Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)on1
Yield: 80.4 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H14) (190 mg, 0.63 mmol) according to the general procedure K. Obtained as a white solid (213 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[Br: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=[CH:21][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2-oxindole (212 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-bromo-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2cccc3ccc(NC(=O)OCc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.933 mmol), benzyl chloroformate (0.147 mL, 1.03 mmol), and potassium carbonate (0.142 g, 1.03 mmol) were combined in a two phase mixture of methylene chloride (10 mL) and water (3 mL) and the mixture was stirred at room temperature overnight. Benzyl chloroformate (0.147 mL, 1.03 mmol) was added and the reaction was stirred 5 hours more. The reaction was diluted with methylene chloride and the phases were separated. The organic layer was washed with brine, dried over calcium sulfate and concentrated to a brown oil which was flash chromatographed on silica gel (1×4 inches). Gradient elution with ethyl acetate/hexane of from 50% to 100% followed by gradient ethanol/ethyl acetate elution of from 5% to 10% gave 0.29 g of a brown foam. This residue was recrystallized from ethyl acetate to give 0.095 g (27%) of the title product in two crops; mp 143°-144° C. Analysis calculated for C23H25N3O2 : C, 73.58; H, 6.71; N, 11.19. Found: C, 73.46; H, 6.71; N, 11.05.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH3:24])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:25]1([N:22]([CH2:23][CH3:24])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(ethyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.3 g, 0.653 mmol) and (4-(morpholinomethyl)phenyl)boronic acid (0.216 g, 0.98 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.249 g, 2.35 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.075 g, 0.065 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 3 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.15 g, 41%). LCMS: 557.35 (M+1)+; HPLC: 99.13% (@254 nm) (Rt; 4.128; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.17 (t, 1H), 7.57 (d, 2H, J=8 Hz), 7.41 (s, 1H), 7.37 (d, 2H, J=8 Hz), 7.20 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.56-3.57 (m, 4H), 3.48 (s, 3H), 3.00-3.02 (m, 2H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.70 (m, 2H), 1.60 (m, 2H), 1.47-1.48 (m, 4H), 0.81 (t, 3H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1>N1C=CC=CC=1.ClCCl>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:11]([CH:8]1[CH2:10][CH2:9]1)=[O:12]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cnccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnccn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g (105 mmol) of 2-aminopyrazine in 100 mL of pyridine was added dropwise a solution of 10.99 g (9.56 mL, 105 mmol) of cyclopropanecarbonyl chloride in 100 mL of dichloromethane. The resultant yellow solution was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and a small amount of water and washed sequentially with 1 M aqueous cuprous sulfate solution and water. The water layer was extracted with three portions of ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, eluting sequentially with 50%, 80% and 100% ethyl acetate/hexane) gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[O:22]=[S:23]1(=[O:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:28][CH:25]3[CH2:26][CH2:27][S:23](=[O:29])(=[O:22])[CH2:24]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: NC1CCS(=O)(=O)C1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NC1CCS(=O)(=O)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 24.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), 1,1-dioxidotetrahydrothien-3-ylamine (10.4 mg, 0.077), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5.1 mg, 24.3%). 1H NMR (400 MHz, CD3OD) δ 0.93 (dd, J=6.57, 1.26 Hz, 3 H) 1.05 (dd, J=6.32, 3.79 Hz, 3 H) 2.06-2.28 (m, 1 H) 2.40-2.59 (m, 2 H) 2.98 (td, J=12.57, 7.45 Hz, 1 H) 3.04-3.18 (m, 1 H) 3.21-3.29 (m, 1 H) 3.35-3.53 (m, 1 H) 4.51-4.66 (m, 1 H) 4.95-5.12 (m, 2 H) 5.40 (dd, J=19.20, 13.39 Hz, 1 H) 7.83-7.89 (m, 1 H) 8.17 (dd, J=3.28, 1.52 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.[N+:21]([O-])([O-:23])=[O:22].[K+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:21]([O-:23])=[O:22])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1c(CCc2ccc(C#N)cc2)cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1c(CCc2ccc(C#N)cc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Within 2 hours 1.7 g (6.53 mmol) of 4-[2-(1-methyl-indol-2-yl)ethyl]benzonitrile is dissolved in 20 ml conc. sulphuric acid at 15° C. and then cooled to 2° C. Then 0.66 g (6.53 mmol) of potassium nitrate are added batchwise (temperature rise to about 10° C.). The mixture is stirred for a further 30 minutes at 2-5° C. and then poured onto ice. The yellowish precipitate formed is filtered off and washed with water.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(N=Cc2ccc(Cl)cc2)cc1
Product: CSc1ccc(NC(C#N)c2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-chlorobenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 84%).
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]([F:24])([F:23])[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][CH2:20][CH2:21]O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>O>[F:7][C:8]([F:24])([F:23])[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][CH2:20][CH2:21][Br:1])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: Br
Reactant: OCCNc1ccnc2cc(C(F)(F)F)ccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc2c(NCCBr)ccnc2c1
Temperature: 165 °C
Yield: 58 %

Procedure:
Hydrobromic acid (0.88 ml, 16.2 mmol) and then sulphuric acid (0.29 ml, 5.5 mmol) are added dropwise to the 7-trifluoromethyl-4-(β-hydroxyethylamino)quinoline 10 (0.67 g, 2.6 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 165° C. for 3 h 30 min, and then poured into 10 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9) and the medium is then extracted at the reflux of toluene (10 ml) for 15 min. The organic phase is then collected and the product 11 is obtained by crystallization at −18° C. overnight, filtration, and then drying under vacuum: 0.48 g (yield=58%). Mp: 106° C. (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[CH2:11](Br)[C:12]#[CH:13]>>[CH2:13]([O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]#[CH:11]
Reactant: OCCCc1ccccn1
Reactant: C#CCBr
Product: C#CCOCCCc1ccccn1

Procedure:
From 2-pyridinepropanol (13.7 g) and propargyl bromide (80% solution in toluene, 12 ml), with a reaction time of 2 h. FCC eluting with hexane-ether (1:1) gave the title compound as an orange oil (9.0 g), t.l.c. (System B 80:20:1) Rf 0.15.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[H-].[Na+].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>CC1C=CC=CC=1C>[C:9]([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: CCOC(N)=O
Reactant: C=C(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To the solution of 8.9 g of ethyl carbamate in 50 g of o-xylene, a slurry of 2.2 g of NaH in 20 g of xylene was added dropwise in 30 minutes, followed by stirring for additional 3 hours at 50° C. Then a solution of 10.5 g of methacryloyl chloride in 30 g of xylene was added dropwise to the reaction mixture and the solution was stirred for 1 hour at 60° C. The resultant white precipitate were filtered off and the filtrate was concentrated. The residue was subjected to column chromatography for purification, thereby obtaining 6.1 g of ethyl N-methacryloylcarbamate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[O:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:23][C:21]([C:18]1[CH:19]=[N:20][C:15]([N:13]2[CH2:12][CH2:11][C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([C:36]5[O:37][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH2:14]2)=[N:16][CH:17]=1)=[O:22]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(Br)cc4c3C2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)o5)cc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.6 %

Procedure:
To a solution of Example 33 (0.25 g, 0.64 mmol) in THF:H20 (4:1) were added Cs2CO3 (1.689 g, 5.16 mmol) and 5-formyl-2-furanboronic acid (0.180 g, 1.29 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (0.186 g, 0.16 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC analysis and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 mL) and water (15 mL). The organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to give methyl-2-{8-[5-(formyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.12 g, 46.2%)
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)C.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[C:17]([C:19](=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCOC(=O)CC#N
Reactant: CCCc1ccc(C(OCC)OCC)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(C=C(C#N)C(=O)OCC)cc1
Yield: 94 %

Procedure:
A mixture of 20.0 g (90 mmole) 4-n-propylbenzaldehyde diethylacetal, 20.4 g (180 mmole) ethyl cyanoacetate, 7.2 g (93.4 mmole) ammonium acetate and 60 ml toluene are heated at reflux for six hours, cooled and poured into water. The resulting mixture was extracted with ethyl ether, dried (MgSO4) and the volatiles evaporated in vacuo to afford 23.0 g crude yellow oil which was purified by chromatography on a silica gel column, eluting with 2:1 methylene chloride/hexane to give 20.58 g (94%) of the desired product. 1H-NMR(CDCl3)ppm(delta): 0.85-1.95 (m, 8H), 2.45-2.70 (t, 2H), 4.15-4.60 (q, 2H), 7.15-8.05 (q, 4H), 8.25 (s, 1H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:18][CH:17]1[CH2:16][NH:15][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[C:3](=[O:14])[NH:19]1
Reactant: CC(N)CN
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1CNc2cccc([N+](=O)[O-])c2C(=O)N1
Yield: 66.6 %

Procedure:
A solution of 2-fluoro-6-nitrobenzoic acid methyl ester (500 mg, 2.51 mmol) in 1,4-dioxane (3 mL) was treated with 1,2-diaminopropane (0.186 mL, 2.51 mmol) and diisopropylethylamine (0.874 mL, 2.51 mmol). The reaction was irradiated at 140° C. for 20 minutes. The reaction mixture was then reduced en vacuo and purified by flash column chromatography (0% ethyl acetate/hexanes-100% ethyl acetate/hexanes) to afford 370 mg of 3-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 2-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (mixture of regioisomers) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 4-(benzyloxy)pyridin-3-amine (6.2 g, 15.8 mmol), triethylamine (11 mL, 79 mmol), and dichloromethane (163 mL) was added methanesufonylchloride (1.2 mL, 15.8 mmol) in dichloromethane (100 mL) drop wise over 90 min. The solution was maintained at room temperature for 6 h and concentrated to afford N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide which was used without further purification. LCMS: retention time: 1.305 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Xterra, 5 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 279 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)[CH3:2].[BH4-].[Na+].CO>O1CCCC1>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:2]
Reactant: CCNc1nc(C(=O)OCC)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1nc(CO)cs1

Procedure:
The reaction described in Preparation 17 was repeated but using 10 g of ethyl 2-ethylaminothiazole-4-carboxylate, 3.8 g of sodium borohydride, 70 ml of methanol and 150 ml of tetrahydrofuran, giving the title compound as a yellow oil.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: [NH4+]
Reactant: COC(=O)C1=C(O)CCC(C)(C)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: COC(=O)C1=C(N)CCC(C)(C)C1
Yield: 75 %

Procedure:
A solution of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (10.0 g, 54 mmol) and ammonium acetate (10 g, 130 mmol) in ethanol (50 mL) was heated to reflux for 2 hours. The reaction was concentrated to one third original volume, and then diluted with ethyl acetate (100 mL). The organic solution was washed with water (100 mL) and brine (50 mL) and then dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:8) to afford methyl 2-amino-5,5-dimethylcyclohex-1-enecarboxylate (7.42 g, 75% yield) as a yellow solid. MS (EI) for C10H17NO2: 184 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:31](OCC)(=O)[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:31][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccc([N+](=O)[O-])cc3s2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)C1)c1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
Dissolve 3-[(6-nitro-benzothiazol-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.55 g, 14.7 mmol) in DMF (30 mL) and cool to 5° C. Add 60% NaH in mineral oil (1.12 g, 16.13 mmol) and stir for 5 min. Add iodomethane (6.0 mL, 74 mmol) and stir at 5° C. for 30 min. Quench the reaction with water and dilute with ethyl acetate. Wash the organic layer with water (5×20 mL), then wash with brine. Collect the organic layer, dry over Na2SO4, filter, and concentrate in vacuo. Chromatograph (silica gel, eluting with 20-60% Ethyl acetate:Hexane) to yield 1.96 g (34%) of the title compound. mass spectrum (ion-spray): (m/z)=393.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH:30]=3)[C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)n1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-isopropyl-1H-pyrazole.