Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:9][C@@H:8]([C@@H:10]([CH3:11])[CH2:12][CH3:13])[C:7]([O:6][C:2]([CH3:4])([CH3:5])[CH3:3])=[O:14])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of (L)-iso-leucine tert-butyl ester hydrochloride (5 g, 22.34 mmol) in N,N-dimethylformamide (30 mL) was added triethylamine (3.1 mL, 22.34 mmol), and the mixture was stirred for 1 h. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stirred for 3 h at 25° C. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 5.7 g (93%) of the product which was used without further purification.
Reaction SMILES: [S:1]([N:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:23](=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])\[CH3:24]>C1COCC1>[CH3:29][C:28]([CH3:31])([S@@:26]([NH:25][C@@H:23]([C:12]1[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:15]=[CH:14][C:13]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:24])=[O:27])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2)cc1
Reactant: C/C=N/[S@@](=O)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](C)N[S@@](=O)C(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
To a solution of tert-butyl 1-tosyl-1H-pyrrole-3-carboxylate (,287a 1.67 g, 5.20 mmol) in 40 mL of THF at −78° C. was added LDA(Aldrich) (1.7 M solution in heptane/THF/ethylbenzene, 3.67 mL, 6.24 mmol) slowly dropwise. After 45 min, a solution of (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (Prepared according to PCT Int. Appl., WO2005103020; 0.765 g, 5.20 mmol) in THF was added slowly dropwise via syringe over several min. After 15 min, the acetone/dry ice bath was removed and the reaction was quenched by dropwise addition of saturated aq. NH4Cl and Et2O. The organic layer was washed with saturated aq. NH4Cl once, saturated aq. NaCl once and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g ISCO redisep gold column) using 0-50% EtOAc/hexanes. The product-containing fractions were concentrated to afford tert-butyl 2-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1-tosyl-1H-pyrrole-3-carboxylate (287b; 1.05 g, 2.24 mmol, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (2H, d, J=8.2 Hz), 7.28-7.34 (3H, m), 6.58 (1H, d, J=3.3 Hz), 5.95 (1H, d, J=9.2 Hz), 5.14 (1H, br. s.), 2.43 (3H, s), 1.50-1.54 (12H, m), 0.96 (9H, s). m/z (ESI, +ve) 469.1 (MA-1)11.
Reaction SMILES: [CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH:4]=[CH:3]1.O=O.[CH3:10][O:11][P:12]([CH3:14])[OH:13]>>[CH3:10][O:11][P:12]([CH:3]1[CH2:4][CH2:5][CH2:6][P:2]1([CH3:1])=[O:7])([CH3:14])=[O:13]
Reactant: COP(C)O
Reactant: CP1(=O)C=CCC1
Agent: O=O
Product: COP(C)(=O)C1CCCP1(C)=O
Reaction time: 1.5 h
Yield: 277.5 %

Procedure:
A total of 116 g of 1-methyl-1-oxophospholine and 6 g of tert.-butyl peroctoate in 30 g of methane phosphonous acid methyl ester are simultaneously added dropwise with stirring at 120° C to 282 g of oxygen-free methane phosphonous acid methyl ester. The reaction time is 90 minutes. Excess methane phosphonous acid methyl ester and a little 1-methyl oxophospholine are distilled off. For purification, the residue of 205 g of 1-methyl-1-oxophospholanyl methyl phosphinic acid methyl ester is distilled in vacuo (b.p. 210° -220° C) and gives 186 g of a pure product which hardens very slowly into star-shaped crystals which become liquid again at a temperature above 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]C)=[O:9])[N:5]([CH3:7])[CH:6]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[N:5]([CH3:7])[CH:6]=1
Reactant: COC(=O)c1cc(Cl)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of methyl 4-chloro-1-methyl-1H-pyrrole-2-carboxylate (130 mg, 0.75 mmol) in MeOH (4 mL), aq. 1N NaOH (3 mL) was added. After being stirred at room temperature overnight, the mixture was acidified with 1N HCl to pH 1-2. The product was extracted with EtOAc. The EtOAc phase was separated, dried over Na2SO4, concentrated in vacuo to give 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid as a solid (111 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1.[CH3:23][N:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([CH3:39])[C:25]1=[O:40].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[C:4]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:3]=[C:2]([C:28]2[CH:27]=[C:26]([CH3:39])[C:25](=[O:40])[N:24]([CH3:23])[CH:29]=2)[CH:7]=1
Reactant: CCS(=O)(=O)Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1cc(Oc2ccc(F)cc2F)cc(-c2cc(C)c(=O)n(C)c2)c1
Temperature: 75 °C
Yield: 93.4 %

Procedure:
A mixture of N-[3-bromo-5-(2,4-difluorophenoxyl)phenyl]ethanesulfonamide (70 mg, 0.17 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (44 mg, 0.18 mmol), Pd(dppf)Cl2 (12 mg) and K3PO4 (92 mg, 0.42 mmol) in dioxane (1 mL) and water (133 uL) was purged with nitrogen, capped, and heated to 75° C. for 1 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to afford the title compound (69 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.22 (m, 3H) 2.07 (s, 3H) 3.08-3.20 (m, 2H) 3.50 (s, 3H) 6.65-6.70 (m, 1H) 6.92-6.96 (m, 1H) 7.05-7.10 (m, 1H) 7.12-7.19 (m, 1H) 7.28-7.37 (m, 1H) 7.47-7.55 (m, 1H) 7.56-7.59 (m, 1H) 7.87-7.95 (m, 1H) 9.76-9.94 (m, 1H). LCMS (M+H)+=435.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C=O)C.[CH3:10][C:11]1([CH3:23])[O:16][C:15](=[O:17])[CH:14]=[C:13]([CH2:18][C:19](=[O:22])[CH2:20]Cl)[O:12]1>C(OCC)(=O)C>[CH3:10][C:11]1([CH3:23])[O:16][C:15](=[O:17])[CH:14]=[C:13]([CH2:18][C:19](=[O:22])[CH2:20][N:1]=[N+:2]=[N-:3])[O:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OC(=O)C=C(CC(=O)CCl)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C=C(CC(=O)CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
195 mg (3.0 mmol) of sodium azide were added to 2 ml of a DMF solution containing 328 mg (1.5 mmol) of 2,2-dimethyl-6-(3-chloro-2-oxopropyl)-1,3-dioxin-4-one prepared in Example 1, followed by stirring at room temperature for 10 minutes. Afterward, the solution was poured into ice water, extracted with ether, and then dried with anhydrous magnesium sulfate. After ether was distilled off, the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=1:1), thereby obtaining 278 mg (yield 82%) of 2,2-dimethyl-6-(3-azido-2-oxopropyl)-1,3-dioxin-4-one.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:15]2[CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)c2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), 4-methylpiperidine (0.44 ml, 3.72 mmol), N,N-diisopropylethylamine (0.65 ml, 3.72 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 4 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 677 mg of white solid (97%).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[CH:11]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccc(Cl)c1

Procedure:
Following the general method as outlined in Example 1, starting from tert-butyl(2-bromo-4-chlorophenoxy)acetate (Intermediate 1) and 3-chloro-1-ethynylbenzene (Aldrich), the title compound was obtained as a brown solid after purification by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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]>[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)=[O:21]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccc(C=O)cc4)cc3)nc12
Temperature: 95 °C

Procedure:
A solution of EXAMPLE 3A (1.18 g, 3.8 mmol) and 4-formylphenylboronic acid (0.57 g, 3.8 mmol) in dioxane (15 mL) was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (0.32 g, 0.4 mmol) and sodium carbonate (1.8 g, 17 mmol). The mixture was heated at 95° C. for 24 hours, then cooled and filtered. The filtrate was concentrated to provide the crude product, which was used without further purification. MS (ESI) m/e 342 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:42])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]3([CH2:32][OH:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.ClCCl>[F:42][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]3([CH2:32][OH:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(CO)CCOCC2)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CO)CCOCC4)c3n2)c2cc(OC(F)F)ccc21
Yield: 51.1 %

Procedure:
To a solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 66.4 μmol) in acetonitrile (6 mL) was added CsF (50.4 mg, 332 μmol, Eq: 5.00) and 18-crown-6 (17.5 mg, 66.4 μmol), the reaction mixture was heated to reflux for 72 h, then diluted with dichloromethane (20 mL), filtered over celite and concentrated. The residue was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and cyclohexane added to allow solid formation, which was separated by filtration and dried to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 33.9 μmol, 51.0%) as an off-white solid. MS (M+H)+=473 (>90% purity); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.40 (s, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.78-7.88 (m, 2H), 7.37-7.43 (m, 1H), 7.21 (t, J=74.4 Hz, 1H), 4.92 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.73 (d, J=5.7 Hz, 2H), 3.50-3.69 (m, 4H), 2.21 (d, J=13.6 Hz, 2H), 1.70-1.89 (m, 2H). Unreacted starting material (11 mg, 27%) was also recovered.
Reaction SMILES: [C:1]1([CH:8]=[CH:7]C(O)=[CH:4][CH:3]=1)O.B(F)(F)F.[CH3:13][CH2:14][O:15][CH2:16][CH3:17].O1CCOCC1>C(OCC)C>[O:15]1[C:16]2[C:8](=[CH:1][CH:3]=[CH:4][CH:17]=2)[CH2:7][CH2:13][CH2:14]1
Reactant: Oc1ccc(O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of hydroquinone 1 (0.01 mol) and a catalyst, preferably boron trifluoride diethyl etherate (0.016 mol) In an organic solvent, preferably dry dioxane (10 mL), is added vinyl lactone 2 (0.016 mol) in an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes, at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL) The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.Cl[C:19]1[N:20]=[CH:21][C:22]2[CH:27]=[C:26]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[N:25]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:23]=2[N:24]=1>>[CH:33]1([N:25]2[C:23]3[N:24]=[C:19]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH:14]6[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]6)[CH2:10][C:9]5=[O:17])=[CH:6][N:7]=4)[N:20]=[CH:21][C:22]=3[CH:27]=[C:26]2[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccc(N2C(=O)CN3CCC2CC3)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C(=O)CN5CCC4CC5)cn3)nc2n1C1CCCC1
Yield: 86 %

Procedure:
Following general N—C coupling procedure 1, 4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one was combined with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and gave 7-cyclopentyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, 99 mg in 86% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.55 (d, J=9.09 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 8.09 (s, 1H), 7.55 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.47 (s, 1H), 4.81 (m, 1H), 3.93 (s, 2H), 3.82 (m, 1H), 3.19 (m, 10H), 2.59 (m, 2H), 2.41 (m, 2H), 2.07 (m, 6H), 1.74 (m, 2H); HRMS m/z 489.2740 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH2:14][CH2:15][CH3:16])C.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:17])=[C:8]([CH2:14][CH2:15][CH3:16])[CH:9]=1
Reactant: CCCc1cc(S)ccc1OCC(=O)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc(SCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a mixture of (4-mercapto-2-propyl-phenoxy)-acetic acid ethyl ester (127 mg, 0.5 mmol) and 4-Chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (131 mg, 0.48 mmol) in acetonitrile (2 mL) was added cesium carbonate (326 mg, 1 mmol). After 4 h at room temperature, the reaction was quenched by water, extracted with ethyl acetate. Combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. The residue was taken into THF (2 mL) and treated with lithium hydroxide (1N, 0.5 mL) at room temperature for 2 h. THF was evaporated, the residue was treated with water (0.5 mL) and extracted with ether. The aqueous was acidified with 5 N HCl, extracted with ether, dried over sodium sulfate and concentrated. The crude product was purified by reversed phase HPLC to give the title compound (125 mg, 53.7%)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C1COCCN1
Reactant: Clc1nccnc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Clc1nccnc1N1CCOCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of 2,3-dichloropyrazine (894 mg, 6 mmol), morpholine (523 mg, 6 mmol) and DIEA (1.55 g, 12 mmol) in DMSO (8 mL) was stirred at 70° C. for 2 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 2N aq HCl (30 mL), water (2×30 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(3-chloropyrazin-2-yl)morpholine as a light yellow solid (1.01 g, 92.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.4 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 3.86 (t, J=9.3 Hz, 4H), 3.45 (t, J=9.6 Hz, 4H). LCMS (ESI) m/z 200 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])C(=O)OC(C)(C)C)[CH3:2].[ClH:16]>CO>[ClH:16].[CH2:1]([NH:3][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCN(CCC(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNCCC(C)C

Procedure:
A solution of tert-butyl ethyl(iso-pentyl)carbamate (490 mg, 2.28 mmol, 1.00 equiv) in methanol (3 mL) and 12N hydrochloric acid (2 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to give 0.55 g of crude N-ethyl-3-methylbutan-1-amine hydrochloride as a white solid. 1H-NMR (300 MHz, D2O): δ 3.01-2.91 (m, 4H), 1.60-1.14 (m, 3H), 1.19 (t, J=7.5 Hz, 3H), 0.82 (d, J=7.8 Hz, 6H) ppm.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.O.[CH3:17][N:18](C=O)C>>[C:17]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2)#[N:18]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Solvent: O
Product: CCOC(=O)c1cc2c(C#N)cccc2[nH]1
Temperature: 150 °C
Yield: 82 %

Procedure:
To a stirred solution of ethyl 4-bromo-1H-indole-2-carboxylate (500 mg, 1.86 mmol) in DMF (10 mL) was added Cu(I)CN (501 mg, 5.59 mmol) and heated to 150° C. for 24 h. The reaction mixture was cooled to room temperature, the water (25 mL) was added and the reaction mixture extracted with ethyl acetate (4×50 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 10% ethyl acetate in petroleum ether to afford 330 mg (82%) of ethyl 4-cyano-1H-indole-2-carboxylate (I-3a) as an off-white solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])=[O:27]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:14](=[O:16])[NH:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
82 g of carbobenzoxy-L-alanine are dissolved in 100 ml of absolute tetrahydrofuran, the solution is cooled to -40° C and treated with 80 g of phosphorus pentachloride. The mixture is stirred at -30° C for 20 minutes and subsequently added to a shaken solution of 80 g of 2-amino-5-nitro-2'-chlorobenzophenone in 100 ml of absolute tetrahydrofuran. The solution is concentrated on a rotary evaporator at 50°-60° C, treated twice with toluene and evaporated each time. By crystallisation of the residue from ether, there is obtained (-)-benzyl-[1-[{2-(o-chlorobenzoyl)4-nitrophenyl}carbamoyl]-ethyl]carbamate which melts at 147° C and exhibits a rotation of [α]25D =-18.2° (in methylene chloride, 1%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[CH:17](O)=[O:18]>>[CH:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)=[O:18]
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: O=CO
Product: O=COCc1cc2c3ccccc3[nH]c(=O)n2n1
Yield: 75 %

Procedure:
2-(Hydroxymethyl)pyrazolo[1,5-C]quinazolin-5(6H)-one (3.3 g, 0.0153 mole) is suspended in 250 ml of 97-100% formic acid and refluxed overnight under nitrogen. The solution is stripped to dryness and the solid is recrystallized from dioxane to give 2.8 g (75% yield) of analytically pure title compound, m.p. 190°-192°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:25])(=O)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:12]=2)[C:10]=1[Cl:25])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc(-c2cnc(-c3ccccc3)s2)n[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 25 mg (0.084 mmol) of the above-prepared 5-(2-phenyl-thiazol-5-yl) -2H-pyrazole-3-carboxylic acid ethyl ester in dichloromethane was added 23 mg (0.168 mmol) of sulfuryl chloride and allowed to stir overnight at room temperature. The solution was diluted with ethyl acetate, washed once with aqueous sodium bicarbonate, once with water once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 7:93 ethyl acetate:hexanes as eluant to give 23 mg of the title compound (82%). 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H) 7.94 (d, 2H) 7.40 (m, 2H) 4.40 (q, 2H) 1.38 (t, 3H).