Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:44][C:45]1[CH:46]=[C:47]([NH2:56])[C:48]2[CH:49]=[N:50][N:51]([CH2:54][CH3:55])[C:52]=2[CH:53]=1>CN(C=O)C>[Br:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[N:50][N:51]2[CH2:54][CH3:55])=[C:47]([NH:56][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[N:16]=2)=[O:19])[CH:46]=1
Reactant: CCn1ncc2c(N)cc(Br)cc21
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC(=O)c3cccc(C)n3)cc(Br)cc21
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
DIPEA (0.161 ml, 0.93 mmol) was added to 6-methyl-2-pyridinecarboxylic acid (available from Fluorochem, 51 mg, 0.37 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (174 mg, 0.46 mmol) in DMF (3 ml). The reaction was stirred for 30 mins under nitrogen then 6-bromo-1-ethyl-1H-indazol-4-amine (100 mg, 0.42 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and water (5 ml) was added before extraction into DCM (2×20 ml). The compound was loaded onto an aminopropyl cartridge (20 g), eluted with 10% MeOH in DCM and evaporated to dryness. The residue was purified by silica chromatography, eluting with 0-50% ethyl acetate in DCM over 60 mins. Appropriate fractions were evaporated to give the title compound (107 mg).
Reaction SMILES: O=[C:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1.[ClH:29].Cl.[NH2:31][CH2:32][CH2:33][O:34][NH2:35].N1C=CC=CC=1>C(O)C>[ClH:28].[ClH:29].[NH2:31][CH2:32][CH2:33][O:34][N:35]=[C:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1
Reactant: NCCON
Reactant: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 105.3 %

Procedure:
A mixture of 1-{1-[4-oxo-4-(4-chlorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2-benzimidazolone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.35 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. The solvent was evaporated, and the residue was taken up in hot 2-propanol and chilled. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 2.1 g (53%) of product, mp 140°-145° C. (dec).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-])=O)=[CH:16][C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1>C1COCC1>[Cl:5][C:6]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:16]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[NH:21][CH:2]=[CH:1]2
Reactant: Cc1cc(Cl)c(COC2CCCCO2)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(COC2CCCCO2)c2cc[nH]c12
Reaction time: 2 h

Procedure:
To a suspension of vinylmagnesium bromide (1M in THF, 200 mL, 200 mmol) was added dropwise (±)-2-((2-chloro-4-methyl-5-nitrobenzyl)oxy)tetrahydro-2H-pyran (14 g, 49.0 mmol) in THF (40 mL) below −20° C. After completion of the addition, the flask was removed from the ice bath with stirring. After 2 h, the reaction mixture was cooled to below −20° C. The reaction was quenched with MeOH with maintaining the temperature below 0° C. The mixture was diluted with CH2Cl2 and H2O. The mixture was filtered through Celite®. The Celite® cake was washed with CH2Cl2. The layers were separated and the organic phase was washed with H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. For an analytical purpose, the crude was purified by SiO2 column chromatography [heptane/(30% EtOAc in CH2Cl2)]=69/31] to afford the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 9.43 (br. s., 1H), 7.29-7.36 (m, 1H), 6.99 (s, 1H), 6.58-6.70 (m, 1H), 5.05 (d, J=11.12 Hz, 1H), 4.84 (d, J=11.10 Hz, 1H), 4.67-4.77 (m, 1H), 3.89-4.03 (m, 1H), 3.46-3.60 (m, 1H), 2.47 (s, 3H), 1.59-1.75 (m, 2H), 1.43-1.59 (m, 4H)
Reaction SMILES: COC1C=CC(C([O:22][C@@H:23]2[C@@H:27]([CH2:28]OC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[O:26][C@@H:25]([N:53]3[CH:60]=[CH:59][C:57](=[O:58])[NH:56][C:54]3=[O:55])[C@@H:24]2[F:61])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(O)(=O)C>CO>[F:61][C@@H:24]1[C@H:23]([OH:22])[C@@H:27]([CH3:28])[O:26][C@H:25]1[N:53]1[CH:60]=[CH:59][C:57](=[O:58])[NH:56][C:54]1=[O:55]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](F)[C@@H]1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The residue obtained in the above described (iv) was dissolved in MeOH, 100 mL of 80% acetic acid was then added thereto. After stirring at 80° C. for 6 hours, the reaction solution was concentrated, and dissolved in 150 mL of H2O. Subsequently, extraction and washing were carried out three times with 150 mL each of CHCl3, then the solvent of the aqueous layer was evaporated. The resulting residue was dissolved in 15 mL of chloroform, then isolated and purified by silica gel column chromatography (chloroform: methanol=1:0 to 7:1). The solvent was evaporated to obtain white crystal of the compound(3) (yield: 1.68 g, 6.8 mmol, 58%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[C:8]([C:25](=[O:26])[CH2:24][CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: CC(=O)N1CCC(CCC(=O)Cl)CC1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)N1CCC(CCC(=O)c2ccc3[nH]c4ccccc4c3c2)CC1
Temperature: 70 °C
Reaction time: 11 h
Yield: 25 %

Procedure:
To a 90 ml solution of 5.0 g of carbazole and 7.2 g of 3-(1-acetylpiperidin-4-yl)propionyl chloride in nitromethane, 9.3 g of aluminum chloride was added little by little, followed by stirring at 70° C. for 11 hours. The reaction mixture was poured over 100 ml of ice water, and the organic layer was separated and then washed by sequential additions of a 50 ml saturated aqueous sodium hydrogen carbonate solution and 50 ml of distilled water. After the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off to yield an oily residue. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-methanol=20:1 (v/v)) to yield 2.6 g of the title compound as a light yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]1=[O:16].[CH:17]([NH2:20])([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][C:3](=[O:16])[N:2]([CH3:1])[C:7]=2[N:8]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: Cn1c(=O)ccc2cnc(S(C)(=O)=O)nc21
Product: CC(C)Nc1ncc2ccc(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A mixture of 8-methyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (194 mg, 0.81 mmol) and 2 mL of isopropylamine was stirred at room temperature for 15 minutes. Excess amine was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate, followed by brine, dried over magnesium sulfate, and concentrated to give 168 mg (95%) of 2-isopropylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 148-149° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@@H](CC(=O)O)c1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2ccccc2F)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 150 °C
Yield: 91 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-amino-3-(2-fluoro-phenyl)-propionic acid (86 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1800) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 91% yield. LC-MS ESI+: 472 (M+1)+; ESI−: 470 (M−1)−.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N+:30]([O-:32])=[O:31])=[CH:22][CH:23]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
To a solution of 0.199 g (1.13 mmol) of 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine in 5 mL of anhydrous dimethylformamide was added 0.050 g (1.25 mmol) of a 60% mineral oil dispersion of sodium hydride. The reaction mixture was magnetically stirred under a nitrogen atmosphere for 30 minutes, at which point 0.365 g (1.25 mmol) of 4-bromomethyl-2'-nitrobiphenyl was added as a solid. The reaction mixture was stirred an additional 1.5 hours at room temperature, then partitioned between ethyl acetate and water. The organic layer was extracted, washed with brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 50% ethyl acetate-hexane, which after evaporation of the pure fractions and drying in vacuo afforded 0.340 g (77%) of the product as a tan solid: NMR (CDCl3) δ1.31 (t, J=10 Hz, 3H), 2.58 (s, 3H), 2.62 (s, 3H), 2.78 (q, J=10 Hz, 2H), 5.48 (s, 2H), 6.88 (s, 1H), 7.14-7.24 (m, 4H), 7.34-7.38 (m, 1H), 7.42-7.48 (m, 1H), 7.54-7.60 (m, 1H), 7.83, (d, J=10 Hz, 1H); MS (FAB) m/e 387 (MH+).
Reaction SMILES: [C:1]([Li])(C)(C)[CH3:2].[CH2:6]([C:10]1[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[S:13][C:14]=1[CH3:15])[CH:7]([CH3:9])[CH3:8].ICC>C1COCC1>[CH2:1]([C:11]1[C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[C:14]([CH3:15])[S:13][C:12]=1[C:16]([OH:18])=[O:17])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(C(=O)O)sc(C)c1CC(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
At −78° C., tert.-butyllithium (20 mL, 1.5 M in pentane) is slowly added to a solution of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (2.0 g, 10.1 mmol) in THF (100 mL). The mixture turns dark. The mixture is stirred at −78° C. for 15 min, then a solution of iodoethane (6.18 g, 39.6 mmol) in THF (10 mL) is added. The mixture is stirred for 1 h at −78° C. Further iodoethane (6.18 g, 39.6 mmol) is added and the mixture allowed to warm to rt over a period of 15 h. The reaction is quenched by adding 1 M aq. NaH2PO4 (20 mL) and 1 N aq. HCl (50 mL) and the mixture is extracted with chloroform (1×100 mL, 3×30 mL). The combined organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in hexane to give 3-ethyl-4-isobutyl-5-methyl-thiophene-2-carboxylic acid (1.29 g) as a yellow solid; LC-MS: tR=1.00 min, [M+1+CH3CN]=268.29; 1H NMR (CDCl3): δ 2.92 (q, J=7.0 Hz, 2H), 2.40 (s, 3H), 2.37 (d, J=7.6 Hz, 2H), 1.80 (m, J=7.0 Hz, 1H), 1.15 (t, J=7.6 Hz, 3H), 0.92 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]#[N:27])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-:29].[K+].[K+].CS(C)=O>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]([NH2:27])=[O:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C#N)CC5)cc4)nc23)cn1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C(N)=O)CC5)cc4)nc23)cn1
Reaction time: 5 h

Procedure:
1-{4-[8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino]-phenyl}-cyclopropanecarbonitrile is dissolved in methanol before potassiumcarbonate (5 eq.), DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) are added. The mixture is stirred for 5 h and monitored via LCMS MS. DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) ares added and the mixture iss stirred at rt for 16 h. The mixture is concentrated and the crude material purified via column chromatographie. LCMS purity (Method D): 100%, Rt: 1.70 min, observed [M+H]=375.1;
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A solution of 0.19 g methyl 4-({3-cyclohexyl-5-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}methyl)benzoate from Step C Example 1 in 6 mL ethanol and 2.5 mL water was treated with 2.4 equivalents of 5 N NaOH solution till the hydrolysis was complete based on HPLC. After evaporating ethanol under reduced pressure, the residue was acidified with 20% molar excess of 2 N HCl to precipitate the acid product. Extract the reaction mixture with 2×35 mL EtOAc. Wash the combined organic layer with saturated brine, dry over anhydrous Na2SO4, and evaporate to give the title compound as a white solid. It can be recrystallized from 5:3 MeCN and water to give fine crystalline needles. 1H NMR (CDCl3, 500 MHz) δ 7.89 (d, J=8.3 Hz, 2H), 7.39˜7.42 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.3 Hz, 2H), 6.30 (s, 1H), 5.38 (s, 2H), 2.67 (tt, J=3.5 & 11.5 Hz, 1H), 1.97˜2.01 (m, 2H), 1.80˜1.85 (m, 2H), 1.71˜1.75 (m, 1H), 1.38˜1.53 (m, 4H), 1.26˜1.33 (m, 1H). LC-MS: 2.47 min. (M+H=445.3).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:14][CH:10]([F:15])[O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cccnc1Br
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of 2-bromo-3-pyridinol (1.26 g, 7.23 mmol) in DMF (35 mL) and water (5 mL) was added sodium chlorodifluoroacetate (2.93 g, 18.1 mmol) followed by cesium carbonate (4.71 g, 14.5 mmol). The reaction was heated to 100° C. for 36 hours before partitioning between EtOAc and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:3 to afford the title compound as a colourless oil (570 mg, 35%).
Reaction SMILES: Br[CH:2]([CH2:13][C:14]([Cl:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:17][C:14]([F:15])([F:16])[CH:13]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCCCCCCCC(Br)CC(F)(F)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: OCCCCCCCCCC=CC(F)(F)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The stirred intermediate 10-bromo-12-chloro-12,12-difluorododecanol, 31.9 grams (0.095 mole), was cooled, and 15.9 grams (0.11 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. After this time the reaction mixture was warmed to 70° C. where it was stirred for one hour. The reaction mixture was cooled, and then it was taken up in 200 mL of methylene chloride. The solution was washed in turn with one 150 mL portion of aqueous 1N hydrochloric acid, one 100 mL portion of water, one 100 mL portion of an aqueous solution saturated with sodium bicarbonate, one 100 mL portion of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under high vacuum yielding 14.3 grams of 12-chloro-12,12-difluoro-10-dodecenol, b.p. 130°-131° C./1.1-1.2 mm.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.N#N.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([F:28])([CH3:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
In a cooled solution (−78° C.) of 4-(dibenzylamino)-2-methylbutan-2-ol (110.0 g, 0.39 mol) in DCM (1 L), add diethylaminosulfur trifluoride (75 g, 0.47 mol) dropwise under N2, allow it to warm to RT and stir overnight. Re-cool the mixture to −78° C., add dropwise with saturated NaHCO3 (300 mL), warm to RT, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (0.1-0.2% EtOAc/pet ether) to afford the title compound (44.0 g, 40% yield). MS (m/z): 286.2 (M+1).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[CH3:15]S(O)(=O)=O>CO>[C:1]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH2:4][C:5]([O:7][CH3:15])=[O:6])#[N:2]
Reactant: N#CC(CC(=O)O)c1ccc(O)cc1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(C#N)c1ccc(O)cc1
Yield: 93.3 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with methanol (15 mL). To the stirred solvent was added 3-cyano-3-(4-hydroxyphenyl)propanoic acid (0.6 g, 3.1 mmol), followed by the addition of methanesulfonic acid (1 mL). The reaction mixture was refluxed for 1 h. After completion of the reaction, the reaction mixture was concentrated to distill off the solvent. Water (10 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with water (5 mL) and saturated brine solution (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow liquid (0.6 g, yield: 93.3%). 1H NMR (300 MHz, CDCl3): δ 7.13-7.15 (d, 2H), 6.75-6.78 (d, 2H), 4.14-4.19 (t, 1H), 3.65 (s, 3H), 2.89-2.97 (m, 1H), 2.71-2.79 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(O[C:28]1(O[Si](C)(C)C)[CH2:30][CH2:29]1)C.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:28]1[CH2:30][CH2:29]1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)C1CC1
Yield: 15.4 %

Procedure:
A mixture of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (115 mg, 0.35 mmol), (1-Ethoxy-cyclopropoxy)-trimethylsilane (360 mg, 2.0 mmol), AcOH (0.2 ml, 3.5 mmol), NaCNBH3 (110 mg, 1.75 mmol) and 4 Å molecular sieves (100 mg) in MeOH (5 ml) was heated to reflux for 18 hours. The mixture was cooled, concentrated in vacuo and partitioned between 2M NaOH (10 ml) and DCM (10 ml). The organic phase was separated and the aqueous phase extracted with DCM (2×10 ml). The combined organic phases were concentrated in vacuo and purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (20 mg, 0.054 mmol, 15%). 1H NMR (400 MHz, CDCl3) δ 0.15 (m, 2H), 0.29 (m, 2H), 1.68 (m, 1H), 1.70-1.90 (m, 6H), 1.85 (s, 3H), 2.00-2.10 (m, 4H), 2.60 (m, 4H), 2.65 (s, 2H), 2.68 (m, 2H), 3.50 (t, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.85 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 373.2844 [MH]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:15]1C(=O)N([Cl:22])C(=O)C1.[ClH:23]>CC(O)=O.CCOCC>[ClH:22].[Cl:23][CH2:15][C:9]([C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:1])([F:14])[F:13])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cnccc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CCl)c1cnccc1C(F)(F)F
Reaction time: 18 h
Yield: 49 %

Procedure:
In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4-trifluoromethylnicotinate in 25 mL of 1 M HCl in CH3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed to stir overnight (18 h). The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCl in Et2O with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-1-[4-(trifluoromethyl)-3-pyridinyl]ethanone hydrochloride as a white solid. 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H).