Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([O:9]CC)=[O:8]>C(O)C>[OH:3][CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCC(O)C#CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(O)C#CC(=O)O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35 ml) was added to ethyl 4-hydroxytridec-2-ynoate (2.68 g, 10.5 mmol) in the same solvent (5 ml) at 0°. After stirring at room temperature for 9 hours, most of the solvent was removed and water (20 ml) was added. The mixture was extracted thoroughly with dichloromethane (discarded), acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate)ethyl acetate extracts gave an off-white solid, which on recrystallization from petroleum ether (at -78°) gave the title acid as colorless prisms: mp 65°-6°.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:20]([CH:19]2[NH:18][CH:17]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[CH:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 44.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.31 g, 2.6 mmol) to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white foam (Yield 0.18 g, 45%).
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12].[NH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1)=[S:19]>C(O)(C)C>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1)=[S:19])#[N:12]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: COc1cc(NC(=S)NCCN)cc(OC)c1
Solvent: CC(C)O
Product: COc1cc(NC(=S)NCCNCC(O)COc2ccccc2C#N)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
A solution of 1.28 g (7.3 mmoles) of 2,3-epoxy-1-(2-cyanophenoxy)propane, 7, in 30 ml of isopropyl alcohol (warmed and sonicated) was treated with 1.86 g (7.3 mmoles) of 14 all at once. This was heated under reflux for 2 hours and stirred overnight at room temperature. After this, a small amount of solid (860 mg) was removed and the solution was concentrated to 2.3 g of semi-solid gum. This was chromatographed over 150 g of silica gel 60 using 10% (v/v) CH3OH/CHCl3 saturated with NH3. Three fractions of 150 ml each were taken after an 800-ml forerun. The third fraction provided 1.31 g of a white foam. This was chromatographed again, taking 10-ml fractions. Cuts 17, 18 and 19 provided 80 mg (2.5%) of 15, m.p., 45°-55° C. Mass spectrum, m/e 430 (M+), base peak, m/e 195. Liquid chromatography showed 93.6% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:10]2[O:16][CH:11]2[C:12](=[N:14]O)[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:13][C:12]1[CH:11]=[C:10]([CH:3]2[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=[C:2]2[CH3:1])[O:16][N:14]=1
Reactant: CC1=CCCC(C)(C)C1C1OC1C(C)=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=CCCC(C)(C)C1c1cc(C)no1

Procedure:
54 g of 4-[2,6,6-trimethyl-cyclohex-2-en-1-yl]-3,4-epoxy-2-butanone-oxime, which can be prepared as indicated above, in 500 ml of benzene were refluxed in the presence of 2 g of p-toluenesulphonic acid for about 4 hours. The water formed in the course of the reaction was removed as it formed by azeotropic distillation.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CO.[Pd]>[OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH:14][S:18]([CH3:17])(=[O:20])=[O:19])[CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)[C@@H](O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C[C@H](O)C(=O)O)ccc1O
Reaction time: 24 h
Yield: 60.2 %

Procedure:
A solution of (S)-2-hydroxy-3-(4-hydroxy-3-nitrophenyl)propanoic acid (9.2 g, 41 mmol) in 150 mL of methanol was hydrogenated, after addition of 0.5 g of 10% palladium on carbon, for 24 h at 45 psi using a Parr shaker. After filtration through Celite under a blanket of nitrogen gas, the volatiles were removed using a rotary evaporator. The flask was flushed with nitrogen before addition of 30 mL of dry pyridine. Once the stirred suspension formed a homogeneous solution, the flask was cooled-under nitrogen to −20° and methanesulfonyl chloride (5.0 g, 44 mmol) was added over 5 min. After stirring for 1 h at −20°, the flask was placed in a −12° freezer for 24 h. To quench the reaction, 50 mL of water was added and the volatiles were removed using a rotary evaporator with a bath temperature of 50°. A second 50 mL portion of water was added and removed as previously described. The resultant crude red oil was chromatographed on Mitsubishi Chemical Industries CHP-20P resin (75-150 micron) using 15-25% methanol/water to elute the product. After evaporative removal of methanol, the residual solution was lyophilized to yield 6.8 g (63%) of (S)-2-hydroxy-3-(4-hydroxy-3-(methylsulfonyl)aminophenyl)propanoic acid.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=2)=[CH:18][C:17]=1[CH2:31][CH2:32][C:33]1[CH:34]=[C:35]([NH:39]C(=O)OC(C)(C)C)[CH:36]=[N:37][CH:38]=1)=O)(C)(C)C>CO>[ClH:29].[ClH:1].[ClH:29].[NH2:39][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][C:17]2[CH:18]=[C:19]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=3)[CH:20]=[CH:21][C:16]=2[NH2:15])[CH:38]=[N:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2N)c1
Yield: 73 %

Procedure:
A solution of 4.0 M of hydrogen chloride in 1,4-dioxane (30 mL, 120 mmol), tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (860 mg, 1.49 mmol) and methanol (15 mL) was stirred at 25° C. for 1 hour. The solvent was removed in vacuo. The crude residue was dissolved in DCM and triturated with ether to give the desired product (0.57 g, 73%). LCMS calculated for C17H17Cl2N6(M+H)+: m/z=375.0, 377.0.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3](=[CH:5][C:6](=[CH:8][CH:9]=1)[OH:7])[OH:4].[CH3:11]I>C[O-].[Na+]>[CH3:11][O:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2](=[CH:9][CH:8]=1)[CH:1]=[O:10]
Reactant: CI
Reactant: O=Cc1ccc(O)cc1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C=O)c(O)c1

Procedure:
Beta-resorcyl aldehyde (13.8 grams) is dissolved in sodium methoxide (in amount equivalent to 2.3 grams of sodium), and 14.2 grams of methyl iodide are added. The mixture is refluxed for 4 hours. Alcohol (methanol) is distilled off and dilute HCl added. The resulting red liquid is separated from the aqueous layer, dried and steam distilled.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(-c2ccc(C)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(6-methyl-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.084 mmol), β-alanine (600 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 4.8 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1.Cl>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)cc1N(C)S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1cc(Cl)ccc1C(=O)O)S(C)(=O)=O
Yield: 93.8 %

Procedure:
2N Sodium hydroxide solution (20 ml) was added to a stirred solution of methyl 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (2.75 g) in methanol. The mixture was stirred at reflux for 0.5 hours. After cooling, the mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to yield 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoic acid as a white solid (2.45 g), m.p. 161°-164° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH2:7][CH2:6][CH2:5][N+:4]=1[CH3:8].[CH3:10][O:11]S([O-])(=O)=O.C[O-].[Na+]>C(OCC)C>[CH3:1][N:2]([CH3:9])[C:3]1([O:11][CH3:10])[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8]
Reactant: COS(=O)(=O)[O-]
Reactant: CN(C)C1=[N+](C)CCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC1(N(C)C)CCCN1C
Yield: 27.1 %

Procedure:
Add (dropwise, at room temperature, with stirring) 50.0 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate to 12.65 g of sodium methylate, suspended in 120 ml of absolute diethyl ether and boil the resulting reaction mixture under reflux for 1 hour. After cooling the refluxed material, filter the precipitated salt therefrom. Draw off the ether from the filtrate and distil under a vacuum what remains of the filtrate to obtain 9.0 g of the title compound as a liquid (with a very marked tendency to decomposition) of b.p. 45° to 47° at 11 mm of Hg.
Reaction SMILES: [C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C(=O)N([Br:30])C(=O)C1>C(#N)C.C(O)(=O)C>[Br:30][C:16]1[CH:17]=[CH:18][C:11]2[N:12]([CH:15]=1)[C:13](=[O:14])[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:9]([C:19]([O:21][CH3:22])=[O:20])[N:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc2ccccn2c(=O)c1OC(=O)C(C)(C)C
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1nc2ccc(Br)cn2c(=O)c1OC(=O)C(C)(C)C
Reaction time: 96 h

Procedure:
Methyl 3-[(pivaloyl)oxy]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (see Example 1, Step 2a) and NBS (5 eqs.) were dissolved in a 3:1 mixture of acetonitrile and acetic acid. The solution was left standing at 5° C. with occasional shaking for 4 days. The solvents were removed under reduced pressure and the residue was suspended in chloroform. The precipitate was removed by filtration and the solution concentrated under vacuum. The residue was dissolved in dichloromethane, and triethylamine (7 eqs.) was added. The mixture was stirred for 1.5 hours at room temperature, the solvent removed under vacuum, and the residue partitioned between EtOAc and 1N aqueous HCl. The organic phase was washed with 1N aqueous HCl and the combined aqueous phases extracted with EtOAc. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was isolated by flash chromatography (SiO2, eluant: PE/EtOAc, 4.5:5.5). The product was obtained as a light yellow solid.
Reaction SMILES: [N:1]1([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:44][C:45]([NH:47][CH2:48][C:49]1[N:50]=[C:51]2[C:56](=[C:57]3[C:62]=1[CH:61]=[CH:60][CH:59]=[CH:58]3)[CH:55]=[CH:54][CH:53]=[CH:52]2)=[O:46]>CC#N.CC#N.CN(C=O)C>[O:46]=[C:45]([NH:47][CH2:48][C:49]1[N:50]=[C:51]2[C:56](=[C:57]3[C:62]=1[CH:61]=[CH:60][CH:59]=[CH:58]3)[CH:55]=[CH:54][CH:53]=[CH:52]2)[CH2:44][N:10]1[CH2:9][CH2:8][N:7]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:3][CH2:2][N:1]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCc2nc3ccccc3c3ccccc23)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1

Procedure:
Tri-tert-butyl 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (33.5 mg, 65.1 mop was dissolved in dry CH3CN (10 mL) and magnetically stirred under N2(g). Anhydrous K2CO3 (30.0 mg, 0.217 mmol) was added, followed by 2-chloro-N-(phenanthridin-6-ylmethyl)acetamide (Weitz et al., J. Am. Chem. Soc., 2012, 134, 16099-16102) (15.4 mg, 54.2 mmol) dissolved in 15 mL CH3CN/DMF (2:1), and the reaction mixture was heated to reflux for 27 hours under N2(g). The reaction mixture was then filtered and concentrated under reduced pressure to yield a colorless glass that was used without further purification in the next step. 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 27H), 2.70-3.21 (m, 16H), 3.37-3.42 (m, 6H), 5.41 (d, J=15 Hz, 2H), 7.66-7.87 (m, 3H), 8.02 (d, J=7.0 Hz, 1H), 8.22 8.28 (d, J=6.5 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.63 (d, J=7.5 Hz, 1H), 8.77 (d, J=7.0 Hz, 1H). HRMS (ESI): calc for [C42H62N6O7]+ ([M+H]+): m/z 763.4753. found: 763.4739.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([NH:15][C:16]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:17]=2[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)=[O:19])[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[O:30]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][NH:20][C:18](=[O:19])[C:17]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:16]=1[NH:15][C@H:10]1[CH2:11][C@@H:12]([CH2:13][OH:14])[NH:8][CH2:9]1)[CH3:31]
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@@H]2CN[C@H](CO)C2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
A mixture of 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (326 mg) and 4N-hydrogen chloride solution in ethyl acetate (5 mL) was stirred for one day at ambient temperature. After evaporation of the solvent, the residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over magnesium sulfate. The filtrate was evaporated to give N-(3,4-dimethoxylbenzyl)-2-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylamino]-5-nitrobenzamide (242 mg) as pale yellow foams.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:2][N:3]([CH2:4][CH2:5][CH2:6][S:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)[CH3:8]
Reactant: Sc1ccc(Br)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCSc1ccc(Br)cc1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
3-(Dimethylamino)propyl chloride hydrochloride (3.48 g, 22 mmol) was added in portions to a suspension of 4-bromothiophenol (3.78 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in DMF (40 ml) and the reaction mixture heated to 60° C. for 15 minutes. The mixture was allowed to cool to ambient temperature and poured into water (100 ml) and extracted with EtOAc (2×100 ml). The extracts were combined, washed with brine (3×100 ml), dried (Chemelut column 1010) and evaporated to give the title compound (5.25 g, 96%) as a pale yellow oil. NMR 1.76 (m, 2H), 2.20 (s, 6H, 2.35 (t, 2H, 2.93 (t, 2H), 7.18 (d, 2H, 7.38 (d, 2H); m/z 276.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][C:43]([C:49]([F:52])([F:51])[F:50])=[N:42][CH:41]=1>>[F:39][C:40]1[C:45]([C:46]([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]4[CH:18]=[C:17]([C:19]5[C:20]6[CH:27]=[CH:26][NH:25][C:21]=6[N:22]=[CH:23][N:24]=5)[CH:16]=[N:15]4)[CH2:11]3)[CH2:6][CH2:5]2)=[O:47])=[CH:44][C:43]([C:49]([F:51])([F:50])[F:52])=[N:42][CH:41]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1cc(C(F)(F)F)ncc1F
Agent: Cl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(C(F)(F)F)ncc3F)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-fluoro-2-trifluoromethylisonicotinoic acid following the procedure described for Example 1, followed by HPLC purification (method B) provided the title compound. LC-MS: 554.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.08 (brs, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.09 (d, J=4.80 Hz, 1H), 7.55 (d, J=3.60 Hz, 1H), 7.00 (d, J=3.60 Hz, 1H), 4.02 (m, 1H), 3.69 (m, 2H), 3.52 (m, 2H), 3.49 (s, 2H), 3.34 (m, 1H), 3.20 (m, 1H), 3.00 (m, 1H), 2.49 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]([CH2:15][OH:16])[NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]([CH2:15][OH:16])[N:12]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CCN[C@H](CO)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CCN(S(=O)(=O)c3ccc(C)cc3)[C@H](CO)C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 72.0 g of [(S)-4-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-2-yl]-methanol in 1.5 l of ethyl acetate and 1.5 l of 2N aqueous sodium carbonate are added 57.7 g of p-toluenesulfonyl chloride at 0° C. The reaction mixture is stirred overnight, extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The crude product is used for the next step without any further purification. Rf=0.1 (EtOAc-heptane 1:1); Rt=4.20.
Reaction SMILES: O[CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[CH3:16][C:17]([CH3:19])=[O:18]>[OH-].[Na+]>[CH2:16]([CH:2]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12)[C:17]([CH3:19])=[O:18]
Reactant: CC(C)=O
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC1NC(=O)c2sccc2-n2cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
1 g (0.0045 mol) of 6-hydroxy-5,6-dihydro-4-oxo -4H-pyrrol-o[1,2-a]thieno[2,3-f][1,4]diazepine is added in a single portion to an emulsion of 20 ml of acetone in 10 ml of 10N sodium hydroxide, and the reaction mixture is stirred vigorously at room temperature for 3 hours. The acetone is then removed under vacuum and 100 ml of water are poured onto the liquid residue. The yellow precipitate obtained is drained, washed with water and recrystallized. 0.7 g of 6-acetonyl-5,6-dihydro-4-oxo-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is obtained in the form of white crystals, melting point 268° C. (isopropanol).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10]3([C:14](=[O:15])[NH:13][C:12](=O)[NH:11]3)[C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10]3([C:14](=[O:15])[NH:13][C:12](=[S:26])[NH:11]3)[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)C2(CCCc3sc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CCCc1sc(Br)cc12
Temperature: 110 °C
Yield: 97 %

Procedure:
2-Bromo-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazolidine]-2′,5′-dione (0.5 g, 1.67 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (0.371 g, 0.91 mmol) were suspended in 1,4-dioxane (5 mL). The mixture was heated by microwave irradiation at 110° C. for 2×30 min. The solution was concentrated in vacuo and the crude residue purified on silica gel using ethyl acetate in 40-60 petroleum ether (1:1) to afford the title compound as a colourless solid (0.28 g, 53%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH2:21][CH3:22])[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[C:2]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH2:21][CH3:22])[CH2:15]1)([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCC1CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=O)C(CC)C1
Reaction time: 16 h

Procedure:
Ethyl chloroformate (37.49 g, 346 mmol) was added to a stirred solution of 1-benzyl-3-ethyl-4-piperidone (24.0 g, 110 mmol) in benzene (200 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 16 hr and concentrated to dryness to give 1-carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96%), C10H17NO3, m/z 200 (M+1).