Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:18]([NH:20]C(CCl)=O)=[O:19])[C@H:10]1[O:25][CH3:26])[CH3:8].[CH3:28][SH:29].[Na]>C(O)C>[C:18]([O:17][CH:11]1[CH2:12][CH2:13][C:14]([CH2:15][S:29][CH3:28])([OH:16])[CH:9]([C:6]2([CH3:8])[O:7][CH:5]2[CH2:4][CH:3]=[C:2]([CH3:27])[CH3:1])[CH:10]1[O:25][CH3:26])(=[O:19])[NH2:20]
Reactant: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Reactant: CS
Agent: [Na]
Solvent: CCO
Product: COC1C(OC(N)=O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Yield: 70 %

Procedure:
To a solution of O-chloroacetylcarbamoyl fumagillol (209 mg) in ethanol (2 ml) was added a 15% aqueous solution of methanethiol.sodium salt (500 μl), and the mixture was stirred for one hour at room temperatures. The reaction mixture was concentrated, to which was added ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: hexane-ethyl acetate=2:1) to afford 4-O-carbamoyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl) -3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (136 mg: yield 70%) as colorless powder.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[N+:13]([CH3:16])([O-:15])=[O:14].[CH3:17][OH:18]>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([C@@H:11]([CH2:17][OH:18])[OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[N+:13]([CH2:16][C@@H:2]([C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[OH:1])([O-:15])=[O:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: C[N+](=O)[O-]
Reactant: CO
Product: O=C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=[N+]([O-])C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
The heptose was prepared by the condensation of D-galactose with nitromethane in alkaline methanol. The crystalline 1-deoxy-1-nitro-D-glycero-L-manno-heptitol obtained from the aqueous solution of the deionized products (mp 158° C., 21% yield) was converted to its sodium salt. On treatment with dilute sulphuric acid (35° C.), followed by deionization with Rexyn 101(H+) and Amberlite A4(OH−) ion-exchange resins, the solution was lyophilized to give the heptose as a syrup (80% yield). The product was fractionated by cellulose column chromatography using butan-1-ol-water (1:10 v/v) as the eluant. Fractions containing the heptose were concentrated to dryness under reduced pressure. The D-glycero-L-manno-heptose having [α]D −14° (c 0.2, water) was pure by paper chromatography and its reduced (NaBH4) and acetylated product on GLC gave a single peak corresponding in retention time with that of authentic hepta-O-acetyl-D-glycero-L-manno-heptitol, establishing its purity.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.I[CH3:16]>CN(C=O)C>[Cl:3][C:4]1[N:5]([CH3:16])[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Temperature: 0 °C
Yield: 75.5 %

Procedure:
NaH (60% dispersion in mineral oil) (0.9 g, 22.5 mmole) was added portionwise over 5 min to a solution of 2-chloro-1H-indole-3-carboxaldehyde (3.8 g, 21.2 mmole) and iodomethane (1.5 mL, 24 mmole) in DMF (50 mL) with stirring at 0° C. The reaction was allowed to warm to RT and stir for 4 h, then was concentrated under vacuum. The remaining residue was taken up in EtOAc, and the solution was washed with water then brine, dried (MgSO4), and concentrated to dryness. Trituration with 1:1 Et2O/petroleum ether, filtration, and drying under vacuum gave the title compound (3.10 g, 76%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1 H), 8.29 (m, 1 H), 7.33 (m, 3 H), 3.81 (s, 3 H); MS (ES) m/e 194.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C[CH2:25][O:26]CC.C([Li])(C)(C)C.CN(C)C=O>O1CCCC1.O>[C:12]([O:11][C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:2]([CH:25]=[O:26])[CH:7]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mole) of tert.butyl (2-bromo-4-tert.butoxycarbonylaminophenyl)carbamate from step A was dissolved in 100 mL of anhydrous tetrahydrofuran under argon. Then, 17 mL (0.03 mole) of a 1.6-molar ether solution of methyllitrium was added stepwise. The reaction mixture was cooled to −20° C. and to it was added stepwise 7 mL (0.01 mole) of a 1.5-molar tert.butyllithium solution. At the end of the addition, the solution was allowed to agitate for an additional 30 min at −20° C. Then, 1.2 g (0.02 mole) of dimethylformamide was added, and the reaction mixture was allowed to agitate for one hour at −20° C. The reaction mixture was then slowly warmed up to room temperature, hydrolyzed with water and poured onto diethyl ether. The aqueous phase was then extracted with diethyl ether, and the organic phase was dried with magnesium sulfate. The solvent was distilled off in a rotary evaporator, and the residue was purified on silica gel with petroleum ether/ethyl acetate (9:1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:52]([N:71]1[CH:75]=[C:74]([C:76]2[CH:77]=[C:78]([NH2:82])[CH:79]=[CH:80][CH:81]=2)[N:73]=[CH:72]1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)CC)C>CN(C=O)C.O>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([NH:82][C:78]4[CH:79]=[CH:80][CH:81]=[C:76]([C:74]5[N:73]=[CH:72][N:71]([C:52]([C:65]6[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=6)([C:59]6[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=6)[C:53]6[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=6)[CH:75]=5)[CH:77]=4)=[O:18])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12
Reactant: Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 6-Oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 50 mg, 0.20 mmol) and PyBOP (159 mg, 0.31 mmol) in DMF (1.5 mL) is stirred for 30 min. 3-(1-Trityl-1H-imidazol-4-yl)-phenylamine (86 mg, 0.21 mmol) and triethylamine (57 μL, 0.41 mmol) are added and the reaction is stirred at room temperature for 16 h. The mixture is poured into H2O and the resulting white solid is collected by filtration and dried in vacuo to afford the title compound (86 mg, 67%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][OH:48])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][O:48][S:59]([CH3:58])(=[O:61])=[O:60])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCO)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOS(C)(=O)=O)c2)n1
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 113e (163 mg, 0.25 mmol) in DCM (3 mL) was added DIPEA (174 μL, 1.0 mmol) followed by methanesulfonyl chloride (39 μL, 0.50 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.12 min, m/z 731 [MH+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]([N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])[C:6]([N:8]1[C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7].[H][H]>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]([N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])[C:6]([N:8]1[C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=[CH:10][NH:9]1)=[O:7]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1=CC=CN(C(=O)OCc2ccccc2)N1C(=O)C(CCCBr)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1=CC=CNN1C(=O)C(CCCBr)N1C(=O)c2ccccc2C1=O
Yield: 96.2 %

Procedure:
2.37 g of 1-benzyl 3-tert.butyl 2-(5-bromo-2-phthalimidovaleryl)-1,3-pyridazinedicarboxylate (2 diastereomers) were dissolved in 25 ml of ethanol and the solution was hydrogenated at atmospheric pressure over 50 mg of 10% palladium-on-carbon until the uptake of hydrogen had ceased. The catalyst was removed by filtration and the filtrate was evaporated to give 1.79 g (96%) of tert.butyl 2-(5-bromo-2-phthalimidovaleryl)-3-pyridazinecarboxylate (2 diastereomers) in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([C:22](O)=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.O>[C:11]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C@@H:20]([C:22]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[NH2:9])=[O:23])[CH2:21]1)=[O:16])([CH3:13])([CH3:12])[CH3:10]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)N(N)c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a brown solution of (5-fluoro-pyridin-2-yl)-hydrazine (590 mg, 4.64 mmol), (R)-1-N-BOC-beta proline (Manchester Organics, 1.00 g, 4.64 mmol) and HOBt.H2O (71.1 mg, 0.464 mmol) in DCM (20 mL) at RT was added EDC (1.07 g, 5.57 mmol) (CARE: exotherm to 35° C.) and the resulting solution stirred at RT for 4 h. Water (20 mL) was added and the mixture shaken. The aqueous was extracted with DCM (20 mL), then the combined organics were passed through a hydrophobic frit and concentrated in vacuo to 1 mL volume. FCC, using 1-10% MeOH in DCM, gave the title compound as a pale brown foam (1.37 g, 91%). LCMS (Method 3): Rt 2.93 min, m/z 347 [MNa+].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]([CH2:11][C:12](O)=[O:13])[CH3:10].[ClH:15]>>[OH2:13].[ClH:15].[ClH:15].[CH3:10][NH:9][CH2:11][C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: CNCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Product: CNCc1nc2ccccc2[nH]1
Product: O
Temperature: -15 °C

Procedure:
Combine o-phenylenediamine (10.8 g, 100 mmol) and sarcosine (13.4 g, 150 mmol) in 6 N HCl (100 mL). Heat at reflux 90 hours, allow to cool, and concentrate in vacuo to 45 g. Add EtOH (50 mL) and chill at −15° C. Filter the solid and wash with cold 90% EtOH. Dissolve in 80% EtOH (150 mL) and decolorize with charcoal. Concentrate in vacuo to 28 g, warm with 95% EtOH (160 mL), allow to cool, and filter to provide colorless rods.
Reaction SMILES: Cl.Cl.[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:30][CH2:31][N:32]([CH3:37])[CH2:33][CH2:34]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Reaction time: 2 h

Procedure:
To a solution of 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.079 mmol, 0.04 g) and aqueous formaldehyde (37%, 0.39 mmol, 0.035 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.47 mmol, 0.20 g). The mixture was shaken for 2 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 4-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.04 g). LCMS: m/z 451 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.63-7.79 (1 H, m), 7.38-7.43 (2 H, m), 7.10-7.14 (2 H, m), 5.33-5.57 (1 H, m), 4.40-4.51 (1 H, m), 3.66-3.69 (1 H, m), 3.11-3.54 (3 H, m), 2.94 (3 H, s), 2.37-2.62 (2 H, m), 2.20-2.30 (1 H, m), 1.20-2.17 (22 H, m).
Reaction SMILES: CN1C2=NC=C(C[N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)C=C2OC1=O.[CH3:25][N:26]1[C:30]2=[N:31][CH:32]=[C:33]([C:35](=[O:38])[CH2:36]Br)[CH:34]=[C:29]2[O:28][C:27]1=[O:39].CN1C2=NC=C(CBr)C=C2OC1=O>>[CH3:25][N:26]1[C:30]2=[N:31][CH:32]=[C:33]([C:35](=[O:38])[CH2:36][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:34]=[C:29]2[O:28][C:27]1=[O:39]
Reactant: Cn1c(=O)oc2cc(CN3CCN(c4ccccc4)CC3)cnc21
Reactant: Cn1c(=O)oc2cc(C(=O)CBr)cnc21
Agent: Cn1c(=O)oc2cc(CBr)cnc21
Product: Cn1c(=O)oc2cc(C(=O)CN3CCN(c4ccccc4)CC3)cnc21

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 16, 3-methyl-6-(bromoacetyl)oxazolo[4,5-b]pyridin-2(3H)-one from Preparation 17 being used instead of 3-methyl-6-(bromomethyl)oxazolo[4,5-b]pyridin-2(3H)-one. The yield obtained is 84%. ##STR70##
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][Li].C(OCC)C.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]#[N:28])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].C(N1CCNCC1)C1C=CC=CC=1>O1CCCC1>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]2([NH2:28])[CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [Li]CCCC[Li]
Reactant: N#CCCN1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(CN2CCNCC2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
CeCl3 (50.0 g,/203 mmol) was dried in vacuo for 20 hours at 150° C. After cooling to room temperature, tetrahydrofuran (500 ml) was added under nitrogen and the resulting suspension was stirred for 1 d. After cooling to −78° C., to the suspension was added dropwise butanediyl dilithium in diethylether (90 mmol), which was prepared according to the literature (J. Org. Chem., 1990, 55, 5406) and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of 3-(4-benzyl-1-piperazinyl)propanenitrile (16.0 g/70.0 mmol) in tetrahydrofuran (100 ml) and stirred for 1 d at room temperature. The mixture was poured into 2 N—NaOH (200 ml) and the whole was extracted with dichloromethane (200 ml×2). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel, 230-400 mesh/dichloromethane) to give a mixture of the titled compound and 1-benzylpiperazine (5.9 g).
Reaction SMILES: [C:1]1([N:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][C@H:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]([NH:12][NH2:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40](Cl)(Cl)=[O:41].C1(C)C=CC=CC=1>C(Cl)Cl>[C:34]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C@H:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]2[O:11][C:40](=[O:41])[NH:13][N:12]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccc4)C(=O)NN)ccc3[nH]2)n1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ccccc4)c4n[nH]c(=O)o4)ccc3[nH]2)n1

Procedure:
200 mg (0.384 mmol) of N-((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide (27) were suspended in 20 ml of methylene chloride, and a 20% solution of phosgene in toluene (0.398 mmol) was added dropwise at 0° C. and while stirring. The mixture was stirred at room temperature for a further 15 h and the solvent was evaporated. The oxadiazolone 28 was then isolated by flash chromatography on silica gel (DCM:MeOH=9:1). Yield: 160 mg (76%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].CCN(CC)CC>O1CCOCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Yield: 75.3 %

Procedure:
A mixture of compound 47 (6.0 g, 20.27 mmol), 5-chloropyrazine-2-carboxylic acid methyl ester (5.3 g, 30.30 mmol), Et3N (6.2 g, 60.60 mmol) and dioxane (100 mL) is heated to reflux overnight. Solvent is removed. Saturated NH4Cl solution is added and extracted with EtOAc. The organic layer is concentrated to afford the crude product that is purified by chromatography on silica gel (EtOAc/heptane: 50%˜100%) to give the title compound (6.6 g, 76%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1Cl
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2Cl)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (100 mg, 0.269 mmol), 2-chlorophenylboronic acid (50.5 mg) and cesium carbonate (350 mg) in THF (10.5 mL) and degassed water (2.5 mL) was added tetrakis(triphenylphosphine)palladium (8.4 mg) and the reaction mixture was stirred under argon for 2 hours at 80° C. After such time water was added and the precipitate was isolated, washed with water and dried in vacuo to yield 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][OH:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Cl.C(O[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=N)C.C(N(CC)CC)C>O>[CH3:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C@H:3]2[O:4][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:1][C@@H:2]2[CH2:15][OH:16])=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CCOC(=N)c1ccccc1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1

Procedure:
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) (about 10 g, 0.04077 moles) is reacted at about 0° C. in a reaction vessel with 2,2-dichloro-ethanimidic acid ethyl ester hydrochloride (Compound IV hydrochloride wherein R2 is dichloromethyl and R4 is ethyl) (about 8.6 g, 0.0448 moles) in 1,2-dichloromethane (about 250 mL) containing triethylamine (about 4.1 g, 0.04077 moles). Next, water (about 125 mL) is added. The resulting solids are filtered, then dried to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).
Reaction SMILES: [Na].[I:2]Cl.[O:4]=[C:5]1[CH:10]([CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(=O)O[C:7](C)(C)[O:6]1.S([O-])([O-])=O.[Na+:33].[Na+]>CO.O1CCCC1.ClCCl>[CH3:5][O-:4].[Na+:33].[CH3:7][O:6][C:5](=[O:4])[CH:10]([I:2])[CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)C(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(I)CCn1cccc1C(=O)c1ccccc1
Product: C[O-]
Temperature: -30 °C
Reaction time: 0.03 h
Yield: 91.5 %

Procedure:
Sodium methoxide solution was prepared by dissolving metallic sodium (1.38 g, 60 mmol) in methanol (30 mL). This solution was diluted with anhydrous tetrahydrofuran (100 mL) and cooled to -30° C. A solution of iodine monochloride (8.97 g, 55.3 mmol) in dichloromethane (30 mL) was added dropwise to the stirred alkoxide solution. The resulting solution was stirred for 2 minutes, then the sodium salt of 1-[2-(4,6-dioxo-2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-2-benzoylpyrrole (VI, 18.15 g, 50 mmol) was added as a solid. The mixture was stirred for 90 minutes at -30° C., then allowed to warm to 22° C. and stirred for an additional 18 hours. The reaction mixture was poured into 150 mL of 2% aqueous sodium sulfite solution in a separatory funnel, and the reaction flask was washed with 10 mL of diethyl ether, which was added to the separatory funnel. The mixture was shaken thoroughly, and the phases were separated. The aqueous phase was extracted with diethyl ether (2×20 mL), and the combined organic phase was washed with brine, dried over magnesium sulfate, and evaporated to afford 4-(2-benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV, 18.16 g, 91.5%), identical to the material prepared by the method described above.