Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:17].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:15][C:14]([CH:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:17])[CH:4]=2)[CH2:9]1)=[O:16]
Reactant: CO
Reactant: Cc1cc(N2CC(C(=O)O)CC2=O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(=O)N(c2ccc(O)c(C)c2)C1

Procedure:
In analogy to the esterification described in Example 2b), the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is reacted with methanol in presence of sulfuric acid to yield the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light brown solid; MS: m/e=250 (M+H)+.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]#[N:34])=[O:27]>CN(C)C=O>[CH2:13]([O:12][C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:25][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]#[N:34])=[O:27])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)=[O:11])[CH3:14]
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (115 mg) was dissolved in N,N-dimethylformamide (1.5 mL) and diisopropylethylamine (100 μL) was added to the solution. (2S)-1-(2-Bromoacetyl)pyrrolidine-2-carbonitrile (120 mg) in N,N-dimethylformamide (1 mL) was then added dropwise at room temperature. The mixture was stirred for 2 hours at room temperature and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:chloroform:methanol=10:1) to give (2S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (95.1 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[NH2:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1[S:37][CH2:38][CH2:39]O>C1COCC1.C(OCC)(=O)C>[I:25][CH2:39][CH2:38][S:37][C:29]1[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=1[NH2:27]
Reactant: Nc1cc([N+](=O)[O-])ccc1SCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc([N+](=O)[O-])ccc1SCCI
Reaction time: 0.08 h

Procedure:
To a stirred solution of triphenylphosphine (1.81 g, 6.93 mmol) and imidazole (1.887 mL, 13.86 mmol) in THF (15 mL) at 0° C. was added iodine (1.759 g, 6.93 mmol). After stirring for 5 minutes, 2-(2-amino-4-nitrophenylthio)ethanol (990 mg, 4.62 mmol) was added as a solution in THF (5 mL). The resulting mixture was stirred at 0° C. for 1 hour, then diluted with ethyl acetate and washed with water (3×) and brine. The organic phase was dried, filtered, and concentrated then chromatographed in 4:1 hexanes:ethyl acetate giving the desired compound (1.18 g, 79%) as an orange solid. 1H NMR (DMSO-d6) δ 7.55 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4, 2.4 Hz, 1H), 5.89 (brs, 2H), 3.38-3.26 (m, 4H); EI-MS (m/z, %): 324 (M+, 46), 196 (81), 154 (100), 126 (95).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1.[Cu]I>[CH:10]1([C:13]#[C:14][NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccc(F)cc1I
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(NC#CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol) in THF (15 mL) and cyclopropylacetylene (1.4 mL, 16.9 mmol) is treated with PdCl2(PPh3)4 (177 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) and triethylamine (3.5 mL, 25.2 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane to afford 2-cyclopropylethynyl-4-fluoro-phenylamine (1.1 g, 74%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.93 (m, 1H), 6.81 (m, 1H), 6.59 (m, 1H), 4.00 (s, NH2, 2H), 1.49 (m, 1H), 0.82 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[C:6]#[N:7].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:8]([C:9]([F:10])([F:11])[F:12])=[N:20][NH:21][C:6]=1[NH2:7]
Reactant: NN
Reactant: N#CC(Cc1cccc(Cl)c1Cl)C(=O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: Nc1[nH]nc(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-4,4,4-trifluoro-3-oxobutanenitrile (10.0 g, 33.77 mmol) in ethanol (800 mL) was added hydrazine hydrate (1.86 g, 37.15 mmol) and the resulting solution was stirred under reflux for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=2/1) and reverse-phase Prep-HPLC to provide the titled compound (1.6 g, 15%) as a yellow oil; LC/MS: MS (ES+) m/e 310 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.85 (s, 2H), 6.78 (dd, J=1.2, 7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.47 (dd, J=1.2, 7.8 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a similar manner as described in Example 211,a mixture of 2.39 g N-methyl-[4-(2-butynyloxy)phenyl]sulfonamide], methyl alpha-bromo(4-chlorophenyl)acetate, and powdered potassium carbonate in DMF was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)acetate as a yellow oil which was then used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].O>C(O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCCC(=O)Nc1cc(OC)c(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(NC(=O)CCCC(=O)O)cc(OC)c1OC

Procedure:
A solution of 8 g of the compound obtained in Step A, 50 ml of 1M sodium hydroxide solution, 50 ml of water and 100 ml of ethanol is stirred for 6 hours at 50° C. The ethanol is then removed by distillation under a partial vacuum. The residual solution is rendered acidic by the addition of 1M hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried with Na2SO4 and evaporated to dryness to yield a colourless oil (quantitative yield).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[CH:12]=1)[O:9][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:7]([CH3:30])[C:6]2=[O:31]>>[Cl:1][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[CH:12]=1)[O:9][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:7]([CH3:30])[C:6]2=[O:31]
Reactant: Cl
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)OCCN3CCOCC3)cc(Br)cc2c1=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCN3CCOCC3)cc(Cl)cc2c1=O

Procedure:
The procedure of Example 13 was repeated with the exception of using 37.3 g (0.10 mole) of methyl 6-bromo-3-methylflavone-8-carboxylate in place of methyl 6-chloro-3-methylflavone-8-carboxylate, giving 44 g (93.2%) of crystals. The hydrochloride of the product melts at 205.0° to 208.0° C. The crystals were found to be identical with the product obtained in Example 9.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18]N(C)C)=[CH:12][CH:11]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3].ClCC[CH2:28][N:29]([CH3:31])[CH3:30]>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:14][CH:15]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3]
Reactant: CN(C)CCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1
Reactant: CN(C)CCCCl
Product: CN(C)CCCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1

Procedure:
Prepared by the method of Example 9(b) using the product of Example 10 (a) and N-(3-chloropropyl)dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(S(F)(F)[F:47])CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:39])[F:40])[CH2:35][CH2:36]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([F:47])[CH2:18][CH2:19]2)[C:10]1=[O:21]
Reactant: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Treat a 0° C. solution of 1-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-3-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.090 g, 0.15 mmol) in CH2Cl2 (5 mL) with (diethylamino)sulfur trifluoride (0.049 g, 0.305 mmol) and stir for 1 hour at 0° C. under N2. Quench the reaction with saturated NaHCO3, dilute with ethyl acetate, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.019 g (85%) of the titled product. Rf=0.56 (9/1 CH2Cl2/methanol). ES MS (m/z): 600 (M+).
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6]O.[CH2:9]([O:13][CH:14]=[CH2:15])[CH:10]([CH3:12])[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][CH:14]([O:13][CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:15]
Reactant: CSC(=S)NCCO
Reactant: C=COCC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CSC(=S)NCCC(C)OCC(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (1.513 g) and isobutoxyethylene (2.59 ml) is added toluene-p-sulfonic acid monohydrate (9.5 mg). After stirring for 30 minutes, triethylamine (8 μl) is added to the mixture, and the resulting solution is concentrated under reduced pressure to give N-[2-(1-isobutoxyethyl)ethyl]dithiocarbamic acid methyl ester (3.2 g). Yield: 95%.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH2:10]([CH:26]1[CH2:31][C:30](=[O:32])[O:29][C:27]1=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C>C(#N)C>[OH:3][NH:2][C:30](=[O:32])[CH2:31][CH:26]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:27]([OH:29])=[O:28]
Reactant: NO
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCC(CC(=O)NO)C(=O)O

Procedure:
HA-4 (2-[2-(hydroxyamino)-2-oxoethl]heptadecanoic acid) was prepared as follows. Hydroxylamine hydrochloride (18.07 g, 0.26 moles) was dissolved in pyridine (18.49 g, 0.26 moles) by stirring the mixture for one-half hour at 26° C. n-Hexadecyl succinic anhydride (88.14 g, 0.27 moles, available from Tokyo Kasei Kogyo Co. Ltd., Tokyo, Japan) was added to the solution followed by the addition of acetonitrile (about 50 ml). The resulting mixture was refluxed for two hours, cooled, and the solvent removed under reduced pressure using a rotary evaporator. Hydrochloric acid (10%) in water (100 ml) was added to the resulting residue and the mixture filtered to recover the suspended solids. The filtrate was dispersed in water to dissolve the pyridinium hydrochloride by-product of the reaction and the dispersion filtered and the solid retained. The process of washing with water and filtering was repeated several times, yielding 2-[2-(hydroxyamino)-2-oxoethyl]heptadecanoic acid as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([O:32][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28]2)=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](O)C3)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](OS(C)(=O)=O)C3)cc2)C1
Reaction time: 0.33 h
Yield: 101.7 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-hydroxy pyrrolidino)phenyl)piperazine (733 mg, 1.64 mmol) and triethylamine (0.34 mL, 2.46 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.152 mL, 1.97 mmol) at 0° C. After stirring for 20 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-(methansulfonyloxy)pyrrolidin-1-yl) phenyl)piperazine (877 mg, quant.) as a brown solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C1(=O)O[CH2:28][CH2:27][O:26]1.[OH-].[K+].C(=O)=O>CN(C)C=O.O>[C:1]([C:4]1[C:5](=[O:24])[N:6]([CH2:28][CH2:27][OH:26])[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: O=C1OCCO1
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nn(CCO)c1=O
Temperature: 5 °C
Yield: 68 %

Procedure:
4-Acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one (3.1 g), ethylene carbonate (2.0 g), and potassium hydroxide (powdered) were dissolved in dimethylformamide (50 ml) and the flask placed in an oil bath (110°-120° C.) until CO2 evolution ceased (ca. 3.5 hours). The reaction mixture was poured into water (400 ml) and chilled at 5° C. for 1 hour. The resulting precipitate was separated by filtration and recrystallized from methanol (85 ml) to afford 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one (68 percent yield) as pale yellow crystals, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=[S:11].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[C:15]2[S:9][C:10](=[S:11])[NH:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C=C2SC(=S)NC2=O)o1
Yield: 89.1 %

Procedure:
A mixture of 5.51 g (50.0 mmol) of 5-methylfuran-2-carboxaldehyde (purchased from Wako Junyaku Kogyo), 6.66 g (50.0 mmol) of rhodanine (purchased from Tokyo Kasei) 12.3 g (150 mmol) of anhydrous sodium acetate (purchased from Kokusan Kagaku) in 35 ml of acetic acid (purchased from Wako Junyaku Kogyo) was refluxed for 30 minutes, cooled and added to 500 ml of water, and the precipitate was collected, washed with water, ethanol and ether in order and dried to give 10.04 g (yield: 89.1%) of of (5-methylfurfurylidene)rhodanine as an orange brown crystalline.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:29][CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[S:49][C:48]3[C:43](=[N:44][CH:45]=[CH:46][C:47]=3[O:50][C:51]3[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=3[F:58])[CH:42]=2)=[CH:37][CH:36]=1)[CH3:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[S:49][C:48]3[C:43](=[N:44][CH:45]=[CH:46][C:47]=3[O:50][C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:1])=[CH:53][C:52]=3[F:58])[CH:42]=2)=[CH:39][CH:40]=1)[CH3:33]
Reactant: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of the acid 1 (142 mg, 2 eq, 1.58 mmol) in dry DCM (10 ml), at 0° C., was added, BOPCl (502 mg, 2 eq, 0.826 mmol) and the reaction mixture was stirred for 10 minutes. A solution of the amine 87 (348 mg, 0.79 mmol) and iPr2NEt (610 mg, 6 eq, 4.72 mmol) in dry DCM (7 ml) was then added and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and satd NaHCO3 soln, the organic phase was washed twice with saturated NaHCO3 then collected, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was purified by column chromatography (EtOAc) to afford the desired product 88 as an off-white solid (102 mg, 21% yield). 1H NMR (DMSO-d6) δ (ppm): 10.58 (s, 1H), 10.22 (s, 1H), 8.48 (d, J=5.28 Hz, 1H), 8.03 (s, 1H), 7.85 (m, 3H), 7.59 (m, 2H), 7.43 (m, 4H), 7.32 (m, 2H), 7.05 (t, J=7.43 Hz, 1H), 6.61 (m, 1H), 3.70 (t, J=6.65 Hz, 2H), 3.59 (s, 2H), 3.50 (s, 2H), 2.69 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][C:14]([OH:17])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][C:14]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 67.1 %

Procedure:
The process was carried out essentially like that of Example 5, using 0.8 g of sodium, 20 ml of methanol, 100 ml of dimethylsulfoxide, 8 g of 1-(3,4-dichlorophenyl)-3-hydroxy-1,2,4-1H-triazole and 6.3 g of ethyl 2-bromopropionate. The product was 7.7 g of the desired product, m.p. 69°-71°.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
Acetaldehyde (84.5 μL, 1.51 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (91.0 mg, 0.188 mmol) in anhydrous methanol (10 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.638 g, 3.01 mmol) was then added in one portion and the reaction was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (35 mL) and sat. aq. NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×35 mL), the combined organic layers were washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue dissolved in DCM (5 mL) and MeOH (2 mL). Cyclohexane (20 mL) was added and the solvent removed in vacuo to afford a tan solid which was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.; then 0-75% MeOH in EtOAc) to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (31) (40.7 mg, 42%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.26-7.12 (m, 6H), 6.92 (s, 1H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.05-2.92 (m, 4H), 2.43 (tt, J=11.7, 3.7 Hz, 1H), 2.33 (q, J=7.2 Hz, 2H), 1.93 (td, J=11.5, 2.1 Hz, 2H), 1.73 (dd, J=11.8, 2.0 Hz, 2H), 1.62 (ddd, J=24.8, 12.4, 3.6 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); LCMS Method C: rt 4.90 min; m/z 512 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36]CCCN)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].[CH2:41]([NH:45]C(=O)OC(C)(C)C)[CH2:42]C=C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:42][CH2:41][NH2:45])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCCNC(=O)OC(C)(C)C
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The same procedure was employed as used for the synthesis of (2S,3S,4R,5S,6R)-2-(3-(4-(5-aminopentyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (16), using tert-butyl but-3-en-1-ylcarbamate as the reagent for the Heck reaction.