Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CCC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.07 mmol, intermediate 9), tert-butyl 3-bromopropanoate (0.22 mL, 1.29 mmol) and potassium carbonate (0.22 g, 1.61 mmol) were combined in DMF (5 mL) and heated at 100° C. for 24 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×50 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to leave a white solid. This solid was purified using a 25 g silica gel flash column eluted with 10% ethyl acetate/hexanes to give tert-butyl 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate (0.26 g, 41% yield) as a white solid. LCMS retention time=4.841 min and 99% purity, LCMS MH+=595. 1H NMR (CDCl3) δ 7.12-7.46 (m, 8H), 5.41 (s, 2H), 4.29 (t, 2H, J=8 Hz), 3.53 (s, 3H), 2.61 (t, 2H, J=8 Hz), 1.43 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a stirred suspension of 50 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)acetamide (XV) (0.17 mmol) in N,N-dimethylformamide (3 mL), 0.09 mL of (3-amino-propyl)-carbamic acid tert-butyl ester (0.51 mmol) and 0.036 mL of triethylamine (0.26 mmol) were added. The reaction mixture was stirred at room temperature overnight, evaporated to dryness and then purified through preparative HPLC on a Waters X Terra RP 18 (19×250 mm, 5 □m) column. Mobile phase A was 0.05% ammonia/acetonitrile:95/5 and mobile phase B was acetonitrile/water:95/5. Gradient from 10 to 75% B in 15 min. Fractions containing the desired compound were dried, affording 32 mg (44% yield) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18](OC)=[O:19])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[N:7]1([CH2:13][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[CH2:18][OH:19])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1cccc(C(=O)N2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(CN2CCCCC2)c1

Procedure:
Lithium aluminium hydride (5 g) was added portionwise to a stirred solution of methyl 3-piperidinocarbonylbenzoate (12.9 g) in dry tetrahydrofuran (200 ml) under nitrogen and the mixture was stirred under reflux for 3 hours. Excess reducing agent was destroyed by the dropwise addition of water under nitrogen with cooling. The reaction mixture was filtered through diatomaceous earth (sold under the trade name CELITE) which was washed with water and ethyl acetate and then the organic layer was separated. The aqueous layer was washed with ethyl acetate. The combined extracts were washed with water, dried and evaporated to give 3-piperidinomethylbenzylalcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:6][CH:7]=1)=[O:24]
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)CCl)cc2)C1
Reaction time: 1.25 h
Yield: 85.9 %

Procedure:
To a solution of (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (3.0 g, 11.01 mmol) and TEA (3.1 ml, 22.03 mmol) in dry THF (100 ml) was added dropwise chloroacetyl chloride (1.05 ml, 13.22 mmol). The mixture was stirred for 75 min. and evaporated followed by addition of water 75 (ml). The aqueous phase was extracted with EtOAc (2×50 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was dissolved in EtOAc (40 ml) and filtered through a 2.5 cm path of silicagel. The filtrated was evaporated to dryness affording 3.3 g (86%) of 2-chloro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11](O)[CH:10]([C:13]2[C:14](=[O:26])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]#[N:28])[CH:8]=2)[O:3]1.[OH-:30].[K+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:29])[CH:11]=[C:10]([C:13]2[C:14](=[O:26])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27](=[O:30])[NH2:28])[CH:8]=2)[O:3]1
Reactant: [OH-]
Reactant: CC1(C)Oc2ccc(C#N)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C=C(c2cccn(Cc3ccccc3)c2=O)c2cc(C(N)=O)ccc2O1
Reaction time: 0.83 h

Procedure:
A mixture of 5.8 g of 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromanol, 11.6 g of KOH and 90 ml of tert.-butanol is boiled for 50 min., cooled and poured onto ice. Customary working up gives 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6carbamoyl-3-chromene, m.p. 199°-202°.
Reaction SMILES: C[Si]([N-:5][Si:6]([CH3:9])([CH3:8])[CH3:7])(C)C.[Li+].[CH3:11][Si:12]([CH3:18])([CH3:17])[C:13]#[C:14][CH:15]=O.C[Si](Cl)(C)C>>[CH3:9][Si:6]([CH3:7])([CH3:8])[N:5]=[CH:15][C:14]#[C:13][Si:12]([CH3:18])([CH3:17])[CH3:11]
Reactant: C[Si](C)(C)C#CC=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Product: C[Si](C)(C)C#CC=N[Si](C)(C)C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide is placed in a reaction vessel to which 3-(trimethylsilyl)-2-propynal of step 1 is added in an aprotic solvent. During the addition of 3-(trimethylsilyl)-2-propynal the pot temperature should be maintained between -40° to -20° C. to ensure stability of the intermediate imine. To the resulting solution is added trimethylsilyl chloride and the resulting mixture stirred at a temperature ranging from -40° to -20° C. for 1 hour. This reaction step yields N,3-bis(trimethylsilyl)-2-propyn-1-imine which is not isolated from the vessel but is confirmed by GC. To the reaction vessel is now added t-butyl acetate and a catalytic amount of lithium bis(trimethylsilyl)amide. The reaction mixture is allowed to stir for 2 h at a temperature ranging from -40° to -20° C. to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate which is isolated after an aqueous ammonium chloride quench and used in the next step. In order to insure complete cleavage of the nitrogen-silicon bond the stir time for this phase should not be less than 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[F:28])=[C:10]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:11]=[CH:12][CH:13]=[O:14].[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32]>O1CCCC1>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[C:10]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:11]=[CH:12][CH:13]([OH:14])[CH2:33][C:31](=[O:32])[CH2:30][C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 5,5-bis(2-fluoro-4-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (1.3 g, 3.4 mmoles) in tetrahydrofuran (15 mL) at -50 ° C. was added the dianion of t-butyl acetoacetate (3.4 mL of a 1M solution, 3.4 mmoles). After stirring for 2 hours, another 0.7 mL of dianion solution was added and the solution stirred for an additional hour. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with methylene chloride. The extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 1.3 g of the title compound; m.p.=55°-63° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]1([CH3:26])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23].O.Cl>[OH-].[Na+].O1CCOCC1>[C:14]1([CH3:26])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:23])=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)O)c(C)c1
Yield: 45.3 %

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in aqueous sodium hydroxide (10 ml)-dioxane (10 ml), and dioxane (5 ml) solution of mesitylenesulfonylchloride (2.19 g, 10 mmole) was added dropwise to the solution while cooling and stirring while keeping pH value thereof to 10 to 11 with 1N aqueous sodium hydroxide. After that; the mixture was stirred further for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture thus obtained was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 2.0 with 1N hydrochloric acid while cooling and stirring to precipitate white solid material. The material was dissolved in 0.5N aqueous sodium hydroxide and the solution thus obtained was crystallized by addition of 1N aqueous hydrochloric acid to give N-mesitylenesulfonyl-L-alanyl-L-proline yield: 1.67 g, 45.3%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][C:6]([N:8]([CH3:24])[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7].C(Cl)(Cl)Cl>CO>[C:18]1([C:9]2([N:8]([CH3:24])[C:6](=[O:7])[CH2:5][N:2]([CH3:3])[CH3:1])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C(=O)CCl)C1(c2ccccc2)Cc2ccccc2C1
Reactant: CNC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=O)N(C)C1(c2ccccc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96.1 %

Procedure:
To a stirred solution of dimethylamine (30 mL, 0.45 mol) in methanol (150 mL) at 0° C. under nitrogen were added 2-chloro-N-methyl-N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)acetamide (8.0 g, 0.027 mol) and chloroform (110 mL). The mixture was stirred at ambient temperature for 60 hours. The solvents were evaporated, the residue was dissolved in chloroform (250 mL) and 5% NaOH (250 mL), and the phases were separated. The aqueous phase was extracted with chloroform (3×200 mL). The combined chloroform extracts were washed with brine (200 mL), dried over magnesium sulfate and the solvent evaporated. The residual solid (8.1 g) was dissolved in ethanol (175 mL) and acidified with HCl gas. The solid which formed was collected by filtration and vacuum dried at 65° C. for 48 hours to provide 8.0 g of N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)-N-methyl-2(dimethylamino)acetamide, mp 244°-245° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC>O1CCOCC1.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>[S:27]1[CH:28]=[C:24]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]23)[N:25]=[CH:26]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1C=C2c3cccc(-c4cscn4)c3CCN2C(=O)CN1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
104-1. To a degassed solution of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1 g, 2.82 mmol) and 4-(tributylstannyl)thiazole (1.48 g, 3.95 mmol) in dioxane (16 mL) was added Pd(PPh3)4 (130 mg, 0.11 mmol) and the mixture was heated in the microwave at 150° C. for 2 h. The solvent was removed under reduced pressure. The crude product was crystallized from DCM to yield the title compound (760 mg). UPLC-MS: MS 312.1 (M+H+); UPLC rt 0.66 min.
Reaction SMILES: ClCl.[OH-:3].[Na+].[F:5][C:6]([F:13])([F:12])[C:7]([F:11])=[C:8]([F:10])[F:9]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].Cl[O-].[Na+]>[F:5][C:6]([F:13])([F:12])[C:7]1([F:11])[O:3][C:8]1([F:10])[F:9]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: [OH-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: ClCl
Agent: [Cl-]
Product: FC(F)(F)C1(F)OC1(F)F
Temperature: -5 °C

Procedure:
A 300 ml pressure resistant glass reactor equipped with a fluorine resin-coated stirring bar, a pressure gauge, a nozzle for a thermocouple, a cooling device, a nozzle (A) for sampling and a nozzle (B) for supplying a reaction solution and withdrawing a reaction product was charged with 160 ml of an F-113 solution containing 0.580 g (1.44 millimoles) of TOMAC and 70 ml of an aqueous sodium hypochlorite solution with an available chlorine content of 6% containing 1.5% by weight of sodium hydroxide. After the contents of the reactor were cooled to -5° C., 4.20 g of hexafluoropropylene cooled to -5° C. were charged in the reactor and the reactants were vigorously stirred to initiate reaction. During the reaction, the reactor was cooled so as to maintain the temperature of the reaction solution at a temperature of -5° C. to -3° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1.[H-].[Na+]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([O:6][CH:4]2[CH2:5][N:2]([CH3:1])[CH2:3]2)[N:9]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CN1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(Oc2cncc(Cl)n2)C1

Procedure:
2-chloro-6-((1-methylazetidin-3-yl)oxy)pyrazine (129) was prepared by reacting 1-methylazetidin-3-ol (50 mg, 0.336 mmol, 1 eq) and 2,6-dichloropyrazine (32) (29.2 mg, 0.336 mmol, 1 eq) in DMF (5 mL) and sodium hydride (16.11 mg, 0.671 mmol, 2 eq) under refluxing temperature for 8 hrs.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:29]([NH2:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:23])[NH:31][CH2:29][CH3:30])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
A mixture of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (143 mg), ethylamine hydrochloride (39 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg) and triethylamine (49 mg) in dichloromethane (2 ml) and N,N-dimethylformamide (1 ml) was stirred at room temperature for 3 hours. The mixture was poured into ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to preparative thin layer chromatography (hexane-ethyl acetate, 1:4) to afford 2-benzyl-4-(3-ethylcarbamoylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (16 mg) as powder.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.O1CCC[CH2:12]1.C(NC(C)C)(C)C.[Li].C1CCCCC1.CI>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: Brc1csc2ccncc12
Reactant: C1CCOC1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1sc2ccncc2c1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
291 mg of 3-Bromo-thieno[3,2-c]pyridine (1.36 mmol) is dissolved in 3 ml of dry THF and cooled to −78° C. 1.00 ml of lithium diisopropylamine mono(tetrahydrofuran) 1.5M solution in cyclohexane (1.5 mmol) is added to the mixture at −78° C. and stirred at −78° C. for 20 min. 213 mg of methyl iodide (1.5 mmol) is added to the mixture and stirred at −78° C.→room temperature for 1 h. The reaction mixture is quenched by sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 225 mg of the title compound. Yield 72%. mass spectrum (m/e): 230 (M+1); 1H-NMR (CDCl3): 9.01 (s, 1H), 8.52 (d, 1H, J=5.5 Hz), 7.72 (d, 1H, J=5.5 Hz), 2.61 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(Cl)CCl>[N+:13]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1
Solvent: ClCCCl
Product: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Next is the mixing of one part 4-tert-butylanisole with between substantially 0-9 parts (by volume) organic solvent such as ethylene dichloride. Next is the cooling of the reaction mixture of 4-tert-butylamine and organic solvent to a temperature below 5° C. This is followed by the adding of 70% concentrated nitric acid while maintaining the temperature of the reaction mixture below 10° C. to produce 2-nitro-4-tertbutylanisole and a 4-nitroanisole byproduct. These are separated by means of vacuum distillation. Specifically, the 4-nitroanisole byproduct has a boiling point of 86° C. while the desired 2-nitro-4-tertbutylanisole has a boiling point of 102°-105° C. at a pressure of 1 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:31]1[CH:32]=[N:33][S:34][CH:35]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:31]3[CH:32]=[N:33][S:34][CH:35]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cnsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnsc3)c3cc(Cl)ccc23)c1
Temperature: 145 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.250 g, 0.723 mmol) was combined with CuO (0.118 g, 1.48 mmol), potassium carbonate (0.130 g, 0.941 mmol) and 4-bromoisothiazole (0.250 g, 1.52 mmol) in pyridine (2 mL) and the reaction was heated to 145° C. overnight. After cooling the reaction was partitioned between H2O and DCM and the aqueous layer was extracted with DCM. The combined organics were dried over MgSO4 and concentrated then submitted to silica gel chromatography (0-20% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:13]2[CH:21]=[CH:20][N:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]3[C:13]4[CH:21]=[CH:20][N:19]=[CH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2cnccc12
Product: c1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cn1
Yield: 15 %

Procedure:
This product was prepared in 15% yield from 5-aminoindole (1.1 eq.) and 4-chloropyrido[3,4-d]pyrimidine (1 eq.). MP 265° C.; LC-MS: 262 (MH+).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1)[CH2:18][CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CC(N(C)C)=O>[CH2:17]([N:20]1[CH:24]=[C:23]([C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:22]=[N:21]1)[CH2:18][CH3:19]
Reactant: CCCn1cc(B(O)O)cn1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCn1cc(-c2cccc3nc(NC(=O)C4CC4)nn23)cn1
Temperature: 150 °C

Procedure:
Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.05 g, 0.178 mmol), 1-propyl-1H-pyrazole-4-boronic acid, pinacol ester (0.054 g, 0.231 mmol) and dimethylacetamide (1 mL) were added to a microwave tube containing a stirrer bar, potassium phosphate solution (0.5M in water, 0.7 mL, 0.356 mmol) and tetrakis(triphenylphosphine)palladium (0.02 g, 0.018 mmol). The reaction was heated to 150° C. for 10 min under microwave heating. The crude was purified straight away by preparatory chromatography after filtration. LCMS method: 2, RT: 3.75 min; MI: 311 [M+1]; NMR 1H (DMSO): 0.80-0.88 (m, 7H), 1.78-1.90 (m, 2H), 2.05 (brs, 1H), 4.16 (t, 2H), 7.52 (dd, 1H), 7.55 (d, 1H), 7.66 (t, 1H), 8.51 (s, 1H), 8.86 (s, 1H), 11.11 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19](=[N:21][OH:22])[NH2:20])=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=O)[CH3:33]>N#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:20]=[C:32]([CH3:33])[O:22][N:21]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: N#N
Product: Cc1nc(-c2ccc3c(=O)n(-c4ccc(F)cc4)c(SCC(=O)OC(C)(C)C)nc3c2)no1

Procedure:
A solution of tert-butyl 2-(3-(4-fluorophenyl)-7-(N′-hydroxycarbamimidoyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10B, 30 mg, 0.0676 mmol) in 3 mL of acetic anhydride was heated in N2 atmosphere 110° C. for 4 hours. The reaction was concentrated to yield tert-butyl 2-(3-(4-fluorophenyl)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10C). MS (M+H)=469.