Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]2[C:4](=[O:30])[CH:5]=[C:6]3[C@:27]([CH3:28])([CH:2]12)[C@@H:26]1[C@H:9]([C@H:10]2[C@:23]([CH3:29])([CH2:24][CH2:25]1)[C@@H:13]([C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([F:21])([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.N.[Cl-].[NH4+].[Li]>O1CCCC1>[F:21][C:18]([CH2:17][CH2:16][CH2:15][C@H:14]([C@@H:13]1[C@:23]2([CH3:29])[C@H:10]([C@H:9]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:28])[C:6]([CH2:5][C@H:4]([CH2:3][C@@H:2]2[OH:1])[OH:30])=[CH:7][CH2:8]3)[CH2:11][CH2:12]1)[CH3:22])([CH3:19])[CH3:20]
Reactant: C[C@H](CCCC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C5OC5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1,2-Epoxy-25-fluoro-4,6-cholestadien-3-one (0.01 moles) prepared according to 1D above is dissolved in 100 ml. of a 1:1 solvent mixture of tetrahydrofuran and liquid ammonia containing 0.04 moles of ammonium chloride. The mixture is stirred at reflux using a dry ice condenser and reduced by adding 0.42 grams of finally divided metalic lithium (0.06 gm. atoms) over a period of 10 minutes. The mixture is refluxed for one hour after which time the ammonia is allowed to evaporate from the mixture. The solvent is removed from the remainder of the mixture by evaporation to near dryness at room temperature. The residue is washed in 50 ml of ice water containing 5.0 g of ammonium chloride. The ice water is extracted three times with 50 ml of chloroform. The chloroform extracts are combined and the solvent is removed by evaporation to yield crude 25-fluoro-1α-hydroxycholesterol. 25-Fluoro-1α-hydroxycholesterol can be purified by chromatographing the crude product on a silica gel column using a solvent of petroleum ether and diethyl ether.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]([NH:12][C:13](=[O:30])[CH2:14][O:15][C:16]3[N:21]=[C:20]4[N:22]([CH3:28])[N:23]=[C:24]([CH:25]5[CH2:27][CH2:26]5)[C:19]4=[C:18]([CH3:29])[CH:17]=3)[CH3:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:31]I.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[CH:25]1([C:24]2[C:19]3[C:20](=[N:21][C:16]([O:15][CH2:14][C:13]([NH:12][CH:10]([C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][N:1]([CH3:31])[C:5]5=[N:6][CH:7]=4)[CH3:11])=[O:30])=[CH:17][C:18]=3[CH3:29])[N:22]([CH3:28])[N:23]=2)[CH2:27][CH2:26]1
Reactant: CI
Reactant: Cc1cc(OCC(=O)NC(C)c2cnc3[nH]ccc3c2)nc2c1c(C1CC1)nn2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(=O)NC(C)c2cnc3c(ccn3C)c2)nc2c1c(C1CC1)nn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
N-(1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)-2-(3-cyclopropyl-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetamide (example 6.57, 25 mg, 0.062 mmol) was dissolved in DMF (1 ml) and methyliodide (4.25 μl, 0.068 mmol) was added, followed by NaH (60% in mineral oil, 2.7 mg, 0.068 mmol). After stirring for 1 h at rt the reaction was diluted with EtOAc (1 ml) and water (2 ml) and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. The crude product was purified on preparative TLC (DCM/MeOH 95/5) to give the product as colorless solid (15 mg, 58%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.58 (d, 1H), 8.23 (s, 1H), 7.83 (s, 1H), 7.48 (d, 1H), 6.47 (s, 1H, 6.30 (d, 1H, 5.13-5.09 (m, 1H), 4.81 (d, 1H), 4.76 (d, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 2.65 (s, 3H), 2.27-2.22 (m, 1H), 3.06 (d, 3H), 0.93-0.84 (m, 4H); LCMS RtL=2.901 min; [M+H]+=419.2]
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1.C(Cl)CCl.C(OCC)(=O)C>CCCCCC>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][CH2:15][NH:14][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=2)=[CH:18]1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(/C=C/c1ccc(O)cc1)NCCc1c[nH]c2ccccc12

Procedure:
(E)-N-(2-(1H-indol-3-yl)ethyl)-3-(4-hydroxyphenyl) acrylamide (2e) was synthesized by the condensation of 4-hydroxy cinnamic acid (150 mg, 0.914 mmol) and tryptamine hydrochloride (215 mg, 1.09 mmol) using standard EDC coupling method. 2e was isolated as yellowish solid (178 mg, 64%) by elution with 45% ethyl acetate in hexane. Rf: 0.593 (80% ethyl acetate in hexane); mp: 135-138° C.;
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([O:37][S:38](=[O:43])(=[O:42])[NH:39][CH2:40][CH3:41])[C:34]([CH3:44])=[CH:33][C:32]=1[S:45]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.CO.C(Cl)(Cl)Cl>[C:27]([C:31]1[C:32]([S:45][C:3]2[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[CH2:7][C:2]=2[OH:1])=[CH:33][C:34]([CH3:44])=[C:35]([O:37][S:38](=[O:42])(=[O:43])[NH:39][CH2:40][CH3:41])[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP; 0.100 g, 0.280 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-ethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example VVV; 0.128 g, 0.280 mmol), K2CO3 (0.154 g, 1.12 mmol), and DMF (8 mL), as described in General Method 9. The reaction was stirred at room temperature for 2 hours and then worked up in the usual manner. The residue was submitted to flash chromatography (95% CHCl3 :5% MeOH). The product obtained was taken up in a small amount of EtOAc, triturated with hexane, filtered and dried overnight under high vacuum to yield the title compound, m.p. 130° C. (dec.). 1H NMR (CDCl3) δ 1.22 (t, 3 H), 1.52 (s, 9 H), 1.92 (s, 3 H), 2.11 (m, 4 H), 2.66 (m, 4 H), 2.87 (s, 2 H), 3.31 (m, 2 H), 4.52 (br t, 1 H), 4.78 (br s, 2 H), 6.73 (d, 4 H), 6.98 (d, 4 H), 7.25 (s, 1 H), 7.70 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][CH:6]=[CH:5]2
Reactant: Oc1nccc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2cc(Br)ccc12
Yield: 62 %

Procedure:
A solution of 6-bromo-1-hydroxylisoquinoline (9.205 g, 41.0 mmol) in POCl3 (100 mL) was heated to 100° C. for 4 h. The reaction was concentrated to dryness. The residue was dissolved in ethyl acetate and the organic layer was washed with 5% NaHCO3, water, brine, dried over MgSO4 and concentrated. The residue was was chromatographed on silica gel eluting with CH2Cl2:hexane (3:7) to give the title compound (6.176 g, 62%). MS (DCI/NH3) m/z 241, 243 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1ccc([N+](=O)[O-])n1
Yield: 84.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 300 mg, 2.65 mmol) was dissolved in anhydrous N,N-dimethylformamide (6.6 mL) and a 60% dispersion of sodium hydride in mineral oil (106 mg, 2.66 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, 1-bromo-2-methoxy-ethane (250 μL, 2.66 mmol) was added. The reaction continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (100 mL), washed with 1.0 M aqueous hydrochloric acid solution (25 mL), water (25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded 1-(2-methoxy-ethyl)-3-nitro-1H-pyrazole (384 mg, 85%) as a white solid: H1-NMR (400 MHz, CDCl3) δ 3.34 (3H, s), 3.77 (2H, t, J=4.4 Hz), 4.36 (2H, t, J=4.8 Hz), 6.87 (1H, d, J=2.8 Hz), 7.54 (1H, d, J=2.4 Hz).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[O:5][C:6]1C=CC=CC=1)#[N:2].C[O-].[Na+].[Na]>C1COCC1.CO>[C:1]([N:3]=[C:4]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[O:5][CH3:6])#[N:2]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=NC#N)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a stirred solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate 6 (35 mg, 0.06 mmol) in THF (1 mL) was added sodium methoxide in methanol (100 μL, ˜0.8 M, freshly made from methanol and sodium). The resulting mixture was stirred at ambient temperature for 30 minutes before evaporation of the solvent. The crude product was then purified by flash chromatography on silical gel, eluting with a gradient of 0-15% methanol in ethyl acetate to afford methyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate as amorphous solid (21.8 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.69-7.66 (m, 1H), 7.42-7.37 (m, 2H), 7.32-7.24 (m, 4H), 7.21-7.13 (m, 2H), 4.64 (br, 1H), 4.19-4.07 (br, 2H), 3.92 (s, 3H), 3.40-3.27 (m, 4H), 2.59 (s, 3H), 2.35-2.30 (m, 4H), 1.97-1.83 (m, 10H), 1.66-1.63 (m, 2H). HRMS m/z (M+H)+ calcd 511.3185; obsd 511.3211.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[C:21]([Cl:28])[CH:20]=1.CN(C)C1C=CC=CC=1.C(OC1C(=CC=CC=1)C(Cl)=O)(=O)C.Cl>CC(C)=O>[Cl:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([Cl:28])[C:22]=1[O:26][CH3:27])[NH:18][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: COc1c(Cl)cc(N)cc1Cl
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: COc1c(Cl)cc(NC(=O)c2ccccc2O)cc1Cl
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
Acetylsalicylic acid (1.8 g.) was converted to its acid chloride by conventional method using thionyl chloride and dissolved in acetone (30 ml.). 4-Amino-2,6-dichloroanisole (2.13 g.) with N,N-dimethylaniline (1.27 ml.) was dissolved in acetone (25 ml.) to which, with stirring in the cold at 0°-10° C., the above acetone solution of acetylsalicyloyl chloride was added dropwise over 20-30 minutes. Reaction continued for 1-2 hours, then the solution was evaporated to dryness under reduced pressure, the residue being put in sodium hydroxide solution and gently agitated for 1-2 hours for cleavage of the acetyl group. After reaction was complete the solution was made acidic by the addition of 2 N hydrochloric acid and the precipitate which formed was collected by filtration and recrystallized from aqueous acetone to give needle-like crystals (2.0 g.) of 3',5'-dichloro-2-hydroxy-4'-methoxybenzanilide. Yield 64%. The melting point of the product is 226°- 228° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl-].[In+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([CH:23]1[CH2:25][CH:24]1[C:26]#[N:27])(O)[CH3:21].[CH3:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([CH:23]1[CH2:25][CH:24]1[C:26]#[N:27])([C:36]1[C:35]2[C:39](=[C:31]([CH2:30][S:29][CH3:28])[CH:32]=[CH:33][CH:34]=2)[NH:38][CH:37]=1)[CH3:21]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
0.08 ml (1.08 mmol) of trifluoroacetic acid and 218 mg (0.99 mmol) of indium(III) chloride were added to 200 mg (0.90 mmol) of the compound from Example 133A and 318 mg (1.79 mmol) of the compound from Example 8A in 8 ml of dichloromethane at RT, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 128 mg (37% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:18])=[C:13]([C:15](O)=[O:16])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.[H-].C([Al+]C(C)C)(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]2[C:12]([CH3:18])=[C:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCCc1cccc2oc(C(=O)O)c(C)c12
Agent: CC(C)[Al+]C(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COCCCc1cccc2oc(CO)c(C)c12
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To 4-(3-methoxy-propyl)-3-methyl-benzofuran-2-carboxylic acid (0.2354 g, 0.853 mmol) in tetrahydrofuran (10 mL) cooled at 0° C. was added diisopropylaluminium hydride (3.41 mL, of a 1.0M solution in toluene) dropwise. After stirring for 1 hour methanol (5 mL) was added followed by saturated aqueous sodium potassium tartrate (5 mL). The resulting mixture was stirred for 15 minutes and was then thrice extracted with ethyl acetate. Combined organic extracts were dried over sodium sulfate, filtered, reduced to dryness and the resulting residue was subjected to silica gel gradient flash chromatography (hexanes/ ethyl acetate 10:1-3:1) which furnished 0.192 g (96%) of [4-(3-methoxypropyl)-3-methyl-1-benzofuran-2-yl]methanol as a white solid. MS (ES) m/z: 234.1 (M+).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: CO
Reactant: NC(CCC(=O)O)c1cccc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC(N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
680 mg (2.49 mmol) 4-Amino-4-(3-nitro-phenyl)-butyric acid were suspended in 5 ml methanol and 635 μl (8.75 mmol) thionyl chloride were added. The mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, methanol was added and again evaporated to dryness.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][C:20]([CH3:30])([CH2:26][O:27]CC)[C:21]([O:23][CH2:24][CH3:25])=O>C1COCC1.O.C(O)(=O)C>[CH3:19][C:20]([CH3:30])([CH2:21][O:23][CH2:24][CH3:25])[C:26](=[O:27])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of dimethyl methylphosphonate (7.18 g, 57.5 mmol) in anhydrous THF (100 ml) was added under argon atmosphere a solution of n-butyl lithium in hexane (1.61N, 35.7 ml, 57.5 mmol) at 31 78° C. The reaction mixture was stirred for 30 min. and a solution of ethyl 2,2-dimethyl-4-oxahexanoate (4.00 g, 23.0 mmol) in anhydrous THF (15 ml) was added at -78° C. The resulting mixture was stirred for 30 min., allowed to warm to room temperature and stirred for one hour. The resulting mixture was then neutralized with acetic acid, then water (20 ml) was added, and the mixture was concentrated. Ethyl acetate (120 ml) and water (30 ml) were added to the residue. The organic layer was separated, washed with water (50 ml) and with brine, dried over anhydrous magnesium sulfate, and concentrated. Distillation of the residue (b.p. 106°-110° C./0.4 mmHg) gave dimethyl 3,3-dimethyl- 2-oxo-5-oxaheptylphosphonate (4.19 g, 16.6 mmol, 72.2%) as an oily material. The product was assigned the structure by the following data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].[CH:14]1[CH:19]=[C:18]2[CH:20]=[CH:21][O:22][C:17]2=[CH:16][CH:15]=1>O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:21]1[O:22][C:17]2[CH:16]=[CH:15][CH:14]=[CH:19][C:18]=2[CH:20]=1)([CH3:12])[CH3:11]
Reactant: COc1ccc(C(C)(C)O)c(Br)c1
Reactant: c1ccc2occc2c1
Solvent: O
Product: COc1ccc(C(C)(C)c2cc3ccccc3o2)c(Br)c1
Temperature: 90 °C
Yield: 51 %

Procedure:
Mixture comprising 2-(2-bromo-4-methoxyphenyl)-propan-2-ol (100 mg), 2,3-benzofuran (0.19 ml) and polyphosphoric acid (1 g) was stirred and heated at 90° C. for 30 min. The reaction mixture was added with water and extracted with DCM. The residues obtained after concentration under reduced pressure were purified by silica gel column (DCM/hexane) to obtain the title compound (143 mg, 51%).
Reaction SMILES: BrC1C=CC([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=2)=[O:10])=C(F)C=1.CC1(C)C(C)(C)OB(C2C=CC=NC=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH3:8])=[CH:13][C:14]=2[C:27]([F:29])([F:28])[F:30])[CH2:20][CH2:21]1)[CH3:26]
Reactant: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(Br)cc3F)cc2C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2cccnc2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCN(Cc2ccc(NC(C)=O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A suspension of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added to a solution of 3-ethoxy-2-(4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (317 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL). PdCl2(dppf) (60.2 mg, 0.082 mmol) and Cs2CO3 (536 mg, 1.644 mmol) were added and the mixture was at 110° C. for 30 min in a microwave. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1, Rf=0.5) to yield a light yellow solid of 2-(4-(5-ethoxy-6-(4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) acetamide (405 mg, 0.595 mmol, 72.4% yield): 1H NMR (400 MHz, CD3OD) δ 8.02-7.87 (m, 2H), 7.82-7.64 (m, 2H), 7.60-7.30 (m, 6H), 6.98-6.80 (m, 2H), 5.34 (s, 2H), 4.18-4.04 (m, 2H), 3.84-3.72 (m, 4H), 3.68-3.57 (m, 2H), 2.91-2.38 (m, 10H), 1.47-1.31 (m, 3H), 1.14 (s, 3H); ES-LCMS m/z 681.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=1[F:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (500 mg, 1.90 mmol) in DMF (20 mL) were added 3-chloro-2-fluoro-benzylamine (330 mg, 2.1 mmol), HBTU (1.4 g, 3.8 mmol) and DIPEA (1.32 mL, 7.6 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water (50 mL). After extraction with ETOAc (3×30 mL), the organic phases were joined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.37; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.12 min. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.59 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.20 (br.d, 1H), 4.47-4.26 (m, 3H), 4.19 (ddd, 1H), 3.81-3.65 (m, 1H), 3.54-3.40 (m, 1H), 3.36 (s, 3H), 1.42 and 1.27 (2 s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[C:16]([F:15])=[CH:24][CH:23]=[CH:22][C:21]=2[F:25])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cc1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 66.3 %

Procedure:
To a stirred and 0° C. cooled solution of 4-bromoaniline (1.0 g, 5.8 mmol, 1.0 eq) and pyridine (0.61 mL, 7 mmol, 1.2 eq) in DCM (20 mL) was added drop wise a solution of 2,6-difluorobenzoyl chloride (0.8 mL, 6.4 mmol, 1.1 eq) in DCM (5 mL). After stirring the resulting mixture at the same temperature for 1 h, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (20 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 1.20 g of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.78 (brs, 1H, D2O exchangeable), 7.53-7.37 (m, 5H), 7.02-6.95 (m, 2H); ESI-MS (m/z) 312, 314 [(MH)+ Br79,81].