Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[O:23])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Nc1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(=O)Nc2cccc3cccnc23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of 8-aminoquinoline (48.50 g) in dimethylformamide (300 ml) was stirred at 80° C., under nitrogen, as a mixture of 1-acetylpiperidine-4-carbonyl chloride hydrochloride (106.30 g) and potassium carbonate (93.0 g) was added in portions. The slurry was stirred at 80° C. overnight, quenched with water (1200 ml) and extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified first by high performance liquid chromatography (silica; 25:1 dichloromethane-methanol), followed by flash chromatography (silica; 50:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated to give 58.5 g (58.6%) of product, as an oil.
Reaction SMILES: CO[C:3]1[C:4]2[N:11]=[C:10]([C:12]3[N:16]([CH3:17])[C:15]([C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)=[N:14][C:13]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH3:29]>O1CCOCC1>[CH3:17][N:16]1[C:12]([C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([NH2:29])[C:4]=3[N:11]=2)=[C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:14]=[C:15]1[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1
Reactant: COc1ncnc2sc(-c3c(-c4ccccc4)nc(-c4ccsc4)n3C)nc12
Reactant: N
Solvent: C1COCCO1
Product: Cn1c(-c2ccsc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 150 °C
Yield: 68 %

Procedure:
7-Methoxy-2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazol-5-yl][1,3]thiazolo[5,4-d]pyrimidine (Intermediate 44) (26 mg) was dissolved in 0.5M NH3 in 1,4-dioxane (3 mL)/concentrated aqueous NH3 (0.6 mL), sealed and heated under microwave conditions (CEM explorer, 150° C., 150 W) for 1 hour. After which the reaction mixture was concentrated in vacuo, dissolved in EtOAc (20 mL), washed: with 2M NaOH (2×10 mL) then brine (1×15 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 4% MeOH/DCM gave the title compound as an off-white solid (17 mg, 68%);
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[CH:49]([Mg]Br)=[CH2:50]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:6]([CH2:5][C:4](=[O:47])[CH:49]=[CH2:50])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: C=C[Mg]Br
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Product: C=CC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Similar to example 29b, using N-methoxy-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide (from example 29c) and vinyl magnesiumbromide to afford the title compound as a yellow oil. Rf=0.50 (EtOAc-heptane 1:1); Rt=5.23.
Reaction SMILES: [CH2:1]([S:7]([CH2:10][C@@H:11]([CH3:30])[C:12]([NH:14][C@H:15]([C@@H:23]1[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]1)[CH2:16][C@H:17]([CH3:22])[CH2:18][CH2:19]C=C)=[O:13])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH3:30][C@H:11]1[C:12](=[O:13])[NH:14][C@H:15]([C@@H:23]2[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]2)[CH2:16][C@H:17]([CH3:22])[CH2:18][CH2:19][CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH2:1][S:7](=[O:9])(=[O:8])[CH2:10]1
Reactant: C=CCCCCS(=O)(=O)C[C@@H](C)C(=O)N[C@@H](C[C@H](C)CCC=C)[C@@H]1C[C@@H](C)C(=O)O1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: C[C@@H]1CCC=CCCCCS(=O)(=O)C[C@@H](C)C(=O)N[C@H]([C@@H]2C[C@@H](C)C(=O)O2)C1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere to 200 ml refluxing DCM is added a solution of 10 mg (0.01 mmol) tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride (‘Grubbs 2’ catalyst) in 1 ml DCM, followed by the dropwise addition of a solution of 100 mg (0.218 mmol) (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-N-[(1S,3R)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)hept-6-enyl]-propionamide in 5 ml DCM. After 2 h the mixture is cooled to rt and quenched by the addition of 0.05 ml butyl vinyl ether and 0.2 g activated charcoal. The mixture is passed through a pad of silica gel (EtOAc/hexane 1:1) to yield the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20]>C(O)C.C(OCC)C.O>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:20]
Reactant: CCI
Reactant: COc1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOc1cc(OC)ccc1C#N
Yield: 82.9 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (9.637 g, 64.61 mmol) in ethanol (50 mL) were added potassium carbonate (17.88 g, 129.2 mmol) and iodoethane (15.7 mL, 193.8 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to afford a yellow-brown paste. It was then taken in diethyl ether (50 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic extracts were washed with water (1×20 mL), brine (1×20 mL), and dried over anhydrous sodium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 10–15% ethyl acetate in hexanes yielded 2-ethoxy-4-methoxy-benzonitrile as yellow solids (9.487 g, 83%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)c1
Yield: 61.7 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (126 mg, 62%). MS (ISP) 409.2 [(M+H)+]; mp 171° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[CH3:29].[ClH:39]>C(C(C)=O)C.C(OCC)(=O)C.O>[ClH:39].[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH2:35][CH2:34]1)=[O:32])[CH3:29]
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(3-Bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (3.00 g, 0.0096 mol), potassium carbonate (8.3 g, 0.060 mol), potassium iodide (3.3 g, 0.020 mol) and 4-piperidinecarboxylic acid ethyl ester (3.1 ml, 0.020 mol) was mixed in methyl ethyl ketone (100 ml) and heated at reflux temperature for 20 h and stirred at room temperature for 3 days. Water (100 ml) was added, the phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated in vacuo to give the crude product in almost quantitative yield. The crude product was treated with 1 N hydrochloric acid and ethyl acetate, evaporated to dryness and crystallised from ethyl acetate to give 2.89 g of 1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)4-piperidinecarboxylic acid ethyl ester hydrochloride as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][N:29]3[Si](C(C)C)(C(C)C)C(C)C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.CN(C=O)C.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)C1C=CC=CC=1C1C=CC=CC=1N(C)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: Nc1ccc(Br)cc1C(=O)c1cccnc1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccc3[nH]ccc23)cc1C(=O)c1cccnc1
Temperature: 120 °C

Procedure:
To (2-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.120 g, 0.43 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (0.210 g, 0.52 mmol) in 1 mL of dioxane and 0.5 mL of DMF was added chloro(di-2-norbornylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) and 2M aqueous K3PO4 (0.5 mL, 1 mmol). The resulting reaction mixture was heated at 120° C. for 1 h. Ethyl acetate was then added to the reaction mixture and the organic phase was washed with water and brine, dried, filtered and concentrated. The crude product was purified by preparative TLC to afford [2-amino-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone. 1H NMR (400 MHz, CD3OD): δ 8.82 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.47 (dd, J=7.8, 5.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.21 (d, J=3.2 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.97-6.93 (m, 2H), 6.48 (d, J=3.3 Hz, 1H).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:20]=[CH:19][N:10]([C@@H:11]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]2)[C:9](=[O:21])[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:22][O:23][C:24]1[CH:45]=[CH:44][C:27]([C:28](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1.CO>N1C=CC=CC=1>[C:1]([NH:6][C:7]1[CH:20]=[CH:19][N:10]([C@@H:11]2[O:18][C@H:15]([CH:16]([C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:45][CH:44]=3)[OH:17])[C@@H:13]([OH:14])[CH2:12]2)[C:9](=[O:21])[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@H](n3ccc(NC(=O)C(C)C)nc3=O)C[C@@H]2O)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
2.5 mmol of compound 5 are dried by successive additions and evaporations of anhydrous pyridine. There is taking up with 25 ml of pyridine, cooling to 0° C. and the addition of 2.75 mmol (1.1 equivalent) of 4,4'-dimethoxy trityl chloride in 25 ml of pyridine at 0° C. The reaction is allowed to continue for 17 hours at 5° C. and then 2 ml of methanol are added to the reaction medium. After 30 minutes, the solvent is expelled with the rotary evaporator and the oily residue taken up by 100 ml of ethyl acetate, followed by washing 3 times with 50 ml of aqueous 5% NaHOO solution and once with 50 ml of bidistilled water. The organic phase is then dried on sodium sulphate and concentrated. By fractionating on a silica gel column, the thus obtained compound 6 is isolated and corresponds to formula (I), in which B is radical of formula (III) derived from cytosine, R1 and R2 are methyl radicals, R3 the 4,4'-dimethoxy trityl radical, R4 a hydrogen atom and R a hydrogen atom.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:26]([O:25][C:24]1[C:19]2[N:20]([C:2]([CH3:17])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=4[CH:16]=3)[N:18]=2)[CH:21]=[CH:22][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: Nc1ncccc1OCc1ccccc1
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(C)O3)nc2c(OCc3ccccc3)cccn12
Yield: 80.9 %

Procedure:
6-(8-Benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.6 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazine (2.4 g) and 2-amino-3-benzyloxypyridine (4.8 g). mp. 261°-262° C. (dec.).
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:8]([Br:17])=[CH:7]C=1)(=O)C.BrC1C(C(O)=O)=N[C:22]([S:25]C)=NC=1>>[Br:17][C:8]1[C:9]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:10][C:5]([S:25][CH3:22])=[N:4][CH:7]=1
Reactant: CON(C)C(=O)c1nc(NC(C)=O)ccc1Br
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Product: CON(C)C(=O)c1nc(SC)ncc1Br

Procedure:
The title compound (11A) was prepared according to the method presented for the synthesis of compound 1B of Example 1 utilizing 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid. MS (m/z) 292.16 [M+H]+.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si](C(C)(C)C)(C)C)[CH:13]=2)[C:8]([CH2:23][CH2:24][CH3:25])=[CH:7]1)(C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:23]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[NH:6][CH:7]=1)[CH2:24][CH3:25]
Reactant: CCCc1cn([Si](C)(C)C(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCCc1c[nH]c2cc(O)ccc12

Procedure:
In analogy to the procedure described in example 3 b], 1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-3-propyl-1H-indole was treated with tetrabutylammonium fluoride hydrate to obtain 3-propyl-1H-indol-6-ol as white crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C@@H:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C@@:6]([Cl:10])([CH3:9])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:10][C@@:6]1([CH3:9])[C@H:5]([C:11]([O:13][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])[N:4]2[C:27](=[O:28])[C@@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:3]2[S:8][CH2:7]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of benzhydryl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (209 mg) in methylene chloride (3 ml) is added triethylamine (56 mg), and the mixture is mixed with a solution of phenoxyacetyl chloride (79 mg) in methylene chloride (2 ml) under ice cooling. After being left to stand for 2 hours, the mixture is washed successively with dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate, and water, then dried, and evaporated in vacuo. Recrystallization of the residue with a mixture of ether and petroleum ether gives benzhydryl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (220 mg). Yield: 82%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Br[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=1.C(O)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)O)c3)CC1)C(=O)N2

Procedure:
7.0 g (25 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.5 g (12 mmol) 4-bromopicolinic acid in 25 mL NMP were stirred for 2 h at 110° C. The reaction mixture was combined with some formic acid and purified by preparative HPLC-MS. The product-containing fractions were combined and evaporated down. The residue was stirred with MeOH, suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([NH:8][CH3:9])[CH:7]=1>[Ni].O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6]([NH:8][CH3:9])[CH:7]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (5-bromo-2-nitro-phenyl)-methyl-amine (2.60 g) and Raney nickel (0.25 g) in tetrahydrofuran (100 mL) was shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to give the crude title compound as a brown oil that was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:39])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(=O)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 6-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (2.19 g, 5.48 mmol) by reaction with m-CPBA (1.35 g, 6.03 mmol) to provide 6-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one followed by reaction with p-toluenesulfonyl chloride (1.15 g, 6.03 mmol) and ammonium hydroxide solution (9 mL) to provide 6-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (0.50 g) as a white solid after chromatography on silica gel (elution with 10% methanol in dichloromethane) and recrystallization from ethanol, mp 149-151° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C@@H:10]2[C:9]2[C:4]3=[C:5]([CH2:22][CH2:23][N:3]13)[CH:6]=[CH:7][CH:8]=2.FC(F)(F)C(O)=O.CCOCC.[ClH:36]>C(Cl)Cl.C(O)C>[ClH:36].[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:22][CH2:23][N:3]3[C:4]=2[C:9]=1[C@H:10]1[CH2:14][NH:13][CH2:12][C@H:11]1[C:2]3=[O:1]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc4c3N(CC4)C(=O)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1[C@@H]2CNC[C@@H]2c2cccc3c2N1CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of (±)-cis tert-butyl 7-oxo-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate (100 mg, 0.32 mmol) in 5 mL of methylene chloride was added trifluoroacetic acid (1 mL). This mixture was stirred at ambient temperature for 2 h and then concentrated in vacuo. The residue was basified with sat'd aq Na2CO3 and extracted with chloroform. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo to afford the free base. This residue was dissolved in 1 mL absolute ethanol and 5 mL ether and then 2M HCl in ether (0.32 mL, 0.64 mmol) was added and a solid fell out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 40 mg (50%) of the title compound of EXAMPLE 108 as an off white powder. 1H NMR (dmso-D6) δ: 9.42 (broad s, 1H), 9.20 (broad s, 1H), 7.16 (app t, 2H, J=8.0 Hz), 6.97 (app t, 1H, J=7.5 Hz), 4.05-3.95 (m, 3H), 3.79-3.70 (m, 1H), 3.68-3.53 (m, 2H), 3.51-3.42 (m, 1H), 3.20-3.10 (m, 2H), 2.90-2.80 (m, 1H). LRMS (ES)+: 214.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([B:25]([OH:28])[OH:26])=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1Cc2cc(Br)c(OCc3ccccc3)cc2S1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1Cc2cc(B(O)O)c(OCc3ccccc3)cc2S1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-benzyloxy-5-bromo-2-methyl-2,3-dihydrobenzo[b]thiophene (1.0 g, 3.0 mmol) in THF at 0° C. is added n-BuLi (1.8 mL, 4.5 mmol, 2.5 M in hexane) and the mixture is stirred for 1.5 h at 0° C. B(OMe)3 (1.67 mL, 15 mmol) is added dropwise and it is warmed to RT and stirred for 1.5 h. 3M HCl solution is added slowly at 0° C. and EtOAc is added to extract the product. The organic phase is dried with MgSO4 and concentrated. The residue is purified by chromatography to give the title compound as a white solid: (M+H)+=301.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[CH3:15]>CC(C)=O>[CH3:15][C:14]1[CH:1]=[C:2]2[N:7]([CH:13]=1)[CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]2
Reactant: COC(=O)c1ccc(C)nc1
Reactant: CC(=O)CBr
Solvent: CC(C)=O
Product: COC(=O)c1ccc2cc(C)cn2c1
Yield: 48.3 %

Procedure:
Methyl 6-methyl-3-pyridinecarboxylate (9.83 g) and bromoacetone (11.8 g) were mixed in acetone (98 ml) and the mixture was refluxed under heating for 20 hr. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (98 ml). Sodium hydrogencarbonate (16.4 g) was added and the mixture was refluxed under heating for 24 hr. The reaction mixture was concentrated under reduced pressure, water was added and the precipitate was collected by filtration. This was recrystallized from hexane-ethyl acetate to give the objective compound (5.94 g) as a pale-yellow solid.