Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2C=C[C:19]([F:22])=[CH:18][C:17]=2F)=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:27]([C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]#[N:36])[CH2:26][C:25](=[O:37])[NH:24][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(F)cc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K96) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (87 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CC(C)=O>[NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:25][CH3:26])=[O:8])=[CH:4][C:3]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]
Reactant: Nc1sc(C(=O)O)cc1C(=O)c1ccccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(N)s1

Procedure:
5-Amino-4-(2-chlorobenzoyl)thiophene-2-carboxylic acid (240 g), potassium carbonate (176 g) and ethyl iodide (150 ml) were added to acetone (5 l), and the mixture was refluxed overnight. The solvent was evaporated, and ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added. The precipitated layer was taken out, washed with brine, dried over sodium sulfate and concentrated. The resulting crystals were collected by filtration and washed with ethyl acetate to give 126 g of ethyl 5-amino-4-(2-chlorobenzoyl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:13](=[N:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CN=Cc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g of 2,4-dimethoxybenzylamine hydrochloride is added to 100 ml of 1N sodium hydroxide solution and the mixture is extracted with 125 ml of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and stripped of solvent to give 10.2 g of 2,4-dimethoxybenzylamine as an oil. This amine is dissolved in 150 ml of benzene; 6.47 g of benzaldehyde and 0.6 g of p-toluenesulfonic acid monohydrate are added. The mixture is heated under reflux removing water with a Dean-Stark separator and in two hours the calculated amount of water (1.1 ml) separates out. The mixture is cooled to room temperature. Upon further cooling the benzene solution deposits some precipitate. Benzene is removed under reduced pressure and 60 ml of petroleum ether is added to the residue. An oily layer separates out with more precipitate. Benzene (10 ml) is added to make the layers homogeneous and the remaining precipitate is filtered. The filtrate is stripped of solvent to give 14.2 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[NH2:21][C@H:22]([CH3:25])[CH2:23][OH:24]>>[NH2:21][C@H:22]([CH3:25])[CH2:23][O:24][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: C[C@@H](N)CO
Product: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) and (2R)-2-aminopropan-1-ol to give 4-[(5-{[(2R)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol in 100% yield; NMR spectrum (DMSO-d6) 1.16 (d, 3H), 3.29-3.44 (m, 1H), 3.98 (dd, 1H), 4.22 (dd, 1H), 6.96 (d, 1H), 7.09 (d, 1H), 7.30 (d, 1H), 7.58 (dd, 1H), 7.69 (t, 1H), 8.10 (d, 1H), 8.47 (s, 1H) (4 exchangeables); Mass spectrum MH+ 344.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH2:15]>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:15][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CN
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A mixture of 1 g (4 mmol) 2-Chloro-5-sulfino-benzoic acid and 0.62 g (20 mmol) Methylamine in 10 ml dioxane was stirred for 3 h at room temperature. After evaporation of the volatiles 15 ml 5N HCl was added and the mixture was extracted 3× with ethylacetate. The solvent was removed under vacuum to yield 0.724 g (72%) of the title compound as amorphous white solid. MS (m/e): 248.1 (MH−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH:9]=[CH:16][N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Temperature: 120 °C

Procedure:
A mixture of 3-(4-chlorophenoxy)-2-butanone (34.50 g) and N,N-dimethylformamide dimethylacetal (20.70 g) was heated under argon in an oil bath at 120° C. for 13 hours. The methanol produced in the reaction was removed under reduced pressure and the residual oil was triturated with n-hexane. The solid was collected by filtration and washed with cold diethyl ether to give 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one. Yield 32.50 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[ClH:35]>CC(O)C.CO>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH:29]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]5)(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)c1cccnc1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)C1CCCNC1
Yield: 20 %

Procedure:
N-(2-(1-(1-(4-chlorophenyl)cyclobutyl)-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl)pyridine-3-sulfonamide (110 mg, 0.221 mmol, example 10) and a 6 molar solution of HCl in 2-propanol were dissolved in methanol (10 ml) and treated in an hydrogenation flow reactor (H-Cube®, Platinium (IV) oxide cartridge THS02119, ThalesNano) at 30 bar and 30° C. with a flow of 0.5 mV min under circulating conditions for 14 h. The final product was purified by HPLC using . . . to yield the final product as a white powder (25.0 mg, 0.043 mmol, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:13]([O-:15])=[O:14])[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: CC1Cc2cc(Cl)ccc2C1=O
Product: CC1Cc2cc(Cl)c([N+](=O)[O-])cc2C1=O

Procedure:
According to Example 1 (a), 28.0 g (0.155 mole) of 5-chloro-2-methyl-1-indanone and 180 ml of fuming nitric acid yield the nitro compound having a melting point of from 75° to 78° C., which after recrystallization from ethanol rises to 87° to 89° C.
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:12])[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: CCOC=C(C)C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c[nH]nc1C(F)(F)F
Yield: 84.9 %

Procedure:
1.7 g (10.2 mmol) of 4-ethoxy-3-methyl-1,1,1-trifluoro-3-buten-2-on and 0.6 g (12.0 mmol) hydrazine hydrate were stirred in 50 ml of ethanol at room temperature for 2 hours. The ethanol was distilled off under reduced pressure, and the residue was separated with ethyl acetate and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of 4-methyl-3-trifluoromethylpyrazol (yield 86.7%).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:10][CH2:11]C1C=CC=C(C=1)C=O.C=O.Cl>>[Cl:10][CH2:11][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH:8]=1)[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: O=Cc1cccc(CCl)c1
Agent: C=O
Agent: Cl
Product: O=Cc1cc(CCl)ccc1O

Procedure:
The salicylaldehyde is convened to the 5-chloromethylbenzaldehyde by combining the aldehyde with aqueous formaldehyde (37%) and concentrated hydrochloric acid, at a reduced temperature in the range of -10° to +10° C. or thereabouts. Gaseous HCl is then bubbled through the solution to saturate with HCl after which the solution is stirred for a period sufficient to effect the reaction at a reduced temperature, one which is about that of the temperature at which the reactants were combined initially. The product, the 5-(chloromethyl)-2-hydroxybenzaldehyde, should be formed as a white precipitate which can be recovered by conventional means.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:9]1)C1C=CC=CC=1>[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Product: COCCC[C@H]1CNCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step C, except using 4-benzyl-1-tert-butoxycarbonyl-2(S)-(3-methoxy-1-propyl)piperazine (0.870 g, 2.50 mmol) and 10% palladium on carbon (200 mg). The title compound was obtained as an oil (0.450 g). NMR (CDCl3, 300 MHz) δ 4.05 (1H, m), 3.85 (1H, m), 3.40 (2H, m), 3.35 (3H, s), 2.90 (5H, m), 2.70 (1H, dt, J=4, 7 Hz), 1.50-2.0 (4H, m), 1.45 (9H, s).
Reaction SMILES: [I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.C([Li])CCC.COC1C=C(/C=C/C(OCC)=O)C=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:57][O:58][C:59]1[CH:60]=[C:61]([CH:65]2[CH:67]([C:68]([O:70]CC)=[O:69])[C:66]2([CH3:74])[CH3:73])[CH:62]=[CH:63][CH:64]=1.[Li+].[OH-]>C1COCC1.C(O)C.O>[CH3:57][O:58][C:59]1[CH:60]=[C:61]([CH:65]2[CH:67]([C:68]([OH:70])=[O:69])[C:66]2([CH3:74])[CH3:73])[CH:62]=[CH:63][CH:64]=1
Reactant: CCOC(=O)C1C(c2cccc(OC)c2)C1(C)C
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/C=C/c1cccc(OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(C2C(C(=O)O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(3-methoxyphenyl)acrylic acid (25 g) in ethanol (150 mL) was added conc HCl (25 mL) and the solution refluxed for 3 hours. The solvent was evaporated and residue dissolved in ethyl acetate. The organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give ethyl (2E)-3-(3-methoxyphenyl)acrylate as yellow oil in quantitative yield. To a solution of isopropyl(triphenyl)phosphonium iodide (75 g, 0.173 mol) in dry THF (200 mL) at −78° C. was added butyl lithium (1.6M in Hexanes, 119 mL, 0.191 mol). The reaction was stirred for 1 hour at room temperature and then cooled to −78° C. To the solution was added ethyl (2E)-3-(3-methoxyphenyl)acrylate (2.91 g, 0.014 mol) in THF (200 mL). The solution was stirred at room temperature for few hours and then refluxed overnight. The reaction mixture was poured into 5% aqueous citric acid and extracted with ethyl acetate. The organic portion washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4 and concentrated. The concentrated residue was chromatographed on silica gel using 5% ethyl acetate/hexane to afford viscous yellow oil. To the solution ethyl 3-(3-methoxyphenyl)-2,2-dimethylcyclopropanecarboxylate (15 g) in ethanol (60 mL) and water (20 mL) was added LiOH (12.74 g). The reaction mixture was heated for 3 hours at 50° C. and concentrated to remove ethanol. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give 3-(3-methoxyphenyl)-2,2-dimethylcycloprop-anecarboxylic acid as yellow oil. 1H NMR (CDCl3) δ 7.15 (m, 1H), 6.74 (m, 3H), 3.8 (s, 3H), 2.67 (m, 1H), 2.05 (m, 1H), 1.38 (s, 3H), 1.06 (s, 3H). M−=219. Step 2. Synthesis of [3-(3-methoxyphenyl)-2,2-dimethylcyclopropyl]methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:9]([C:11](OC)=[O:12])[CH3:10])[C:5]([N+:20]([O-])=O)=[CH:4][N:3]=1>[Fe].C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:20][C:11](=[O:12])[CH:9]([CH3:10])[N:8]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[N:7]=1
Reactant: COC(=O)[C@H](C)N(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1C
Temperature: 60 °C
Yield: 61 %

Procedure:
A mixture of methyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(3-methylbutyl)alaninate (16.2 g, 49 mmol), iron powder (6.9 g, 123 mmol) and glacial acetic acid (165 mL) was heated at 60° C. for 2 h. The reaction mixture was then filtered while hot over celite and washed with hot acetic acid (40 mL) followed by ethyl acetate (250 mL). The filtrate after evaporation was taken up in ethyl acetate and washed two times with aq. saturated sodium bicarbonate solution followed by brine. It was dried over sodium sulfate and evaporated. The residue was triturated with hot isopropyl ether to give titled product (yield: 61%). 1HNMR (300 MHz, CDCl3): δ 0.92-1.01 (m, 7H), 1.43-1.75 (m, 5H), 3.01-3.20 (m, 1H), 4.10-4.25 (m, 2H), 7.63 (s, 1H), 9.13 (s, 1H).
Reaction SMILES: C([N:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([S:23][C:24]#[N:25])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=1)C(=O)O)(C)(C)C.FC1C=CC2N=CN(C3N=C(SC#N)C([N+]([O-])=O)=CN=3)C=2C=1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52].C(Cl)Cl>>[F:15][C:12]1[CH:11]=[C:10]([NH:16][C:17]2[N:22]=[C:21]([S:23][C:24]#[N:25])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[C:9]([NH2:5])=[CH:14][CH:13]=1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: CC(C)(C)N(C(=O)O)c1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: N#CSc1nc(-n2cnc3ccc(F)cc32)ncc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CSc1nc(Nc2cc(F)ccc2N)ncc1[N+](=O)[O-]

Procedure:
6-Fluoro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole tert-Butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (4.06 g) was dissolved in 30% TFA/DCM (50 mL) and stirred until no starting material remained (90 min). The reaction solvents were removed, to yield crude 5-fluoro-N1-(5-nitro-4-thiocyanatopyrimidin-2-yl)benzene-1,2-diamine (MH+=306) as a TFA salt that was used immediately as such in the next step. Trimethyl ortho formate (15 mL) and MeOH (100 mL) were added to the above diamine and the solution was stirred for 16 hrs. The resulting orange ppt was collected via filtration, washed with MeOH and dried under reduced pressure to yield the titled compound (2.62 g), 1H-NMR (400 MHz, d6-DMSO) δ 9.2 (s, 1H), 9.1 (s, 1H), 8.5 (dd, 1H), 7.8 (dd, 1H), 7.3 (dd, 1H) ppm; MH+=317.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH2:19][OH:20])=[O:16])=[CH:8][C:7]=2C)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH:19]=[O:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (240 mg) in dry CH2Cl2 (15 ml) was treated with Dess-Martin periodinane (341 mg). The mixture was stirred at room temperature during 1 h then poured on sat aq NaHCO3. After separation the water phase was washed twice with CH2Cl2 The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (cyclohexane/ethyl acetate 1:1) to give (3-ethynyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (215 mg) as yellowish oil as a mixture of diastereoisomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.Cl>CC(O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([NH:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(NCCN3CCOCC3)ncc2[N+](=O)[O-])CC1

Procedure:
A glass microwave reaction vessel was charged with cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (200 mg, 0.587 mmol) and 2-morpholinoethanamine (0.092 mL, 0.704 mmol) in 2-propanol. A drop of HCl (2N in ether) was added, and the reaction mixture was stirred and irradiated in a microwave at 175° C. for 2 hours. Additional 2-morpholinoethanamine (0.030 mL, 0.24 mmol) was added, and the mixture was heated an additional 20 minutes. The mixture was evaporated and the residue diluted with 10% IPA/DCM, washed with water, brine, and the organic layer dried over Na2SO4. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% of 1% NH4OH in MeOH in DCM. Intermediate cis-N-isopropyl-4-(2-(2-morpholinoethylamino)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide was isolated as a yellow film (128 mg).
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([O:32]C)=[O:31])[CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@](c2ccc(-c3ccccc3)cc2)(S(=O)(=O)CCC)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@](c2ccc(-c3ccccc3)cc2)(S(=O)(=O)CCC)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(propylsulfonyl)pyrrolidine-2-carboxylate (1.52 g, 2.372 mmol) in THF (20.00 mL) and MeOH (20 mL) was added pre-made solution of lithium hydroxide (0.199 g, 4.74 mmol) in water (20.00 mL). The formed cloudy solution was stirred at rt for 3 h. Removed the volatiles in vacuo. The residue was acidified with 1M HCl to pH 3, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated in vacuo to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(propylsulfonyl)pyrrolidine-2-carboxylic acid (1.45 g, 2.198 mmol, 93% yield) as a white foam. 1H NMR (400 MHz, MeOD) δ ppm 0.97 (t, J=7.53 Hz, 3 H) 1.36-1.55 (m, 12 H) 1.55-1.82 (m, 4 H) 2.10 (q, J=6.61 Hz, 2 H) 2.81 (dd, J=8.66, 6.65 Hz, 2 H) 2.91 (dd, J=12.92, 10.42 Hz, 1 H) 3.28 (d, J=7.28 Hz, 1 H) 4.20 (dd, J=9.91, 7.40 Hz, 1 H) 4.37 (d, J=11.04 Hz, 1 H) 4.52 (t, J=6.90 Hz, 1 H) 4.95 (dd, J=10.16, 1.13 Hz, 2 H) 4.98-5.07 (m, 1 H) 5.13 (d, J=11.04 Hz, 1 H) 5.77-5.94 (m, 1 H) 7.33-7.42 (m, 1 H) 7.48 (t, J=7.53 Hz, 2 H) 7.65 (d, J=7.53 Hz, 2 H) 7.72-7.78 (m, 2 H) 7.93 (d, J=8.28 Hz, 2 H). LC-MS (retention time: 1.99 min, method A), MS m/z 627 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]2[C:6]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)([CH2:7]2)[C:5]1=[O:20])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:6]23[CH2:7][CH:8]2[C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:20])=[CH:16][CH:15]=1
Reactant: CC(C)N1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
Following the procedure of Example 3, a solution of 3-isopropyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 100 ml of ethanol is hydrogenated in the presence of 0.17 g of 5% palladium on carbon and worked up, affording the title compound which melts at 160°-163° C. after recrystallisation from ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1)[C:24]([O:26]C)=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1)[C:24]([OH:26])=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
(S)-methyl 2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoate (140 mg, 0.225 mmol) was taken up in 2 mL of THF along with an aqueous solution of NaOH (35 mg in 2 mL of H2O). The resulting reaction mixture was stirred at room temperature for 2 h. It was then acidified to pH 4 with 2 N HCl and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 31 mg of (S)-2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoic acid. MS calculated for C34H47N3O4: 561.36; found: [M+H]+562. MS calculated for C32H45N3O4: 535.34. Found: [M+H]+536.