Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:26][NH2:27]>C(O)CC>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:5]3[CH:4]=[C:3]4[O:2][CH2:1][O:9][C:8]4=[CH:7][C:6]=3[CH2:10][C:11](=[O:12])[NH:27][N:26]=2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(OC)cc1)OCO2
Solvent: O
Solvent: CCCO
Product: COc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(4-methoxybenzoyl)phenylacetate (102 mg, 0.31 mmol) and hydrazine hydrate (30 μL, 0.53 mmol) in 1-propanol (8 mL), mp: 194°-196° C. 1H NMR (CDCl3) 8.48 (s, 1H), 7.55 (d, 2H, J=8.8), 6.94 (d, 2H, J=8.8), 6.83 (s, 1H), 6.66 (s, 1H), 6.03 (s, 2H), 3.86 (s, 3H), 3.44 (s, 2H). Anal. calcd. for C17H14N2O4 : C, 65.80; H, 4.55; N, 9.03. Found: C, 65.56; H, 4.57; N, 8.72.
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[C@H:5](CO)N.[C:10](=[NH:20])([O:17][CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.ClCCl>[C:11]1([C:10]2[O:17][CH2:18][CH:19]([CH2:5][C:4]([OH:9])=[O:3])[N:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)CC1COC(c2ccccc2)=N1

Procedure:
567 mg (3.6 mmol) of L-serine methyl ester hydrochloride are dissolved in 0.5 ml of water, and 610 mg (3.6 mmol) of ethyl benzimidate in 10 ml of dichloromethane are added thereto. After 48 h at reflux, the mixture is concentrated to a volume of 50 ml of dichloromethane and washed with NaHCO3 (3×10 ml), and the aqueous phase is extracted with ethyl acetate (2×10 ml). Column chromatography (15×5 cm, hexane/ethyl acetate 1:1) yields 3.0 g of A2a (91% of theory).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:31])[C@@H:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[NH:20]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:16][O:17][C:18](=[O:31])[C@@H:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[N:20]1[C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10]
Reactant: COC(=O)[C@@H]1CCC(c2cccc(O)c2)N1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCC(c2cccc(O)c2)N1C(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.6 g of Z-glycine dissolved in dichloromethane is coupled with 0.83 g of 5-(meta-hydroxyphenyl)proline methyl ester in the presence of 2.06 g of PyBrOP and 2.6 ml of diisopropylethylamine. After stirring for 4 hours at room temperature, the organic phase is washed (sodium hydrogen carbonate, water, citric acid, water), dried over sodium sulphate, filtered and evaporated to dryness. The oily residue is chromatographed on silica gel (n-hexane/ethyl acetate. 4:6). A white solid corresponding to the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 66.2 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-2-phenyl-ethan-1-one (Step 1) (12.5 g, 53.88 mmol), hydroxylamine hydrochloride (9.4 g, 135.4 mmol) and sodium acetate (268.5 mmol) in ethanol water (1:1, 250 mL) was heated at reflux for 4 hours, then was diluted with water (200 mL). The precipitate formed was filtered, dried and was recrystallized from hexane to afford 10 g (75%) of the desired product: mp 81°-82° C. 1H NMR (CDCl3) 7.50-7.06 (m, 9H), 4.18 (s, 2H). Found: Anal. Calc'd for C14H11NOCl2 :
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:15][C:16]([O-:18])=[O:17].C(O)(=O)CCC(O)=O>C(O)(C)C>[CH2:2]([O:18][C:16](=[O:17])[CH3:15])[CH3:3].[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C([O-])CCl
Agent: C1CNCCN1
Agent: O=C(O)CCC(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(C)=O
Temperature: 25 °C

Procedure:
To a reaction blend containing 100 g (3 Eq, 0.515 mol, MW=194) of piperazine, 26.3 mL (1.1 Eq, 0.189 mol, MW=101, d=0.726) of triethylamine in 200 mL of isopropanol, add to a solution previously prepared of 18.4 mL (1 Eq., 0.172 mol, MW=122.55, d=1.15) of chloroacetate of ethyl in 140 mL of isopropanol under stirring, at room temperature. Keep the reaction medium under stirring, monitoring the reaction termination by means of a chromatography of the thin layer (about 2–3 hours). Add a solution of 40.6 g (0.344 mol) of succinic acid in 140 mL of isopropanol. Keep the system under stirring for about 30 minutes to assure total precipitation of the succinate salt of piperazine formed. Filter this salt and concentrate the filtrate containing the mono and dialkyled derivatives. We obtain a slightly yellowish oil, which is used in later phases without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[CH3:24][O:23][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:22]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(NC(=O)OC)nc1C
Reaction time: 6 h
Yield: 81 %

Procedure:
2.0g of ethyl 2-amino-4-methyl-thiazole-5-carboxylate and 2.7ml of triethylamine were dissolved in 40ml of dichloromethane and then 1.1ml of methyl chloroformate was added thereto at 0° C. The reaction mixture was stirred for 6 hours at normal temperature, evaporated to remove the solvent and then extracted with 10% aqueous sodium hydroxide solution and ethylacetate. The organic layer was separated, dried over anhydrous magnesium sulfate and then evaporated to obtain 2.1g (Yield 81%) of ethyl 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylate as a pale yellow solid. The resulting product was hydrolyzed according to the same procedure as PREPARATION 1 to obtain 1.4g (Yield 75%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:17][C:8]2=[CH:9][NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([C:7]=32)[C:5]1([OH:19])[CH3:18])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:27][C:28](Cl)=[O:29]>C(OCC)(=O)C>[CH2:1]([N:3]1[C@@H:4]2[CH2:17][C:8]3[C:7]4[C:11]([NH:10][CH:9]=3)=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:6]=4[C@@:5]2([CH3:18])[O:19][CH2:27][C:28]1=[O:29])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCNC1Cc2c[nH]c3ccc(OC)c(c23)C1(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN1C(=O)CO[C@]2(C)c3c(OC)ccc4[nH]cc(c34)C[C@@H]12
Yield: 72 %

Procedure:
To a solution of 3,4-dihydro-4-ethylamino-5-hydroxy-6-methoxy-5-methyl-5H-benz[cd]indole (646 mg 2.48 mmol) in ethyl acetate (25 ml) was added a saturated aqueous solution of sodium carbonate (24 ml). To the mixture was added, while stirring vigorously, chloroacetyl chloride (1.2 equivalent). After completion of the reaction, the organic layer was separated and washed with an aqueous saline solution, followed by drying (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was cyclized and, then, purified by means of silica gel column chromatography (eluting with n-hexane-ethyl acetate (2:7)) to afford 517 mg (72%) of the title compound as an amorphous crystalline product.
Reaction SMILES: CC(CC(C)C)=O.[CH2:8]([C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:34]=[N:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].[OH-].[K+:58].C>CO>[CH3:11][CH2:10][CH2:9][CH2:8][C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]=[N:36][N-:35][N:34]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1.[K+:58]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Under nitrogen, in a 500 ml flask a mixture of 200 ml of dry methanol, 20 g (0.026 mol) of 2-n-butyl-4-chloro 1-[(2′-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1′biphenyl-4-yl) -methyl]-1H-imidazol-5-methanol methyl-isobutyl ketone solvate and 1.45 g (0.026 mol) of potassium hydroxide was refluxed for 3 h, treated with 0.4 g of charcoal and filtered at room temperature. The filtrate was concentrated to a volume of 30 ml under diminished pressure, and after addition of 160 ml of heptane again to a volume of 130 ml. The suspension was stirred at 0° C. for 2 h, the precipitated crystals were filtered, washed with cold heptane and dried at 70° C. to give 11.3 g (92.5%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[C:14]2[C:15](=[O:29])[N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]=2[NH:12][N:11]=1.C(O)(=O)C.[O-:34][C:35]#[N:36].[K+]>O>[C:23]1([N:16]2[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]3[NH:12][N:11]=[C:10]([CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:35]([NH2:36])=[O:34])[C:14]=3[C:15]2=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#C[O-]
Reactant: Nc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 35 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a suspension of 3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (38 mg, 0.09 mmol, prepared in Example 36) in a mixture solvent of acetic acid (1 mL) and water (1 mL) was added potassium cyanate (12 mg, 0.15 mmol, 1.7 eq) at room temperature. The mixture was stirred overnight at 35° C., and filtered to give precipitates which were washed with water and then dried to afford 5-phenyl-3-[2-(2-ureidophenyl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (40 mg, 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.CC(C)([O-])C.[K+].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@:28]1([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@@H:30]([CH3:31])[O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@:28]([OH:29])([C@H:30]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[CH3:31])[CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: OC1CCN(c2ncccn2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCN(c2ncccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 1-(pyrimidin-2-yl)piperidin-4-ol (19.4 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL) was added potassium tert-butoxide (10.7 mg, 0.01 mmol), followed by stirring at room temperature for 2 hrs. The resulting solution was mixed with 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (20.0 mg, 0.08 mmol) and anhydrous potassium carbonate (13.2 mg, 0.01 mmol) and stirred at room temperature for one hr. The resulting reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous ammonium chloride solution and then with saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated by evaporation at reduced pressure. The concentrate was purified using silica gel chromatography to afford the title compound (yield 21%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.CC(O)=O.[Br:27]N1C(=O)CCC1=O>CC#N>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([Br:27])[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product of Example 29F (150 mg, 0.5 mmol) was treated with HOAc (36 μL, 36 mg, 0.6 mmol) in MeCN (5 mL) at ambient temperature for 5 min. N-bromosuccinimide (Aldrich, 100 mg, 0.55 mol) in MeCN (5 mL) was then added to the above solution at 0° C. and stirred at 0° C. for 1 h. It was then concentrated under reduced pressure. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) (100 mg, yield, 53%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.65 (m, 1H), 1.65-1.94 (m, 2H), 1.93-2.16 (m, 1H), 2.19-2.39 (m, 1H), 2.67-3.11 (m, 5H), 3.37-3.54 (m, 1H), 5.18-5.35 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 7.70 (dd, J=8.5, 2.0 Hz, 1H), 7.95 (d, J=9.5 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H) ppm. MS (DCl/NH3): 375 (M+H)+, 377 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([S:9][C:10](=[N:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:11]C(OC(C)(C)C)=O)[CH:7]=[CH2:8].[I:27]I.O>ClCCl>[I:27][CH2:8][CH:7]1[CH2:6][S:9][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11]1
Reactant: C=CCSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CI)CS1
Yield: 74.6 %

Procedure:
17 g of sodium bicarbonate are added, at a temperature in the region of 20° C., to a suspension of 25.4 g of tert-butyl allylsulfanyl-[(tert-butoxycarbonyl)amino]methylidene-carbamate in 650 cm3 of dichloromethane, followed by addition of a solution of 24.4 g of iodine predissolved in 850 cm3 of dichloromethane. After 72 hours at a temperature in the region of 20° C., 500 cm3 of water and 500 cm3 of saturated sodium bicarbonate solution are added to the reaction medium and the resulting mixture is then extracted with twice 1 dm3 of ethyl acetate. The organic phases are washed with saturated sodium sulfite solution and then with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is crystallized from ethyl acetate. 20.5 g of tert-butyl N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate are obtained in the form of a yellow solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.41 (s: 9H); 2.97 (dd, J=11.5 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 3H); 4.12 (mt: 1H); 9.89 (unresolved complex: 1H)].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:24][CH2:25][C:26](=[O:30])[NH:27][C:28]=3[N:29]=2)[CH2:11][CH2:10]1.C(OCC)(=O)C>C1COCC1.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:24][CH2:25][C:26](=[O:30])[NH:27][C:28]=3[N:29]=2)[CH2:11][CH2:10]1
Reactant: O=C1COc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Yield: 83 %

Procedure:
6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.774 g, 1.73 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 16 hours. The reaction was filtered and concentrated to give an oil. Ethyl acetate was added and the product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.645 g, 83%). MS: APCI: M+1: 449.1 (Exact Mass: 448.14).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)=[C:21]2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]4[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[CH:19]=[CH:20][C:21]=34)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
N,N-Diisopropylethylamine (1.0 mL, 6.0 mmol) was added to a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.96 g, 2.0 mmol) and methyl 5-chloropyrazine-2-carboxylate (0.34 g, 2.0 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 120° C. overnight. The mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-60%) to afford the desired product (0.13 g, 12%). LCMS (M+H)+: m/z=545.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(O)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)OC(C)(C)C)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(4-(1-(4-hydroxyphenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (300 mg, 0.580 mmol) in DMF (Volume: 4 mL) was added ethyl 2-bromoacetate (0.067 mL, 0.609 mmol) and POTASSIUM CARBONATE (401 mg, 2.90 mmol). The mixture was at rt for 16 h. After cooling to rt, the mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography using 40% EtOAc/Hexanes to give tert-butyl 4-(4-(1-(4-(2-ethoxy-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (350 mg). LC-MS (Condition C), MS m/z (M++H) 576.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2(O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)cc1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 100 °C

Procedure:
A suspension of rac-5-chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (1.0 g, 3.45 mmol) (from Example 1a supra) in a mixture of triethylsilane (2 mL, 12.5 mmol) (Aldrich) and trifluoroacetic acid (5 mL, 65 mmol) was heated at 100° C. for 24 hours. After cooling, mixture was diluted with toluene and concentrated to almost dryness. Residue was dissolved in dichloromethane and purified by flash chromatography (Biotage 40M, 5% then 10% ethyl acetate in dichloromethane as solvent). Fractions containing product were combined and concentrated. Residue was recrystallized from dichloromethane-hexanes in two crops to give rac-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.60 g, 63.5%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([O:8]2)[CH2:6]1)(=[O:4])=[O:3].[Br-:12].[Li+].Cl>O1CCCC1.[Cu](Br)Br>[Br:12][CH:9]1[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]1[OH:8]
Reactant: CS(=O)(=O)N1CCC2OC2C1
Reactant: [Br-]
Agent: Br[Cu]Br
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Br)C(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the epoxide (177 mg, 1 mmol, Example 303) in tetrahydrofuran (8 mL), lithium bromide (543 mg, 6.25 mmol, Aldrich) and copper(II)bromide (725 mg, 3.25 mmol, Aldrich) were added and the mixture was stirred at room temperature overnight. The mixture was poured into 0.1N hydrochloric acid (33 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, washed with water, brine and dried with MgSO4. The solvent was removed to give the desired product as colorless oil after passing through an aluminum column (eluted with 5% methanol/dichloromethane). 237 mg, 92%. H1NMR (300 MHz, CDCl3), ppm: 2.00–2.20 (m), 1H; 2.38–2.52 (m), 1H; 2.70 (br), 1H (OH); 2.99 (s), 3H; 3.0–3.20 (m), 2H; 3.50–3.51 (m), 1H; 3.80–3.97 (m), 2H; 4.0–4.10 (m), 1H. The compound was used directly for the next step.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])[C:4](O)=[O:5].[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:37])[C:4]([C@@H:3]([NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])[CH2:2][OH:1])=[O:5]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N[C@@H](CO)C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H](CO)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-2-hydroxy-ethyl)-amide (68 mg) was prepared by following General Procedure F starting from (S)-3-hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (50 mg), dimethylamine (56 uL, 2 M in THF), HBTU (46 mg), and DIEA (27 uL). LC/MS: m/z 524.0.