.09 mmol, 1 eq) and 1-(2-iodoethyl)-4-phenyl-1H-imidazole (623 mg, 2.09 mmol, 1 eq) in DMF (7 mL) was added Cs2CO3(1.70 g, 5.22 mmol, 2.5 eq) and the reaction mixture was allowed to stir overnight at RT, then for a further 24 h at 45° C. EtOAc was added and the mixture was washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The crude product mixture was purified by flash chromatography on silica gel eluting with 10-95% ethyl acetate in heptanes to give ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoate (335 mg, 46% yield). LC-MS M+H+351.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([Cl:19])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (664 mg) in DCM (10 mL) at 0° C. was added oxalyl chloride (4.7 mmol), followed by one drop of DMF. After stirring at rt for 2 hours, the solvent was concentrated to give S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (350 mg, 2.6 mmol) was added TEA (362μL) and (S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (dissolved in 10 mL of DCM). After stirring at rt for overnight, the reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 410 mg of (S)-2-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCCS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CCCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
1 g of 4-fluorobenzonitrile was used in Procedure Q with 1-propanethiol to afford 4-(propylthio)benzonitrile. 860 mg of 4-(propylthio)benzonitrile was reacted via Procedure T to give 4-(propylthio)benzoic acid. 700 mg of 4-(propylthio)benzoic acid was reacted via Procedure R to give 4-(propylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(propylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].[F-:20].[Cs+].O>CN(C)C=O>[F:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: [F-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1=C(F)c2ccccc2OC1c1ccccc1

Procedure:
A solution of 1.35 g 4-chloro-3-formyl-flav-3-ene and 7.6 g cesium fluoride in 10 ml dimethylformamide is stirred at 110° C. over 40 minutes. After cooling to room temperature water is added and the solution is extracted with methylene chloride. The organic phase is washed with water, and dried over magnesium sulfate. The solid residue is purified by column chromatography and the best fractions are crystallised in hexane. Pure 4-fluoro-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 114°-115° C.
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>O>[F:9][C:8]([F:11])([F:10])[CH:7]([NH:12][C:13]1[O:14][CH2:17][CH2:16][N:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCl)NC(c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)C(NC1=NCCO1)c1ccccc1
Yield: 95 %

Procedure:
7.6 g of N-(α-phenyl trifluoroethyl) N'-(β-Chloroethyl) Urea are suspended in 60 ml water, then 4.3 ml triethylamine are added and the whole mixture is heated to reflux under stirring for 30 mn. The reaction mixture is let to revert to about 20°, the precipitate is separated which is dried, washed with water until the washings are neutral and dried under vacuum-6.3 g 2-[α-trifluoromethyl) benzylamino] oxazoline are obtained i.e. a yield of 95%. For analytical purpose the compound is recrystallized from isopropanol with a yield of 73%. The analytical sample melts at 162°-168° (sublim).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=[CH2:13]>C(#N)C.[I-].[Na+]>[Cl:10][CH2:11][C:12]([CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH2:13]
Reactant: [O-]c1ccc(Cl)cc1
Reactant: C=C(CCl)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(CCl)COc1ccc(Cl)cc1
Yield: 54 %

Procedure:
0.5 mol of sodium 4-chlorophenolate in acetonitrile are added dropwise to a solution of 125 g (1 mol) of 3-chloro-2-chloromethylpropene in 50 ml of acetonitrile. After addition of 0.5 g of sodium iodide, the reaction mixture is heated under reflux for 12 hours and is then filtered cold. The filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride and the solution is washed with water, dried over sodium sulphate and concentrated. 58.6 g of about 60% pure 2-chloromethyl-3-(4-chlorophenoxy)-propene are obtained and are dissolved in 500 ml of methylene chloride, and 43 g (0.25 mol) of 3-chloroperbenzoic acid are added.
Reaction SMILES: [C:1]1([C:7]2([CH2:17]/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]32[O:12][CH2:11][CH2:10][O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]32[O:12][CH2:11][CH2:10][O:9]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)/C=C/CC1(c2ccccc2)CCCCC12OCCO2
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCC1(c2ccccc2)CCCCC12OCCO2
Reaction time: 3.5 h

Procedure:
To a solution of (E)-methyl 4-(6-phenyl-1,4-dioxaspiro[4.5]decan-6-yl)but-2-enoate (136 mg, 0.430 mmol) in MeOH (15 mL) was added about 50 mg of 10% Pd/C and the mixture was stirred under H2 (25 psi) for 3.5 hrs. It was filtered through Celite and evaporated to give an oily residue. LC/MS: m/e 319.10 (M+H)+.
Reaction SMILES: [C:1](OC)(=[O:3])[CH3:2].[CH3:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>C(OCC)C>[CH3:2][C:1](=[O:3])[CH2:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(C)=O
Reactant: COC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CCCCCC(=O)CC(C)=O
Temperature: 0 °C
Yield: 64 %

Procedure:
To a stirred solution of methyl acetate 15 (27.8 ml; 25.9 g; 350 mmol) in diethyl ether (200 ml) NaH (60% w/w; 4.80 g; 200 mmol) was added and resulted slurry was brought to boiling. Then a solution of 2-heptanone 16 (24.4 ml; 20.0 g; 175 mmol) in diethyl ether (150 ml) was added dropwise over 3 h. Refluxing was maintained for next 5 h. Then 10% aqueous solution of HCl with crushed ice (ca. 100 ml) was added carefully and organic phase was separated. Water phase was extracted with diethyl ether (150 ml) and combined organic phases were washed with saturated aqueous solution of NaHCO3 (50 ml), dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give 15.6 g (99.7 mmol; 64% yield) of 17. 1H NMR (500 MHz, CDCl3) δ 0.90 (3H, m), 1.31 (2H, m), 1.60 (2H, m), 2.05 (2.1H, s), 2.13 (0.3H, s), 2.17 (0.3H, s), 2.24 (0.3H, s), 2.26 (1.4H, t, J=7.5 Hz), 2.42 (0.15H, t, J=7.5 Hz), 2.50 (0.25H, t, J=7.4 Hz), 3.57 (0.25H, s), 5.49 (0.7H, s); 13C NMR (126 MHz, CDCl3) δ 14.0, 22.5, 22.6, 23.1, 25.0, 25.5, 30.9, 31.2, 31.5, 38.3, 43.8, 58.0, 69.1, 191.5, 194.4, 202.2, 204.3, 204.6; MS (EI) m/z 157 ([M+H]+, 52), 156 (M+, 9), 141 (8), 113 (17), 100 (45), 85 (100); exact mass calculated for C9H16O2 156.1150. found 156.1151.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.Br[CH:21]([OH:23])[CH3:22].[Li]CCCC>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:22][CH2:21][OH:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)Br
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1CCO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
Solution A was prepared by combining pyridin-4-yl-carbamic acid tert-butyl ester (388 mg, 2 mmol) in THF (5 mL) and cooling to −78° C. t-BuLi (2.8 mL, 1.7M solution in pentane) was added dropwise. Once the addition was complete, the solution was stirred at −78° C. for 15 minutes, then warmed to −15° C. and stirred for 90 minutes. In a separate flask, solution B was prepared by combining bromoethanol (0.21 mL, 3 mmol) in THF (5 mL) and cooling to −78° C. n-BuLi (1.44 mL, 2.5M solution in hexanes) was added dropwise. Once the addition was complete, the solution was stirred at −78° C. for 10 minutes. Solution A was recooled to −78° C., and solution B was added to solution A via cannula. Stirred with warming to room temperature for 2 hours. The reaction was recooled, and quenched with water. Partitioned between CH2Cl2 and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide 91 mg (19%) of [3-(2-hydroxy-ethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[O:23][CH3:24].[I:25]Cl>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([I:25])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[O:23][CH3:24]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(F)c(N)c1OC
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(I)cc2)c(F)c(N)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.9 %

Procedure:
Methyl 4-amino-5-fluoro-3-methoxy-6-(4-(trimethylsilyl)phenyl)picolinate (239 mg, 0.686 mmol) was dissolved in 1,2-dichloroethane (3.4 mL) and iodine monochloride (78 μL, 1.557 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was quenched with 10% Na2S2O3 (2 mL) and stirred at room temperature for 1 h. The mixture was extracted with CH2Cl2 (3×5 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The product was purified via RP-HPLC (CH3CN/H2O) to yield the title compound as an orange solid (270 mg, 98%): 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=8.5 Hz, 2H), 7.65-7.53 (m, 2H), 6.54 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −140.64; ESIMS m/z 403.61 ([M+H]+).