Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccccc1Sc1ccc(C=O)c(Cl)c1Cl
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccccc1Sc1ccc(C=CC(=O)O)c(Cl)c1Cl
Yield: 75.3 %

Procedure:
A mixture of 2,3-dichloro-4-(2-methoxyphenylthio)-benzaldehyde (2.03 g), 1.44 g malonic acid, 5 mL pyridine, and 0.100 g piperidine was heated to 115 degrees for 1.5 hours. The mixture was cooled, and ice and HCl were added. The resulting solid was: filtered, washed with water and dissolved in tetrahydrofuran. This solution was dried over sodium sulfate, the solvent removed and ether added to give 1.733 g of product, m.p. 187-188 C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:13]=[CH:14][NH:15][C:16]=1[C:17]([NH:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH2:30][C:31](OCC)=[O:32])=[CH:28][C:22]=2[N:21]=1)=[O:18])=[O:11].[NH2:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40].CC(N(C)C)=O>C1COCC1>[OH:41][CH:38]([CH2:39][OH:40])[CH2:37][NH:36][C:31](=[O:32])[CH2:30][O:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:19][C:17]([C:16]3[NH:15][CH:14]=[N:13][C:12]=3[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:11])=[O:18])[NH:21][C:22]=2[CH:28]=1
Reactant: NCC(O)CO
Reactant: CCOC(=O)COc1ccc2[nH]c(NC(=O)c3[nH]cnc3C(=O)Nc3ccc(C)cc3C)nc2c1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2nc[nH]c2C(=O)Nc2nc3ccc(OCC(=O)NCC(O)CO)cc3[nH]2)c(C)c1
Temperature: 90 °C
Yield: 24.5 %

Procedure:
To a seal tube was added ethyl 2-(2-(4-(2,4-dimethylphenylcarbamoyl)-1H-imidazole-5-carboxamido)-1H-benzo[d]imidazol-5-yloxy)acetate (230 mg, 0.5 mmol), 3-aminopropane-1,2-diol (180 mg, 2 mmol), DMA (3 mL) and THF (3 mL), the mixture was heated to 90° C. overnight. The reaction was allowed to cool to room temperature, concentrated under reduced pressure and purified by preparative reverse phase HPLC (aqueous ammonium acetate—acetonitrile) to give 64 mg of N5-[6-({2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}oxy)-1H benzimidazol-2-yl]-N4-(2,4-dimethylphenyl)-1H-imidazole-4,5-dicarboxamide as the desired product. 1H-NMR (DMSO-d6) δ 8.05 (s, 1H), 7.68 (d, 2H), 7.43 (s, br 2H), 7.05 (dd, 2H), 6.93 (d, 2H), 4.31 (m, 1H), 2.65 (m, 2H), 2.29 (q, 2H), 2.14 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.95 (t, 3H). MS (EI): 474 (MH+).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)#N.[N:11]1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[C:9]([C:6]1[N:7]=[CH:8][C:3]([NH:11][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:4][CH:5]=1)#[N:10]
Reactant: N#Cc1ccc(C#N)nc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 5-cyanopyridine-2-carbonitrile (1.00 g, 8.39 mmol) and pyridine (0.821 ml, 10.1 mmol) in tetrahydrofuran (28 ml) was added 2,2,2-trichloroethyl chloroformate (1.39 ml, 10.1 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue was added hexane and a solid was collected by filtration to obtain the desired product (2.27 g, 92.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:13][C:14](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:15]>O>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:15])[CH3:13]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC(C)=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
17.0 g of 3-Hydroxy-4-methoxy-benzoic acid were added to 51.6 g of acetic ahydride and the mixture stirred at 140° C. for 3 h. The mixture was then allowed to cool to 100° C., 50 ml of water added dropwise and the temperature kept at 100° C. Then, 200 ml of water were added and the mixture was stirred at 100° C. for 30 minutes. The mixture was then cooled and stirred at 0° C. for 1 h. The product was then isolated by filtration, washed with 50 ml of water and dried under reduced pressure to yield 18.8 g of the title compound that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:23]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:21][C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)[N:23]=3)[C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2noc(CCl)n2)cc1
Reactant: O=C1NCCC1c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(c2ccc(F)cc2)CCN1Cc1nc(-c2ccc(C(F)(F)F)cc2)no1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 3-(4-fluorophenyl)pyrrolidin-2-one (0.106 g, 0.592 mmol; Example 189B) as suspension in tetrahydrofuran (0.5 mL) was added potassium t-butoxide (1.0 Min tetrahydrofuran) (0.651 mL, 0.651 mmol) dropwise at room temperature. After stirring for 15 minutes, 5-(chloromethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.171 g, 0.651 mmol) was added dropwise as a solution in tetrahydrofuran (0.5 mL). The reaction was heated to 50° C. for 1 hour. The reaction was concentrated, loaded onto silica gel SF15-12 g (Analogix®) and the product eluted using a gradient of 5% to 50% ethyl acetate/hexanes over 30 minutes (Flow rate=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=8.1, 2H), 7.76 (d, J=8.2, 2H), 7.39-7.23 (m, 2H), 7.17-6.97 (m, 2H), 4.96 (d, J=17.0, 1H), 4.84 (d, J=16.5, 1H), 3.78 (t, J=8.9, 1H), 3.74-3.59 (m, 2H), 2.77-2.57 (m, 1H), 2.25 (ddt, J=8.0, 12.9, 20.7, 1H); MS (ESI+) m/z 406.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[C:28]([CH3:39])=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[C:28]([CH3:39])=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2nc1C(=O)O
Temperature: 90 °C
Yield: 97.2 %

Procedure:
A 1 N solution of sodium hydroxide (150.5 μL, 150.5 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-methyl-2-quinolinecarboxylate (43.3 mg, 75.2 μmol) in tetrahydrofuran and methanol (1:1, 1.5 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (150.5 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 40.0 mg (97%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-methyl-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.44 (br s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 8.08-8.00 (m, 2H), 7.72 (s, 1H), 7.70 (s, 1H), 7.64 (d, J=8 Hz, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.93 (d, J=9 Hz, 2H), 4.89 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 2.57 (s, 3H), 1.34 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1196 (M+H)+Obs.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[N:26]1([CH2:31][CH2:32][CH2:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[N:26]1([CH2:31][CH2:32][CH2:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([C:23]([C:19]3[N:20]=[CH:21][N:22]=[C:17]([N:14]4[CH2:13][CH2:12][CH:11]([N:3]5[C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:16][CH2:15]4)[CH:18]=3)=[O:24])[CH2:35]2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: c1ccc2c(c1)NCC2CCCN1CCCC1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC(CCCN2CCCC2)c2ccccc21

Procedure:
140 mg (0.41 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 94.4 mg (0.41 mmol) 3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-1H-indole, 138.2 mg (0.43 mmol) TBTU and 112 μL (0.8 mmol) triethylamine in 4 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:22][O:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][O:6][CH2:5]2)[CH2:3][O:2]1.[OH2:23]>>[OH:2][CH2:3][C:4]1([CH2:1][OH:23])[CH2:22][O:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][O:6][CH2:5]1
Reactant: C1COCCOCCNCCOCC2(COCCN1)COC2
Reactant: O
Product: OCC1(CO)COCCNCCOCCOCCNCCOC1

Procedure:
The oxetane ring in these macrocycles can be opened, by addition of water as well as of alcohols. For example, acid-catalysed hydrolysis of 2,6,12,15,21-pentaoxa-9,18-diazaspiro[3.18]docosane yields 12,12-bis(hydroxymethyl)-1,4,10,14-tetraoxa-7,17-diazacyclononadecane. ##EQU16##
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20](OCC)=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-:27].[Na+].[NH2:29]O.C(O)(=O)C>CO>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([NH:29][OH:27])=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Reactant: [OH-]
Reactant: NO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NO)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.4 %

Procedure:
To a solution of ethyl 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (22 mg, 0.06 mmol) in MeOH (3 mL) was added sodium hydroxide (15 mg, 0.38 mmol) and hydroxylamine (50 wt. % in water) (82.5 mg, 1.25 mmol). The resulting mixture was stirred for 18 h at room temperature. The mixture was neutralized by acetic acid and concentrated. The title compound was purified by preparative HPLC to provide the title compound as a white powder (4 mg, 19% yield). 1H NMR (300 MHz, MeOH) δ ppm 8.53 (s, 1H) 7.63 (d, J=3.20 Hz, 1H) 7.20-7.27 (m, J=8.57, 5.37 Hz, 2H) 7.05 (t, J=8.76 Hz, 2H) 6.81 (d, J=2.83 Hz, 1H) 5.52 (s, 2H) 3.60 (t, J=6.31 Hz, 2H) 1.90-2.04 (m, 4H). LC-MS (APCI, M+H+): 344.2. HPLC: 90% purity.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH3:29].[CH2:30]1COCC1>>[C:26]([CH:25]([CH3:30])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:2]([CH3:1])[C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:13]=2)=[CH:19][CH:20]=1)(=[O:27])[NH2:29]
Reactant: CN(Cc1cccc(-c2ccc(CCC(=O)Cl)cc2)c1)C(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: N
Product: CC(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(N)=O

Procedure:
By reacting a solution of 1.7 g (4.1 mmol) of 3-(3′-{[methyl-(1-phenylmethanoyl)amino]-methyl}biphenyl-4-yl)propionyl chloride in 5 ml of THF with 10 ml of aqueous ammonia, and after purification by chromatography on a column of silica, 200 mg (32%) of N-[4′-(2-carbamoylpropyl)biphenyl-3-ylmethyl]-N-methylbenzamide, with a melting point of 47-48° C., are obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][N:9]([CH3:42])[C:10]([C:12]1[CH:13]=[C:14]([CH2:37][CH2:38]C(O)=O)[CH:15]=[CH:16][C:17]=1[NH:18][C:19]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])=[O:11].CCN=C=NCCCN(C)C.Cl.C[C:56](C)=[O:57]>CN(C)C1C=CN=CC=1>[C:1]1([O:7][C:56](=[O:57])[CH:37]([C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[C:12]([C:10](=[O:11])[N:9]([CH3:8])[CH3:42])[CH:13]=2)[CH3:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(=O)c1cc(CCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Reactant: Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(C(=O)Oc1ccccc1)c1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Dimethylaminopyridine (30 mg), phenol (23 mg), and 3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}propionic acid (100 mg) were dissolved in acetone (1 mL). After addition of WSC hydrochloride (50 mg), the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated, and purified by column chromatography on silica gel (ethyl acetate:hexane=1:1, v/v) to give the title compound (Compound 1-1) (0.088 g) as a colorless solid.
Reaction SMILES: [C:1]1([C@:7]23[NH:14][C@H:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][C@H:8]3[O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[CH2:23]([N:14]1[C@@H:11]2[CH2:12][CH2:13][C@@:7]1([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:8]([O:15][Si:16]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:9][CH2:10]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[Si](CC)(CC)O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of (1R,2R,5R)-1-phenyl-2-triethylsilyloxy-8-azabicyclo[3.2.1]octane (Description 51; 100 mg, 0.315 mmol), benzyl bromide (0.5 ml), potassium carbonate (380 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 30 minutes. The reaction mixture was treated with diethyl ether, washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (107 mg, 83%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[CH:23](/B(O)O)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH:23](/[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCC/C=C/B(O)O
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC/C=C/c1nc(CON=C(c2ccccc2)c2nnnn2C)cs1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
In a dried and purged vessel were added N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.527 mmol, 1 eq.), (1E)-hex-1-en-1-ylboronic acid (0.074 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.117 g, 1.107 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-({2-[(1E)-hex-1-en-1-yl]-1,3-thiazol-4-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.170 g, 80% yield) as a colorless gum.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]1([OH:45])[CH2:20][C@H:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][C@@H:17]2[C@H:13]1[CH2:14][N:15]([C:33](=[O:44])[C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43])[CH3:35])[CH2:16]2>CS(C)=O.O>[C:1]([CH2:21][C@@H:19]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:33](=[O:44])[C@H:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[CH3:35])[CH2:16]2)[C@@:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH3:4])([OH:45])[CH2:20]1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 45 °C
Yield: 68.5 %

Procedure:
1.0 g of potassium cyanide is added to a solution of 5.6 g of (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethylperhydroisoindol-4-ol in 50 cm3 of dimethyl sulphoxide. After stirring at 45° C. for hours, the reaction mixture is cooled to 20° C., diluted with 300 cm3 of water and then extracted twice with 50 cm3 of ethyl acetate. The organic phase is subsequently washed with 150 cm3 of water, dried. over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, diameter 4.4 cm, height 50 cm), eluting under a pressure of 0.2 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (40:60 by volume) and collecting fractions of 120 cm3. Evaporation to dryness of fractions 11 to 20 under reduced pressure (2.7 kPa) gives 2.9 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][C@@H:37]([CH3:64])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]([NH:41][NH:42][C:43](=O)[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1)=[O:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CCOC(C)=O>[Si:29]([O:36][C@@H:37]([CH3:64])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]1[O:40][C:43]([C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[N:42][N:41]=1)([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:30])[CH3:31]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To a 1 L round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (12.3 g, 47.0 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (500 mL) followed by addition of solid iodine (11.91 g, 47.0 mmol). This was allowed to stir at room temperature for a period of 10 min. then cooled to 0° C. Triethylamine (13.1 mL, 94 mmol) was then slowly added to this reaction (CAUTION: Exotherm). This mixture was allowed to stir at room temperature for an additional ten min., during which the reaction became a thick slurry. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenyl-amino) butanoyl)-4-cyanobenzohydrazide (12.35 g, 23.5 mmol) was taken up in methylene chloride (200 mL) and slowly added to the heavily stirred reaction mixture. After a period of 10 min, TLC (1:1 EtOAc:hexanes) showed product formation and no starting material. The reaction was then quenched by slow addition of 10% Na2S2O3/H2O (500 mL). The organic layer was then isolated and washed with additional 10% sodium thiosulfate/water (1×200 mL), brine (1×200 mL), then dried (Na2SO4). The solution was then filtered and concentrated under reduced pressure to reveal a brown oil/solid. This was purified via silica gel chromatography eluted with 25% EtOAc/hexanes to provide the title compound as a white solid (9.98 g, 84%): 1H NMR (400 MHz, CDCl3, δ in ppm) (AA′XX′, J=8.8 Hz, 2H), 7.79 (AA′XX′, J=8.8 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 6.44 (d, J 8.7 Hz, 1H), 5.35 (d, J=8.8 Hz, 1H), 4.82 (dd, J=2.0, 8.7 Hz, 1H), 3.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H), −0.22 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([N:64]5[CH2:65][CH2:66][N:61]([CH2:60][CH:57]6[CH2:59][CH2:58]6)[CH2:62][CH2:63]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(CC3CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-(cyclopropylmethyl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.07 (br. s., 2H) 0.47 (br. s., 2H) 1.55 (br. s., 5H) 1.68 (br. s., 2H) 1.90 (br. s., 2H) 2.21 (br. s., 1H) 2.40-2.48 (m, 3H) 3.31 (s, 4H) 3.32 (br. s., 3H) 3.88 (s, 3H) 4.03 (t, J=13.89 Hz, 2H) 4.64-4.76 (m, 1H) 6.96 (d, J=8.84 Hz, 1H) 7.04 (s, 1H) 8.00 (s, 1H) 8.15 (d, J=7.83 Hz, 1H) 8.23 (s, 1H). [M+H] calculated for C29H37F2N7O3, 570. found 570.