Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH:12]([O:14][CH3:15])[CH2:11][CH2:10][CH:9]1[CH2:16][CH:17]([OH:48])[CH:18]([NH:26][C:27](=[O:47])[CH:28]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:29][S:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH:12]([O:14][CH3:15])[CH2:11][CH2:10][CH:9]1[CH2:16][CH:17]([OH:48])[CH:18]([NH:26][C:27](=[O:47])[CH:28]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:29][S:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:57])=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1CCC(CC(O)C(Cc2ccccc2)NC(=O)C(CS(=O)c2ccc3ccccc3c2)NS(C)(=O)=O)C(C(=O)NC(C)(C)C)C1
Solvent: ClCCl
Product: COC1CCC(CC(O)C(Cc2ccccc2)NC(=O)C(CS(=O)(=O)c2ccc3ccccc3c2)NS(C)(=O)=O)C(C(=O)NC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 2-{2-hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-sulfinyl)-propionylamino]-4-phenyl-butyl}-5-methoxy-cyclohexanecarboxylic acid tert-butylamide in dichloromethane (2 ml) was treated with a solution of meta-chloroperbenzoic acid (13 mg) in dichloromethane (1 ml) and the reaction mixture stirred at room temperature for 2 hours. The solution was then washed with 5% aqueous sodium hydrogen carbonate solution, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give 2-{2-hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-sulfonyl)-propionylamino]-4-phenyl-butyl}-5-methoxy-cyclohexanecarboxylic acid tert-butylamide (23 mg, 92%) as a white foam. Mass spectrum, 717 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[SH:12][CH2:13][CH2:14][OH:15].[OH-].[K+]>>[CH3:11][C:4]1[N:3]=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: OCCS
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
To a solution of 2-fluoro-5-nitro-6-picoline (5.0 g, 32 mmol) and 2-mercaptoethanol (4.5 ml, 64 mmol), KOH (2 g, 36 mmol) was added at 0° C. The mixture was stirred at the same temperature for 15 minutes. The crude mixture was extracted with AcOEt and brine. Organic phase was dried over MgSO4, filtered, and concentrated to provide the crude 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol as an oil (7.238 g). 1HNMR (DMSO-d4, 400 MHz) δ 2.75 (s, 3H), 3.30-3.33 (m, 2H), 3.63-3.67 (m, 2H), 4.65-4.68 (m, 1H), 7.40-7.43 (m, 1H), 8.24-8.26 (m, 1H). Exact mass calculated for C8H10N2O3S 214.04 found 215.1 (MH+).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH2:5][NH:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.[Cl-].[NH4+]>CN(C=O)C.O>[CH2:1]([CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH2:5][N:4]1[CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=1)[CH3:2]
Reactant: CCC1Cc2cc(OCc3ccccc3)c(OC)cc2CN1
Reactant: COc1cccc(CBr)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC1CC2CC(OCc3ccccc3)=C(OC)C=C2CN1Cc1cccc(OC)c1
Temperature: 25 °C

Procedure:
A solution of 261 (297 mg, 1.0 mmol) in anhydrous DMF (3.0 mL), DIPEA (263 mg, 2.0 mmol) and 3-methoxybenzyl bromide (222 mg, 1.1 mmol) was heated to 80° C. for 12 h, cooled to room temperature and poured into water (50 mL) and ammonium chloride (saturated, 2 mL). The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using Flashmaster (SiO2: 20 g, hexane 100% to hexane/ethyl acetate 70:30). The title compound was obtained as pale yellow oil (323 mg, 77%). 1H NMR (270 MHz, CDCl3) δ 1.02 (3H, t, J 7.4, CH2CH3), 1.46 (1H, sept, J 7.2, one of CH2CH3), 1.73 (1H, sept, J 6.8, one of CH2CH3), 2.55 (1H, dd, J 16.2, 6.1, one of ArCH2CH), 2.82 (1H, dd, J 16.2, 5.0, one of ArCH2CH), 2.85-2.98 (1H, m, CHN), 3.61-3.77 (4H, m, 2×ArCH2N), 3.84 (6H, s, 2×OCH3), 5.16 (2H, s, OCH2Ph), 6.52 (1H, s, CH), 6.67 (1H, s, CH), 6.81-6.87 (1H, m, CH), 6.95-7.02 (2H, m, 2×CH), 7.23-7.52 (5H, m, OCH2C6H5), 7.27 (1H, t, J 6.9, CH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1(B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=2)=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2C2=CCCCC2)=NO1
Yield: 58.9 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-bromophenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (200 mg), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (114 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (26.8 mg), a 2 M aqueous cesium carbonate solution (0.366 mL), and DME (2 mL) was stirred overnight at 90 C in a nitrogen atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (118 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[N:14]=[N+]=[N-])=[CH:4][CH:3]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH2:14])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
A solution of cis-2-azidocyclopentyl 4-bromophenyl ether from the previous step (2.59 g, 9.18 mmol) in tetrahydrofuran (63 mL) and water (5.0 mL) was treated with polymer-supported triphenylphosphine (3 mmol/g, 7.15 g, 21.5 mmol). The reaction was stirred for 18 hours, then filtered through Celite®. The filter pad was rinsed with tetrahydrofuran, then with a mixture of methylene chloride and methanol, and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol. The residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in ethyl acetate) to afford product as a light brown oil. Yield: 1.43 g, 5.58 mmol, 61%. MS (APCI) m/z 257.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.47 (br s, 2H), 1.56-1.68 (m, 2H), 1.78-1.88 (m, 2H), 1.91-1.99 (m, 2H), 3.35 (ddd, J=8.6, 7.0, 4.7 Hz, 1H), 4.42 (m, 1H), 6.80 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH3:15])=[CH:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.[C:25](=O)(OC(Cl)(Cl)Cl)[O:26]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:25](=[O:26])[N:10]2[CH2:11][C@H:6]1[CH:7]=[C:8]([CH3:15])[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1C=C(C)[C@@H](C(N)=O)NC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 204.9 %

Procedure:
A solution of (2S,5R)-5-(allyloxyamino)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 85, 0.758 g, 3.59 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.507 mL, 14.35 mmol) in acetonitrile (350 mL) was cooled to below 0° C. in an ice-salt bath and added a solution of bis(trichloromethyl) carbonate (0.426 g, 1.44 mmol) in ACN (15 mL) at a rate of 0.1 mL/min. The reaction mixture was stirred at rt overnight. The solvents were evaporated at 30° C., and the crude mixture was redissolved in EtOAc. The crude organic solution was washed with sat. NaHCO3, brine, dried over MgSO4, and filtered. The organics were evaporated and the crude product was loaded onto silica gel at 30° C. and Purified via flash chromatography (80 g, 0-100% EtOAc/Hexanes), to obtain the desired product (0.700 g, 82%) as pale yellow oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8-acetyl -3-methylflavone (2.5 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.3 g of product m.p. 145-47° C., 1H-NMR (CDCl3)δ:1.77 (s, 3H); 2.20 (s, 3H); 4.73 (d, 2H, J=5.1 Hz); 5.25-5.45 (m, 2H); 5.91-6.02 (m, 1 H); 7.05 (d, 1H, J=16 Hz); 7.11 (d, 1H, J=8.9 Hz); 7.38-7.48 (m, 7H); 7.53-7.59 (m, 4H); 8.34 (d, 1H, J=8.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C(O)C.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(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(-c3ccc(N(C)C)cc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
Ethyl 5-bromo-N-(3,4dichlorobenzyl)indole-2-carboxylate (0.3 g), 4-dimethylaminobenzene boronic acid (0.13 g) and tetrakis triphenylphosphine-palladium(0) (20 mg) were dissolved in degassed toluene/ethanol/2M potassium carbonate (2:2:1) under argon and warmed at 80° C. for 16 hours. The reaction was then cooled to room temperature and partitioned between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using i-hexane-15% ethyl acetate as eluent to give the desired end product as a pale brown solid (0.25 g, 76%); NMR δ(CDCl3) 1.38 (t, 3H), 2.98 (s, 6H), 4.38 (q, 2H), 5.78 (s, 2H), 6.80-7.80 (m, 11H); M/z (+) 467 (M+), 319, 280, 239.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:27]1([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([NH:36][C:37](=O)[O:38]C3C=CC=CC=3)[CH:31]=2)[CH2:29][CH2:28]1.[H-].[Na+]>CN(C=O)C>[CH:27]1([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([NH:36][C:37]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([O:10][C:11]5[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=5)=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[O:38])[CH:31]=2)[CH2:28][CH2:29]1
Reactant: CN(Cc1cc(Oc2ccc3[nH]ccc3c2)ccn1)C(=O)OC(C)(C)C
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)n(C)n3)c2)ccn1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate (115 mg, 0.325 mmol), in DMF (5 ml) is added phenyl 5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamate (126 mg, 0.488 mmol), prepared as described in Example 5-N. The resulting mixture is placed at 0° C. and sodium hydride (60% dispersion in oil; 39.0 mg, 0.98 mmol) is added. The reaction is permitted to stir at 0° C. for 30 min at which time the reaction is quenched with saturated aqueous NH4Cl. The resulting mixture is diluted with brine and DCM. The resulting layers are separated and the aqueous layer is extracted twice with DCM. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 517.6 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][S:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][S:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 34 (62 mg, 0.14 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated in vacuo. The residue was purified by preparative HPLC to give 35 (58 mg, 76%)as a white solid. MS(ESI): 511 (M+H)+.
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][CH2:6][NH2:7].C(=O)([O-])O.[Na+].[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClC(Cl)Cl.O>[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([N:7]1[CH2:6][CH2:5]1)=[O:17]
Reactant: NCCCl
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Cl)ccc1Cl)N1CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 21 parts of sodium hydroxide in 75 parts of water is added a solution of 29 parts of 2-chloroethanamine hydrochloride in 75 parts of water. The whole is stirred and heated for 10 minutes at 90° C. After cooling to 0° C, 19 parts of sodium hydrogen carbonate are added. While stirring vigorously, there is added dropwise, during a 45 minutes-period, a solution of 49 parts of 2,5-dichlorobenzoyl chloride in 75 parts of trichloromethane at a temperature below 0° C. Upon completion, stirring is continued for 30 minutes without cooling. The reaction mixture is warmed to 25° C and adjusted to pH 8 with a diluted sodium hydroxide solution. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried filtered and evaporated, yielding 62 parts of 1-(2,5-dichlorobenzoyl)-aziridine as a residue.
Reaction SMILES: C(P([CH2:7][S:8]([O:11][CH2:12][CH3:13])(=[O:10])=[O:9])(CC)=O)C.C([Li])CCC.[CH:19]([CH:21]([N:25]([CH3:48])[C:26]([CH:28]([NH:33][C:34](=[O:47])[CH:35]([NH:45][CH3:46])[C:36]([CH3:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:37])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]([CH3:24])[CH3:23])=O>C1COCC1>[CH3:46][NH:45][C@H:35]([C:34]([NH:33][C@H:28]([C:26]([N:25]([C@@H:21]([CH:22]([CH3:24])[CH3:23])/[CH:19]=[CH:7]/[S:8]([O:11][CH2:12][CH3:13])(=[O:9])=[O:10])[CH3:48])=[O:27])[C:29]([CH3:30])([CH3:31])[CH3:32])=[O:47])[C:36]([CH3:37])([CH3:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: CCOS(=O)(=O)CP(=O)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)/C=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
To a solution of ethyl diethylphosphorylmethanesulfonate (260 mg, 1.0 mmol) in anhydrous THF (3 mL) at −78° C. is added n-butyllithium (in hexanes, 0.44 mL, 1.1 mmol). After stirring for 20 min at −78° C., a solution of N-{1-[(1-Formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide (1.0 mmol) in anhydrous THF (7 mL), which is freshly prepared as described in Reference Example 12, is added. The reaction mixture is stirred at −78° C. for additional 30 min, and then gradually warmed to room temperature. After 40 h, the reaction is quenched with water and extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated. The residue is chromatographed on a silica gel column, eluting with 4:1 CH2Cl2/EtOAc to give 160 mg (31%) of the title compound as a yellow oil. HRMS (ESI) calcd for C27H45N3O5S [M+H] 524.3153, found 524.3157.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]#[N:37])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:42])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]([NH2:37])=[O:42])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CN(C)Cc1ccc2c(C#N)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Solvent: O
Product: CN(C)Cc1ccc2c(C(N)=O)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (8 mg, 15.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (655 μg, 1.53 μmol, Eq: 0.1) were combined with Ethanol (1 mL) and Water (1 mL) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The LCMS of crude shows the desired product. The reaction mixture was diluted with acetonitrile and water and filtered and passed through HPLC purification followed by lyophalization to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (2.5 mg, 30%, [M+H]+ 543)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I-].[Na+].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: [I-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)CCCNC1CC1

Procedure:
To cyclopropylamine (50 ml) was added dropwise t-butyl 4-bromobutyrate (33.5 g) at 40° C. To the mixture was added sodium iodide (22.6 g), and the mixture was refluxed overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by distillation under reduced pressure to give t-butyl N-cyclopropyl-4-aminobutyrate (12.6 g) as colorless oil.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].CN(C)/[CH:9]=[CH:10]/[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][N:14]=1)=O.[Cl-].[NH4+]>C(O)C>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:11]2[CH:10]=[CH:9][N:3]=[C:4]([NH2:6])[N:5]=2)=[N:14]1
Reactant: CN(C)/C=C/C(=O)c1n[nH]c2ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1nccc(-c2n[nH]c3ccccc23)n1
Yield: 65.9 %

Procedure:
A total of 20 mg of metallic sodium was dissolved in 5 ml of dry ethanol. To the resulting solution were added 76 mg of guanidine hydrochloride and 85 mg of (E)-3-(dimethylamino)-1-(1H-3-indazolyl)-2-propen-1-one, followed by heating under reflux for 12 hours. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=7:5), to give 55 mg of the title compound as a colorless powder.
Reaction SMILES: C([Li])CCC.[C:6]1([OH:17])[C:15]([F:16])=[C:13]([F:14])[C:11]([F:12])=[C:9]([F:10])[C:7]=1[F:8].Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CCCCCC>[C:6]1([O:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([F:8])=[C:9]([F:10])[C:11]([F:12])=[C:13]([F:14])[C:15]=1[F:16]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(C)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 59.8 %

Procedure:
n-Butyllithium (9.75 mL, 22.39 mmol, 2.5 M in hexane) was added dropwise, at 0° C., to a 200 mL hexane solution of C6F5OH (4.08 g, 22.17 mmol). After the addition of n-butyllithium was complete, the reaction mixture was allowed to warm to room temperature. Chlorotrimethylsilane (2.65 g, 24.39 mmol) was added to the reaction at −40° C. After slowly warming to room temperature, the reaction was refluxed for 19 hours. Isolation of the crude product was achieved by ether extraction. The organic was washed with ammonium chloride, water, brine, and dried over sodium sulfate. Solvent was removed in vacuo to yield 4.0 g of crude product. The resulting liquid was purified by vacuum distillation to give 3.4 g (60%) of a colorless liquid. 1H NMR(C6D6): δ 0.081 (br. s).