Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.Cl[C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24]([OH:26])=[O:25]>CN(C)C=O>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1c(F)cccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 140 °C
Yield: 35.8 %

Procedure:
Potassium carbonate (8.9 g), 4-amino-1-benzyl-piperidine (18.5 g), cupric oxide (0.6 g) and dimethylformamide (25 ml) are added to 2-chloro-6-fluorobenzoic acid (11.3 g) and the mixture is reacted with heating at 140° C. for 6 hours. After the reaction, the solvent is concentrated and to the resulting residue are added water (200 ml) and active carbon (1 g). The mixture is refluxed for 30 minutes. After filtration, the filtrate is cooled and then adjusted to pH 8.0 with diluted hydrochloric acid. The precipitated crystal is collected by filtration and washed successively with water and methanol to give 2-(1-benzyl-4-piperidinylamino)-6-fluorobenzoic acid (7.6 g) as white powders, m.p.: 233°-236° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([CH2:39][C:40]([OH:42])=O)[CH:36]=[CH:37][CH:38]=1>>[OH:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:42])[CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:44])[F:43])[CH:34]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: CC(C)(CO)n1cc(C(=O)c2cc(NC(=O)Cc3cccc(C(F)(F)F)c3)ccn2)c2cnccc21

Procedure:
Prepared according to Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and 3-trifluoromethylphenylacetic acid at 70° C. The residue was purified over neutral alumina eluting with 50%-60% EtOAc in hexane followed by acid deprotection using 10% HCl in dioxane at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[O:11]=[C:12]1[C:20]2([CH2:24][O:23][C:22]3[CH:25]=[C:26]4[C:30](=[CH:31][C:21]2=3)[CH2:29][CH2:28][O:27]4)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:32][C:33]1[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=1)[O:36][CH2:37][C:38](Cl)=[O:39]>ClCCl>[CH3:4][NH:6][C:38](=[O:39])[CH2:37][O:36][C:35]1[CH:41]=[CH:42][CH:43]=[C:33]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:12]2=[O:11])[CH:34]=1
Reactant: O=C(Cl)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a stirred solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid (0.22 g, 0.5 mmol) in dry chloroform (5 mL) was added at ambient temperature oxalyl chloride (0.43 mL, 5.0 mmol) followed by 1 drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 2 h and evaporated to dryness in vacuo to afford crude {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The crude product was dissolved in dry dichloromethane (5 mL), and used in the next step. To a solution of methylamine hydrochloride (0.07 mg, 1.0 mmol) in dry dichloromethane (5 mL) containing triethylamine (0.35 mL, 2.5 mmol) was added at 0° C. 5.0 mL (0.50 mmol) of the stock solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane (20 mL), washed with 7% aqueous solution of citric acid (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:3) to afford N-methyl-2-{3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetamide (0.09 g, 40%) as a colorless solid: mp 175-176° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 3H), 7.09-6.98 (m, 2H), 6.90 (s, 1H), 6.87-6.76 (m, 2H), 6.55 (br s, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.09-4.96 (m, 2H), 4.88-4.79 (m, 1H), 4.75-4.69 (m, 1H), 4.60-4.51 (m, 2H), 4.47 (s, 2H), 3.11-2.92 (m, 2H), 2.92-2.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 168.4, 161.9, 161.3, 157.6, 142.0, 137.9, 132.7, 130.3, 128.7, 123.9, 123.5, 121.0, 120.1, 120.0, 118.8, 113.9, 113.6, 109.1, 93.3, 80.6, 72.4, 67.2, 57.7, 43.9, 29.0, 25.7; MS (ES+) m/z 457.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH3:3].CCCCCC.[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O.O>[CH3:12][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[NH:13][C:14](=[O:15])[N:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCN(OCc1ccccc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 60 °C
Yield: 63 %

Procedure:
A solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-(phenylmethoxy)-urea (1.62 g, 5 mmol) in 5 ml of dry dimethylformamide is added dropwise to a room temperature suspension of hexane washed sodium hydride (0.13 g, 5.5 mmol) in 3 ml of dry dimethylformamide with stirring. When gas evolution is complete, the suspension is warmed to 60° C. and 1-bromodecane (1 ml, 5 mmol) is added dropwise. The mixture is stirred for 30 minutes, cooled to room temperature, poured into water and extracted with diethyl ether. The diethyl ether extract is diluted with hexane and washed with water, dried, filtered, and evaporated to provide a colorless solid which is triturated with hexane to give 1.47 g of N'-[2,6-bis(1-methylethyl)phenyl]-N-decyl-N-(phenylmethoxy)-urea; mp 91°-93° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[CH2:15]([NH2:17])[CH3:16]>C(O)C>[CH2:15]([NH:17][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:16]
Reactant: CCN
Reactant: ClCc1ncc(-c2ccc(Cl)cc2)o1
Solvent: CCO
Product: CCNCc1ncc(-c2ccc(Cl)cc2)o1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole in 50 ml of ethanol was added 3.2 g of 70% ethylamine aqueous solution, and the resultant solution was allowed to stand at room temperature overnight. At the end of this time, the solvent and the excess ethylamine were distilled off under reduced pressure, and then 30 ml of water, 10 ml of 2N NaOH solution and 50 ml of chloroform were added. The chloroform layer was separated and the aqueous layer was extracted twice with 30 ml of chloroform. The combined chloroform layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 2.1 g of crude 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole. This was dissolved in 15 ml of ethanol, and 5 ml of ethanolic saturated hydrogen chloride solution was added. Evaporation of the solvent followed by recrystallization from ethanol afforded 2.0 g (73 percent) of 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole hydrochloride, M. P. 194°-6° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Br.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:29]=[C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)[CH:28]=[CH:27][NH:26]1
Reactant: NCCc1cc[nH]c(=O)c1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(C(=O)NCCc3cc[nH]c(=O)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100 mg, 0.4 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (96 mg, 0.44 mmol), HATU (182 mg, 0.48 mmol) and DIEA (155 mg, 1.20 mmol) in 30 mL of DCM was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (160 mg) and used without further purification. LC-MS: 369 [M+H]+, tR=1.35 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[C:31]([C:34]([F:35])([F:37])[F:36])[CH:32]=[CH:33][C:26]=2[F:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Fc1ccc(C(F)(F)F)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-fluoro-5-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 507.9.
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])(CC)C.CN(C)[CH:27]=[O:28]>O1CCCC1.C(OCC)(=O)C>[F:19][C:14]1[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:27]=[O:28]
Reactant: CCCCCCCCCCC#Cc1ccccc1F
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene in tetrahydrofuran (60 ml) at -78° C. was added slowly sec-butyllithium (1.3M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30 min, and dimethylformamide (2.8 ml) was added dropwise. The mixture was stirred for 5 min at -78° C. and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel (eluted with ethyl acetate/heptane/1:10). The appropriate fractions were collected and evaporated. The residue was chromatographed a second time over silica gel (eluted with dichloromethane) to afford 7.10 g (91%) of product.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH:9]([CH2:12][O:13][CH3:14])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([CH2:19][CH2:20][C:21](Cl)=[O:22])([O:17][CH3:18])=[O:16].[OH-].[Na+]>C1C=CC=CC=1>[C:1]1([C:7]2([C:21](=[O:22])[CH2:20][CH2:19][C:15]([O:17][CH3:18])=[O:16])[NH:11][CH2:10][CH:9]([CH2:12][O:13][CH3:14])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COCC1CNC(c2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COCC1CNC(C(=O)CCC(=O)OC)(c2ccccc2)O1

Procedure:
To 19.3 milliliters of 25 percent w/v, 2-phenyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene with 3.8 grams of 3-carbomethoxyproprionyl chloride was added 2.0 grams of 50% sodium hydroxide. After the reaction was complete the mixture was washed with water, separated, dried and the organic solvent removed in vacuo. There was obtained 6.8 grams of the title compound, nD30 1.4913. Analytical data supports the structure.
Reaction SMILES: [Cl-].[Li+].[C:3]([N:10]1[CH2:13][CH:12](I)[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(Cl)Cl>C1COCC1.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH:12]2[CH2:13][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]2)=[N:17][CH:18]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: N#Cc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C#N)cn2)C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 16.5 %

Procedure:
Zinc dust was purified by washing with HCl and dried thoroughly prior to use in this reaction. Zinc dust (325 mesh, 1.38 g, 21.2 mmol) and anhydrous lithium chloride (0.9 g, 21.2 mmol) were placed in a nitrogen-purged flask and freshly distilled THF (5.0 mL) was added, followed by 1,2-dibromoethane (0.2 mL). The reaction mixture was heated to 80° C. for 5 min and then cooled to room temperature. The process of heating and cooling was repeated for 2 times. Trimethylsilyl chloride (0.1 mL) was added to the reaction mixture and the suspension was stirred at room temperature for 20 min. A solution of N-Boc-3-iodo azetidine (2 g, 7.0 mmol) in dry THF (5 mL) was added dropwise to the activated zinc. The reaction mixture was stirred at room temperature for 2 h. In a separate dry flask were taken 6-bromonicotinonitrile (770 mg, 4.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (115 mg, 0.14 mmol) in dry THF (4 mL) and stirred for 5 min. The resulting reaction mixture was added dropwise to the organozinc compound. The reaction mixture was stirred at room temperature for 10 h, quenched with saturated ammonium chloride solution, and diluted with EtOAc. The product was extracted with EtOAc and the combined extracts were washed with H2O and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 3-(5-cyanopyridin-2-yl)azetidine-1-carboxylate (180 mg, yield 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.04-9.03 (m, 1H), 8.27-8.23 (dd, J=8.1 Hz, 2.2 Hz, 1H), 7.56-7.53 (m, 1H), 4.20-4.16 (m, 2H), 4.02-3.97 (m, 2H), 3.58-3.53 (m, 1H), 1.38 (s, 9H). MS (ESI) m/z: Calculated for C14H17N3O2: 259.13. found: 160.2 (M+H-Boc)+
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[N:22]1[C:29]([Cl:30])=[N:28][C:26](Cl)=[N:25][C:23]=1[Cl:24].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:19][C:4]1([CH3:20])[CH2:5][CH:6]([N:8]([C:26]2[N:28]=[C:29]([Cl:30])[N:22]=[C:23]([Cl:24])[N:25]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:7][C:2]([CH3:21])([CH3:1])[NH:3]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(N(c2nc(Cl)nc(Cl)n2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
29.5 g (0.1 mol) of bis(2,2,6,6-tetramethyl-4-piperidyl)amine are slowly added to a solution, cooled to -10° C., of 18.45 g (0.1 mol) of cyanuric chloride in 160 ml of xylene, maintaining the temperature at about 0° C. After the end of the addition, the mixture is stirred for 3 hours at room temperature, 4.4 g (0.11 mol) of powdered sodium hydroxide are added and stirring is continued for a further 2 hours at room temperature.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-:21].[Na+].Cl>C(OCC)(=O)C>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:2])=[O:20])[N:12]=[CH:13][C:14]=1[OH:21]
Reactant: [OH-]
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(CC1CCCC1)n1ncc(O)c(Cl)c1=O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of 3-cyclopentyl-2-(4,5-dichloro-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (Intermediate 79 step 1, 18.0 g, 56.4 mmol) in a 4N aqueous sodium hydroxide solution (140 mL) was stirred at 60° C. overnight. The reaction solution was acidified with a 6N aqueous hydrochloric acid solution to pH=2˜3. Ethyl acetate was added to the solution and was stirred for 10 min. The aqueous phase was extracted with ethyl acetate, the combined organics were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was washed with diethyl ether (50 mL) to afford 2-(5-chloro-4-hydroxy-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-propionic acid as a white solid (14.5 g, 90%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:13]=[C:14]([C@H:19]2[NH:24][C:23](=O)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1.C([Al]CC(C)C)C(C)C>C1(C)C=CC=CC=1.C1COCC1>[F:18][C:16]1[CH:15]=[C:14]([C@@H:19]2[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][NH:24]2)[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[Al]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7.0 mL (7.0 mmol) of a 1 molar diisobutyl-aluminium hydride solution in toluene were added to 0.48 g (2.0 mmol) (S)-6-(3,5-difluorophenyl)-3,3-dimethylpiperidin-2-one in 10 mL THF while cooling with ice and the mixture was stirred for 20 h at RT. Then the reaction mixture was refluxed for 8 h. A 1 M diisobutylaluminium hdyride solution in toluene was added twice more and the mixture was refluxed for 8 h and 24 h, respectively. After hydrolysis of the reaction mixture the precipitate formed was suction filtered and washed with THF. The filtrate was evaporated down and the residue was purified by flash chromatography (aluminium oxide).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2[O:33][C:32]([CH2:34][CH2:35][NH2:36])=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2[O:33][C:32]([CH2:34][CH2:35][NH:36][C:17]([C:8]3[CH:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:9]=3)=[O:19])=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=C(O)c1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(-c2ccco2)n(-c2ccccc2)n1

Procedure:
The title compound was prepared as in Example 12 starting from 5-(2-furyl)-1-phenyl-1H-pyrazole-3-carboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]-ethylamine hydrochloride. The crude product was purified twice by flash chromatography using first CH2Cl2-MeOH as a gradient eluent (100:0-99:1). Then another purification by flash chromatography was done by using heptane/EtOAc (8:2) as an eluent. 1H NMR (400 MHz, DMSO-d6): 2.96 (2H, t), 3.58 (2H, m), 6.16 (1H, d), 6.34 (1H, d), 6.51 (1H, dd), 7.01 (1H, d), 7.07 (1H, s), 7.45-7.48 (2H, m), 7.54-7.56 (4H, m), 7.61 (1H, distorted dd), 7.73 (1H, d), 7.84 (1H, d), 8.49 (1H, t, 3J=5.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCCCCN
Solvent: CCN(CC)CC
Product: CCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(hexylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-hexylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [OH-].[Na+].[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:25])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([C:19]#[CH:20])[CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:25])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)N1CC(=O)Nc2ccc(C#C[Si](C)(C)C)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(=O)N(C(C)(C)C)CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
1N Sodium hydroxide solution (3.4 mL) is added to a suspension of 4-tert-butyl-3,4-dihydro-7-[(trimethylsilyl)ethynyl]-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 3.0 mmol) in methanol. The reaction mixture is stirred at room temperature for 2 hours, concentrated in vacuo and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a light brown solid (0.66 g, mp 216°-219° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C:20]1[C:21](=[O:35])[N:22]([CH3:34])[C:23](=[O:33])[N:24]([CH2:26][CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:25]=1.C(N(CC)CC)C>C(O)CCC.O>[CH3:14][C:8]([O:7][C:6]1[CH:16]=[CH:17][CH:18]=[C:4]([CH2:3][CH2:2][NH:1][C:20]2[C:21](=[O:35])[N:22]([CH3:34])[C:23](=[O:33])[N:24]([CH2:26][CH2:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:25]=2)[CH:5]=1)([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNc2nn(CCCC(F)(F)F)c(=O)n(C)c2=O)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
Compound 56 is prepared according to synthesis method 1: 1.1 g (4.4 mmol) of derivative 13b and 1 g (3.7 mmol) of triazine 4a are placed in 10 ml of nBuOH in the presence of 1.3 ml (9.3 mmol) of triethylamine. This mixture is stirred at 120° C. for 24 h. After dry concentration of the reaction medium, the residue obtained is taken up in H2O and extracted with AcOEt. The organic phases are dried on MgSO4, then dry concentrated. The oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 90:10). 0.4 g of compound 56 is isolated in the form of an oil (yield=27%).