Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1.[Na]>O>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(C(C)C)C2)ncc1Cl
Temperature: 120 °C
Yield: 20.7 %

Procedure:
10-Isopropy-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (30 mg, 0.14 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (45 mg, 0.14 mmol) and 4N HCl in dioxane (28 μl, 0.15 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 8 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (14.85 mg, 20%) as a beige foam. 1H-NMR (CDCl3) δ 9.08 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.13 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.21 (m, 2H), 7.08 (d, J=7.8 Hz), 6.93 (s, 1H), 4.52 (d, J=2 Hz, 1H), 3.08 (br s, 1H), (3.02 br s, 1H), 2.71 (m, 2H), 2.63 (d, J=5.3 Hz, 3H), 2.56 (m, 3H), 2.30-2.20 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 0.87 (q, J=1.8, 6.6 Hz, 6H); LC/MS (ESI+): 513 (M+H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11](Cl)(Cl)C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of benzoic acid (1.53 g, 0.0125 mole), methyl trichloroacetate (2.22 g, 0.0125 mole), potassium carbonate (0.035 g) and 18-crown-6 cyclic polyether (0.066 g) was placed in a 25 ml round-bottom flask fitted with a stirrer, distillation head, dry ice receiver and trap. The mixture was heated with stirring to 150° C. Gas evolution was observed to begin at about 90° C. After about 3 hours, the heating was discontinued. The trap contained CHCl3 (approx. 1.5 g). Distillation of the remaining mixture gave methylbenzoate identified by gas-liquid chromatography and nuclear magnetic resonance spectroscopy. Purified yield was 85 percent.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][C:21](=[O:23])[CH3:22])[CH3:10])[CH:6]=[N:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: C[C@@H](N)c1cncc(Br)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial is added (1R)-1-(5-bromo(3-pyridyl))ethylamine HCl (500 mg, 2.1 mmol) in 2.5 ml of DCM, followed by the addition of N,N-diisopropylethylamine (816 mg, 2.52 mmol). Then acetyl chloride 1M in DCM solution (2.5 ml, 2.5 mmol) is added at 0° C. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 273 mg of N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-acetamide.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[CH:26][CH:25]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O1CCCC1>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])=[CH:26][CH:25]=2)[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](Cc2ccc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)c3ccccc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc12)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl]pyrrolidine (144 mg, 0.21 mmol) in methanol-tetrahydrofuran (3:1) (4 ml), 1N aqueous sodium hydroxide (0.24 ml, 0.24 mmol) was added in a nitrogen stream under cooling with ice. This reaction solution was stirred for 10 minutes and then 1N hydrochloric acid (0.24 ml, 0.24 mmol) was added thereto. Then the resulting solution was concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product of (2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl]-pyrrolidine as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Sn](CCCC)(CCCC)CCCC)[CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:26][CH:27]=1>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.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:22]2[N:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:26][CH:27]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccn2)nn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2ccc(-c3ccccn3)nn2)n1

Procedure:
The 3-(6-methylpyridin-2-yl)-6-(pyridin-2-yl)pyridazine 44 was prepared according to the general Stille coupling method, starting from a mixture of 2 g (5.23 mmol) of 6-methyl-2-tributylstannylpyridine 22, 666 mg (3.49 mmol) of 3-chloro-6-(pyridin-2-yl)pyridazine 8a, 208 mg (0.18 mmol) of tetrakis(triphenylphosphine)palladium(0) and 50 ml of freshly distilled toluene. The reaction medium is stirred at reflux for 18 h. The residue obtained is chromatographed on silica gel (eluent: ethyl acetate/petroleum ether=2/8). The coupling product 44 is isolated with a yield of 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:22])=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (7.53 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate were dissolved in 18 ml of tert-butanol, and 5 ml of water were then added. After cooling to 0° C., 2.35 g (15.1 mmol) sodium dihydrogenphosphate dihydrate, 2.73 g (30.1 mmol) of sodium chlorite and 3.17 g (45.2 mmol) of 2-methyl-2-butene were added in succession. After 1 hour at 20° C., water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure (logP: 1.38)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:30])[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C1COCC1>[CH3:10][N:11]([CH3:30])[C:12]([CH:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:18][CH2:19]1)=[O:13]
Reactant: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
Diisopropylethylamine (0.1 ml, 0.7 mmol) was added in one portion to a stirred solution of 1-(4-amino-benzenesulfonyl)-piperidine-4-carboxylic acid dimethylamide (0.15 g, 0.49 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.05 ml, 0.58 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (0.03 g, 15% yield) as a white solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1)([O-:15])=[O:14].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:27]([C:25]3[O:26][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N+:13]([O-:15])=[O:14])=[CH:23][CH:24]=3)=[O:28])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-nitrophenyl)-2-furoic acid (Aldrich) according to methods A and C; yield 87 mg, 0.21 mmol (58%): 1H NMR (300 MHz, methanol-d4) δ 2.05-2.28 (m, 5H), 2.45 (s, 2H), 3.50 (s, 1H), 3.52-3.60 (m, 3H), 3.77 (d, J=13 Hz, 2H), 4.26 (s, 1H), 6.91 (d, J=4 Hz, 1H), 7.29 (d, J=3 Hz, 1H), 7.62 (dt, J=8, 2 Hz, 1H), 7.74 (dt, J=8, 1 Hz, 1H), 7.85 (dd, J=8, 1 Hz, 1H), 7.94 (dd, J=8, 1 Hz, 1H); MS (DCI/NH3) m/z 368 (M+H)+; Anal. C20H21N3O4.HCl.0.7H2O: C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Fc1cccc(I)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-3-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 470.1 (M+H)+.
Reaction SMILES: C([N:4]([CH:7](C)C)[CH2:5][CH3:6])(C)C.[CH2:10]([O:12][C:13]([C:15]1([NH:20][C:21]([CH:23]2[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]2[C:29]([OH:31])=O)=[O:22])[CH2:17][CH:16]1[CH:18]=[CH2:19])=[O:14])[CH3:11].CN(C=O)C.CN(C(ON1N=N[C:47]2[CH:48]=[CH:49]C=N[C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1([NH:20][C:21]([CH:23]2[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]2[C:29](=[O:31])[N:4]([CH2:5][CH2:6][CH2:49][CH2:48][CH:47]=[CH2:46])[CH3:7])=[O:22])[CH2:17][CH:16]1[CH:18]=[CH2:19])=[O:14])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
The crude compound 4 (5.5 mmol) was dissolved in DCM (50 ml) and DMF (14 ml) followed by addition of HATU (2.09 g, 5.5 mmol), 5 (678 mg, 6.0 mmol) and DIPEA (3.08 ml, 17.5 mmol) at room temperature. The reaction was stirred at ambient temperature for 1 h. LC/MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was re-dissolved in ethyl acetate (100 ml) and the organic layer washed with 0.1 M HCl (aqueous), K2CO3 (aqueous) and brine, dried (MgSO4) and filtered. Evaporation of the solvent in vacuo gave an oil which was purified by flash chromatography (Silica, ethyl acetate/methanol) to afford the target compound 6 (1.65 g, 74%). TLC (Silica): methanol/ethyl acetate 5:95, Rf=0.5; LC/MS (Method A): tR=3.44 min, >95%, m/z (ESI+)=407 (MH+).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:28])[CH2:27][CH2:26][N:25]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:24][CH2:23]1
Reactant: FC1(F)CCNCC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCC(F)(F)CC2)ncn1

Procedure:
250 mg (0.8 mmol) of the compound from Example 12A, 158 mg (1.0 mmol) of 4,4-difluoropiperidine hydrochloride and 435 μl (323 mg, 2.5 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 5 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After pre-purification by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient), the product is additionally purified by column chromatography on silica gel (mobile phase dichloromethane/methanol, 10/1). Yield: 29 mg (10% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a stirred suspension of 4-(5-bromo-2-chlorobenzyl)phenol (60 g, 0.202 mol) and tert-butylchlorodimethylsilane (37.9 g, 0.252 mol) in acetonitrile (300 mL) was added dropwise triethylamine (54.4 mL, 0.390 mol) so that the reaction temperature did not exceed 5° C. After the addition was completed, the reaction mixture was stirred for 2 hours at 10˜15° C. This reaction mixture was filtered, and the filter cake was washed with petroleum ether (2×50 mL). The combined organic layers were evaporated under reduced pressure (30° C.), and the residue was dissolved in petroleum ether (300 mL). The solution was washed with water (100 mL×2) and evaporated, and the residue was dissolved in ethanol (180 mL) at 35° C. with stirring. This solution was cooled to 5˜10° C. and kept for 4 h. The solids were filtered, the filter cake was washed with cold ethanol (0˜5° C., 60 mL) and then dried under vacuum at 25° C. overnight to give 22f as a white solid (72 g, 86.6% yield; HPLC purity 99%, retention time 6.6 min). 1H-NMR (CDCl3, 400 MHz): δ 7.21˜7.28 (m, 3H), 7.06 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 4.00 (s, 2H), 1.00 (s, 9H), 0.21 (s, 6H); MS ESI (m/z) 411 [M+1]+, calc. 410.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([N:29]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:32]4[CH:31]=[CH:30]3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([N:29]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:32]4[CH:31]=[CH:30]3)[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Yield: 62.5 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (403) (900 mg. 1.8 mmol) in a mixture of tetrahydrofuran:water (2:1) (30 mL) was added lithium hydroxide monohydrate (756 g, 18.0 mmol) and the mixture was refluxed for 24 h (TLC, ethyl acetate, Rf=0.1). After completion of reaction, volatiles were evaporated and the aqueous part was washed with ethyl acetate (3×30 mL). The aqueous layer was acidified with HCl (6N) to pH 3 and extracted with ethyl acetate (3×50 mL). The organic phase was thereafter dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl methyl)-pyrimidine-4-carboxylic acid (404) (500 mg, 62%) as an off-white sticky solid.
Reaction SMILES: C(OC1C=CC=CC=1C([NH2:10])=O)CCC.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:24]=1)[C:21]([NH2:23])=O>>[ClH:15].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:24]=1)[C:21]([NH2:10])=[NH:23]
Reactant: CCCCOc1ccccc1C(N)=O
Reactant: CCOc1ccc(Cl)cc1C(N)=O
Product: CCOc1ccc(Cl)cc1C(=N)N
Product: Cl

Procedure:
If the procedure of Preparation 10 is repeated with the 2-n-butoxybenzamide used therein replaced by an equimolar amount of 5-chloro-2-ethoxybenzamide, there is produced the title product, m.p. 227° with decomposition.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].Br[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29](NC(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:25].[C:40](=[O:43])([O-])[O-:41].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:23][C:24]([N:26]4[CH2:27][CH2:28][N:29]([C:40]([O:41][C:16]([CH3:7])([CH3:15])[CH3:11])=[O:43])[CH2:30][CH2:31]4)=[O:25])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NN1CCN(C(=O)CBr)CC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2cnc3ccc(OCC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c21
Temperature: 55 °C
Reaction time: 16 h

Procedure:
The synthesis of 2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described in Parts A-I of Example 2. A mixture of 2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (4.5 g, 15.8 mmol), tert-butyl 4-(2-bromoacetyl)piperazine-1-carbamate (4.57 g, 14.9 mmol), and potassium carbonate (3.27 g, 23.7 mmol) in DMF (158 mL) was heated to 55° C. for 2.5 hours, then was allowed to cool to room temperature and was stirred for 16 hours. The solution was poured into water (500 mL), which was extracted with diethyl ether (300 mL), ethyl acetate (300 mL) and dichloromethane (300 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 0-5% methanol in dichloromethane to provide 7.9 g of tert-butyl 4-({[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}acetyl)piperazine-1-carboxylate as a tan waxy solid that contained 15% of DMF by weight.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[OH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[OH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(O)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-hydroxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31-8.30 (s, 1H), 8.05-8.01 (m, 1H), 8.01-7.96 (m, 1H), 7.93-7.89 (s, 1H), 7.17-7.13 (m, 1H), 6.86-6.77 (m, 2H), 6.68 (dd, J=7.8, 2.0, 1H), 3.87-3.78 (m, 4H), 3.57 (s, 2H), 3.14-3.03 (m, 4H); MS (ESI+) M/Z 381 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][O-:26].[Na+]>CO>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([O:26][CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: C[O-]
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Agent: [Na+]
Solvent: CO
Product: COc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 18 h

Procedure:
To 25 ml of methanol was added 1.0 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine and 0.18 g (0.00335 mol) of sodium methoxide. The reaction was stirred for 18 hr, and evaporated to dryness. The solid was dissolved in 50 ml of dichloromethane and washed with 40 ml of water, dried and evaporated to dryness. The oil was crystallized and recrystallized from ether/petrol and then from ether to give the end product as white prisms, mp 137°-141°.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[Cl:25]>>[Cl:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[NH:18][C:15]([C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:16]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: Nc1ccncc1Cl
Product: O=C(Nc1ccncc1Cl)c1cc2c(s1)-c1ccccc1OCC2

Procedure:
Following Example 17, 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride and 4-amino-3-chloropyridine were reacted to give N-(3-chloropyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide. To a solution of N-(3-chloropyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.340 g, 0.953 mmol) in DMF (5 mL, 60 mmol) was added sodium hydride (0.0381 g, 0.953 mmol). The reaction mixture was stirred at room temperature for about 10 min. followed by the addition of methyl iodide (65.25 uL, 1.048 mmol) and stirred at room temperature for another 1 hr. An aliquot was analyzed by LC/MS showing clean conversion to desired product. The reaction mix was diluted with EtOAc and washed with water/saline, dried (Na2SO4) then concentrated to a residue which was analyzed by LC/MS and 1H NMR. The crude product was taken into DMF at about 100 mg/mL, but was not totally soluble. Soluble material was purified by preparative RP-HPLC to give 184 (yield 30% of theoretical). MS: (ESI+) 372.2