Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([OH:15])[C@@H:9]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>ClCCl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C:10](=[O:15])[C@@H:9]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H]1C[C@H](O)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1CC(=O)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of (2S,3S,5R)-2-benzyl-5-ethyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.138 mmol; 42 mg) in dichloromethane (1.4 mL) is added Dess-Martin periodinane (0.166 mmol; 70.4 mg) at 0° C. The mixture is stirred at the same temperature for 1.5 hours. To the mixture, brine and EtOAc are added. The organic layer is separated, washed with saturated aqueous Na2S2O3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give (2S,5R)-2-benzyl-5-ethyl-3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (29.8 mg, 71%); ESI-MS m/z: 248 [M+−tBu+2], Retention time 2.49 min (condition A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:21])[CH2:19][CH3:20]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([CH2:19][CH3:20])=[N:21][N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: COC(=O)/C=C(/C)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccc([N+](=O)[O-])cc2)c(C)c1C(=O)OC
Yield: 65 %

Procedure:
According to AVV A, (Z-3-(4-nitrophenylamino)-but-2-enoic acid methylester (236.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 21 hours at 120° C. The green solid obtained as raw product 100:0→90:10→0:100), whereby the pure product was obtained in the form of a slightly yellowish solid (188.3 mg, 0.65 mmol, 65%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:27])[NH2:26])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:25](=[O:27])[NH2:26])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(OCc3ccccc3)ccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Benzyloxy-3-carbamoyl-indol-1-yl)-acetic acid tert-butyl ester (250 mg, 0.657 mmol) was suspended in THF (13 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (25 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere and stirred at RT overnight. The catalyst was removed through a 0.45 microns filter and concentrated in vacuo. The crude material was purified by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give after lyophilization of the purified fractions the desired compound as a white solid. MS: 291 [M+H]+, 313 [M+Na]+, 581 [2M+H]+, 603 [2M+Na]+; tR (HPLC conditions c): 3.75 min.
Reaction SMILES: [I-].[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:34]([O:38][C:39]([NH:41][C@:42]([CH3:54])([CH2:45][O:46][C:47](=[O:53])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:43]O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[Cl-].[NH4+]>O1CCCC1>[C:34]([O:38][C:39]([NH:41][C@:42]([CH3:43])([CH:54]=[CH:8][C:4]1[N:3]([CH3:2])[CH:7]=[CH:6][CH:5]=1)[CH2:45][O:46][C:47](=[O:53])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCCCC(=O)OC[C@](C)(CO)NC(=O)OC(C)(C)C
Reactant: Cn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCCC(=O)OC[C@@](C)(C=Cc1cccn1C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
(1-Methylpyrrol-2-yl)methyltriphenylphosphonium iodide (58.0 g, 120 mmol) obtained in Reference example 1 (1c) was suspended in tetrahydrofuran (300 mL) and a solution of potassium t-butoxide (13.5 g, 120 mmol) in tetrahydrofuran (180 mL) was added thereto under ice-cooling with stirring over 30 minutes, followed by further stirring of the mixture under ice-cooling for 80 minutes. A solution of (2S)-2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (30.3 g, 101 mmol) obtained in Reference example 1 (1b) in tetrahydrofuran (120 mL) was added to the reaction mixture over 30 minutes and the mixture was stirred under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction and the temperature of the liquid was returned to room temperature. The mixture was concentrated under reduced pressure and water and ethyl acetate were added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 9:1) to obtain the title compound (37.0 g, yield: 97%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:15][CH2:14]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 74.1 %

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 2) (0.70 g, 2.5 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (1.25 g, 7.5 mmol, 3 eq) and TFA (1.43 g, 12.5 mmol, 5 eq) were heated to reflux in TFE (25 mL) for 18 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with MeOH to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (0.81 g, 74%).
Reaction SMILES: [C:1]([N:4]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2].[CH2:18]([C:20]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:19]>>[C:1]([N:4]([CH2:13][CH2:14][C:15]([N:22]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:20]=1[CH2:18][CH3:19])=[O:17])[C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCNc1c(C)cccc1CC
Reactant: CC(=O)N(CCC(=O)O)c1c(C)cccc1C
Product: CCOC(=O)CCCN(C(=O)CCN(C(C)=O)c1c(C)cccc1C)c1c(C)cccc1CC

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-3-(2,6-dimethylanilino)propionic acid and ethyl 4-(2-ethyl-6-methylanilino)butyrate and suitable processing produces ethyl N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(2-ethyl-6-methylanilino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(2-ethyl-6-methylanilino)butyric acid (M.P. 139° to 141°).
Reaction SMILES: Cl.CO[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1OC)[NH:9][C:8](C)=[C:7]2CCN1CCC(C2C=CC=CC=2)CC1.C([SiH](CC)CC)C.[Sn].Cl>FC(F)(F)C(O)=O.C(O)C>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COc1cc2[nH]c(C)c(CCN3CCC(c4ccccc4)CC3)c2cc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: [Sn]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: c1ccc2c(c1)CCN2

Procedure:
The appropriately substituted intermediate indoles (5) are dissolved in trifluoroacetic acid and are treated with triethylsilane at 45°-50° C. for 48-96 hours, or are heated at reflux in ethanol for 48 hours in the presence of tin and hydrochloric acid, and in each case the mixture is then poured onto cracked ice. The resultant mixtures are made basic and are extracted with solvents such as chloroform, methylene chloride, or ethyl acetate. The extracts are evaporated to give the substituted-2-methyl-3-[2-(4-phenylpiperidino), (4-phenyl-1-piperazinyl) and [4-(2pyridyl)-1-piperazinyl]ethyl]-indoline compounds (6). The acid salts are obtained by treating the indoline (6) with hydrogen chloride in a solvent such as ethyl ether, ethyl acetate, or ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH2:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCN)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCCc1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine (0.0324 mmol) [Example 35] in tetrahydrofuran (1.5 mL) was treated with acetyl chloride (0.0324 mmol) and triethylamine (0.0788 mmol). The solution was stirred at room temperature for 12 hours and then treated with water and ethyl acetate. The organic phase was dried over magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica eluting with ethyl acetate followed by a mixture of ethyl acetate and methanol (9:1, v/v)) to give the title compound as a yellow solid. MS: 351 (MH+). HPLC (Method C): RT=3.05 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])N.N([O-])=O.[Na+].N#N.[ClH:20].O>O.Cl.Cl[Cu]>[Cl:20][C:5]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl[Cu]
Agent: N#N
Agent: O=N[O-]
Solvent: O
Product: COc1cc(Cl)cc(OC)c1OC
Temperature: 25 °C
Yield: 67 %

Procedure:
To a stirred suspension of 3,4,5-trimethoxyaniline (6.27 g, 34.2 mmol) in 37% HCl:H2O (75:25) at 0° C. was added dropwise a solution of NaNO2 (2.51 g, 36.4 mmol) in H2O. The temperature was maintained below 5° C. during the addition. Upon complete addition of NaNO2, an ice cold solution of CuCl (4.41 g, 44.6 mmol) in 37% HCl was added and the solution allowed to warm to room temperature. The stirred suspension was warmed to 60° C. until evolution of N2 ceased. The product was filtered and washed with cold H2O. The crude product was purified by flash chromatography (silica gel, EtOAc/Petroleum Spirit 3:17) to give the title compound as a white solid (4.68 g, 67%). 1H NMR (300 MHz, CDCl3) δ 6.58 (s, 2H), 3.85 (s, 6H), 3.82 (s, 3H), ESIMS m/z [M+H]+ 203.2.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21][NH:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCc1cccc(N)n1
Product: CCCc1cccc(NC=C(C(=O)OCC)C(=O)OCC)n1

Procedure:
The product from Example 2c (223 mg, 1.52 mmol) was reacted with 2-ethoxymethylene-malonic acid diethyl ester 0.350 mL, 1.75 mmol) following the procedure in Example 1a to give the title compound after silica gel column chromatography eluting with EtOAc/hexane (386 mg, 80%).
Reaction SMILES: [C:1]([O-])(=[O:8])C1C=CC=CC=1.[Zn+2:10].C([O-])(=O)C1C=CC=CC=1.C(=O)([O-])O.[NH4+].[C:25]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:26].C=O>>[Zn:10].[C:25]([C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:26])[CH3:27].[CH2:1]=[O:8]
Reactant: O=C([O-])c1ccccc1
Reactant: [Zn+2]
Agent: C=O
Agent: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])O
Product: [Zn]

Procedure:
A mixture of 12.75 g of zinc benzoate and 7.5 g of ammonium hydrogen carbonate was added gradually to 100 g of the resulting p-tert-octylphenol/formaldehyde condensate kept at 170° C. to give a yellow zinc salt of the p-tert-octylphenol/formaldehyde condensate.
Reaction SMILES: [C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:27]([F:30])([F:29])[F:28])[OH:26])([O:3]CC)=[O:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:27]([F:30])([F:28])[F:29])[OH:26])([OH:3])=[O:2]
Reactant: CCOC(=O)C1C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)NC1(O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C(C(=O)O)C(O)(C(F)(F)F)N2
Temperature: 90 °C
Yield: 31.6 %

Procedure:
A suspension of 3-carboethoxy-2-trifluoromethyl-2-hydroxy-4(3-nitrophenyl)-2,3,4,6,7,8-hexahydro-5(1H)-quinolone (7.02 g) in ethanol (40 ml) and water (40 ml) was treated with lithium hydroxide monohydrate (1.44 g). The mixture was heated at 90° C. for 30 minutes, diluted with water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed (water and brine), dried, filtered and the solvent stripped to yield a brown oil which was further purified by chromatography (ethyl acetate and ethyl acetate/methanol, 4:1). 3-Carboxy-2-trifluoromethyl-2-hydroxy-4-(3-nitrophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (2.07 g) was obtained as a white solid. NMR: 1.85 (m,2, CH2), 2.10 (m,2, CH2), 2.33-2.60 (m,3, CH2, CH), 4.21 (d,1, J=8.7, CH), 7.47 (m,2, Ar), 7.81 (s,2, OH or NH, Ar), 7.96 (m,1H, Ar); MS: m/z=400(M).
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21].CCOCC.O>CN(C)C=O>[CH3:13][C:2]([O:1][Si:20]([CH3:22])([CH3:21])[CH3:19])([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[CH:4]
Reactant: C#CC(C)(O)COc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)(COc1ccccc1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The hydroxyl group of this alkyne is protected by dissolving 2 parts of the butyne in 5 parts by volume of dimethylformamide and successively treating the reaction mixture with 2 parts of imidazole and 1.2 parts of trimethylsilylchloride. The reaction mixture is stirred at room temperature for 1 hour and poured into ether/water. The ethereal layer is washed with water and dried over anhydrous sodium sulfate. Isolation by low pressure liquid chromatography on silica gel provides 3-methyl-3-trimethylsilyloxy-4-phenoxy-1-butyne.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[O-]CC.[Na+]>C(O)C>[C:13]1(=[O:15])[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[N:4]2[CH2:3][CH2:2][NH:1]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCCn2c1cc1c2CCCC1
Temperature: 55 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 104i (1.80 g, 7.63 mmol), sodium ethoxide (1.55 g, 22.8 mmol) and ethanol (50 mL). The mixture was stirred at 55° C. for 5 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromato-graphy to afford a 42% yield (605 mg) of 104j as a white solid: mp 207-209° C.; 1H NMR (500 MHz, DMSO-d6) δ7.41 (s, 1H), 6.36 (s, 1H), 3.84 (t, 2H, J=6.0 Hz), 3.42 (m, 2H), 2.51 (t, 2H, J=6.0 Hz), 2.42 (t, 2H, J=6.0 Hz), 1.76 (m, 2H), 1.65 (m, 2H); (APCI+) m/z 191.3 (M+H)
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]([CH3:32])[C:20]2[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=2[O:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])=[CH:15][C:14]=1[C:35]1[CH:36]=[N:37][C:38]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:40]=1[C:41]#[N:42].[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[NH:48][NH2:49].C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.ClCCl>[C:52]([O:51][C:47]([NH:48][NH:49][C:25](=[O:26])[CH2:24][CH2:23][O:22][C:21]1[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=1[N:19]([C:17](=[O:18])[C:16]1[CH:33]=[CH:34][C:13]([Cl:12])=[C:14]([C:35]2[CH:36]=[N:37][C:38]([C:43]([F:44])([F:46])[F:45])=[CH:39][C:40]=2[C:41]#[N:42])[CH:15]=1)[CH3:32])=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
EDCI (19.9 mg, 0.104 mmol) was added to a solution of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (36.3 mg, 0.069 mmol), t-butyl carbazate (13.7 mg, 0.104 mmol), HOBt (14.0 mg, 0.104 mmol) and Na2CO3 (8.7 mg, 0.104 mmol) in a mixture of DMF (1 mL) and dichloromethane (4 mL). The mixture was stirred at room temperature for approximately 16 hrs and was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, and was dried over MgSO4. The organic filtrate was evaporated and purified by prep. TLC plate eluted with hexane and ethyl acetate (1/1) to yield N′-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylic acid tert-butyl ester (40.1 mg, 94%). MS [M+H]+: 619.0; tR=2.40 min. (method 1)
Reaction SMILES: N[C:2]1[C:3]2[C:27]3([CH2:31][CH2:30][O:29][CH2:28]3)[C:26](=[O:32])[NH:25][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:7]=1.[I-:33].[Cs+].II.N(OCCC(C)C)=O>COCCOC.[Cu]I>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[C:2]([I:33])[C:3]3[C:27]4([CH2:31][CH2:30][O:29][CH2:28]4)[C:26](=[O:32])[NH:25][C:4]=3[N:5]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C1(CCOC1)C(=O)N2
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: O=C1Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c2C12CCOC2
Temperature: 60 °C

Procedure:
563 mg (1.305 mmol) of the compound obtained in Example 15A were initially charged in 1,2-dimethoxyethane (7.5 ml), and 339 mg (1.305 mmol) of caesium iodide, 165 mg (0.652 mmol) of iodine and 74 mg (0.391 mmol) of copper(I) iodide were then added. Isopentyl nitrite (1.04 ml) was then added, and the mixture was heated at 60° C. for 2 days. After cooling, the mixture was filtered, the filter cake was washed with ethyl acetate and the filtrate was washed twice with 5% strength aqueous sodium thiosulphate solution and once with saturated aqueous sodium chloride solution. The organic phase was then dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile/water (+0.05% formic acid) gradient). This gave 98 mg of the title compound (14% of theory).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:27][CH2:26][CH2:25][NH:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:28])=[N:5]1)([CH3:3])[CH3:2].C(O)(=O)C.[O-:33][C:34]#[N:35].[K+].CN(C)C=O>O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C@@H:23]5[CH2:27][CH2:26][CH2:25][N:24]5[C:34]([NH2:35])=[O:33])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:28])=[N:5]1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCCN4)cc2OCC3)n(C(C)C)n1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@@H]4CCCN4C(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.009 g, 0.00002 mol) in Acetic acid (4.06 uL, 0.0713 mmol) and water (0.13 mL) was added a solution of Potassium cyanate (0.00579 g, 0.0713 mmol) in water (0.13 mL) dropwise. N,N-Dimethylformamide (0.13 mL, 0.0017 mol) was added to solubilize the reagents. The reaction was stirred at 50° C. overnight, cooled down, filtered, and rinsed with cold water. The crude was purified by precipitation in MeOH/water to give 10 mg of each enantiomer 379 and 380. MS (ESI+) 422.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 6.95 (dd, J=8.3, 1.6 Hz, 1H), 6.79 (d, J=1.3 Hz, 1H), 5.90-5.76 (m, 1H), 5.69 (br, 2H), 4.89 (dd, J=7.9, 1.3 Hz, 1H), 4.53-4.44 (m, 4H), 3.58-3.49 (m, 1H), 3.42-3.34 (m, 1H), 2.25 (s, 3H), 2.25-2.17 (m, 1H), 1.92-1.65 (m, 3H), 1.45 (dd, J=6.6, 3.9 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH2:23])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[O:36])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25]
Reactant: COc1cc2c(Sc3ccc(N)s3)ccnc2cc1OCCCN(C)C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Sc3ccc(NC(=O)Nc4ccc(F)cc4)s3)ccnc2cc1OCCCN(C)C
Yield: 6.2 %

Procedure:
5-((7-[3-(Dimethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine (190 mg), para-fluorophenyl isocyanate (69 mg) and tetrahydrofuran (30 ml) were stirred together at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=10:1) using NH type silica gel. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for solidification to obtain 16 mg of a yellowish-brown solid.