Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][C:20]4[N:19]5[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:18]5=[CH:17][C:16]=4[CH:15]=3)=[CH:10][C:9]=2[C:36]([F:39])([F:38])[F:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][C:20]4[N:19]5[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([OH:29])=[O:28])[C:18]5=[CH:17][C:16]=4[CH:15]=3)=[CH:10][C:9]=2[C:36]([F:39])([F:37])[F:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)ccc12
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl 2-(7-(4-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.092 mmol) in DCM (1 mL) was added thioanisole (0.738 mmol) and TFA (1.85 mmol). The reaction mixture was stirred for 3 h. The solvent was removed under vacuum. The residue was purified by preparative HPLC/MS to give the title compound as a solid (26.1 mg). LCMS m/z=486.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.04 (m, 2H), 1.08-1.20 (m, 3H), 1.54-1.70 (m, 6H), 2.15-2.26 (m, 1H), 2.55 (dd, J=16.29, 8.08 Hz, 1H), 2.62 (d, J=6.44 Hz, 2H), 2.65-2.72 (m, 1H), 2.72-2:83 (m, 1H), 3.52-3.63 (m, 1H), 3.91-4.01 (m, 1H), 4.05-4.14 (m, 1H), 5.12 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.59 Hz, 1H), 7.44 (d, J=8.08 Hz, 1H), 7.66 (d, J=7.71 Hz, 1H), 7.74 (s, 1H), 12.27 (bs, 1H).
Reaction SMILES: [CH3:1][NH:2][OH:3].[CH3:4][N:5]([CH3:20])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:17][CH2:16]C(=O)[CH:14]=[CH:13][C:12]=2[CH:19]=1)=[O:7].[CH3:21]O>>[CH3:21][O:3][N:2]=[C:1]1[CH:14]=[CH:13][C:12]2[CH:19]=[C:8]([C:6]([N:5]([CH3:20])[CH3:4])=[O:7])[CH:9]=[CH:10][C:11]=2[O:17][CH2:16]1
Reactant: CN(C)C(=O)c1ccc2c(c1)C=CC(=O)CO2
Reactant: CNO
Reactant: CO
Product: CON=C1C=Cc2cc(C(=O)N(C)C)ccc2OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
37 mg of N-methylhydroxylamine are added to 150 mg (0.65 mmol) of N,N-dimethyl-3-oxo-2,3-dihydro-1-benzoxepin-7-carboxamide, prepared according to example 53, in solution in 1 ml of methanol, and the medium is stirred at ambient temperature for 2 hours. After evaporating the methanol, followed by the conventional treatments, the crude product is purified to provide 65 mg (38%) of 3-(methoxyimino)-N,N-dimethyl-2,3-dihydro-1-benzoxepin-7-carboxamide, as an equimolecular mixture of the E and Z isomers, in the form of a yellow oil:mass (APCI) M+1:261
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][N:18]2[CH2:23][CH2:22][C@@H:21]3[C:24](=[O:27])[NH:25][CH2:26][C@@H:20]3[CH2:19]2)=[CH:6]1.Cl.[CH3:34][NH:35][OH:36]>>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:35]([OH:36])[CH3:34])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]2[CH2:23][CH2:22][C@@H:21]3[C:24](=[O:27])[NH:25][CH2:26][C@@H:20]3[CH2:19]2)=[CH:6]1
Reactant: O=C(O)c1cc2c(CN3CC[C@@H]4C(=O)NC[C@@H]4C3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CNO
Agent: Cl
Product: CN(O)C(=O)c1cc2c(CN3CC[C@@H]4C(=O)NC[C@@H]4C3)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared from rac-1-(2,4-difluorobenzyl)-3-{[(3aR*,7aS*)-1-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methylhydroxylamine hydrochloride in a manner similar to step 2 of example 17. 1H NMR (MeOH-d4) δ ppm 8.80 (s, 1H), 8.28 (b, 1H), 7.72 (s, 1H), 7.32-7.31 (m, 1H), 7.05-7.02 (m, 1H), 7.00-6.93 (m, 1H), 5.59 (s, 2H), 3.88 (s, 2H), 3.42 (s, 3H), 3.28-3.26 (m, 2H), 2.98-2.96 (m, 1H), 2.83-2.80 (m, 1H), 2.58-2.56 (m, 1H), 2.48-2.44 (m, 2H), 2.27-2.25 (m, 1H), 1.85-1.82 (m, 1H), 1.63-1.59 (m, 1H). LCMS (APCI, M+H+): 470.15. HPLC: 96% purity.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[I:12].[CH2:13](OCC)C>C(O)C>[IH:12].[C:1]1([NH:7][C:8]([S:9][CH3:13])=[NH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: CI
Reactant: NC(=S)Nc1ccccc1
Solvent: CCO
Product: CSC(=N)Nc1ccccc1
Product: I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred, chilled (+3° C.) suspension of phenyl-thiourea (15.66 g, 0.1029 mol) in absolute ethanol under nitrogen atmosphere was added in one portion methyl iodide (6.4 mL, 0.10 mol), and the mixture was stirred for 1.5 hours. The suspension was allowed to warm to room temperature over 1.5 hours and was stirred. All of the solids dissolved within 5 hours at room temperature to give a yellow solution. After 6 hours a thick off-white precipitate formed. After 40 hours diethyl ether (400 mL) was added dropwise. The solids were filtered off, washed with diethyl ether, and dried in vacuo (25° C.), yield 28.26 g (97%), mp=142°-144° C.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C1(C)C=CC=CC=1.[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][C:16]([O:15][S:2](=[O:3])(=[O:4])[NH2:5])=[CH:17][CH:18]=1)=[O:21]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OS(N)(=O)=O)cc1

Procedure:
Chlorosulfonylisocyanate (8.8 ml, 0.1 mole) was added to 200 ml toluene. Solid methyl 4-hydroxybenzoate (15.2 g, 0.1 mole) was added to the stirred solution. The mixture was heated at reflux for 1.5 hr then cooled and treated with about 8 ml water and some tetrahydrofuran. Solvents were then removed by evaporation. The residue was triturated with ethyl acetate-isopropyl ether. The insoluble solid was removed by filtration. The filtrate was concentrated and then triturated in isopropyl ether. The solid was collected and weighed 8.6 g. Recrystallization from acetone-isopropyl ether gave a white solid which was dried under vacuum overnight at room temperature to 3.9 g, mp 116°-118° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:14][CH:13]([CH3:15])[CH2:12][C@@H:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(N[C@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@@H](Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A round bottom flask was charged with (R)-methyl-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (41.5 g, 93.8 mmol), methanol (200 mL) and tetrahydrofuran (200 mL). 1.0N NaOH (188 mL) was then added and the resulting solution was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the organic solvents removed under reduced pressure. Water (300 mL) was added and the mixture was acidified with 10% citric acid to pH=3. A white precipitate formed and the heterogeneous mixture was stirred for 30 minutes at 0° C. The mixture was then filtered and the solid was dried under reduced pressure to afford (R)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (36.2 g, 90.0%). 1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J=6.46 Hz, 3H) 1.03 (d, J=6.46 Hz, 3H) 1.66-1.78 (m, 1H) 1.78-1.89 (m, 1H) 1.96-2.05 (m, 1H) 4.49-4.63 (m, 1H) 6.44 (d, J=9.00 Hz, 1H) 7.44-7.50 (m, 2H) 7.53-7.58 (m, 2H) 7.63-7.70 (m, 4H) 8.17 (d, J=9.19 Hz, 1H) 8.69-8.74 (m, 1H) 9.44 (br. s., 1H). MS (M+1): 429.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C1(C[C:13](=O)[C:14]([O-:16])=[O:15])C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: NCC(=O)O
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 120 h
Yield: 30 %

Procedure:
Additionally, the strains were inoculated into 100 ml of a similar medium containing glycine instead of the aspartic acid. The cultures were inoculated at 30° C. on a shaking machine for 5 days. Samples were taken after 3 and 5 days. 7 strains from the cultures tested converted phenylpyruvate into phenylalanine in a yield of 30% to 60%, and these were therefore suitable for further adaptation.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:32](Cl)=[O:33]>>[F:28][C:29]1[CH:30]=[C:31]([C:32]([N:8]2[CH2:13][CH2:12][C@H:11]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C@H:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9]2)=[O:33])[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CN1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Product: CN1CCN([C@H]2CCN(C(=O)c3cc(F)cc(F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=400.5 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-phenyl-piperidin-4-one, N-methyl-piperazine and 3,5-difluoro-benzoyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C1([Li])C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21]>O1CCCC1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:20]([C:19]2[CH:30]=[CH:31][CH:32]=[C:17]([O:16][CH3:15])[CH:18]=2)([OH:21])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccncc1
Reactant: COc1cccc(C(=O)c2cccc(OC)c2)c1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C(O)(Cc2ccncc2)c2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred solution of 4-picoline (32,5 g) in tetrahydrofuran (140 ml), was added dropwise under argon a solution of phenyl lithium in 7:3 cyclohexane-ether (1.9M; 184 ml) at such a rate that the reaction temperature could be maintained at 10°-20° by means of an external cooling bath. After the addition was completed, the reaction was cooled to -5°, and then a solution of 3,3'-dimethoxybenzophenone (77.4 g) in dry tetrahydrofuran (140 ml) was added so that the reaction temperature did not exceed 0°. The cooling bath was removed and the mixture was stirred at room temperature for two hours, whereupon water (140 ml) was added slowly followed by tetrahydrofuran (140 ml). The layers were separated, and after sodium chloride (~30 g) was added to the aqueous phase, it was reextracted with tetrahydrofuran (2×100 ml). The combined organic layers were washed with brine (50 ml), then were dried (over sodium sulfate) and evaporated. The crude product was triturated with hot hexane (2×300 ml) and the resulting solid was filtered to give 93.5 g of alpha,alpha-bis(3-methoxyphenyl)-4-pyridineethanol, mp 134°-135°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].CN(C)C(=O)C.COC(OC)(N(C)C)C.[NH2:27][NH2:28]>C(O)C.O1CCCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[NH:28][N:27]=[C:9]([CH3:10])[CH:8]=1
Reactant: Cn1ccnc1
Reactant: NN
Reactant: [Li]CCCC
Agent: COC(C)(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nccn2C)[nH]n1
Reaction time: 3 h
Yield: 83 %

Procedure:
A 100 ml two-necked reaction flask is dried under vacuum and baked by fire and then cooled by nitrogen gas flow. 50 ml of anhydrous tetrahydrofuran and 1-Methylimidazole (10 mmol, 0.8 ml) are added. n-Butyl lithium agent (12 mmol, 4.8 ml) is slowly added at −78° C. After the reaction has been taken place for 15 minutes, N,N-Dimethylacetamide (12 mmole, 1.12 ml) is added into the flask to react at the room temperature. Extraction with ether and water is carried out and the organic layer is concentrated to obtain a liquid product. The yield is 83%. The obtained product is then reacted with N,N-Dimethylacetamide dimethyl acetal (12.45 mmol, 1.82 ml) without any solvent at 100° C. for 10 hrs. Extraction with methylene chloride and water is carried out and the organic layer is concentrated to obtain solids. The yield is 90%. The obtained product is dissolved in ethanol and then added with hydrazine (28.01 mmol, 1.36 ml). The reaction is carried out for 3 hrs at 90° C. The reaction solution is concentrated and extracted by methylene chloride and water. The organic layer is concentrated and separated by n-hexane and ethyl acetate through chromatographic column. The product mimp is thus obtained and the yield is 75%. 1H NMR (400 MHz, CD2Cl2): δ 7.04 (s, 1 H), 6.94 (s, 1 H), 6.74 (s, 1 H), 3.91 (s, 3 H), 2.34 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17]C)[CH:8]=2)[C:3]1=[O:21].Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([OH:17])[CH:8]=2)[C:3]1=[O:21]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 180 °C

Procedure:
A stirred mixture of 2,2-dimethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (6.5 g., 0.02 mole) and pyridine hydrochloride (60 g.) is heated at 180° C. for two hours, then poured into water (800 ml.). The 2,2-dimethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone which separate (5.10 g.) melts at 259°-262° C. after recrystallization from ethanol:water, 2:1.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Yield: 83.4 %

Procedure:
Diethyl[(4-nitrophenyl)(difluoro)methyl]phosphonate (Compound 188B, 267 mg) was hydrogenated in the presence of 10% Pd/C (30 mg) in MeOH (10 mL) under 1 atmosphere for 4 h. The catalyst was filtered off, the filtrate was concentrated, and the residue was purified by silica gel chromatography (2% MeOH in DCM) to afford 201 mg of the desired product (yield: 83%). 1H NMR (CDCl3, 400 MHz): δ=1.35 (t, J=7.6 Hz, 6H), 4.08 (s, br, 2), 4.31 (q, J=7.6 Hz, 4H), 6.64 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=O)[CH3:13])=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1.C(O)C>[OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=[N:16][OH:17])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)c2c1OCCO2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(O)c2c1OCCO2
Yield: 57.4 %

Procedure:
A solution of 19.4 g (0.1 mole) of 5-hydroxyl 8-acetyl-1,4-benzodioxane (VIIi) and 10.4 g (0.15 mole) of hydroxylamine hydrochloride in 50 ml of pyridine and 50 ml of ethanol was brought to reflux for 7 hours. Then, the solvents were evaporated and the residue crystallized in water. 12 g of product were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@@H:19]2[O:23][C@H:22]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C@@H:21]([OH:29])[C@H:20]2[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:11]=1.[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>N1C=CC=CC=1.C(#N)C.C(OCC)(=O)C>[C:40]1([CH:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][NH:31][C:12]2[N:11]=[C:10]([CH2:9][NH:8][S:4]([CH2:3][CH2:2][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)(=[O:6])=[O:5])[N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[C@@H:19]2[O:23][C@H:22]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C@@H:21]([OH:29])[C@H:20]2[OH:30])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C1CCNCC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.6 %

Procedure:
2-Chloroethanesulfonyl chloride (0.12 ml, 1.16 mmol) was added to a solution of (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 27) (600 mg, 1.16 mmol) in a mixture of pyridine (2.5 ml ) and acetonitrile (10 ml). The reaction mixture was stirred for 1 hour at room temperature. Piperidine (1.0 ml, 10 mmol) was then added and the reaction mixture was heated under reflux for 16 hours. The reaction mixture was then diluted with ethyl acetate (50 ml) and washed with water (30 ml). The ethyl acetate layer was dried (anhydrous magnesium sulphate) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) increasing in polarity to dichloromethane:methanol:ammonia (90:10:1 by volume). The solvent was removed under reduced pressure and the residue repurified by column chromatography on silica gel eluting with ethyl acetate:methanol:ammonia (95:5:0.5 by volume) increasing in polarity to ethyl acetate:methanol:ammonia (90:10:1 by volume). The solvent was removed under reduced pressure and the residue was repurified by column chromatography on silica gel eluting with ethyl acetate:methanol (95:5 by volume) increasing in polarity to ethyl acetate:methanol (90:10 by volume) then ethyl acetate:methanol:ammonia (90:10:1 by volume). The solvent was removed under reduced pressure to give the title compound (21 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[C:14]2[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(F)(F)F)sc1N
Product: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-5-trifluoromethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.[NH2:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[C:15]([Cl:26])[N:14]=1.S([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C)C.C(OC(C)C)(C)C.O>[NH2:12][C:13]1[N+:18]([O-:5])=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[C:15]([Cl:26])[N:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCNc1cc(Cl)nc(N)n1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: O
Product: CCCCCCNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
5.95 g of urea/H2O2 complex and 9.07 g of phthalic anhydride were suspended in 90 ml of isopropanol, in a three-necked flask. The mixture was stirred for 30 min at room temperature (20-25° C.). 10 g of 2-amino-4-hexylamino-6-chloropyrimidine were then added while controlling the exotherm at +30° C. After reaction for 3 hours, 100 ml of sodium hydrogen sulfite were poured thereinin to destroy the residual oxidizing agents. The mixture was permitted to separate out by settling and the upper phase was concentrated under vacuum. The residue obtained was taken up in a water (80 ml)/30% sodium hydroxide (20 ml) mixture. The solid obtained was reimpasted in 150 ml of isopropyl ether. The solid was filtered off and washed. It was dried in a heated desiccator. 4.52 g of the expected compound were thus obtained, for a yield of 42%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27](Br)[CH:26]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[CH:32]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a flamed dried round bottom flask charged with 8-phenyloctylamine (688 mg, 3.35 mmol, 6.68 μL) in 5 mL THF at −78° C. was added n-BuLi (2.2 mL, 4.4 mmol) as a solution in hexanes. The solution was stirred at −78° C. for 30 min then stirred at room temperature for 15 min. The solution was cooled back down to −40° C. and a cooled (−40° C.) solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 10 mL THF via cannula. After the addition was completed, the reaction was warmed up to room temperature, stirred for 10 min, then worked up as in Step 2 of Example 135. The crude yellow oil that was obtained was dissolved in 1:1 EtOAc/Hexanes and filtered through a pad of silica gel with the same solvent system to yield 200 mg, 43% of the amide as a yellow oil. 1H NMR (CDCl3) δ 1.25–1.40 (m, 2H); 1.54–1.65 (m, 2H); 1.80 (bs, 1H); 2.57 (t, J=8.18 Hz, 2H); 3.41 (q, J=6.54 Hz, 2H); 3.90 (t, J=6.13, 2H); 4.12 (t, J=6.13 Hz, 2H); 6.07 (m, 1H); 6.99 (d, J=8.13 Hz, 1H); 7.08–7.18 (m, 3H); 7.20–7.27 (m, 2H); 7.33–7.40 (m, 1H); 7.56 (dd, J=6.54 Hz, 3.27 Hz, 1H); 7.65–7.69 (m, 1H); 7.73 (dd, J=8.13 Hz, 2.58 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:23])[CH2:21][CH3:22])=[C:13]3[NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]3)=[N:29][CH:30]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[ClH:1].[ClH:1].[ClH:1].[NH2:37][C@H:33]1[CH2:34][CH2:35][CH2:36][N:31]([C:28]2[N:29]=[CH:30][C:25]([NH:24][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=5)[N:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:23])[CH2:21][CH3:22])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](N)C2)nc1
Product: Cl
Yield: 247.4 %

Procedure:
Following general procedure IV-2, (S)-tert-butyl (1-(5-((6-(3,5-dichloro-4-hydroxyphenyl)-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (0.195 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (78 mg, 62% over two steps) as an orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.32 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 7.76 (dd, J=9.0, 2.5 Hz, 1H), 7.61 (s, 2H), 7.11 (d, J=9.0 Hz, 1H), 4.41-4.38 (m, 1H), 3.97-3.95 (m, 1H), 3.48-3.16 (m, 5H), 2.24-2.15 (m, 1H), 2.03-1.91 (m, 1H), 1.82-1.74 (m, 2H), 1.32-1.19 (m, 3H); ESI MS m/z 537 [M+H]+; HPLC>99% (AUC), tR=9.92 min.