Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[F:19][C:20]([F:33])([F:32])[C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][CH:22]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:24]2[S:25][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:22][N:23]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 50 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A22) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the tide compound as a white foam (yield 50%). MS (m/e): 494.4 (M+H+, 100%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1>CS(C)=O>[F:14][C:13]([F:16])([F:15])[S:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Sodium cyanide (3.9 g, 0.08 mol) is added to 40 ml of dimethylsulfoxide at 65° C. under N2. The heat is removed and α-bromo-4-trifluoromethylthiotoluene (14.3 g real, 0.053 mol) is added dropwise at such a rate that the exotherm never raises the temperature above 75° C. The red-colored reaction is heated to 90°-95° C. for about 45 minutes, then cooled to room temperature and treated with 50-100 ml of ice water. The aqueous suspension is extracted with several portions of ether which are combined, washed with water, and dried over sodium sulfate. Evaporation in vacuo gives 9.7 g of a dark red oil 95% pure by glc.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[N:24]=[C:23]([C:25](O)=[O:26])[O:22][N:21]=1>CC#N.CO>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[O:22][N:21]=[C:20]([CH3:19])[N:24]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1noc(C(=O)O)n1
Solvent: CO
Solvent: CC#N
Product: Cc1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 5 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (219 mg, 0.84 mmol) was coupled with 3-methyl-1,2,4-oxadiazole-5-carboxylic acid using the method of Example 34(d). Crude product was suspended in MeCN and MeOH. Suspension was filtered to give 16 mg (5%) the title compound as a colourless solid. Filtrate was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water). Fractions containing the title compound were combined and suspended in MeCN. Suspension was filtered to give 9 mg (3%) the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 2.44 (s, 3H), 4.34 (d, 2H), 4.39-4.53 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 9.42 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid diethyl ester (0.520 g) in ethanol (5 mL) was treated with sodium hydroxide (2.91 mL, 1 N) and then stirred at room temperature for 8 h. The reaction mixture was diluted with water and acidified with HCl and the product was then extracted with ethyl acetate to give 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid monoethyl ester (0.461 g).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[I-:30].[Na+]>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][I:30])#[N:2]
Reactant: CC(C)C(C#N)(CCCO)c1sccc1C#N
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(C#N)(CCCI)c1sccc1C#N
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
244 mg (0.98 mmol) of 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexanol was dissolved in 10 ml of acetonitrile and 0.16 ml (1.18 mmol) of triethylamine, and 83.6 μl (108 mmol) of mesyl chloride was added thereto. After about 5 minutes, 1.47 g (9.80 mmol) of sodium iodide was added. After completion of the reaction, brine and ethyl acetate were added, and the ethyl acetate layer was washed with an aqueous sodium thiosulfate aqueous solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to silica gel (eluted at ethyl acetate:hexane=1:10), to give 334 mg (0.93 mmol, 95.1%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH3:40]O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([O:34][CH3:40])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (1.8 g) in methanol (18 ml) and conc. sulfuric acid (14.4 g) was heated for 24 hours under reflux. After removal of the solvent by evaporation, the residue was suspended with water, whose pH was adjusted to 3-4 with 1N-NaOH, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel. Recrystallization from ethanol afforded colorless prisms (1.05 g), m.p. 153°-155° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([Cl:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[Cl:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3Cl)ccc21
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1Cl

Procedure:
In analogy to the procedure described in example 76, 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 218) has been reacted with propionyl chloride to give the title compound as an off-white solid. MS: 358.4 (M+H+).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:20][C:21]1([CH3:29])[CH2:26][CH:25]([CH3:27])[CH2:24][CH:23]([OH:28])[CH2:22]1.[H-].[Na+]>O1CCOCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:28][CH:23]3[CH2:24][CH:25]([CH3:27])[CH2:26][C:21]([CH3:29])([CH3:20])[CH2:22]3)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CC1CC(O)CC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(COC2CC(C)CC(C)(C)C2)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (0.8 g, 2.9 mmol) is partly solved in dioxane (23 mL) at 80° C. 3,3,5-Trimethyl-cyclohexanol (12.3 g, 86 mmol) and sodium hydride (200 mg, 5 mmol, 60% in mineral oil) are added subsequently. The orange reaction mixture is stirred at 70° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:4) to yield 0.8 g of 2-(2H-Benzotriazol-2-yl)-6-(3,3,5-trimethyl-cyclohexyloxymethyl)-4-methyl-phenol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]([C:12]2[N:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][CH3:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:11]=1)=[O:4].[CH2:28](N)[CH2:29][CH2:30]C>>[CH2:26]([NH:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:14]=[N:13][C:12]([N:10]3[CH:11]=[C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:8]=[CH:9]3)=[CH:17][CH:16]=2)=[CH:19][CH:20]=1)=[NH:27])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN
Reactant: CNC(=N)c1ccc(-c2ccc(-n3cnc(CCC(=O)OC)c3)nn2)cc1
Product: CCCCNC(=N)c1ccc(-c2ccc(-n3cnc(CCC(=O)OC)c3)nn2)cc1

Procedure:
Prepared analogously to (97) with n-butylamine.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:8]=1)[CH2:2][CH3:3].C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[CH2:1]([C:4]1[S:5][C:6]([CH:25]=[O:26])=[C:7]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(COC2CCCCO2)cs1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1nc(COC2CCCCO2)c(C=O)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
A solution of 2-propyl-4-((2-tetrahydropyranyloxy)methyl)thiazole (12.0 g, 49.8 mmol), from step 548 above, in 120 mL of THF was cooled to -78° C. and treated with n-butyllithium (20.0 mL, 2.5M solution in hexanes). The reaction mixture was stirred at -78° C. for 30 minutes, and 5.46 g (74.7 mmol) of DMF was added. The reaction mixture was stirred at -78° C. for 1.5 hours, then warmed to room temperature and quenched with satd NH4Cl solution. The mixture was partitioned between water and ethyl acetate. The organic extract was washed with water and brine, dried over MgSO4, and concentrated to afford 13.6 g of the title product as a viscous oil, which was taken to the next step without further purification. NMR (CDCl3) δ:10.32 (s, 1H), 5.15 (d, J=12 Hz, 1H), 4.88 (d, J=12 Hz, 1H), 4.81 (t, J=3 Hz, 1H), 3.92-3.82 (m, 1H), 3.61-3.47 (m, 1H), 2.99 (t, J=7 Hz, 2H), 1.9-1.5 (m, 8H), 1.03 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9](OC)=[O:10])[C:3]1=O.[N+]([O-])(O)=O.[NH2:19][C:20]([NH2:22])=[NH:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CC(O)=O>[NH2:22][C:20]1[N:19]=[C:9]([OH:10])[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=2[N:21]=1
Reactant: COC(=O)C1CCCCC(C)(C)C1=O
Reactant: N=C(N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(C)CCCCc2c(O)nc(N)nc21
Temperature: 25 °C

Procedure:
A mixture of Example 1B (1.668 g, 8.41 mmol), guanidine nitrate (2.054 g, 16.83 mmol), and potassium carbonate (2.326 g, 16.83 mmol) was heated in DMF (17 mL) at 120° C. overnight. After this time, the mixture was cooled to room temperature and poured into water. The liquid was adjusted to pH 5 with HOAc, then the precipitate was collected by filtration, washed with water, and air-dried. It was further dried by azeotroping with toluene to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.59 (br, 1H), 6.02 (br, 2H), 2.57 (m, 2H), 1.48-1.71 (m, 6H), 1.19 (s, 6H). MS (DCI+) m/z 208 (M+H)+.
Reaction SMILES: [CH3:1]C1N=C(C)C=C(C)N=1.[Br:10][CH:11]([C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17](SC)[N:16]=1)[C:12](=[O:14])[CH3:13].CC1C=C(C)N=C(SC)N=1>>[Br:10][CH:11]([C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH3:1])[N:16]=1)[C:12](=[O:14])[CH3:13]
Reactant: CSc1nc(C)cc(C(Br)C(C)=O)n1
Reactant: Cc1cc(C)nc(C)n1
Agent: CSc1nc(C)cc(C)n1
Product: CC(=O)C(Br)c1cc(C)nc(C)n1

Procedure:
This material is prepared from 2,4,6-trimethyl-pyrimidine following the 2-step protocol used to prepare 1-bromo-1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (AC3) from 4,6-dimethyl-2-methylsulfanyl-pyrimidine (AC1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:16]1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)nc(Cl)c1
Reaction time: 4 h

Procedure:
2,6-Dichloroisonicotinic acid was (5 g, 26.04 mmol) was suspended in anhydrous toluene (75 ml). Thionyl chloride (19 ml, 260.4 mmol) was added and the mixture was heated to reflux for 4 h. The excess thionyl chloride was removed and solvent was removed in vacuo. Anhydrous MeOH (25 ml) was added and reaction was stirred for a further 4 h. Solvents were removed in vacuo to give a white colored solid which was dried under vacuum (4.8 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:25]>>[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([C:24]#[N:25])[CH2:27][CH2:28]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: N#CC1CCNCC1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Product: N#CC1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 51, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 43(a)) (0.25 g), and 4-cyanopiperidine hydrochloride (0.25 g) to afford the title compound (0.27 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH:13](OCC)=[O:14]>>[Cl:1][C:2](=[CH:13][OH:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CCOC=O
Product: O=C(C(Cl)=CO)c1ccc(Cl)cc1Cl

Procedure:
The above starting material is prepared according to the literature method of Example 1A by reacting 2-chloro-1-(2,4-dichlorophenyl)-ethan-1-one with ethyl formate, m.p. 162°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [K].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH:15][CH2:16][CH:17]1[O:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH:28]([CH3:30])[CH3:29])[CH2:18]1>C(O)(C)(C)C>[CH:28]([N:19]1[CH2:18][CH:17]([CH2:16][O:15][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[CH:6]=[CH:5][N:4]=2)[O:21][CH:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Reactant: COc1ccc2ccnc(Cl)c2c1
Agent: [K]
Solvent: CC(C)(C)O
Product: COc1ccc2ccnc(OCC3CN(C(C)C)C(c4ccccc4)O3)c2c1

Procedure:
0.3 g of potassium are dissolved in 15 cc of absolute tert.butanol, and 1.5 g of 1-chloro-7-methoxyisoquinoline and 1.7 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine are added. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness. The product is digested with water, extracted with ether, the ether phase is dried and the ether is distilled off. 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxyisoquinoline is obtained as an oil.
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][C@@:4]1([C:16]([O:18]C)=[O:17])[CH2:8][C@H:7]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:6]=[CH:5]1.[OH-].[Na+]>CO>[F:20][CH:2]([F:1])[CH2:3][C:4]1([C:16]([OH:18])=[O:17])[CH2:8][CH:7]([N:9]2[C:10]([CH3:15])=[CH:11][CH:12]=[C:13]2[CH3:14])[CH:6]=[CH:5]1
Reactant: COC(=O)[C@@]1(CC(F)F)C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1C1C=CC(CC(F)F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
A solution of methyl (1S,4S)-1-(2,2-difluoroethyl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (7.54 g, 26.6 mmol) in methanol (60 ml) was treated with 2.5 N NaOH (15 ml, 37.5 mmol) and stirred at room temperature for 22 hours. The methanol was removed under reduced pressure and the residue partitioned between diethyl ether and water. The layers were separated and the aqueous was acidified with 4 N HCl, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated under reduced pressure to give (1S,4S)-1-(2,2-difluoroethyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylic acid as a brown oil (6.59 g, 92%). 1NMR (400 MHz, CDCl3) δ ppm 6.12-6.09 (1H), 6.07-6.05 (0.25H), 5.99-5.96 (1H), 5.93-5.91 (0.5H), 5.79-5.76 (0.25H), 5.74 (2H), 5.38-5.32 (1H), 2.54-2.46 (2H), 2.43-2.25 (2H), 2.20 (6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15]2>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]1[NH:9][C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=3[C:16]=1[CH2:15]2
Reactant: Cc1cc(C)cc(NN)c1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c2c3c([nH]c2c1)-c1ccc(F)cc1C3
Temperature: 85 °C

Procedure:
To a solution of 3,5-dimethylphenylhydrazine (2.54 g, 14.7 mmol) and 5-fluoro-1-indanone (2.21 g, 14.7 mmol) in ethanol (24 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting orange solid was dissolved in isopropanol (24 mL). Sulfuric acid (36N, 1.65 mL) was added via syringe and the mixture was stirred at reflux (90° C.) for 17 hours and subsequently cooled to room temperature. The solution was basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of a precipitate. The solid was collected by vacuum filtration to yield 47b in 76% crude yield (2.80 g, 11.2 mmol). Crude product was brought on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.32-7.35 (dd, 1H, J=8.2, 5.2 Hz), 0.24-7.26 (m, 1H), 7.01-7.05 (m, 2H), 6.79 (s, 1H), 3.83 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.7 (d, J=361.5), 150.0 (d, J=12.0 Hz), 140.9, 140.6, 131.8, 131.2, 128.9, 122.6, 122.3, 121.6 (d, J=4.5 Hz), 117.2 (d, J=13.5 Hz), 113.4 (d, J=25.5 Hz), 113.1 (d, J=25.5 Hz), 109.6, 31.7 (d, J=3.0 Hz), 21.8, 19.3; 19F NMR (CD3CD, 376 MHz): δ −117.9 (m).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.C(N=C=NCCCN(C)C)C.OC1C2NN=NC=2C=CC=1>CN(C)C=O.O>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4]
Reactant: CCC(Br)C(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2nn[nH]c12
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Br)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 48.7 %

Procedure:
To a solution of 2-bromobutanoic acid (0.3 mL, 2.81 mmol) in N,N-dimethylformamide (14 mL) are added morpholine (0.3 mL, 3.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (650 mg, 3.39 mmol) and 7-hydroxybenzotriazole (456 mg, 3.38 mmol), and the mixture is stirred at room temperature for 4.5 hours. After the reaction is completed, water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with 1N-hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated, and the obtained residue is purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (323 mg, yield: 49%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:23]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CCOC(=O)c1nc(N2CCN(S(C)(=O)=O)CC2)n(C)c(=O)c1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(N2CCN(S(C)(=O)=O)CC2)n(C)c(=O)c1O

Procedure:
5-Benzyloxy-2-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.22 g, 0.49 mmol) was treated with TFA to yield the title compound as a brown oily TFA salt (0.1564 g). 1H NMR (500 MHz, CDCl3) δ: 4.45 (2H, q, J=7.1 Hz), 3.59 (3H, s), 3.42–3.39 (4H, m), 3.28–3.26 (4H, m), 2.86 (3H, s), 1.42 (3H, t, J=7.0 Hz). HRMS (M−H) calcd for C13H19N4O6S: 359.10253. found: 359.1039.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([CH2:18][OH:19])=[CH:15][CH:14]=[CH:13]2)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([CH:18]=[O:19])=[CH:15][CH:14]=[CH:13]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(CO)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(C=O)c12
Reaction time: 1 h

Procedure:
[8-(tert-Butyl-dimethyl-silanyloxymethyl)-naphthalen-1-yl]-methanol (Aust. J. Chem. 1996, 49, 793-800) (0.2 g, 0.66 mmol) was dissolved in dichloromethane (8 mL). To the solution was then added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, also known as Dess-Martin periodinane (0.56 g, 1.32 mmol). The reaction mixture was stirred for 1 hr then partitioned with an aqueous saturated solution of thiosulfate and dichloromethane. The organic layer was washed with an aqueous saturated solution of thiosulfate, an aqueous saturated solution of sodium bicarbonate, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6.0% ammonia 2.0 M in methanol/dichloromethane) to yield 8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde as a clear oil.