Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:68][C@H:69]([CH2:73][CH2:74][CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)[C:70]([O-:72])=[O:71].[Na+].[BH4-].[Na+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O.CS(C)=O>[CH:75]1([CH2:74][CH2:73][C@@H:69]([NH:68][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[CH2:29][O:28][C:27]2[CH:37]=[CH:38][C:24]([C@@H:9]3[C@@H:10]([S:13][CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[OH:16])[C:11](=[O:12])[N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:25][CH:26]=2)[C:70]([OH:72])=[O:71])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: N[C@H](CCC1CCCCC1)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CS(C)=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CCC1CCCCC1)C(=O)O
Reaction time: 1 h

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.025 g, 0.046 mmol) was dissolved in DMF (2 ml) at 30° C. N-Methyl morpholine (0.034 g, 0.333 mmol) and TBTU (0.043 g, 0.133 mmol) were added. After 1 h, sodium (2R)-2-amino-4-cyclohexylbutanoate (0.039 g, 0.189 mmol), DMSO (2 ml) and tetrabutylammoniumbromide (0.004 g, 0.011 mmol) were added. The mixture was stirred for 1 h and water (1 ml) was added. After 1 h, MeOH (2 ml) and NaBH4 (0.084 g, 2.220 mmol) were added. Full conversion to the corresponding alcohol was obtained after 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml). The mixture was purified by preparative HPLC (eluent 0-50% CH3CN in 0.1M NH4OAc buffer). Freeze-drying of the pure fractions gave the title compound (0.034 g, 43%) as a colourless solid. M/z: 708.1 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.75-1.62 (m, 15H), 2.82-2.99 (m, 2H), 3.68-3.78 (m, 2H), 3.90-3.96 (m, 1H), 4.23-4.35 (m, 1H), 4.50 (s, 2H), 4.69-4.75 (m, 1H), 5.01-5.07 (m, 1H), 6.95-7.39 (m, 12H), 7.68-7.80 (m, 1H), 8.20-8.34 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([NH2:14])([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3]1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH3:31])[C:18]=1[C:19](Cl)=[O:20]>>[CH3:15][O:16][C:17]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([S:30][CH3:31])[C:18]=1[C:19]([NH:14][C:4]1([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[O:20]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: CN1CCCC(N)(C2CCOCC2)C1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(C2CCOCC2)CCCN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-1-methyl-3-(tetrahydro-pyran-4-yl)-piperidin-3-ylamine (Example A.12) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6). MS (m/e): 447.2 (MH+).
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([B:25]2[O:29]C(C)(C)[C:27](C)(C)[O:26]2)[C:16]=1C=O>C1COCC1.[Zn]>[OH:29][B:25]1[C:19]2[CH:16]=[C:15]([O:14][CH3:13])[CH:22]=[C:21]([O:23][CH3:24])[C:20]=2[CH:27]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:26]1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(OC)c(C=O)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(OC)c21
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
To a mixture of zinc powder (0.65 g, 10.0 mmol) in anhydrous THF (15 mL) was added TMSCl (0.13 mL, 1.0 mmol) at 40° C. The resulting mixture was stirred at 55° C. for 15 min and cooled to 37° C., followed by addition of ethyl 2-bromoacetate (0.45 mL, 4.0 mmol). The reaction mixture was stirred at this temperature for an additional 30 min. To the solution of 2,4-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzaldehyde (0.29 g, 1.0 mmol) in anhydrous THF (20 mL) cooled at −78° C., was added above prepared solution dropwise. The reaction mixture was allowed to stir at room temperature for 1.5 hr and quenched by aqueous ammonium chloride (20 mL). The reaction mixture was extracted with ethyl acetate (2×15 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/3) on silica gel to give the title compound as a white solid. (110 mg, Yield: 39.3%). MS (ESI) m/z=281 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[F-].[K+].Br[CH2:18]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH3:14][O:13][C:10]1[C:11]2[O:12][CH2:18][O:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: BrCBr
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Methyl 3,4-dihydroxy-5-methoxybenzoate(48 g, 240 mmol) prepared in Step 2 was dissolved in dimethylformamide(1.2 l), potassium fluoride (42 g, 720 mmol) and dibromomethane(42.0 g, 480 mmol) were added thereto, and the mixture was heated while stirring for 8 hours at 80° C. The reaction solution was cooled down to room temperature and the excess solvent was removed. The residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and then subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3, v/v) to give methyl 7-methoxybenzo [3,4-d]1,3-dioxolan-5-carboxylate(30 g, Yield 59%) as a white solid.
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.Cl.[NH2:38][OH:39].C([O-])(=O)C.[Na+]>O>[N:38](=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:39]
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCC(=O)c2ccccc2)[C@H]1c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1CN[C@H]1CCCN(CCCC(=NO)c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask were placed 445 mg (1 mmol) of (2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2methoxybenzylamino)-2-phenylpiperidine and 6 ml of ethanol. To the system were added 209 mg (3.2 mmol) of hydroxylamine hydrochloride and 417 mg (5 mmol) of sodium acetate in 6 ml of H2O, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between chloroform and water. The layers were separated, and the aqueous phase was extracted two times with chloroform. The combined organic extracts were dried (sodium sulfate) and concentrated to 368 mg of gold oil. The crude product was purified by flash column chromatography using 7% in chloroform as the eluant to obtain 174 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[CH3:22][C:23]([CH3:34])([C:28](=O)[C:29](OC)=[O:30])[C:24]([O:26][CH3:27])=[O:25]>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:28]([C:23]([CH3:34])([CH3:22])[C:24]([O:26][CH3:27])=[O:25])=[C:29]([OH:30])[N:17]=2)=[N:6]1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
6.00 g (14.562 mmol) of the compound from Example 23A were dissolved in 70 ml of ethanol, and 2.740 g (14.562 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124(14), 3680-3691; 2002) were added. The mixture was heated at reflux overnight. After cooling, the solid was filtered off with suction and washed with a little ethanol, and the filtrate was concentrated and dried under high vacuum.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:7](=[O:9])[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:10])[C@H:20]([C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Product: COC(=O)CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.4 %

Procedure:
Proceeding as in Example 1, but substituting 4-methoxy-4-oxobutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 125, methyl 4-((2S,4R)-4-benzyl-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-1-yl)-4-oxobutanoate (8.3 mg, 27.4%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.90 (s, 1H), 7.54-7.60 (m, 2H), 7.28-7.32 (m, 2H), 7.16-7.24 (m, 5H), 6.93-7.02 (m, 4H), 4.45 (m, 1H), 3.64-3.68 (m, 1H), 3.57 (s, 3H), 3.10-3.11 (m, 1H), 2.66 (m, 2H), 2.54 (m, 2H), 2.47 (m, 2H), 19.2 (m, 2H). MS (EI) for C29H29FN2O5. found 505.5 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][N:26]=1.B(O)O>>[CH3:23][O:24][C:25]1[C:30]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: COc1ncccc1-c1nc(N2CCOCC2)nc2c1CCN2c1cccnc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([O:11]CC)=O.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([OH:11])[CH2:15][CH2:14]1
Reactant: CC[Mg+]
Reactant: CCOC(=O)COC1CCCCO1
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(COC2CCCCO2)CC1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To a mixture of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (1 g, 5.3 mmol) and Ti(O-iPr)4 (1.06 mL, 3.5 mmol) in 18 mL THF was added EtMgBr (4.5 mL, 13.25 mmol, Aldrich) dropwise over 2 hrs under N2. The reaction temperature was kept between 15 to 20° C. After stirring for 2 hrs, the reaction was quenched with 15 mL of saturated NH4Cl solution and extracted with EtOAc (20 mL×5). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=5:1) to afford the title compound as colorless oil (500 mg, 55%).
Reaction SMILES: O1CCCC1.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.C([Li])CCC.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>O.CCCCCC>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:13]1[O:12][C:11]([CH:7]2[O:8][CH2:9][CH2:10][O:6]2)=[CH:15][CH:14]=1)[CH2:31][CH2:32][CH3:33]
Reactant: c1coc(C2OCCO2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Tetrahydrofuran (10 mL) solution of 2-(1,3-dioxolan-2-yl)furan (1.0 g, 7.1 mmol) was cooled to −78° C., and n-hexane solution of 1.6 mol/L n-butyllithium (4.5 mL, 7.2 mmol) was dropwise added thereto, and stirred for 3 hours. Tributyltin chloride (2.6 g, 7.9 mmol) was dropwise added to the reaction mixture, and stirred for 5 hours with heating up to room temperature. Water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (n-hexane to ethyl acetate/n-hexane=1/20) to obtain tributyl[5-(1,3-dioxolan-2-yl)furan-2-yl]tin (2.3 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.80 g, 5.73 mmol) in DCM (20 ml) was added TsCl (1.09 g, 5.73 mmol) and TEA (1.60 mL, 11.46 mmol), followed by DMAP (70 mg, 0.573 mmol). After stirring for 1 h at room temperature, the solution was concentrated, and the residue was partitioned between EtOAc and H2O, the organic layer was separated, washed with 1N HCl, 5% NaHCO3, dried and concentrated to give 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:36]([OH:39])[C:37]#[CH:38]>O.[Cu]I.[Cu](I)I>[OH:39][CH2:36][C:37]#[C:38][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(I)cc2)cc1
Agent: I[Cu]I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCO)cc2)cc1
Reaction time: 3 h

Procedure:
The product from Step 1 (214 mg, 0.43 mmol) was combined with triethylamine (35 mL), copper (I) iodide (0.4 mg), propargyl alcohol (50 mL, 0.86 mmol), bis-triphenylphosphine palladium dichloride at room temperature. The copper iodide was added last. The reaction was stirred for 3 hours then diluted with water and extracted into methylene chloride. The combined organic layers was dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 1.5% methanol-methylene chloride (gravity column) as eluant the title compound (195 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([S:19]([CH2:22][CH2:23]O)(=[O:21])=[O:20])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCO)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Temperature: 2.5 °C
Yield: 43.5 %

Procedure:
To a 0-5° C. stirred suspension of 2-[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidine-6-sulfonyl]-ethanol (41 mg, 0.1 mmol), and triethylamine (31 μL, 0.22 mmol) in dichloromethane (0.5 mL) under N2 was added dropwise methanesulfonyl chloride (9.3 μL, 0.12 mmol). Additional charges of methanesulfonyl chloride (9.3 μL, 9.3 μL) were added after 45 minutes, and 1.5 hours, the latter with additional triethylamine (50 μL). After reaction for a total of 2.5 hours, the cold solution was quenched with 5% aqueous sodium bicarbonate, then extracted with ethyl acetate (2×). The combined organic extracts were dried (MgSO4) then filtered through a pad of flash SiO2. The filtrate was concentrated to a solid that was crystallized from ethyl acetate to leave the product (17 mg, 44%), Mp 214-217° C.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([NH2:13])[C:6]=2[CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>CS(C)=O.C1(C)C=CC=CC=1>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([N:13]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:31]3)[C:6]=2[CH:5]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Yield: 61.8 %

Procedure:
Heat a suspension of 2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride salt (626 mg) and (S)-2-(2-methoxy-ethyl)-piperazine (863 mg) in DMSO (1.42 mL DMSO per mmol of amine) and toluene (5.68 mL per mmol of amine) at reflux for 48 hours. Evaporate the toluene under vaccuo and pour the resulting solution into water (5.71 mL per mmol of amine). Purify the resulting brown solid by flash chromatography (methylene chloride/methanol (95:5) to afford the title compound as a yellow solid (499 mg, 60%): mp 71-82° C.; 1HNMR (CDCl3) δ 1.75-1.60 (m, 2H), 2.64 (dd, 1H), 3.07-2.94 (m, 4H), 3.31 (s, 3H), 3.48 (ddd, 2H), 3.78 (bs, 2H), 5.09 (s, 1H), 6.69 (dd, 1H), 6.93-6.88 (m, 2H), 7.00 (dt, 1H), 7.10 (dd, 1H), 7.57-7.50 (m, 2H); MS (ESI/pos) m/z (rel intensity) 405.3 (100).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>O(CCO)C>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:32]=[C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][C:19]4[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=4)=[CH:28][CH:27]=3)[N:31]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)Nc1ccc(Cc2ccncc2)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(Cc4ccncc4)cc3)n2)s1

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1 mmol, 0.21 g) and N-(4-pyridin-4-ylmethyl-phenyl)-guanidine hydrochloride (2 mmol, 0.40 mg) in 2-methoxylethanol was treated with NaOH (40 mg). The reaction mixture was allowed to heat at reflux for 2 d. The solvent was evaporated and the residue was crystallised from EtOAc/MeOH to afford the title compound as an orange solid. 1H-NMR (300 MHz, d6-DMSO) δ3.00 (s, 3H, CH3), 3.02 (s, 3H, CH3), 4.29 (s, 2H, CH2), 7.44 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-H), 7.61 (m, 2H, Ar—H), 8.09 (m, 2H, Ph-H), 8.82 (m, 2H, Ar—H), 8.87 (d, 1H, J=5.5 Hz, pyrimidinyl-H). DE MALDI-TOF MS: {M+H}+=377.52 (C21H19N5S requires 373.48).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:29])[C@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O)([CH3:4])[CH3:3]>CCO.C(Cl)(Cl)Cl>[CH3:4][C:2]([O:5][C:6](=[O:29])[C@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH2:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Yield: 71.2 %

Procedure:
To a solution of N-[(phenylmethoxy)carbonyl]-L-tryptophan 1,1-dimethylethyl ester (36 g; 98 mmol) in EtOH (150 mL) Pd/C 10% (5 g) was added. A H2 atmosphere was set and hydrogenation was performed with the aid of a Venturi type stirrer. Reaction conversion was estimated by HPLC (Chromatographic method L/46). After 6 h at r.t. the suspension was filtered through paper, then through Millipore® HA 0.45 μm and the filtrate was concentrated under reduced pressure to give a crude oil. The crude was dissolved in CHCl3 (200 mL) and washed with 5% aq. Na2CO3 (200 mL) and brine (150 mL). The organic layer was dried over Na2SO4 and concentrated to give L-tryptophan-1,1-dimethylethyl ester (18.16 g), which was used in the following step without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C:19](=[O:25])[CH2:18]2.[OH-].[Na+]>C(OCC)C>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:19]1([OH:25])[CH:20]2[CH2:23][CH2:24][N:17]([CH2:22][CH2:21]2)[CH2:18]1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OC1(c2ccc3ccccc3c2)CN2CCC1CC2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (31 ml, 72 mmol) was added to a mixture of 2-bromonaphthalene (14.9 g, 72.1 mmol) and diethyl ether (300 ml) at −70° C. The resulting mixture was stirred at −70° C. for 30 minutes. A mixture of 3-quinuclidinone and diethyl ether (150 ml) was added at −70° C. The mixture was stirred at −70° C. for 1 hour and was then allowed to reach room temperature. Aqueous sodium hydroxide (400 ml, 1 M) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases were purified by chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. Yield 2.03 g (11%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[N:19]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: COc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: c1ccc2c(c1)CCN2
Product: COc1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 2,3-dihydroindole (1.1 equivalents). M.p. >300° C.; FAB-MS: (M+H)+ =343 (corresponds to C21H18N4O).