Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH:27]([CH3:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH:27]([O:26]/[N:25]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH3:30]
Reactant: CC(CO)ON
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Product: C/C(=N\OC(C)CO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 90 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propan-1-ol hydrochloride (intermediate Q) in 90% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 8.93 (m, 1H), 8.15 (m, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.43 (dd, 1H), 6.12 (s, 2H), 4.61 (m, 1H), 3.85 (m, 2H), 2.41 (s, 3H), 2.00 (s, 1H), 1.38 (d, 3H). LCMS (method B): [MH]+=378, tR=1.96 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[BH4-].[Na+]>>[CH2:24]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC=O
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 30 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0260 g, 0.0874 mmol), hexanal (0.0195 mL, 0.162 mmol), and sodium borohydride (0.0076 g, 0.200 mmol) provide 0.0100 g (30%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C23H32N3O2 382.2495, found 382.2513; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.41-7.35 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (d, 1H, J=8.3 Hz), 3.23-3.16 (m, 2H), 2.95 (tt, 1H, J=3.4, 11.7 Hz), 2.63-2.56 (m, 2H), 2.35-2.22 (m, 2H), 2.05-1.90 (m, 2H), 1.83 (tq, 1H, J=3.9, 13.7 Hz), 1.70-1.56 (m, 3H), 1.45-1.30 (m, 6H), 0.96 (t, 3H, J=6.3 Hz).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[CH2:16]([NH:23][C:24]([O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:24](=[O:25])[NH:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:28][CH:29]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(OC(=O)NCc2ccccc2)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(OC(=O)NCc3ccccc3)cc2)C(=O)OC1=O

Procedure:
To a boiling solution of 2.1 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol is added 2.4 g. (0.01 m.) of p-(N-benzylcarbamoyloxy)aniline and the resulting mixture is refluxed for one hour. The cooled reaction mixture is filtered and the solid is recrystallized to furnish 5-acetyl-3-[1-(p-N-benzylcarbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 195°-197° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH:16][C:25](=[O:27])[CH3:26])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([C@H]3C[C@@H]3CN)cccn2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1C[C@@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
To a suspension of 1-[(1S,2S)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added acetic anhydride (388 μL, 4.10 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (623 mg, yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38](O)(=[O:47])[C:39]1[C:40](=[CH:42][CH:43]=[C:44]([CH:46]=1)[OH:45])[OH:41].CCCCCCC>C(O)C>[C:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])(=[O:47])[C:39]1[C:40](=[CH:42][CH:43]=[C:44]([CH:46]=1)[OH:45])[OH:41]
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CCO
Solvent: CCCCCCC
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)c2cc(O)ccc2O)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (0.50 g) in ethanol (1.5 mL) was added a mixture of gentisic acid (150 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added IPE/heptane at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.44 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([I:10])=[CH:7][C:8]=1[I:9])#[N:2].[OH-:17].[Na+].Cl>O>[C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([I:10])=[CH:7][C:8]=1[I:9])(=[O:17])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1c(I)cc(I)c(CCC(=O)O)c1I
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(I)cc(I)c(CCC(=O)O)c1I
Temperature: 60 °C

Procedure:
30 g of 3-(3-cyano-2,4,6-triiodophenyl)propionic acid is introduced into a solution of 8 g of caustic soda in 100 ml of water. The solution is then maintained for 3 hours at 60° C., decolorized by repeated treatment with active carbon, and brought to pH 1 by adding concentrated hydrochloric acid. After several hours of agitation in an ice bath, the precipitate is vacuum-filtered, washed with water, and dried at 50° C. Yield: 29 g (94% of theory) of 3-(3-carbamoyl-2,4,6-triiodophenyl)propionic acid as a white powder, mp>280° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:21]1[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]1)=[O:14])[CH:6]=[CH:5]2
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: CC(C)N1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and N-isopropyl-piperazine (commercially available) according to the procedure described for Example A. MS (m/e): 299.3 (MH+, 100%)
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CN1CCOCC1.[O:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:19]([CH:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)=[O:20]
Reactant: CNOC
Reactant: O=C(Cl)C1CCOCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOCC1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.23 g, 12.7 mmol) and N-methyl morpholine (3.80 mL, 34.5 mmol) were dissolved in DCM (20 mL) and a solution of oxane-4-carbonyl chloride (1.71 g, 11.5 mmol) in DCM (20 mL) was added drop-wise. The reaction mixture was stirred for 2 h, then diluted to 200 mL with DCM, washed with 1 M aq HCl (2×100 mL), 1M aq Na2CO3 (100 mL) and water (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow oil (1.87 g, 94%). LCMS (ES+): 174.1 [MH]+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[K+].C(O[C:14]([S-:16])=[S:15])C.O.Cl>CN(C=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]2[S:16][C:14](=[S:15])[NH:9][C:3]=2[N:4]=1
Reactant: Nc1ncc(Br)c(N)n1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc2sc(=S)[nH]c2n1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
5-Bromo-pyrimidine-2,4-diamine (2.0 g, 10.58 mmol) [prepared in a manner similar to English et. al. J. Am. Chem. Soc. 1946, 68, 453-458] and O-ethylxanthic acid potassium salt (3.39 g, 21.16 mmol) was heated in DMF (25 mL) to 140° C. After 5 h the reaction was cooled to ambient temperature and 25 mL of water was added. The pH was then adjusted to 5.0 using 1 N HCl. A red precipitate formed and was collected by filtration, yielding 900 mg (30%) of a solid: 1H NMR (400 MHz, d6-DMSO) δ 13.85 (s, 1H), 8.33 (br s, 1H), 6.90 (s 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)c(F)ccc12

Procedure:
23 mg (0.36 mmol) of copper powder were added to 3.31 g (7.16 mmol) of the compound from Example 21A in 13 ml of pyridine and 3 ml of ethanol. The reaction mixture was heated under reflux for 4 h and then the pyridine was removed in vacuo. The residue was taken up in ethyl acetate, silica gel was added, and the mixture was concentrated. The crude product-silica gel mixture was initially prepurified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 5/1→3/1), and the product was again purified by preparative HPLC (acetonitrile/water gradient). 2.38 g (82% of theory) of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:38]([F:41])([F:40])[F:39])([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:51])[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:38]([F:41])([F:40])[F:39])([O-:3])=[O:2]
Reactant: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (20 mg; 0.034 mmol, prepared in accordance with Example 165) is reacted with Lawesson's reagent (7 mg; 0.017 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (11 mg; 0.018 mmol). The structure was confirmed using Protocol I-B. Calculated mass=604; observed mass=604; HPLC retention time=4.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: Clc1cc(Cl)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
A suspension of 3,5-dichloro-1H-pyrazole (690 mg, 5.0 mmol) (i.e. the product of Example 12, Step D), potassium carbonate (3 g, 21 mmol) in N,N-dimethylformamide (10 mL) was treated with ethyl bromoacetate (1.0 mL, 9.0 mmol) and stirred at ambient temperature for 12 h. The suspension was diluted with ethyl acetate, washed with water, and dried over MgSO4. The reaction mixture was then concentrated under reduced pressure giving 1.05 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:16](=[O:19])[CH2:17][CH3:18])[CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(C)cccc1C
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1cc(C)c(OC)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
13.6 g of 2,6-dimethylanisole was dissolved in 30 ml of methylene chloride, and 16 g of anhydrous aluminum chloride was added. Then, with water cooling, 11 g of propionyl chloride was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the organic layer was separated and washed with water. The solvent was evaporated to give 18.7 g of 2,6-dimethyl-4-propionylanisole.
Reaction SMILES: [I:1]I.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1>CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([I:1])[C:7]([NH2:10])=[N:8][CH:9]=1
Reactant: Nc1ccc(Br)cn1
Reactant: II
Solvent: CS(C)=O
Product: Nc1ncc(Br)cc1I
Temperature: 100 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
I2 (8.81 g, 34.7 mmol, 1.2 equiv.) was added to a solution of 5-bromopyridin-2-amine (5.00 g, 28.9 mmol) in DMSO (30 mL), and the resulting mixture was stirred at 100° C. for 4 h. After standing at 25° C. for 12 h, the reaction mixture was poured onto a saturated Na2S2O5 aqueous solution (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 15 to 25%) providing 5-bromo-3-iodopyridin-2-amine (4.00 g, 46%) as a pale yellow solid. H1 NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.98 (s, 1H) and 5.05 (bs, 2H). K2CO3 aqueous solution (1 M, 6.8 mL) was added to a suspension of 5-bromo-3-iodopyridin-2-amine (2.00 g, 6.69 mmol), 6-methoxypyridin-3-ylboronic acid (1.12 g, 7.32 s mmol, 1.1 equiv.), and Pd(PPh)3 (380 mg, 5 mol %) in dioxane (20 mL) under N2. The reaction mixture was stirred at 120° C. for 14 h, poured onto H2O (65 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 30 to 40%) providing intermediate 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2-amine (1′) (Formula iv) (993 mg, 53%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[C:3](OC)=[O:4].CC(C[AlH]CC(C)C)C.Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:7][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)Sc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(CO)Sc1ccccc1
Temperature: 25 °C

Procedure:
A −78° C. solution of Example 103B (860 mg, 4.1 mmol) in dichloromethane (10 mL) was treated with 1.0M DIBAL-H in toluene (11 mL), warmed to room temperature over 4 hours, poured into a mixture of 3M HCl (15 mL) and ice (˜10 g), and extracted with ethyl acetate (100 mL). The combined extracts were washed with 1M HCl (10 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 183 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>O.CO>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)CCCC(CC#CCCCC(=O)O)S(C)(=O)=O

Procedure:
Methyl 8-methylsulfonyl-12-acetoxy-5-heptadecynoate (41.6 g., 0.10 mole) is added to a solution of sodium hydroxide (12.0 g., 0.3 mole) in water (120 ml.) and methanol (600 ml.). The resulting solution is heated at 55°-60° C. for 24 hours. Most of the methanol is removed by evaporation in vacuo. The residue is diluted with water and extracted with ether. The aqueous solution is acidified with concentrated hydrochloric acid. The product which separates is taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a viscous yellow oil. Purification is effected by column chromatography on silica gel with 2% methanol in chloroform as eluant. The title compound is obtained as a nearly colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>ClCCCl>[Cl:23][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: Brc1cc(Br)cc(-c2cc[nH]n2)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Clc1c[nH]nc1-c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
4 g (0.0132 mol) of 3-(3,5-dibromophenyl)pyrazole and 1 g of pyridine (0.0132 mol) are dissolved, at room temperature and with stirring, in 50 ml of 1,2-dichloroethane. 2 g (0.0145 mol) of sulphuryl chloride in 10 ml of 1,2-dichloroethane are then added dropwise at 50° C. and stirring is then continued for 30 min days at this temperature. After cooling, the precipitate is filtered and recrystallised from 200 ml of 1,2-dichloroethane. 2.9 g (yield: 66%; melting point: 188° C.) of 4-chloro-3-(3,5-dibromophenyl)pyrazole are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH3:6].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH3:6])[CH2:11][CH2:10]1
Reactant: CCC(=O)CCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)CCN1CCN(C)CC1
Yield: 73.5 %

Procedure:
A mixture of 30.5 g of 1-chloro-3-pentanone, 25 g of 1-methylpiperazine, 41.9 g of potassium carbonate and 400 ml of acetone was refluxed for 3 h. The mixture was filtered and the acetone was evaporated. The residue was dissolved in aqueous hydrochloric acid and the resulting solution was washed twice with diethyl ether. The aqueous phase was basified with potassium carbonate and extracted twice with dichloromethane. The organic phase was washed, dried and evaporated to yield 33.8 g (73.3%) of crude 1-(4-methylpiperazinyl)pentane-3-one.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:18]#[N:19])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>CN(C)C=O>[C:1]1([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH:7]=[C:8]([C:18]#[N:19])[S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=C(C#N)S(=O)(=O)c2ccccc2)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#CC(=Cc1ccc(C=Cc2ccccc2)cc1)S(=O)(=O)c1ccccc1
Yield: 63 %

Procedure:
12.48 g (20 mmole) of the triphenylphosphonium bromide of Example 1 c) were dissolved in 200 ml of absolute dimethylformamide at 70° C, by stirring and under an atmosphere of nitrogen. After the mixture had cooled to 30° to 35° C, 2.24 g (20 mmole) of potassium-tert. butylate were introduced and the whole was stirred again for 5 minutes. The solution of 2.12 g (20 mmole) of benzaldehyde in 20 ml of absolute dimethylformamide was added dropwise within 10 minutes to the violet solution and the whole was further heated for 4 hours to 100° C under an atmosphere of nitrogen. After cooling, the potassium bromide separated was filtered off with suction and the dimethylformamide was eliminated by destillation on a rotary vaporator and under a vacuum produced by a water jet. The residue was combined with 200 ml of hot ethanol. After cooling, 4.65 g of weakly yellow crystals of 1-(stilbene-4-yl)-2-cyano-2-phenylsulfonylethylene having a melting point of 179° to 183° C (corresponding to a yield of 63% of the theory), were obtained. ##STR17##
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>C1COCC1>[O:16]=[C:14]([CH3:15])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(CC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(OCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
To a solution of ethyl[4-(2-oxopropyl)phenoxy]acetate (Intermediate 110, 786 mg, 3.33 mmol) in THF (24 mL) water was added (12 mL) and the mixture was stirred for 10 min. Then, lithium hydroxide monohydrate (420 mg, 10.01 mmol) was added and stirring was continued for 3.5 hours at room temperature. THF was evaporated from the reaction mixture and water was added (25 mL). The solution was acidified with 5N HCl until pH 2 was reached and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The resulting organic extract was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the title compound (392 mg, 57% yield).
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[C@H:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>C(O)C>[F:13][C:14]([F:21])([F:20])[C:15]([NH:12][C@@H:2]([CH3:1])[C@H:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of (−)-4-hydroxynorephedrine (90 g) and ethyl trifluoroacetate (96 mL) in ethanol (543 mL) was stirred at room temperature for 4 hrs. The reaction mixture was concentrated in vacuo, and then ethyl acetate and water were added to the residue. The organic layer was separated, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (128 g).