Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:6](I)[C:5]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:4]1)[CH3:2].[Cu][C:39]#[N:40]>CC(N(C)C)=O>[C:39]([C:6]1[C:5]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)#[N:40]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(I)c1Oc1ccc(C(F)(F)F)cc1
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(C#N)c1Oc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Yield: 32 %

Procedure:
A suspension of N-[2-(3-{1-ethyl-4-iodo-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)propan-2-yl]-2,2,2-trifluoroethanesulfonamide (538 mg, 0.813 mmol), copper (I) cyanide (729 mg, 8.13 mmol) and DMA (0.813 mL) was heated to 150° C. for 16 h. The reaction was cooled, partitioned between EtOAc and sat aq NaHCO3, and filtered. The organic layer was washed with sat aq. NaHCO3 2×, dried (MgSO4) and concentrated to afford a light yellow purified twice via MPLC, 50 g silica, 10-50% EtOAc in heptanes to afford 146 mg of a white solid: MS: cal'd 561 (MH+), exp 561 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5]O)[CH3:2].C(N(S(F)(F)[F:26])CC)C.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][F:26])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN(CCF)CCN1C(=O)c2ccccc2C1=O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of compound 3 (100 mg, 0.38 mmol) in dimethoxyethane (DME, 7 mL) was added at −50° C., under argon, (diethylamino)sulfur trifluoride (DAST, 100 μL, 0.76 mmol). The mixture was stirred at −50° C. for 10 min and then at room temperature for 1.5 h. Dichloromethane (5 mL) and a saturated aqueous sodium carbonate solution (5 mL) were then successively added. The organic layer was dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (SiO2, AcOEt/pentane, 1/1, v/v) to give compound 21 (51 mg, 0.19 mmol) as a white solid. Yield 50%; Rf (SiO2, AcOEt/pentane, 1/1, v/v) 0.53; mp 57-59° C.; IR (KBr) ν 1023, 1403, 1715, 1769, 2700-3000 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.00 (t, 3H, J=7.1 Hz), 2.68 (q, 2H, J=7.1 Hz), 2.86 (m, 4H), 3.78 (t, 2H, J=6.6 Hz), 4.47 (td, 2H, 2JH-F=47.5 Hz, J=5.1 Hz), 7.70 (m, 2H), 7.83 (m, 2H); MS m/z 264 (M+, 1), 104 (100), 76 (38), 56 (18).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([CH:47]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:48][NH2:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)(C)C>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:49][CH2:48][CH:47]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(Cc1ccccc1)Cc1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(Cc4ccccc4)Cc4ccccc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Yield: 80.4 %

Procedure:
A solution of ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) (0.25 g, 0.38 mmol) and 2-benzyl-3-phenylpropylamine (0.16 g, 0.76 mmol) in isopropanol (10 ml) was stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1 by volume) to afford the title compound as a yellow foam (0.26 g, 83%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:25])[NH:17][C@@H:18]([C:22](F)=[O:23])[CH:19]([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:25])[NH:17][C@@H:18]([C:22](=[O:23])[NH:7][CH2:8][CH2:9][SH:10])[CH:19]([CH3:20])[CH3:21])([CH3:12])([CH3:14])[CH3:13]
Reactant: NCCS
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (1 74.0 mg, 2.07 mmol) in 10.1 mL was added 2-aminoethanethiol hydrochloride (126.6 mg, 1.11 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25f (222.2 mg, 1.0 mmol) in 10.1 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to afford 195.2 mg (71% from 24f) of clean 26f as a white solid. FTIR (film) 3289, 1687, 1645 cm −1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCOCC.C([Li])CCC.[CH3:19][C:20]([CH3:22])=[O:21]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:20]([OH:21])([CH3:22])[CH3:19])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
2,5-Dibromopyridine 3.05 g (12.5 mmol) was dissolved in 20 mL of THF and 120 mL of anhydrous ether and cooled to −78° C. 5.0 mL n-butyllithium (2.5 M, 12.5 mmol) was slowly dropped through a syringe in 30 min. After being stirred at −78° C. for 30 minutes, acetone (2 ml, 20 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After crystallization using 20% EtOAc in hexane, 1.30 g of white crystals was obtained (48% yield), MS: 215.0, 217.0 (M++1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:19][O:20][CH:21]([O:25][CH3:26])[CH:22]([NH2:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:19][O:20][CH:21]([O:25][CH3:26])[CH:22]([NH:24][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH3:23]
Reactant: COC(OC)C(C)N
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of benzyl 3-chloro-4-nitrophenyl ether (48.2 g, 0.183 mole), 2-aminopropionaldehyde dimethyl acetal (65.3 g, 0.55 mole), potassium carbonate (101 g, 0.73 mole) and toluene in dry dimethyl sulfoxide, under nitrogen, is stirred at 99°-105° C. for 20 hours, cooled to room temperature and filtered. The filter cake is washed with ether. The combined filtrates are mixed with ice water. The phases are separated and the aqueous phase is extracted with ether. The ether extracts are combined with the organic phase. The combined organic phase is washed with six portions of water, dried (Na2SO4) and concentrated in vacuo to give an oil residue which is crystallized in methanol to afford the title product as a yellow solid, 39.6 g (64.5%). A sample is recrystallized from methanol to afford a yellow solid, mp 57°-62° C., identified by elemental and NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:16])([C:12]([F:13])([F:14])[F:15])[C:8]([OH:10])=[O:9])=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)(Oc1ccc(Cl)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Cl)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (±)-methyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionate (1.41 g.), methanol (4.0 ml.), and 4.5 N-aqueous potassium hydroxide (2.3 ml.) is stirred at ambient temperature for 10 minutes. The resulting solution is diluted with water, washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The extract is washed with water, dried with sodium sulphate and evaporated to a residue which is crystallised from light petroleum (b.p. 60°-80° C.) to give (±)-2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p. 141°-142° C. (0.7 g.).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C(OCC)(=O)C>[OH:4][CH2:3][C@@H:2]([N:1]1[C:9](=[O:10])[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:11])[CH3:5]
Reactant: C[C@H](N)CO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 140 °C
Yield: 99.9 %

Procedure:
A mixture of (2S)-2-aminopropan-1-ol (26 mL, 333 mmol) and phthalic anhydride (51.7 g, 349.4 mmol) is heated at 140° C. overnight. During this time the solid becomes an orange liquid. The reaction is cooled to RT and diluted with ethyl acetate (10 mL/g). The organic phase is washed with saturated NaHCO3 and 10% citric acid, dried over MgSO4, filtered, and concentrated to afford the title compound (68.3 g, 98%) as a white solid that is used without further purification. LC-ES/MS m/z 206 (M+1).
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2[N:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][CH:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[C:19]2[N:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][CH:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)=[O:2]
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C)n43)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)cn2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C)n43)n1COP(=O)(O)O)cn2C
Yield: 40.8 %

Procedure:
Di-tert-butyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)methyl phosphate (0.2 g, 0.361 mmol) was dissolved in DCM (5 mL) then TFA (0.2 mL, 2.60 mmol) was added. After about 20 min at rt the reaction mixture was concentrated under reduced pressure. The material was dissolved in DMF (7.5 mL) then the material was purified by preparative reverse phase HPLC (Table 2, Method i). The fractions were collected and concentrated under reduced pressure to remove most or all of the MeCN. The solid was collected by filtration and dried under vacuum to a constant weight at about 60° C. to provide (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)methyl dihydrogen phosphate (0.065 g, 41%): LC/MS (Table 2, Method a) Rt=1.42 min; MS m/z 442 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[S:27])[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(=O)n3c(nc2c1)CCCCC3
Solvent: Cc1ccccc1
Product: Cc1ccc2c(=S)n3c(nc2c1)CCCCC3

Procedure:
9 g of 3-methyl-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-12-one was treated with 15 g of Lawesson's reagent in toluene at reflux under nitrogen until the starting material was consumed, checked by TLC, using chloroform as eluent (24 hours). The mixture was concentrated in vacuo and chromatographed on silica gel, using chloroform as eluent. The bright yellow material was recrystallized from hexane-ethyl acetate.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH3:7])=S)#[N:2].[CH3:8][C:9]1[NH:13][CH:12]=[N:11][C:10]=1[CH2:14][S:15][CH2:16][CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC#N>[C:1]([N:3]=[C:4]([NH:18][CH2:17][CH2:16][S:15][CH2:14][C:10]1[N:11]=[CH:12][NH:13][C:9]=1[CH3:8])[NH:6][CH3:7])#[N:2]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CNC(=S)NC#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 3.3 %

Procedure:
A suspension of N-cyano-N'-methylthiourea (DBU salt) (0.534 g), 2-(5-methylimidazol-4-ylmethylthio)ethylamine (1.03 g), HgO (0.868 g) and anhydrous sodium sulfate (2 g) in CH3CN (20 ml) was heated under reflux for 20 hrs. with vigorous stirring. The hot reaction mixture was filtered and the filtrate was dried up and subjected to chromatography on SiO2 [eluant: CH3CN-CH3OH (4:1)]. The resulting crude product was purified by preparative thin layer chromatography [SiO2, AcOEt--MeOH--28% aq. NH3 (10:1:1)] and recrystallized from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]-guanidine (38.4 mg). Yield 7.6%, m.p. 136°-138° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:10]([N+:18]([O-])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>CO.O1CCCC1.[Pd]>[NH2:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([OH:1])[C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c(O)nc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c(N2CCOCC2)c(O)nc2ccccc12

Procedure:
The 2-hydroxy-3-morpholino-4-nitroquinoline (1.5 g, 0.0054 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran and subjected to catalytic reduction in the presence of 10g palladium-on-carbon. After completion of the reaction, the palladium-on-carbon catalyst was filtered off and the mother liquor was concentrated. Following purification by chromatography on an alumina column using chloroform as a developing solvent, recrystallization from chloroform was conducted to obtain 4-amino-2-hydroxy-3-morpholinoquinoline in an amount of 0.9 g (yield, 63%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>C1C=CC=CC=1>[C:1]1([N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: CCCCNCCCC
Solvent: c1ccccc1
Product: CCCCN(CCCC)C1=CCCCC1

Procedure:
This example shows a typical preparation of an enamine of this invention using a ketone. A half mole of both cyclohexanone and di-n-butylamine in 100 ml. of benzene were refluxed for 2-3 days using a Dean Stark trap to collect the water as it formed. After about 61/2 ml. of water was collected, the benzene was stripped off, and the enamine was collected as the fraction distilling between 121°-124° C. at 7.5 mm. Hg.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[CH2:19]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][C:16]([CH:30]=[O:31])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)cc1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
In a stream of argon, in tetrahydrofuran was dissolved 3.0 g (0.97 mmol) of dibutyl[4-[2-(thiophene-2-yl)vinyl]phenyl]amine. To this mixture, 9.0 ml of n-butyllithium (1.6 M solution in hexane) (14.4 mmol) was added dropwise under cooling. After the mixture was stirred for 1 hour, 0.87 g (11.9 mmol) of N,N-dimethylformamide was added dropwise thereto. After 20 minutes, the temperature was allowed to rise and 30 ml of water was added dropwise. Tetrahydrofuran was evaporated off. Extraction with chloroform, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 3.12 g of a reddish orange oily matter (yield: 95.5%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) (3.00 g, 12.7 mmol) in DCE (100 mL) was added ethyl 2-amino-2-methylpropanoate hydrochloride (25 mmol, ˜2 equiv.), molecular sieves 4A (5 g), and Et3N (2 equiv.). The mixture was stirred for 6 hours at room temperature and treated with NaBH(OAc)3 (2 equiv.). After the addition was completed, the reaction mixture was stirred overnight under nitrogen. The mixture was diluted with DMC (200 mL), carefully quenched with saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was further extracted with DCM (2×100 mL). The combined organic extract was washed with water (50 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified over silica gel using hexanes/EtOAc (2/8) to give ethyl 2-(3-(tert-butyldimethylsilyloxy)benzylamino)-2-methylpropanoate (4.02 g, 90%). MS 352 (MH+)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.Cl[C:20]([O:22][CH3:23])=[O:21].CC(C)([O-])C.[Li+]>C(OC(C)C)(C)C>[CH3:23][O:22][C:20](=[O:21])[NH:14][C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][CH3:16]
Reactant: COC(=O)Cl
Reactant: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(C)OC(C)C
Product: CC[C@H](CC(=O)NC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Temperature: 2 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (6094 g, 23.42 mol), isopropyl ether (30 L) and methyl chloroformate (2.7 kg, 29 mol). The resulting slurry was cooled to 2° C. The reaction tank was then charged with lithium t-butoxide solution (18-20% in THF, 24.6 kg, ˜58 mol) at such a rate as to maintain the internal temperature below 10° C. and preferably at a temperature of about 5° C. Ten minutes after addition of base was complete, the reaction was quenched by the addition of 1.5 M hydrochloric acid (36 L). The aqueous layer was removed, and the organic phase extracted with saturated NaCl/water solution (10 L). The aqueous layer was removed and the organic phase was concentrated by distillation under vacuum and at a temperature of about 50° C. until the volume was reduced to about 24 L. Cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50° C. under vacuum until the volume of solution in the vessel was reduced to 24 L. A second portion of cyclohexane (48 L) was added to the reaction vessel and distillation was again repeated at an internal temperature of about 45-50° C. under vacuum until the volume of solution in the vessel was reduced to 24 L. While holding the temperature at 50° C., the solution was seeded with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid methyl ester and allowed to granulate while stirring for 2 hours. The solution was then cooled slowly (over 1.5 hours) to room temperature and allowed to granulate while stirring for 15 hours. The mixture was filtered. The resulting solids were rinsed with cyclohexane (10 L) and dried under vacuum at 40° C. to afford 7504 g of the title compound (94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1ccccc1O
Solvent: CC(=O)O
Product: c1ccc2oc(-c3ccncc3)nc2c1
Temperature: 100 °C

Procedure:
A 500 mg portion of pyridine-4-aldehyde was dissolved in 15 ml of acetic acid, and the solution was mixed with 509 mg of o-aminophenol and stirred with heating at 100° C. for 6 hours. The solvent was concentrated under a reduced pressure, and the residual oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (90 mg) in light yellow color.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=O)[C:5]=12)=[O:8])([O-:3])=[O:2].O.[NH2:16][NH2:17]>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:9])[NH:16][NH:17][C:7]2=[O:8])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c([N+](=O)[O-])cccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A glass flask of the volume 1 l provided with an agitator, a thermometer, a condenser and a capillary was filled with 600 ml of icy acetic acid and 154.5 g (0.8 mole) of 3-nitrophthalic acid anhydride, thereafter it was heated to the temperature of 110° C. and gradually 44.1 g (0.88 mole) of hydrazine hydrate was added. Next the reaction mixture was kept at the state of boiling for 30 minutes thereafter it was cooled to the temperature of 80° C., the crystals of 5-nitro-2,3-dihydrophthalazine-1,4-dione were filtered, the sediment was washed on a filter with 50 ml of acetic acid and two times with 40 ml of distilled water. The total amount of 5-nitro-2,3-dihydrophthalazine-1,4-dione was 228.7 g, the yield was 92%.