Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-])=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O.[OH-].[K+]>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2
Reactant: O=[N+]([O-])C=Cc1cccc2[nH]ccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(2-nitrovinyl)indole (II) (3 g, 15.9 mmol) in THF (10 ml) was added to a suspension of DIBAH (1M THF, 159 ml, 159 mmol) under an inert atmosphere and was stirred at room temperature for 30 min, then it was heated at 60° C. and stirred for 5 hours. The obtained mixture was cooled to 0° C., AcOEt, water and KOH 10% were added and the ontained product was filtered. The aqueous layer was extracted with AcOEt and the organic layer was dried and evaporated to obtain 4-[(2-amino)ethyl]indole (III).
Reaction SMILES: [Br:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][NH:16][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2OCc2ccc(Br)cc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(Br)cc2)cc1
Yield: 93 %

Procedure:
A solution of 4.2 g (7.57 mmol) of methyl 4-[({2-[2-(4-bromobenzyloxy)phenyl]ethyl}-tert-butoxycarbonylamino)methyl]benzoate from Example 4A in 15 ml of dichloromethane is stirred with 15 ml of trifluoroacetic acid at room temperature for 4 hours. The reaction solution is then neutralized with aqueous sodium bicarbonate solution, and the organic phase is separated off and dried over sodium sulfate. Filtration is followed by removal of the solvent in vacuo. 3.2 g (7.04 mmol, 92% yield) of a colorless oil are obtained which are employed in the next stage without further purification.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH2:6]([O:5][C:3]([C:2]([F:9])([F:8])[C:11]1([OH:10])[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Powdered zinc (2.82 g, 0.043 mol) was suspended in tetrahydrofuran (50.0 mL) under flow of argon gas, and the suspension was mixed with ethyl bromodifluoroacetate (7.31 g, 0.036 mol) at room temperature, followed by stirring under reflux for five minutes. The mixture was further mixed with a solution of tert-butyl 4-oxopiperidinecarboxylate in tetrahydrofuran (3.00 mol/L, 10.0 mL, 0.030 mol), followed by stirring under reflux for two hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with ethyl acetate and diluted hydrochloric acid (1.00 mol/L), followed by separation. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: chloroform=1:9) and thereby yielded tert-butyl 4-(ethoxycarbonyldifluoromethyl)-4-hydroxy-piperidinecarboxylate (7.39 g, 76%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[CH2:14]1[O:17][CH:15]1[CH3:16].C(C1C=CC=CC=1O)(C)(C)C.C1OC1CC>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH2:14][CH:15]([OH:17])[CH3:16])([CH3:12])[CH3:11]
Reactant: CC1CO1
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: CC(C)(C)c1ccccc1O
Agent: CCC1CO1
Product: CC(O)COc1c(C(C)C)cccc1C(C)C
Yield: 89.9 %

Procedure:
The synthesis was carried out in the same manner as described in Example 3a, except that 50.0 g (0.28 mol) of 2,6-diisopropylphenol and 22.0 g (0.31 mol) of propyleneoxide were used instead of 350 g (2.33 mol) of 2-tert-butylphenol and 176 g (2.45 mol) of 1,2-butyleneoxide. 59.5 g of 1-(2,6-diisopropylphenyloxy)-2-propanol (bp. 138° C./5 mm Hg) were obtained in a 90% yield.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>CN(C=O)C.N1C=CC=CC=1>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Clc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(Cl)cccc32)nc(N2CCOCC2)cc1=S

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 158 mg of 4-chloro-2,3-dihydro-1H-indole.
Reaction SMILES: Cl[CH2:2][C:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])([OH:12])[C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[NH3:21].C(O)C.C(OCC)(=O)C.Cl>C(O)C.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:3]1([O:12][CH2:2]1)[C:4]([F:11])([F:10])[C:5]([NH2:21])=[O:6]
Reactant: CCOC(=O)C(F)(F)C(O)(CCl)c1ccc(Cl)cc1Cl
Reactant: N
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)C(F)(F)C1(c2ccc(Cl)cc2Cl)CO1

Procedure:
In 17 ml of ethanol was dissolved 1.7 g of ethyl 4-chloro-3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxybutyrate. To the resulting solution was added 16.3 ml of a 3N ammonia-ethanol solution. The solution was subjected to reaction at 25°-30° C. for 24 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform) to obtain 0.88 g of 3-(2,4-dichlorophenyl)-3,4-epoxy-2,2-difluorobutanamide.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][C@H:29]([CH2:33][OH:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][C@H:29]([CH2:33][OH:34])[CH2:28]2)[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: OC[C@@H]1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 30.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.30 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:8].CO.[C:16](=O)([O-])[O-:17].[K+].[K+]>>[Cl:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:4]([CH3:13])=[N:3][C:2]=1[O:17][CH3:16]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1nc(Cl)c(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of methyl 5,6-dichloro-3-methylpyrazine-2-carboxylate (6.17 g, 27.9 mmol) in anhydrous methanol (100 ml, 2.47 mol) at 0° C. was added potassium carbonate (4.30 g, 31.1 mmol) slowly. The suspension was stirred at 0° C. for 30 minutes and warmed to ambient temperature in 1 h. The solid was filtered and the filtrate was concentrated to give crude methyl 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (6.2 g, 103% yield) which was used in next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15](I)[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1.[C-:23]#[N:24].[K+]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:23]#[N:24])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1
Reactant: [C-]#N
Reactant: O=C(N1CC(CCl)c2c1ccc1c(I)cccc21)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A mixture of 125 (148 mg, 0.34 mmol), KCN (120 mg, 1.9 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and CuI (50 mg, 0.26 mmol) in dry THF (30 mL) was heated to reflux under N2 with vigorous stirring for 30 min. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and then filtered through Celite. The filtrate was washed with water and brine, dried and concentrated under reduced pressure. Chromatography of the residue on silica gel eluting with EtOAc/petroleum ether (from 1:5 to 1:2) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carbonitrile (126) (97 mg, 85%): mp (EtOAc/petroleum ether) 158-160° C.; 1H NMR (CDCl3) δ 8.63 (d, J=9.1 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.90 (dd, J=7.2, 1.0 Hz, 1H), 7.64 (dd, J=8.2, 7.2 Hz, 1H), 4.70-4.63 (m, 1H), 4.51-4.43 (m, 1H), 4.28-4.20 (m, 1H), 3.95-3.89 (m, 1H), 3.64-3.55 (m, 1H); 13C NMR S 154.7 (q, JC-F 38.3 Hz), 141.5, 132.0, 130.7, 129.0, 127.7, 127.5, 126.7, 119.7, 117.2, 115.9 (q, JC-F 288 Hz), 111.7, 52.7, 45.4, 42.6. Anal. (C16H10ClF3N2O.⅓H2O) C, H, N.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[Na+].[I-:21].[OH-].[Na+].[O-]Cl.[Na+]>CO>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:21])[CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(6,7-Dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-phenol (500 mg, 0.002 mmol) was dissolved in methanol (10 mL) followed by addition of NaI (368 mg, 2.45 mmol) and NaOH (98 mg, 2.45 mmol). The solution was cooled to 0° C. followed by dropwise addition of NaOCl (5.25% aq, 3.8 ml) over 3 minutes. The reaction mixture was stirred at 0° C. for 1 hour followed by warming to room temperature and quenching with sodium thiosulphate (saturated. aq., 6 ml). The pH of the reaction was adjusted to ˜7 by addition of sodium dihydrogen phosphate. The solution was extracted with CH2Cl2. The organic layer was dried and concentrated. The residue was purified on silica gel (10%→60% EtOAc in hexane) to give 4-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-2-iodo-phenol.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=3)[N:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])#[N:35].C(O)(=O)C.N1CCCCC1>C(O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH:24]=[C:36]([C:34]#[N:35])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])=[CH:22][CH:23]=3)[N:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)CC#N
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Yield: 56.8 %

Procedure:
To a 25 ml three necked round bottom flask, N-tert-butyl-2-(4-formylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.022 g, 0.000047 mol) and 2-cyano-N,N-dimethylacetamide (0.021 g, 0.000187 mol) was taken in ethanol (2 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed overnight. After completion of the reaction, the ethanol was distilled out and water was added to the residue. Aqueous was extracted with ethyl acetate, organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product which was purified by triturated with n-pentane. The solid was filtered and dried under vacuum to yield 0.015 g of N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: FC(F)(F)c1cccnc1-c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromophenyl)-3-(trifluoromethyl)-pyridine (0.93 mmol) in H2SO4 (4 mL) cautiously add fuming HNO3 (2 ml). Stir the mixture 30 minutes at room temperature. Pour the mixture onto ice-water (20 mL) and collect the precipitate. Dissolve the precipitate in EtOAc and neutralize with saturated NaHCO3, dry over Na2SO4, concentrate under vacuum to obtain 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.C(O)(=O)C>CC(O)C>[CH3:19][C:18]1[NH:22][C:23]2[CH:28]=[CH:27][NH:26][C:25](=[O:29])[C:24]=2[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:15]#[N:16]
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: Nc1cc[nH]c(=O)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)c2c(cc[nH]c2=O)N1

Procedure:
300 mg (1.59 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 167.5 mg (1.59 mmol) of sodium 1-cyanoprop-1-en-2-olate, 175 mg (1.59 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 137 μl (2.39 mmol) of acetic acid in 12 ml of 2-propanol and heated under reflux under argon for 12 h. After cooling, the reaction mixture is filtered and the remaining solid is washed with diethyl ether (20 ml). 454 mg (82% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#N.C(O)=[O:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:12]
Reactant: O=CO
Reactant: N#Cc1cc(F)cc(F)c1
Product: O=Cc1cc(F)cc(F)c1
Yield: 55 %

Procedure:
A mixture of 3,5-difluorobenzonitrile (0.108 mol) and Raney alloy (15 g) was refluxed 2 hours in 90% formic acid (150 ml). The reaction was filtered hot and the filter cake was washed with water, then hexane. The filtrate was extracted three times with hexane, the combined hexane extracts were washed with water and dried over sodium sulfate. Concentration yielded 8.4 g (55%) of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:24]([CH3:26])[CH3:25])[CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: CC(C)I
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(OC(C)C)c1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-phenyl)-2-methoxy-acetamide was alkylated with 2-iodopropane/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(3-isopropoxy-phenyl)-2-methoxy-acetamide as a colorless oil. MS 339.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])[C:4]=23)[CH2:19]1
Reactant: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 122.6 %

Procedure:
tert-Butyl (R)-1-(5-chloro-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.190 g, 0.420 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95 CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (S)—N-(4-((R)-3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide hydrochloride (0.100 g, 56% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.09 (s, 1H), 7.46 9s, 1H), 4.05-3.99 (q, 1H), 3.67-3.64 (m, 1H), 3.51-3.49 (m, 1H), 3.37 (s, 3H), 3.26-3.21 (m, 3H), 2.11-2.08 (m, 1H), 1.81-1.77 (m, 1H), 1.72-1.67 (m, 1H), 1.53-1.50 (m, 1H). LCMS (APCI+) m/z 352 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:18]1(O[Si](C)(C)C)[CH2:20][CH2:19]1)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH:18]1[CH2:20][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C1CC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic acid tert-butyl ester (3.00 g, 15.13 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (3.96 g, 22.70 mmol) were dissolved in methanol (30 mL), and while stirring the solution at room temperature, acetic acid (0.87 mL, 5.13 mmol) and then sodium cyanoborohydride (1.06 g, 15.13 mmol) were added thereto. Then, the mixture was heated to reflux for 21 hours. The reaction liquor was left to cool naturally, then a saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added thereto, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [chloroform-methanol (10:1)], to obtain the title compound (3.61 g, 100%) as an oily matter.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:10]#N)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-:18].[K+].C(O)C[OH:22]>O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:22])=[O:18])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccc(-c3ccccc3)cc2)CC1
Reactant: OCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1(c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C

Procedure:
1-(Biphenyl-4-yl)cyclopropanecarbonitrile (63 g, 288 mmol), KOH (1130 mmol) and ethylene glycol (350 mL) were heated to 160° C. for 6 hours (reaction complete by LCMS). The solution was cooled to room temperature, water (1.5 L) was added and the solution acidified to precipitate the product. The product was filtered overnight on a large Buchner (product formed a gel like suspension). The resulting wet solid was extracted with CH2Cl2 (˜2 L) and water, dried and evaporated to yield ˜60 g of 1-(biphenyl-4-yl)cyclopropanecarboxylic acid that was used as such in the next step.
Reaction SMILES: C([O:5][P:6]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C@H:20]1[C@H:25]([NH:26][C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][N:22]([C:31]2[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[C:33]([NH:39][C:40]3[N:45]=[C:44]([N:46](CC)[CH2:47][C:48]4C=CC(OC)=CC=4)[C:43]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:42]4[N:41]=3)[C:32]=2[Cl:63])[CH2:21]1)=[O:18])([O:8]C(C)(C)C)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>ClCCCl>[P:6]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C@H:20]1[C@H:25]([NH:26][C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][N:22]([C:31]2[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[C:33]([NH:39][C:40]3[N:45]=[C:44]([NH:46][CH2:47][CH3:48])[C:43]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:42]4[N:41]=3)[C:32]=2[Cl:63])[CH2:21]1)=[O:18])([OH:8])([OH:7])=[O:5]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(O)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg, 0.079 mmol) in DCE (2 mL) at 0° C. was added TFA (25% in DCE) (6.10 mL, 19.79 mmol) followed by anisole (0.035 mL, 0.317 mmol) and stirred at 35° C. for overnight. After completion of the starting material (by LC-MS), reaction was concentrated and purified by reverse phase preparative HPLC and collected fractions were lyophilized to give (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-(phosphonooxy)butanoate (4 mg) as an off white solid.