Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[C:12]([F:31])[C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>CS(C)=O>[CH2:1]([O:8][C:9](=[O:33])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:19]2)=[C:12]([F:31])[C:11]=1[NH:37][CH:34]1[CH2:36][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(F)c2F)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(F)c(C(=O)OCc3ccccc3)c(NC3CC3)c2F)C1
Yield: 86.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5,6-tetrafluorobenzoic acid benzyl ester (Example 2d, 2.5 g, 5.3 mmol), cyclopropylamine (40 mL, 577 mmol), and dimethyl sulfoxide (20 mL) in a sealed glass tube is heated at 80° C. for 24 hours. The excess amine is removed by blowing in compressed air, and the solution is then concentrated under high vacuum. The residue is purified by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to afford the title compound as a solid (2.31 g). 1H NMR (CDCl3): δ 7.47–7.27 (m, 5H), 7.12 (bs, 1H), 5.30 (s, 2H), 4.78–4.62 (m, 1H), 4.35–4.17 (m, 1H), 3.96–3.56 (m, 3H), 3.54–3.39 (m, 1H), 2.91–2.73 (m, 1H), 2.24–2.02 (m, 1H), 1.96–1.77 (m, 1H), 1.45 (s, 9H), 0.69–0.56 (m, 2H), 0.53–0.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([Cl:43])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[Cl:43][C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][N:34]=[C:33]2[NH:19][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C@H:10]2[CH2:21][CH2:22][CH3:23])[C:15]1=[O:20]
Reactant: Clc1ccc2ncnc(Cl)c2c1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(Cl)cc23)C1=O
Temperature: 80 °C

Procedure:
Examples 2r and 2s, Step 1: A solution of (1R,3R,4S)-{4-[(3S)-3-amino-2-oxo-pyrrolidin-1-yl]-3-propyl-cyclohexyl}-carbamic acid tert-butyl ester (0.66 mmol) in EtOH (8 mL) was charged with triethylamine (0.5 mL, 3.3 mmol) and 4,6-dichloroquinazoline (200 mg, 1.0 mmol) before being heated at 80° C. for 12 h. The reaction mixture was cooled and purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-(6-chloroquinazolin-4-ylamino)-2-oxopyrrolidin-1-yl)-3-propylcyclohexylcarbamate. MS found: (M+H)+=502.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N+:3]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:12][OH:17])[N:3]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C)[n+]([O-])c(Cl)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(CO)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 66 %

Procedure:
To a stirring solution of 7.61 g (37.8 mmol) of 2-chloro-4-(methoxycarbonyl)-6-methylpyridine 1-oxide in 60 mL of CH2Cl2 was added 24 mL of trifluoroacetic anhydride slowly. The solution was stirred at r.t. for 15.5 h. The temperature was increased to 50° C., and the solution was stirred at 50° C. for 5.5 h and then concentrated. The crude residue was dissolved in 50 mL of THF, and 7% NaHCO3 solution (aqueous) was added to a pH=8. The solution was stirred at r.t. for about 40 h, and EtOAc was added. The aqueous layer was extracted with EtOAc (3×), and the combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) provided 4.99 g of methyl 2-chloro-6-(hydroxymethyl)isonicotinate as a pale yellow solid in 66% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-:33])=[CH:6][C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (10.75 g, 29.0 mmol) in 150 mL of CHCl3 was chilled in an ice water bath. The solution was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 10.73 g, 43.5 mmol). After stirring for 1.5 h, the reaction mixture was washed with 1% Na2CO3 (3×) solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give a sticky brown solid. The solid was triturated with ether to yield 11.21 g of tert-butyl 2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light tan solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:27]=[CH2:28])[CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]([O:10][P:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:1])[F:15])=[CH:8][CH:7]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH:27]=[CH2:28])[CH:18]=1)=[O:13])[CH3:12]
Reactant: CCO[PH](=O)c1ccc(C(F)(F)F)cc1
Reactant: C=Cc1cc(Br)ccc1OC(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(P(=O)(OCC)c2ccc(C(F)(F)F)cc2)ccc1OC(C)C
Temperature: 70 °C
Yield: 8.6 %

Procedure:
To a degassed solution of ethyl 4-(trifluoromethyl)-phenylphosphinate (1.00 g, 4.20 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (921 mg, 3.81 mmol) in DMF (40 mL) were added the triethylamine (1.1 mL, 7.62 mmol) and tris(dibenzylideneacetone)dipalladium (698 mg, 0.762 mmol). The mixture was heated at 70° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography using 5 to 100% ethyl acetate in petroleum ether to afford compound BA1 (130 mg) as a dark green oil in 8.6% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.37 (d, J=6.0 Hz, 6H), 1.38 (t, J=7.1 Hz, 3H), 4.07-4.17 (m, 2H), 4.63 (sept., J=6.1 Hz, 1H), 5.31 (dd, J=11.2 and 1.1 Hz, 1H), 5.79 (dd, J=17.7 and 1.1 Hz, 1H), 6.92 (dd, J=8.6 and 3.1 Hz, 1H), 6.99 (dd, J=17.3 and 10.8 Hz, 1H), 7.59-7.66 (m, 1H), 7.67-7.72 (m, 2H), 7.87-7.96 (m, 3H); 31P NMR (CDCl3, 161.8 MHz): δ (ppm) 30.7.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6](OCC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][CH2:6][OH:7]
Reactant: CCOC(=O)C=Cc1ccccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC=Cc1ccccc1Br
Temperature: 25 °C
Yield: 61 %

Procedure:
Ethyl o-bromocinnamate (66.3 g; 260 mM) was dissolved in 750 ml of anhydrous toluene under nitrogen in a three-neck round bottom flask equipped with addition funnel and condensor. A toluene solution of diisobutylaluminum hydride (520 mM; 1.53 M) was transferred via canula to the addition funnel and then added dropwise to the reaction mixture, which had been chilled to -78°. After the addition was completed the reaction was warmed to ambient temperature over a 1.5 hour period and quenched by the dropwise addition of 50 ml of water. Some cooling was required. The resulting emulsion was added to 640 ml of 2N aqueous hydrochloric acid. After partitioning, the slightly acidic (pH 5) aqueous layer was extracted twice with ether. The combined organic fractions were dried (MgSO4), filtered (fritted funnel), and evaporated to afford an oil. The oil was chromatographed in two portions on the Waters Prep 500 equipped with two cartridges eluting with a total of two gallons of 35% ethyl acetate in hexane. This produced 33.8 g (61% yield) of o-bromocinnamylalcohol. NMR (CDCl3): δ6.8-7.8 (m; 5H); 6.0-6.6 (AB; 1H); 4.2-4.4 (brd.; 2H); 2-2.6 (brs; 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:48][C:49]([F:60])([F:59])[C:50]1[N:54]2[CH2:55][CH2:56][NH:57][CH2:58][C:53]2=[N:52][N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([C:49]([F:60])([F:48])[F:59])=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2C(F)(F)F)C1
Reaction time: 12 h
Yield: 10.6 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (150 mg, 0.50 mmol, prepared according to a known method disclosed by “patent application WO2004080976”) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 1b (138 mg, 0.60 mmol, prepared according to a known method disclosed by “patent application WO2004080958”) and N,N-diisopropylethylamine (0.2 mL, 1 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 1 (25 mg, yield 10.6%) as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]3([C:35]4=[CH:36][C:37]5[O:41][CH2:40][O:39][C:38]=5[CH:42]=[C:34]4[O:33][CH2:32]3)[C:24]2=[O:43])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]4([C:35]5=[CH:36][C:37]6[O:41][CH2:40][O:39][C:38]=6[CH:42]=[C:34]5[O:33][CH2:32]4)[C:24]3=[O:43])[CH2:17][CH2:16]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: O=C1N(CCC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C1N(CCC2CCN(C3CCCC3)CC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reaction time: 16 h

Procedure:
To a solution of cyclopentanone (0.04 mL, 0.45 mmol) and triethyl amine (0.12 mL, 0.84 mmol) in dichloroethane (5.00 mL) was added 1′-(2-piperidin-4-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrochloride (0.12 g, 0.28 mmol) and sodium triacetoxyborohydride (0.10 g, 0.45 mmol). The reaction mixture was stirred for 16 hrs and concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with ethyl acetate/methanol/ammonium hydroxide (15/1/0.1) to give 1′-[2-(1-cyclopentylpiperidin-4-yl)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one as a white solid, which was treated with 4.0 M HCl in dioxane to give the title compound (0.05 g, 32% yield): mp 153-155° C.; 1H NMR (300 MHz, CD3OD) δ 7.37 (td, 1H), 7.21-7.08 (m, 3H), 6.53 (s, 1H), 6.11 (s, 1H), 5.88 (s, 1H), 5.87 (s, 1H), 4.83 (d, 1H), 4.69 (d, 1H), 3.98-3.75 (m, 2H), 3.68-3.38 (m, 3H), 3.01-2.83 (m, 2H), 2.25-2.08 (m, 4H), 1.92-1.37 (m, 11H); 13C NMR (75 MHz, CD3OD) δ 179.8, 157.6, 150.4, 143.8, 143.4, 133.6, 130.3, 124.9, 124.8, 120.8, 110.3, 103.7, 103.0, 94.3, 81.4, 69.1, 59.8, 53.2, 38.6, 34.3, 32.5, 30.6, 30.5, 29.4, 24.7; MS (ES+) m/z 461 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:8]([OH:10])=[O:9])=[O:5])#[N:2].[Na].N>C(O)C.[Rh]>[CH:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:11][C@H:7]([NH:6][C:4]([CH2:3][CH2:1][NH2:2])=[O:5])[C:8]([OH:10])=[O:9]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Rh]
Agent: N
Agent: [Na]
Solvent: CCO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.3 g of rhodium/activated carbon (5% Rh) was added to a solution of 1.90 g (7.8 mmol) of (S)-2-(cyanoacetylamino)-3-(1H-imidazol-4-yl)propionic acid, sodium salt (prepared according to Example 1) in 50 ml of ethanol/conc. ammonia solution (V:V=4:1). The mixture was hydrogenated at 110° C. and 45 bar for 1 h. This was followed by filtering off the catalyst and adjusting the filtrate to a pH of 8.2 with formic acid. After concentrating the solution under reduced pressure, the residue was suspended in 200 ml of ethanol and heated at 60° C. for 30 min. The product was filtered off, washed successively with ethanol, ethyl acetate and diethyl ether and finally dried.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[C:6]([NH2:8])=[NH:7].Cl[C:15]1[C:23](Cl)=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:30])[N:18]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH:19]12>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])[NH:3][C:26]2([CH2:27][CH2:28][N:18]3[C:17](=[O:30])[C:16]4[C:20]([CH:19]3[CH2:25]2)=[C:21]([Cl:1])[CH:22]=[CH:23][CH:15]=4)[N:8]=1
Reactant: N=C(N)c1c(N)cccc1F
Reactant: O=C1CCN2C(=O)c3c(ccc(Cl)c3Cl)C2C1
Reactant: Cl
Product: NC1=NC2(CCN3C(=O)c4cccc(Cl)c4C3C2)Nc2cccc(F)c21

Procedure:
The compounds of Examples 15 and 16 were prepared from 2-amino-6-fluorobenzamidine dihydrochloride and 7,8-dichloro-1,3,4,10b-tetrahydropyrido[2,1-a]isoindole-2,6-dione (Preparation 5).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][NH:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][NH:12][CH3:13]
Reactant: Fc1ccccn1
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNCCN(C)c1ccccn1
Yield: 98 %

Procedure:
A mixture of 2-fluoropyridine (0.485 g, 5 mmol), N,N′-dimethyl-1,2-ethanediamine (1.32 g, 15 mmol) and sodium carbonate (1.59 g, 15 mmol) in 1,4-dioxane (5 mL) was heated under reflux overnight. The mixture was filtered and the filtrate was concentrated. The residue was co-evaporated with 1,4-dioxane (×2), and then dried to give the desired product (810 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][S:5]2.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.O>[Br:27][CH2:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][S:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)nc2sccn12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)nc2sccn12
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (2.60 g, 12.366 mmol) and azobisisobutyronitrile (AIBN) (0.041 g, 0.247 mmol) in carbon tetrachloride (40 mL) at reflux temperature was added N-bromosuccinimide (2.40 g, 13.602 mmol). After refluxing for 18 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to obtain 1.95 g of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.6 Hz, 3H), 4.36 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.52 (d, J=4.5 Hz, 1H), 8.10 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 291.58 (MH)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].[N+]([C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)([O-])=O>CS(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: CN(C)CCS
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Dimethylaminoethanethiol hydrochloride was suspended in dry DMSO and sodium hydride was added. The reaction mixture was left stirring for 40 minutes before 5-nitro-2-furancarboxaldehyde was added. The reaction mixture was allowed to stir for 30 minutes at room temperature, to give the title compound. This is the starting aldehyde used in the synthesis of compound 5253.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].C1C(=O)N([Br:31])C(=O)C1>ClCCl.[Cl-].[Na+].O>[Br:31][C:21]1[CH:22]=[CH:23][C:18]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2C)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N(c2ccc(Br)cc2)c2ccc(C)cc2C)c(C)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of N-(2,4-dimethylphenyl)-2,4-dimethyl-N-phenylaniline (Compound 15) (12.4 g, 41 mmol) in dichloromethane (200 mL), was added NBS (8.01 g, 45 mmol) at 0° C. The whole was stirred for about 3 hours and worked up with brine. The organic phase was dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes. After removal of solvents, a colorless oil (Compound 16) was obtained (15 g, in 96% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:38][CH:37]=[N:36][CH:35]=3)[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:38][CH:37]=[N:36][CH:35]=3)[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(1,3-oxazol-5-yl)phenyl]piperidin-3-ol (3.36 g, 6 mmol) obtained in Step 1 in 20 ml of dimethyl sulfoxide (DMSO), was added 2.7 ml of triethylamine (19 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (3.04 g, 19 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.67 g of the titled compound.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:20]([C:24]#[N:25])=[CH:19][C:18]([F:26])=[CH:17][C:16]=4[CH2:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[OH2:28].N>C(O)(=O)C.S(=O)(=O)(O)O>[F:27][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:20]([C:24]([NH2:25])=[O:28])=[CH:19][C:18]([F:26])=[CH:17][C:16]=4[CH2:15]3)[CH2:12][CH2:13]2)[CH2:4][CH2:3]1
Reactant: N#Cc1cc(F)cc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NC(=O)c1cc(F)cc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Temperature: 80 °C

Procedure:
To a stirred solution of [2-[1-(4,4-difluorocyclohexyl)-piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (1.44 g, 3.82 mmol) in acetic acid (11 mL), concentrated sulfuric acid (5.8 mL) was added dropwise during 30 min. The reaction was then warmed at 80° C. for 9 hours, cooled at room temperature and poured into cold water (20 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2×12 mL) and brine, dried over sodium sulfate, and evaporated to dryness in vacuo. The title compound was obtained as a white solid (1 g, 67%) after purification through column chromatography, using dichloromethane/ethanol:95/5 as the mobile phase.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:3]1.Cl.Cl.[NH2:22][OH:23].[OH-].[Na+]>>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: NO
Reactant: CC1C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C=NO)CC=CCCC=CCC(N)c1ccccc1
Yield: 100 %

Procedure:
502 g (1.98 mols) of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene are added dropwise in the course of 1.5 hours to 220 g of 37% hydrochloricacid at a rate such that the temperature does not rise above 80° C. The mixture is then cooled to room temperature (20°-25° C.) and 140 g (2.02 mols) of hydroxylamine hydrochloride are added. About 185 g (4.6 mols) of solid sodium hydroxide are added in the course of one hour, the mixture being cooled with a waterbath, until the pH of the aqueous solution is 10-11. The organic phase which separates out is separated off and washed with water until neutral. 567 g (1.98 mols) of 2-methyl-11-phenyl-11-amino-undeca-4,8-dienal oxime are obtained in the form of a highly viscous liquid; yield 100% of theory.
Reaction SMILES: [O:1]=[C:2]1[C:9]2[C:5](=[C:6]([CH3:17])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH3:10])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[C:9]2[C:5](=[C:6]([CH3:17])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH3:10])[CH2:4][CH2:3]1
Reactant: Cc1c2c(c(C)n1-c1ccccc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c2c(c(C)n1-c1ccccc1)C(O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 g. (0.067 mole) of 4-oxo-1,3-dimethyl-2-phenyl-2,4,5,6,-tetrahydrocyclopenta[c]pyrrole, described above in Example 10, and 254 mg. (0.0067 mole) of sodium borohydride in 15 ml. of ethanol was stirred for 16 hours at 0°-5° C., then for an additional eight hours at ambient temperature and poured into ice/water. The mixture was extracted with ether, and the ether extracts were dried and evaporated to dryness to give 4-hydroxy-1,3-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole as an oil.