Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][O:15][CH:14]3[CH:17]([OH:20])[CH2:18][O:19][CH:13]23)(=O)=O)=CC=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[K].O>CS(C)=O>[OH:20][CH:17]1[CH:14]2[O:15][CH2:16][CH:12]([N:23]3[C:24](=[O:31])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]3=[O:21])[CH:13]2[O:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OC2COC3C(O)COC23)cc1
Reactant: O=C1c2ccccc2C(=O)N1[K]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1COC2C(O)COC21
Temperature: 130 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-methylbenzenesulfonate (10.24 g, 34.1 mmol) in DMSO (60 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (8.21 g, 44.3 mmol). The mixture was stirred under N2 atmosphere at 130° C. overnight then cooled down to room temperature, and poured into water. The resulting mixture was extracted with CH2C12 (300 mL×3), and the combined organic layers were washed with water (100 mL×3), dried over Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to afford the title compound as a white solid (2.35 g, 25.0%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH:25]CC5C=CC(OC)=CC=5)[N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(OC1N=C(C2C3C(=CC=C(C4SN=C(N)N=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=CC=1)(C)C.[OH-].[Na+]>C(O)(C(F)(F)F)=O.O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][N:23]=[C:22]([NH2:25])[N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cccc(OC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nc(N)ns4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc(-c2c[nH]c3ccc(-c4nc(N)ns4)cc23)n1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A solution of 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.35 g, 0.56 mmol) in TFA (3.5 mL) was heated in a Biotage microwave at 100° C. for 30 min. The reaction was cooled to RT. TFA was removed in vacuo and the residue was washed with Et2O (7 mL) to get the crude product (250 mg), which was used in next step without further purification. MS (ESI, pos. ion) m/z: 506.1 (M+1). To a solution of crude 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-3-amine (0.25 g, 0.442 mmol) in 1,4-dioxane (2.5 mL) was added 10% aq NaOH (1.3 mL) and the reaction was heated at 100° C. for 2 h. The mixture was treated with ice cold water (10 mL), resulting a white precipitate. The precipitate was filtered and washed with ice cold water (˜10 mL) and dried under vacuum. The solid was purified by preparative HPLC (eluent: 10-70% MeCN:MeOH (1:1) in H2O with 0.01% TFA) to give 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-1,2,4-thiadiazol-3-amine (30 mg, 17.5%). MS (ESI, pos. ion) m/z: 352.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 9.05 (d, J=1.2 Hz, 1H), 8.25 (d, J=2.8 Hz, 1H), 7.76 (dd, J=8.4, 1.6 Hz, 1H), 7.69-7.65 (m, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.46 (t, J=7.2 Hz, 2H), 6.70 (s, 2H), 6.54 (d, J=8 Hz, 1H), 5.61-5.55 (m, 1H), 1.52 (d, J=5.6 Hz, 6H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].O=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[CH2:19][CH:20]=O>C(OCC)C>[N:7]1([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][C:10]=2[CH:19]=[CH:20]1
Reactant: CC(=O)NCCN
Reactant: O=CCC1CCc2ccccc2C1=O
Solvent: CCOCC
Product: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Yield: 63.3 %

Procedure:
Molecular sieve 4 Å and 14.9 g of N-acetylethylenediamine (200 g) was added in succession under argon to a solution of 27.5 g of 1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 275 ml of diethyl ether. The reaction mixture was stirred at boiling temperature for 5 hours and subsequently cooled. The molecular sieve was filtered off, the filtrate was freed from solvent and the crude product was chromatographed on 600 g of silica gel with ethyl acetate as the eluent. There were obtained 23.5 g (79%) of N-[2-(4,5-dihydro-1H-benzo[g]indol-1-yl)ethyl]-acetamide with a melting point of 95°-96° C. (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:28]([O:30][C:31](=[O:46])[CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:28]([O:30][C:31](=[O:46])[CH2:32][CH2:33][N:34]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:29]
Reactant: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Reactant: COc1cc(CC(=O)NCC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(Cc1ccc(OC)c(OC)c1)C(=O)CNC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
Step 1. A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetic acid [50 g, Reference Example 3] and 3-(3,4-dimethoxy-benzylamino)-propionic acid ethyl ester [36 g, Reference Example 2(a)] in dimethylformamide (500 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate] (53.2 g) and diisopropylethylamine (59 ml). After stirring at ambient temperature for 3 hours the reaction mixture was evaporated to dryness and the residue was treated with water (3L). The mixture was extracted twice with ethyl acetate (1L) and then concentrated to dryness. The residue was subjected to flash chromatography on silica eluting initially with ethyl acetate and then with a mixture of ethyl acetate and methanol (9:1, v/v) to give 3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylureido)phenyl]acetylamino}acetamido]propionic acid ethyl ester as a yellow oil (49 g).
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH:4]=[C:5]([CH3:8])[C:6]#[CH:7])[CH3:3].[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12].[Cl-].[NH4+]>C1C=CC=CC=1>[CH3:1][C:2]([OH:9])([CH:4]=[C:5]([CH3:8])[C:6]#[C:7][CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[CH3:3]
Reactant: CC(C)C=O
Reactant: C#CC(C)=CC(C)(C)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CC(C#CC(O)C(C)C)=CC(C)(C)O
Temperature: 10 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
There are then added 150 ml of dry benzene and subsequently, while stirring and at a temperature between 30° C and 40° C, a solution of 55.9 g (0.45 mol) of 2,4-dimethyl-hex-3-en-5-yn-2-ol in 100 ml of dry benzene. After the addition, the mixture is held for 3 hours at 50° C and then cooled to 10° C. There is then added, within 1 hour at a temperature between 10° C and 20° C, a solution of 31.3 g (0.435 mol) of isobutyraldehyde in 100 ml of benzene. The mixture is left to stand for 12 hours at room temperature and then added with stirring to a solution of 40 g of ammonium chloride in 200 ml of ice-water. In order to facilitate separation of the phases, 53 ml of glacial acetic acid are added. The organic phase is separated and the aqueous layer extracted twice with ether. The combined extracts are washed neutral with a saturated sodium bicarbonate solution and a saturated sodium chloride solution and, after the addition of a small amount of hydroquinone, dried over sodium sulphate. After evaporation of the solvent (<40° C), there are obtained 92.3 g of crude 2,4,8-trimethyl-non-3-en-5-yne-2,7-diol which are immediately hydrogenated as follows: To a 1 liter magnetically stirred autoclave having built-in cooling spirals, there are added 92.3 g of crude 2,4,8-trimethyl-non-3-en-5-yne-2,7-diol, 5 g of Raney nickel, 0.5 g of Raney nickel, 0.5 g of anhydrous sodium carbonate and 125 ml of absolute methanol. The mixture is first hydrogenated while cooling with water at a pressure of ca 8 atmospheres. After the initial strongly exothermic reaction has ended, the mixture is hydrogenated up to complete saturation at 30 atmospheres of hydrogen and 80° C. After cooling, the catalyst is filtered off from the mixture, the alcohol removed on a rotary evaporator and the residue distilled over a small amount of sodium carbonate. There are thus obtained 70.6 g (74%) of 2,4,8-trimethyl-nona-2,7-diol of boiling point 130°-133° C/5 mm Hg; nD20 = 1.4600.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2cc(I)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(I)cc21
Yield: 77.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 130 mg 5-iodo-2-oxindole, and 75 L piperidine in 2 mL ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 162 mg (77%) of the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[C:11]1([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N+]=[N-])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:9])[O:4][N:3]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1cc(O)no1
Solvent: CC(C)=O
Product: O=C(Cc1cc(O)no1)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 5.72 g (40 mmoles) of 3-hydroxyisoxazol-5-ylacetic acid in 50 ml of acetone was added dropwise a solution of 7.76 g (40 mmoles) of diphenyldiazomethane in 50 ml of acetone. The mixture was stirred for 1 hour in an ice bath. After confirming that the red colour of the diphenyldiazomethane had disappeared, the solvent was distilled off under reduced pressure and 100 ml of diisopropyl ether were added to the residue to precipitate crystals of the title compound, melting point 105°-106° C. The yield was 9.3 g (75% of theory).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[N:19]([CH2:20][C:21]([OH:23])=[O:22])[N:18]=[N:17][N:16]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:29](O)[CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][O:22][C:21](=[O:23])[CH2:20][N:19]1[C:15]([C:13]2[S:14][C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)=[N:16][N:17]=[N:18]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccc(CCCc2ccccc2)s1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc(CCCc2ccccc2)s1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a solution of 300 mg (0.9 mM) of [5-[5-(3-phenylpropyl)-2-thienyl]tetrazol-1-yl] acetic acid in 2 ml of ethylene glycol was added 0.2 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=30/1) for separation and purification, to give 300 mg (yield 88.2%) of [5-[5-(3-phenylpropyl)2-thienyl]tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:5]1.Cl>CCO>[CH3:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:5]1
Reactant: COC(=O)c1ccc(-c2cn(C)ccc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccc(=O)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
1 M NaOH (1.42 ml) was added to an EtOH suspension (3 ml) of methyl 4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoate (115 mg), followed by stirring at room temperature for 8 hours. 1 M HCl (1.42 ml) was added to the reaction solution, followed by concentration under reduced pressure. Water (20 ml) was added to the residue, followed by stirring for 20 minutes. The precipitate formed was collected by filtration and dried under reduced pressure at 60° C. to obtain 4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoic acid (92 mg).
Reaction SMILES: I.CS[C:4]1[NH:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C(#N)C.C(O)(C(F)(F)F)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][NH:13][C:4]=1[NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CSC1=Nc2ccccc2CN1
Reactant: N[C@@H]1CCc2ccccc21
Agent: I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1ccc2c(c1)CNC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 85 °C
Yield: 24.4 %

Procedure:
2-Methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.28 mmol) and (R)-1-aminoindane (37 mg, 0.28 mmol) were suspended in acetonitrile (1 ml) and heated in a screw-capped vial to 85° C. (6 h). The product was isolated from the reaction mixture by preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) to give the title compound (18 mg, 24%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:1])=[N:15][OH:16])=[CH:12][CH:11]=1
Reactant: ON=Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(F)cc1
Temperature: 40 °C
Yield: 68.7 %

Procedure:
N-Chlorosuccinimide (85.5 g, 438 mmol) was added to a solution of 4-fluorobenzaldehyde oxime (61.0 g, 438 mmol) in DMF (100 mL) at room temperature; an exotherm occurred. After the addition, the solution was heated at 40° C. for 30 minutes under nitrogen. The solution was poured onto ice and extracted with chloroform. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and further dried under high vacuum for 16 hours to provide 52.23 g of 4-fluoro-N-hydroxybenzenecarboximidoyl chloride as an amber oil.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH3:15])C=C.[C:17]1([C:27]([NH:29][CH:30]2[CH2:36][CH:35]=[CH:34][CH2:33][N:32]([CH2:37]C(O)=O)[C:31]2=[O:41])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH2:37][N:32]2[CH2:33][CH:34]=[CH:35][CH2:36][CH:30]([NH:29][C:27]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][N:18]=3)=[O:28])[C:31]2=[O:41])=[O:16])[CH2:11][C:10](=[O:12])[O:9]1)[CH3:15]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Reactant: O=C(O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)CC1NC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reaction time: 0.25 h

Procedure:
A catalytic amount of Pd(Ph3P)4 is added to a solution of (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (338 mg, 1.48 mmol) and N,N-dimethylbarbituric acid (483 mg, 3.1 mmol) in CH2Cl2 (5 mL) at room temperature. The solution is stirred for 15 min then {3-[(isoquinolin-1-carbonyl)amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl} acetic acid, 5, (178 mg) as prepared above is added as a solution in CH2Cl2 (1 mL) followed by 1-hydroxybenzotriazole (416 mg, 3.1 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (584 mg, 3.1 mmol). The solution is stirred for an additional 3 hours, then diluted with EtOAc, washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated in vacuo to afford the desired product in sufficient purity to be used directly.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][N:2]1[C:6]([O:7][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Fc1ccccn1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Product: Cc1nn(C)c(Oc2ccccn2)c1Sc1ccccc1Cl
Yield: 25.6 %

Procedure:
A mixture of 0.5 g (2 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole and 0.97 g (10 mmol) of 2-fluoropyridine was refluxed with heating for 8 hours. After completing the reaction, the reaction mixture was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (3:2 v/v)) to give 0.17 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(pyridine-2-yloxy)pyrazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:13]3[NH:9][C:10]([C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[C:10]4[N:9]=[C:13]([C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[C:10]5[NH:9][C:13](=[C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)[C:10]6[CH:11]=[CH:12][C:13]=2[N:9]=6)[CH:12]=[CH:11]5)[CH:12]=[CH:11]4)=[CH:11][CH:12]=3)[CH:4]=[N:3]1
Reactant: c1cc[nH]c1
Reactant: Cn1cc(C=O)cn1
Solvent: CCC(=O)O
Product: Cn1cc(-c2c3nc(c(-c4cnn(C)c4)c4ccc([nH]4)c(-c4cnn(C)c4)c4nc(c(-c5cnn(C)c5)c5ccc2[nH]5)C=C4)C=C3)cn1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a refluxing solution of propionic acid (200 mL) and 1-methylpyrazole-4-carboxaldehyde (48, 0.92 g, 8.32 mmol), prepared according to literature procedure (Finar, I. L.; Lord, G. H. J. Chem. Soc. 1957, 3314–3315), was added pyrrole (0.63 mL, 8.32 mmol). The reaction was covered with foil and was heated under reflux for 3.5 h. Upon cooling the reaction mixture was exposed to air overnight. The propionic acid was then removed by vacuum distillation. The crude residue was dissolved in 5% MeOH/CH2Cl2, then adsorbed onto silica gel (5.3 g). Purification by column chromatography (5% MeOH/CH2Cl2) provided porphyrin 49 as a purple solid (231 mg, 17.5%): 1H NMR (300 MHz, DMSO-d6) δ 2.74 (s, 2H), 4.28 (s, 12H), 8.31 (s, 4H), 8.67 (s, 4H), 9.16 (s, 8H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1)=[O:7].O1CCCC1>O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)cn1

Procedure:
Lithium hydroxide, monohydrate (0.39 g, 0.0092 mol) was added to a mixture of 5-bromopyridine-2-carboxylic acid methyl ester (0.25 g, 0.0012 mol) in tetrahydrofuran (4.8 mL, 0.059 mol) and water (2.0 mL) and the reaction mixture was refluxed for 30 minutes. The reaction mixture was concentrated and was adjusted to be acidic (pH=˜4) by adding 1 N HCl. The product was extracted with ethyl acetate and the combined extract was concentrated to give the desired product. LC-MS: 202.0/204.0 (M+H+)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]3([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[O:20][CH2:19][CH2:18][O:17]3)[C:11]2=[O:31])[C@H:6]([CH2:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]3([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[O:17][CH2:18][CH2:19][O:20]3)[C:11]2=[O:31])[C@H:6]([CH2:32][S:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 79.5 %

Procedure:
A mixture of 39g-b (222 mg, 375 μmol) and 10% Pd/C (239 mg, 112 μmol) in MeOH (150 mL) was hydrogenated (50 psi) for 2 h. The mixture was filtered through diatomaceous earth (infusorial earth) and the filtrate was evaporated under vacuum to give (R*)-1-((1S*,2R*,4R*)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one (39h-b, 169 mg, 80%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.3 Hz, 2H), 7.68–7.35 (m, 7H), 4.22 (s, 1H), 4.02–3.60 (m, 5H), 3.50–3.14 (m, 4H), 2.80–2.63 (m, 1H), 2.60–1.60 (m, 12H); 19F NMR (282 MHz, CDCl3) δ −62.8; ESI MS m/z 567 [C28H33F3N2O5S+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[C:14]2=[O:32])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Cl)Cl.Cl>CO>[ClH:1].[Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:14]2=[O:32])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3ncc(C(F)(F)F)cc3Cl)C2=O)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 176 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.51 g, 1.1 mmol), DCM (10 mL), methanol (1 mL), and HCl (2.7 mL, 11 mmol) (in dioxane). The reaction mixture was stirred at ambient temperature overnight. The organic solvents were removed under reduced pressure to provide (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-[1,4′-bipiperidin]-2-one hydrochloride (0.40 g, 91% yield). Mass spectrum (apci) m/z=377.2 (M+H).