Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g of (6-bromo-pyridin-2-yl)methanol in 50 ml of N,N-dimethylformamide were successively added 4 g of imidazole and 8.4 g of tert-butyldimethylsilyl chloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. After adding water to the reaction mixture, the mixture was extracted with n-hexane. The resulting hexane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH:19]1[CH3:33])(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:15]([N:18]1[C@@H:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=4[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][C@H:19]1[CH3:33])(=[O:17])[CH3:16]
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2n1
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.25 g, 1.26 mmol), 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (0.43 g, 1.64 mmol), p-toluenesulfonic acid monohydrate (0.53 mg, 2.77 mmol) and sodium bisulfite (0.45 g, 2.52 mmol) in N,N-dimethylacetamide (5.0 mL) was stirred at 135° C. under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and dried over Na2SO4. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 2.5% methanol in dichloromethane) to afford the title compound as yellow solid. Yield: 90 mg (16.3%). MP 279-279.8° C. 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.20 (s, 1H), 4.78 (bs, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 3.70 (d, J=12.0 Hz, 2H) 3.11 (d, J=10 Hz, 2H), 2.18 (s, 3H), 1.40 (bs, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)cc2)CC1
Yield: 57.8 %

Procedure:
1-tert-Butyloxycarbonyl-4-[(4-nitrophenyloxy)methyl]piperidine (1.9 g) was dissolved in ethanol (40 ml) and to the mixture was added conc. hydrochloric acid (0.5 ml). By using 10% palladium/carbon as a catalyst, catalytic reduction was conducted at normal pressure and room temperature overnight. After completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was diluted with methylene chloride and washed with aqueous saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[(4-aminophenyloxy)methyl]piperidine (1.0 g) as white crystals, m.p. 100°-101° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1ccc(F)c(F)c1
Yield: 97.4 %

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 1.14 g of 3,4-difluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 1.32 g of 1-(3,4-difluorobenzyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 97%.
Reaction SMILES: B(F)(F)F.CSC.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:31]3[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([O:38]C)[CH:32]=3)=[N:25][N:26]([CH2:28][C:29]#[N:30])[CH:27]=2)=[CH:19][N:18]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:31]3[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([OH:38])[CH:32]=3)=[N:25][N:26]([CH2:28][C:29]#[N:30])[CH:27]=2)=[CH:19][N:18]=1)(=[O:10])[CH3:9]
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccc(-c3ccccc3C(C)=O)nc2)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)c1ccccc1-c1ccc(-c2cn(CC#N)nc2-c2cc(C)cc(O)c2)cn1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 67 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (27 mg, 55%).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH:5]([OH:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2].O.NN>C(O)C.[Ni]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH:5]([OH:17])[CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:13][CH:12]=1
Reactant: CCN(CC)CC(O)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)CC(O)COc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A suspension of 1-diethylamino-3-(4-nitro-phenoxy)-propan-2-ol (2.41 g, 8.99 mmol) in absolute ethanol (60 mL) was heated to 50° C. To the resulting solution was added hydrazine monohydrate (2.62 mL, 6 equiv.) followed by addition of a small portion of Raney nickel. The reaction mixture was heated at 50° C. with stirring for 1 h at which point all gas evolution had ceased. The reaction mixture was filtered through celite to remove the Raney nickel. The filtrate was concentrated in vacuo to give the 1-(4-Amino-phenoxy)-3-diethylaminopropan-2-ol as a light yellow oil (2.13 g).
Reaction SMILES: COC1C=CC(NN)=CC=1.O=C(CCC)C(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].OCCC1C2C(=CC=C(OC)C=2)NC=1C.[H-].[Na+].[Na].C(Cl)(=O)C1C=CC=CC=1.[C:54]([N:62]1[C:70]2[C:65](=[CH:66][C:67]([O:71][CH3:72])=[CH:68][CH:69]=2)[C:64]([CH2:73][CH2:74]O)=[C:63]1[CH3:76])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.S(Br)([Br:79])=O.C(=O)([O-])[O-].[Ca+2]>C(O)C.O1CCCC1.CN(C=O)C.C1C=CC=CC=1>[C:54]([N:62]1[C:70]2[C:65](=[CH:66][C:67]([O:71][CH3:72])=[CH:68][CH:69]=2)[C:64]([CH2:73][CH2:74][Br:79])=[C:63]1[CH3:76])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COc1ccc2c(c1)c(CCO)c(C)n2C(=O)c1ccccc1
Reactant: O=S(Br)Br
Agent: CCCC(=O)C(=O)OCC
Agent: COc1ccc(NN)cc1
Agent: COc1ccc2[nH]c(C)c(CCO)c2c1
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCBr)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of 4-methoxyphenylhydrazine with ethyl α-ketovalerate in ethanol using the procedure described above in Example 1; reduction with lithium aluminum hydride in tetrahydrofuran of the resulting ethyl α-(5-methoxy-2-methyl-3-indole)acetate; reaction of the resulting 3-(2-hydroxyethyl)-5-methoxy-2-methylindole with sodium hydride in DMF, and reaction of the resulting sodium salt with benzoyl chloride using the procedure described above in Example 1; and reaction of the resulting 1-benzoyl-3-(2-hydroxyethyl)-5-methoxy-2-methylindole with thionyl bromide in benzene in the presence of calcium carbonate using the procedure described in U.S. Pat. No. 3,517,028 affords 1-benzoyl-3-(2-bromoethyl)-5-methoxy-2-methylindole. The latter, on reaction with an appropriate amine in refluxing acetone in the presence of sodium carbonate affords the compounds of formula I in Examples 72-77 below where, in each instance, R1 is 5-CH3O; R2 is CH3 ; A is C6H5CO; and Alk is CH2CH2.
Reaction SMILES: Cl.Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]3[C:18]=2[C:19]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]4[O:37][CH2:38][O:39][C:31]=24)=[N:20][CH:21]=[N:22]3)[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:35]1[C:30]([NH:29][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:17]=3[O:16][CH:13]3[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]3)[N:22]=[CH:21][N:20]=2)=[C:31]2[O:39][CH2:38][O:37][C:32]2=[CH:33][CH:34]=1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A mixture of 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxyquinazoline dihydrochloride (2.39 g), trifluoroacetic acid (10 ml) and methylene chloride (35 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a 1N aqueous sodium hydroxide solution. The organic layer was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (1.44 g); NMR Spectrum: (CDCl3) 1.8–2.0 (m, 2H), 2.15–2.3 (m, 2H), 2.75–2.9 (m, 2H), 3.1–3.2 (m, 2H), 3.9 (s, 3H), 4.65 (m, 1H), 6.0 (s, 2H), 6.46 (d, 1H), 6.72 (d, 1H), 6.8 (d, 1H), 6.91 (d, 1H), 8.5 (s, 1H), 9.21 (s, 1H); Mass Spectrum: M+H+ 429 and 431.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3C(OC(C)(C)C)=O)[O:10][C:5]2=[CH:4][C:3]=1[Cl:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)[O:10][C:5]2=[CH:4][C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(Cl)cc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc2oc([C@H]3CCCN3)cc2nc1Cl
Reaction time: 1 h
Yield: 85.6 %

Procedure:
5,6-Dichloro-2-(1-t-butyloxycarbonyl-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine (355 mg, 1.0 mmol) was dissolved in CH2Cl2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 1 hour, the solvent was removed and the residue was redissolved in CH2Cl2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated. The crude product was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a solid (220 mg, 87%): 1H NMR (CDCl3, 300 MHz) δ 1.81-2.05 (m, 3H), 2.15-2.29 (m, 1H), 3.04-3.20 (m, 2H), 4.39-4.42 (m, 1H), 6.70 (s, 1H), 7.80 (s, 1H); MS (CI/NH3) m/z: 257 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]([CH3:10])[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:5][CH:4]1[OH:20].[NH:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[NH:21][C@H:22]([C:27](=[O:28])[NH:2][CH:3]1[CH2:9][CH:8]([CH3:10])[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:5][CH:4]1[OH:20])[CH2:23][CH:24]([CH3:25])[CH3:26])([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-Amino-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt (0.21 g, 0.59 mmol) was dissolved in 5 ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.88 mmol)and HBTU (0.34 g, 0.90 mmol) and then NMM (0.24 g, 2.4 mmol). The mixture was stirred at RT overnight. DMF was removed under high vacuum. The residue was diluted in EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave the title compound (0.2 g, 68% yield). MS (M+H+): 499.1; 1H-NMR (400 Hz, CDCl3): 8.75(d, 1H), 8.0–7.75(m, 2H), 7.5 5(m, 1H) 5.10(m, 1H), 4.15–2.90(m, 10H), 2.10–1.48(m, 14H), 1.00(m, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:17][C@@H:18]1[CH2:32][C@H:31]2[C@@H:21]([CH2:22][C:23]3[C:33]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]2=4)[NH:25][CH:24]=3)[N:20]([CH3:34])[CH2:19]1)(=O)=O>C(O)C>[CH3:34][N:20]1[C@H:21]2[C@@H:31]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:33]=3[C:23]([CH2:22]2)=[CH:24][NH:25]4)[CH2:32][C@@H:18]([CH2:17][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2ccnc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
1.0 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of imidazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 3 hours. After allowing the mixture to cool, ice-water was added to the reaction mixture, and the precipitated crystals were filtered and washed with water. The crystals thus obtained were dissolved in ethanol, and the solution was concentrated to a volume of about 1/3, followed by allowing to cool to obtain 1.3 g of the titled compound as colorless prisms having a melting point of higher than 260° C. (with decomposition).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].FC1C=CC(OC2C=CC(S(NCCC3C=CC=CC=3O)(=O)=O)=CC=2)=CC=1>>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COc1ccccc1CCNS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(NCCc1ccccc1O)c1ccc(Oc2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NCCc2ccccc2O)cc1

Procedure:
The title compound is prepared starting from N-[2-(2-methoxyphenyl)ethyl]-4-methylbenzenesulfonamide in analogy to the method described under 19B, it likewise being possible for the crude product to be reacted further without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].O1CCCC1.[CH3:11][C:12]1[NH:24][C:15]2=[N:16][C:17]3[C:22]([N:23]=[C:14]2[N:13]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3>N1C=CC=CC=1>[CH3:5][O:4][C:2]([N:13]1[C:14]2=[N:23][C:22]3[C:17]([N:16]=[C:15]2[N:24]=[C:12]1[CH3:11])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:3]
Reactant: Cc1nc2nc3ccccc3nc2[nH]1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)n1c(C)nc2nc3ccccc3nc21
Reaction time: 17 h

Procedure:
A solution of 6 parts of methyl chloroformate in 50 parts of tetrahydrofuran was added over 30 minutes to a suspension of 4 parts of 2-methyl-1H-imidazo[4,5-b]quinoxaline in 200 parts of tetrahydrofuran and 6 parts of pyridine. The heterogeneous reaction mixture was stirred at 25° for 17 hours. Concentration in vacuo, addition of 200 parts of CH2Cl2, washing with 500 parts of 5% HCl, drying over sodium sulfate, and concentrating in vacuo left a pale yellow solid. Recrystallization from chloroform-hexane gave almost colorless 1-methoxycarbonyl-2-methyl-1H-imidazo[4,5-b]quinoxaline, m.p. 184° (dec.).
Reaction SMILES: C([N:5]([CH:10]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][CH2:11]1)[S:6]([CH3:9])(=[O:8])=[O:7])CCC.[H-].[Na+].ICCCC>CN(C=O)C>[CH3:9][S:6]([NH:5][CH:10]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][CH2:11]1)(=[O:7])=[O:8]
Reactant: CCCCN(C1CCCOc2ccc([N+](=O)[O-])cc21)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCI
Product: CS(=O)(=O)NC1CCCOc2ccc([N+](=O)[O-])cc21

Procedure:
From 0.5 g of 5-methylsulfonylamino-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine 0.6 g of 5-(N-butyl-N-methylsulfonylamino)-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine were obtained by reaction with sodium hydride and iodobutane in DMF analogously to Example 11, m.p. 96-98° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:59][CH:58]4[CH:54]([CH2:55][N:56]([CH3:60])[CH2:57]4)[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:59][CH:58]4[CH:54]([CH2:55][N:56]([CH3:60])[CH2:57]4)[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CN1CC2CN(c3ccc(Nc4cc(Br)cn(C)c4=O)nc3)CC2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5CN(C)CC5C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 50.7 %

Procedure:
Following Examples 148h, 142 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (0.29 mmol) and 119 mg of 335e (0.29 mmol) were reacted to give 335f as a yellow solid (100 mg, 51%). LCMS: [M+H]+ 680
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH2:26][CH3:27])[CH3:25])=[CH:20][CH:19]=3)[C:16](=[O:28])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2]>[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:16](=[O:28])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[C:5]2[CH:6]=[N:7][C:2]([N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCNCC
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(Br)nc3)nc3ccccc3c2=O)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCC(C)c1ccc(-n2c(-c3ccc(N(CC)CC)nc3)nc3ccccc3c2=O)cc1
Reaction time: 3 h
Yield: 37.1 %

Procedure:
2-(6-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.110 g, 0.253 mmol), Pd(OAc)2 (0.017 g, 0.076 mmol), DPPF (0.035 g, 0.063 mmol), NaOt-Bu (0.032 g, 0.330 mmol), and diethylamine (0.040 mL, 0.385 mmol) were combined in toluene (2 mL) in a microwave tube under nitrogen. The mixture was microwaved at 90° C., 300 W, for 3 hours. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with 30% ethyl acetate/heptane to 100% ethyl acetate, to afford the title compound as a white solid (0.040 g, 37%). 1H-NMR (300 MHz, DMSO-6): δ 8.14-8.17 (m, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.84-7.90 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.52-7.57 (m, 1H), 7.32-7.35 (m, 1H), 7.18-7.28 (m, 4H), 6.33 (d, J=9.1 Hz, 1H), 3.41 (q, J=6.9 Hz, 4H), 2.57-2.64 (m, 1H), 1.41-1.62 (m, 2H), 1.19 (d, J=6.9 Hz, 3H), 1.01 (t, J=6.9 Hz, 6H), 0.67 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 427 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH2:3]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CS(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
Methyltriphenylphosphonium bromide (9.5 g, 26.7 mmol) was dissolved in THF (33 mL). Sodium hydride (0.675 g, 26.7 mmol) was added portionwise followed by DMSO (33 mL). After stirring for 10 minutes, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25 mmol) in THF (25 mL) was added dropwise. The resulting suspension was stirred at room temp for 30 minutes. Water and ethyl acetate were added and the organic phase was washed with aqueous NaHCO3 and brine and was dried (Na2SO4), filtered, and concentrated. The colorless oil was triturated with diethyl ether and the resulting solids were removed by filtration. Concentration of the solvent gave an oil that was purified by flash chromatography eluting with 30%–50% diethyl ether/hexane to provide the desired product as a colorless oil (2.69 g, 55% yield). 1H NMR (300 MHz, CDCl3) δ: 4.70 (2H, s), 3.38 (4H, t, J=5.7 Hz), 2.14 (4H, t, J=5.8 Hz), 1.43 (9H, s).
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: I
Solvent: c1ccncc1
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a mixture of Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (100 mg; 0.32 mmol) in pyridine (2 mL) was added benzoyl chloride (0.12 mL; 0.96 mmol) dropwise. The mixture was then agitated at 80° C. in a sealed tube overnight. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up into ethyl acetate and the extract allowed to stir with 2M sodium carbonate solution for 2 hours at room temperature. The organic layer was then washed with brine solution, dried over sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (eluent: 10% ethyl acetate/hexanes to 40% ethyl acetate gradient) to provide 53 mg of N-(8H-Indeno[1,2-d]thiazol-2-yl)-benzamide 2. EI-HRMS m/e calcd for C17H12N2OS 292.0670, found 292.0666.