Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:18]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A heterogeneous mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine (31.07 g, 107.3 mmol) (from Example 1c supra) and potassium carbonate (74 g, 536.5 mmol) in acetone (535 mL) was treated with 4-ethylaniline (13.3 mL, 107.3 mmol) (Aldrich). The mixture was stirred at room temperature overnight, then diluted with water (500 mL) and extracted with ethyl acetate. The combined organic layers were successively washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture was purified by flash chromatography (20% ethyl acetate in hexanes) to give (2,4-dichloro-pyrimidin-5-yl-methyl)-(4-ethyl-phenyl)-amine as a beige solid. (Yield 21.4 g, 70%).
Reaction SMILES: [N:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@H:3]([OH:8])[CH2:2]2.[H-].[Na+].[N:11]([C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:25])=[CH2:24])[CH:18]=1)([CH3:16])[CH3:15])=[C:12]=[O:13]>C1COCC1>[N:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@H:3]([O:8][C:12](=[O:13])[NH:11][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:25])=[CH2:24])[CH:18]=1)([CH3:16])[CH3:15])[CH2:2]2
Reactant: O[C@@H]1CN2CC[C@H]1C2
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)O[C@@H]2CN3CC[C@H]2C3)c1
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
To a solution of (+/−)-(3S,4S)-1-azabicyclo[2.2.1]heptan-3-ol (294 mg, 2.6 mmol) in THF (5 mL) at room temperature was added NaH [60%, oil](107 mg, 2.67 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (344 uL, 1.73 mmol) was added dropwise. The reaction was stirred for a period of 30 min and quenched with brine. The solution was extracted with EtOAc and the organic layer was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate as a clear oil (140 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 7.26-7.20 (m, 3H), 7.11 (m, 1H), 5.18 (s, 1H), 5.19 (br s, 1H), 5.01 (s, 1H), 4.81 (br s, 1H), 2.99 (br s, 1H), 2.82 (br s, 1H), 2.70 (br s, 1H), 2.53 (br s, 2H), 2.33 (br s, 1H), 2.02 (s, 3H), 1.76 (br s, 1H) 1.61 (br s, 6H), 1.52 (br s, 1H), 1.37 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 147.1, 143.7, 141.5, 128.5, 124.1, 122.1, 112.7, 75.6, 60.6, 59.4, 55.4, 54.3, 53.9, 41.5, 29.9, 29.8, 29.4, 22.2, 21.6 ppm. Purity: >98% UPLCMS (210 nm); retention time 0.83 min; (M+1) 315
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[CH2:4][C@@H:3]1[CH2:15]O.S(Cl)(Cl)=O.O>COCCOC>[Cl:13][C:11]1[CH:12]=[C:7]([N:5]2[CH2:6][C@@H:2]3[C@@H:3]([CH2:15][NH:1]3)[CH2:4]2)[CH:8]=[N:9][C:10]=1[Cl:14]
Reactant: N[C@@H]1CN(c2cnc(Cl)c(Cl)c2)C[C@@H]1CO
Solvent: O
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(3S,4S)-[4-Amino-1-(5,6-dichloro-pyridin-3-yl)-pyrrolidin-3-yl]-methanol (10 g) was suspended in 1,2-dimethoxyethane (100 mL) and N-methylpyyrolidinone (15 mL). The mixture was heated to 50° C. and then a solution of thionyl chloride (7.9 g) in 1,2-dimethoxyethane (35 mL) was slowly added, while maintaining the temperature below 60° C. The reaction mixture was stirred at 50° C. for about 3 hours and then cooled to room temperature. After adding water (100 mL), the 1,1-dimethoxyethane was removed by distillation. Ethanol (100 mL) and water (100 mL) were added and the pH adjusted to 11–12 with 50% aqueous sodium hydroxide. The resulting mixture was heated at 60° C. for at least 12 hours and then cooled to room temperature. After filtering through a bed of Hy-Flo, the ethanol was removed by vacuum distillation. The pH was adjusted to >12 with 50% aqueous sodium hydroxide and then extracted with isopropyl acetate (2×80 mL). The combined organic extracts were concentrated, and then suspended in isopropyl acetate (˜50 mL). After heating to 80° C., the solution was cooled to room temperature while stirring rapidly. The suspension was cooled to 0° C., filtered, washed with isopropyl acetate and dried in the vacuum oven. 1H NMR (MeOH-d4, 300 MHz) 63.04 (dd, J=10.9, 4.8 Hz, 1H), 3.11 (dd, J=10.2, 6.8 Hz, 1H), 3.26 (dd, J=8.8, 4.4 Hz, 1H), 3.38 (m, 1H), 3.73 (t, J=11.2 Hz, 2H), 3.84 (t, J=8.1 Hz, 1H), 4.55 (dd, J=6.8, 4.8 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 244/246/248 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: Cc1ccc(Br)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Br)cc1C1OCCO1
Temperature: 130 °C
Reaction time: 21 h

Procedure:
To a solution of INT 30 (17.3 g, 87 mmol) in toluene (505 mL) was added ethane-1,2-diol (24.3 mL, 436 mmol) followed by p-toluenesulfonic acid monohydrate (0.83 g, 4.36 mmol). The reaction mixture was stirred at 130° C. for 21 hours. The mixture was washed with saturated aqueous NaHCO3 (2×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by Kugelrohr distillation to give INT 31.
Reaction SMILES: C(OC([C:6]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:19])=O)C.Cl.[OH-].[Na+]>C(O)C>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:7](=[O:19])[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)CCC1Cc1ccccc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
To a solution of 13.5 g (SR)-1,4-dibenzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (38.4 mmol) in 20 ml ethanol were added 47.5 ml HCl (37%) and the yellow solution was refluxed for 48 h. The reaction mixture was cooled to 0° C. and NaOH was added until pH 8 was reached. The aqueous phase was extracted three times with ethyl acetate (200 ml) and the combined organic phases were washed with water (2×100 ml) and brine (2×100 ml). The organic phase was dried over MgSO4, filtrated and the solvent was removed under reduced pressure to give 9.8 g of the product (35 mmol, 91%) as a brown oil.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:15][NH2:16]>C(O)C>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([NH:16][CH3:15])[CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: CN
Solvent: CCO
Product: CNC(C)=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To benzyl acetoacetate (29 g, 151 mmol) in ethanol (30 mL) was added methyl amine (33% in ethanol, 7.02 g, 226 mmol). The solution was stirred for 2 hours at room temperature followed by evaporation to yield a yellow oil (˜30 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8]C(C#N)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>C(O)C.ClCCl>[NH2:1][C:2]1[C:7]2=[CH:8][C:21]([C:20]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cc2c(N)ncnn2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc2c(N)ncnn2c1
Temperature: 25 °C

Procedure:
A solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (3.9 g, 24.5 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883) in ethanol (124.8 ml) was stirred with concentrated sulfuric acid (62.4 ml) at 80° C. overnight. After cooling to rt, the reaction mixture was poured onto 800 g of ice and brought to pH 6-7 with concentrated aq. sodium hydroxide solution. Ethyl acetate (500 ml) and dichloromethane (500 ml) were added to the suspension, and the resulting mixture was filtered over kieselguhr. The organic layer was separated from the aqueous layer. The solid was dissolved in hot water (1 L), and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was triturated with an isopropanol/diethylether mixture, and the solid was filtered off yielding 2.5 g (49% of th.) of the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH2:13])([CH3:4])[CH3:3].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>>[C:2]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[N:13]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, brown oil, MS: m/e=255.3 [(M+H)+], was prepared in accordance with the general method of intermediate E from [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) and 1,4-dibromobutane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:19]([OH:21])=O)[CH2:14][CH:13]1[CH2:33][O:34][CH3:35])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:47]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:46]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)CC)C>ClCCl.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:19](=[O:21])[NH:47][CH3:46])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14][CH:13]1[CH2:33][O:34][CH3:35])=[O:11])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)OC(C)(C)C)C(COC)C1
Yield: 100 %

Procedure:
To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid, 64, (2.7 g, 4.3 mmol) and PyBOP (2.9 g, 5.6 mmol) in anhydrous dichloromethane (15 mL) is added 2M methyl amine solution in THF (4.4 mL, 8.8 mmol) and triethyl amine (1.5 mL, 10.7 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (200 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×100 mL). All organic layers are combined and washed with brine (100 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford 2.6 g (100% yield) of the desired product. 1H NMR (CDCl3, δ): 7.62–7.50 (m, 3H), 7.45 (s, 1H), 7.35–7.12 (m, 3H), 7.05–6.92 (m, 2H), 6.82–6.70 (m, 2H), 5.45 (dd, J=20.5, 8.2 Hz, 0.5H), 4.75–4.45 (m, 1H), 4.05 (d, J=12.3 Hz, 0.5H), 3.5–3.20 (m, 1H), 3.20–3.08 (m, 1H), 3.08–2.98 (m, 1H), 2.92 (s, 8H), 2.84–2.64 (m, 2H), 2.55 (br s, 2H), 2.40–1.85 (m, 1H), 1.6 (s, 7H), 1.22 (d, J=6.6 Hz, 7H); 13C NMR, δ 171.6, 171.4, 171.2, 170.2, 163.5, 160.3, 154.9, 137.3,137.2, 132.6, 132.3, 132.1, 131.2, 127.6, 127.5, 126.0, 125.4, 115.4, 115.1, 114.9, 79.5, 79.3, 70.2, 69.6, 69.3, 58.9, 58.8, 53.3, 51.2, 49.8, 49.6, 48.7, 48.3, 46.3, 42.9, 39.8, 38.9, 38.6, 33.6, 28.3, 26.5, 26.4, 25.8, 25.7.
Reaction SMILES: [OH-].[Na+].[CH2:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1.C=CCCCCCCCCCCCCCCCC.C1(=O)OC(=[O:50])C=C1>[Cl-].C([N+](CCCCCCCCCCCCCCCCCC)(C)C)CCCCCCCCCCCCCCCCC.O>[CH2:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:21]([O-:26])(=[O:27])/[CH:22]=[CH:23]\[C:24]([O-:50])=[O:25]
Reactant: O=C1C=CC(=O)O1
Agent: C=CCCCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: [Cl-]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 85 °C

Procedure:
The ion pair of the distearyl dimethyl ammoniun cation and the octadecene-maleate copolymer anion was prepared as follows. 4 g (0.05 mole) of 50% NaOH was added to 100 ml of water and 29.3 g (0.05 moles) of distearyl dimethyl ammonium chloride was dispersed in the mixture. It was heated to 85° C. and 8.8 g (0.05 moles of carboxylate) of 1:1 copolymer of octadecene and maleic anhydride was added as a powder. The mixture was stirred at 85° to 90° C. for 10 hours, during which the octadecene-maleic anhydride copolymer particles disappeared. The water phase gradually cleared and gelled particles of the ion pair formed. The product was separated by decanting the water. The product weighed 57.5 g and contained 36.1% water. The remaining water was removed by spreading the gelled product in a thin layer and passing air at room temperature across it. It was ground in a Waring Blender to a fine non-tacky powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=1)[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:6]
Reactant: COc1ccc(C(CN)N2CCCCC2)cc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: COc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCCC2)cc1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3.[CH2:25]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:24][N:2]([CH3:1])[N:3]=[C:4]1[C@H:9]([CH3:25])[CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: [Li]CCCC
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NN(C)C)CC[C@@H]12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NN(C)C)[C@H](C)C[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5 g of 3-methoxy-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone in 50 ml of absolute tetrahydrofuran (THF) is combined dropwise at 0° C. with 13 ml of a 15% solution of n-butyllithium in hexane. After this addition the mixture is stirred for 60 minutes under argon at 0° C., then 1.3 ml of methyl iodide is added dropwise thereto at 0° C., and the mixture is stirred for another 30 minutes at room temperature. To work up the mixture, it is poured into saturated ammonium chloride solution and extracted with ethyl acetate. Crystallization from acetonitrile yields 5 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone, m.p. 122°-124° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:8]=2[C:9]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1

Procedure:
reaction of 2-butyl-5-nitrobenzofuran with anisoyl chloride in the presence of tin tetrachloride based on the Friedel-Crafts reaction conditions and hydrolysis to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[NH:9][C:8]=2[CH:7]=[N:6][C:5]=1[C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39](=[N:43]O)([NH2:42])[CH2:40][CH3:41]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[NH:9][C:8]=2[CH:7]=[N:6][C:5]=1[C:24]1[O:25][N:43]=[C:39]([CH2:40][CH3:41])[N:42]=1
Reactant: CCC(N)=NO
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(CN4CCOCC4)c3c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1noc(-c2ncc3[nH]c4cccc(CN5CCOCC5)c4c3c2COC)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A solution of 0.36 g of 4-methoxymethyl-5-morpholinomethyl-beta-carboline-3-carboxylic acid (prepared according to example 4) in 10 ml of absolute dimethylformamide is mixed with 0.2 g of carbonyldiimidazole and stirred for 30 minutes at 60° C. Then 0.4 g of propioamidoxime in 2 ml of DMF is added and the reaction mixture heated to 100° C. for 3 hours. After distilling off of the solvent in a vacuum, the residue is mixed with 20 ml of xylene and refluxed for 3 hours on the water separator, the reaction mixture is filtered hot, the filtrate is concentrated and chromatographed on silica gel. 0.25 g (60%) of oxadiazole derivative is obtained. Melting point 161°-163° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH3:26][S:27][CH2:28][CH2:29]Cl.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:29][CH2:28][S:27][CH3:26])(=[O:3])[CH3:2]
Reactant: CSCCCl
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reaction time: 1 h
Yield: 32 %

Procedure:
1.00 g (2.87 mmol) of Compound 27 obtained in Example 27 was dissolved in 30 ml of dimethylformamide under argon atmosphere, 1.43 ml of chloroethyl methyl sulfide and 354 mg of potassium tert-butoxide were added under ice-cooling and the mixture was stirred at 50° to 60 ° C. for 1 hour. Additional 0.29 ml of chloroethyl methyl sulfide and 322 mg of potassium tert-butoxide were added and the mixture was stirred at the same temperature for 17 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 380 mg (32%) of 2-[4-[N-acetyl-N-(2-methylthioethyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].N1C=CC=CC=1>O1CCCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cnccc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnccc1Cl)c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 3-amino-4-chloropyridine (5 g, 39 mmol), 2-nitrobenzoyl chloride (5.1 mL, 39 mmol) and pyridine (11 mL) in tetrahydrofuran (50 mL) was stirred for 20 hours. The reaction mixture was partitioned between water (200 mL) and dichloromethane (600 mL). The phases were separated and the organic phase was washed with water (150 mL) then brine (150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% ethyl acetate in dichloromethane). The N-(4-chloropyridin-3-yl)-2-nitrobenzamide was obtained as a brown solid (2.0 g). LCMS [M+H]: 279.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[CH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])C>O1CCOCC1.[OH-].[Na+].O>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([C:5](=[CH:6][C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])[C:4]([OH:22])=[O:3])[N:17]=1
Reactant: CCOC(=O)C(=Cc1c(C)cc(C)cc1C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(C=C(C(=O)O)c2csc(N)n2)c(C)c1
Yield: 72 %

Procedure:
6.1 g of the product from Example 25 were dissolved in a mixture of 150 ml of dioxane and 45 ml of 1.5 N sodium hydroxide solution. The solution was boiled under reflux overnight and the dioxane was then stripped off, the residue was diluted with 50 ml of water and the mixture was filtered. The filtrate was adjusted to pH 5 with dilute hydrochloric acid and was filtered off again after 10 minutes. Recrystallization of the residue from methanol gave the desired product in a yield of 72%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39](/[CH:42]=[CH:43]/[CH3:44])=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:33])[F:34])[N:3]=1
Reactant: C/C=C/c1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Reaction time: 12 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 2, Example 53) (200 mg, 0.26 mmol) in EtOH (10 mL) is added 10% Pd/C (200 mg), and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were filtered and the filtrate was concentrated in vacuo to provide (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.