Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.Cl>COCCOC.O>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[C:20]([OH:22])=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2.15 g (4.66 mmol) of the 2,3-dihydro-1-[(4-iodophenyl)sulfonyl]-(2S)-1H-indole-2-carboxylic acid obtained according to Preparation IV(a) in 40 ml of DME is prepared and 13 ml of water are added, followed by 1.24 g (11.6 mmol) of sodium carbonate, 380 mg (0.46 mmol) of PdCl2dppf and 1.77 g (9.3 mmol) of 2-(trifluoromethyl)phenylboronic acid. The reaction medium is stirred at room temperature for 30 min and then at 90° C. for 30 min. After cooling, water is added and the medium is acidified with N hydrochloric acid. The mixture is then extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by reversed phase chromatography on RP18-grafted silica gel using an acetonitrile/water/trifluoroacetic acid mixture (8/2/0.02; v/v/v) as the eluent to give the product in the form of an orange oil (yield=80%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCc4ccccc43)n2)c1

Procedure:
B42 was prepared following the general procedure reported for B10 using A1 and 1,2,3,4-tetrahydroquinoline; yield: 11.9 mg (3%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.91 (quint, J=6.3 Hz, 2H), 2.73 (t, J=6.6 Hz, 2H), 3.98 (t, J=6.2 Hz, 2H), 4.16 (s, 2H), 6.82 (s, 2H), 6.99 (d, J=7.6 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 7.13-7.19 (m, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.62-7.69 (m, 2H), 7.72 (d, J=7.8 Hz, 1H), 8.32 (s, 1H), 9.81 (s, 1H). MS (ES) C19H20N6O2S requires: 396. found: 397 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:9]=[C:8]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-:17].[K+].[K+].OO>CS(C)=O>[F:15][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([C:10]([CH3:13])([CH3:14])[C:11]([NH2:12])=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C#N)c1cccc(OC(F)F)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C(N)=O)c1cccc(OC(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a 1 L round bottom flask was added 2-(6-(difluoromethoxy)pyridin-2-yl)-2-methylpropanenitrile (19.2 g, 91 mmol, 1 equiv), potassium carbonate (37.0 g, 270 mmol, 3 equiv), and DMSO (150 mL). The reaction was cooled to 0° C. and 30% hydrogen peroxide (25 mL) was added slowly in 2 mL portions over ten minutes. The reaction was then warmed to room temperature and stirred for 1 h. After consumption of starting material, the reaction was poured into ethyl acetate (600 mL), washed with brine (3×300 mL), dried over Na2SO4, and concentrated to give 2-(6-(difluoromethoxy)pyridin-2-yl)-2-methylpropanamide (20 g, 97%) as a clear oil.
Reaction SMILES: [C:1](Cl)(=O)C.[S:5]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6]1>CO>[S:5]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:1])=[O:12])=[CH:6]1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccsc1
Solvent: CO
Product: COC(=O)Cc1ccsc1
Reaction time: 8 h

Procedure:
Acteyl chloride (7.50 ml, 106 mmol) was added dropwise to a solution of 3-thiopheneacetic acid (5.00 g, 35.3 mmol) in dry MeOH (150 ml) at 0° C. The mixture was left to slowly reach room temperature and stirred overnight. Solvents were evaporated and residue filtered through a short plug of silica gel (DCM) to give a quantitative yield of the title compound as an oil. 1H NMR (400 MHz, CDCl3): □ 3.64 (s, 2H), 3.70 (s, 3H), 7.03-7.05 (m, 1H), 7.14-7.15 (m, 1H), 7.27-7.29 (m, 1H).
Reaction SMILES: CC([O-])(C)C.[K+].Cl[C:8](=[CH2:21])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18].Cl>>[CH:9]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:18])=[O:19])=[C:8]=[CH2:21]
Reactant: C=C(Cl)COc1ccccc1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: C=C=COc1ccccc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
4.5 g of potassium tert-butylate are added in portions to a solution of 5 g of 2-(2-chloroprop-2-enyloxy)phenylsulfonamide such that the temperature does not exceed 28° C. The reaction mixture is stirred for 20 hours at 20°-25° C. and, after addition of ice-water, adjusted to pH 7 by the dropwise addition of 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and hydrochloric acid, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed through a column of silica gel to give pure 2-allenyloxyphenylsulfonamide of m.p. 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:6]2=[N:7][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2[nH]cc(Cl)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc2[nH]cc(Cl)c2n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 137.4 %

Procedure:
To (R)—N—((S)-1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (1.08 g, 3.23 mmol) in anhydrous MeOH (10 mL) was added HCl (4.0 mol/L) in dioxane (14 mL). The reaction mixture was stirred at 40° C. under N2 for 16 h. Volatile solvent was removed under reduced pressure. The crude product was triturated with DCM until solid is seen. Light yellow solid was filtered and dried under a high vacuum to afford 868.2 mg (89.3%) of (5)-1-(3-chloro-1H-pyrrolo-[3,2-b]pyridin-5-yl)ethanamine as HCl salt. 1H NMR (400 MHz, DMSO) δ 11.90 (br s, 1H), 8.47 (br s, 3H), 7.93 (d, J=8.5 Hz, 1H), 7.90 (d, J=2.9 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.60 (dt, J=12.4, 6.1 Hz, 1H), 1.56 (d, J=6.8 Hz, 3H); MS (ESI) m/z: 196 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][Mg]Cl>C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)([OH:29])[CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30]
Reactant: COCCCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2cccc(F)c2)C1
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of (3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine (0.95 g, 2.37 mmol) in THF (3 mL) at −20° C. was added 1.45 M 4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with satd aq NH4Cl (4 mL) and extracted with Et2O (4×5 mL). The combined organic layers were washed with water and brine, and the solvent was removed in vacuo to give a crude product which was purified by flash column chromatography to afford (R)-tert-butyl 3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 43%).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2c(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Yield: 64.4 %

Procedure:
The title compound (1.246 g, 64%) was prepared from 2-ethyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 5.7 mmol) and 4-[2-bromoethoxy]nitrobenzene (1.696 g, 6.8 mmol) and K2CO3 (1.58 g, 11.49 mmol) as a base by a similar procedure to that described in preparation 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccc(F)c1)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
3-Fluorobenzaldehyde (1s, 0.5 ml, 4.7 mmol) and acetone (19, 0.18 ml, 2.3 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.29 g, 7.3 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was filtered and chromatographed on silica gel with ethyl acetate/hexane to give a solid. The crude was recrystallized from ethanol to afford 0.26 g (42%) of yellow crystals: mp 96-97° C. [expected mp 96-97° C.]; 1H NMR: δ 7.03 (d, 2H, J=16.1 Hz), 7.09 (m, 2H), 7.35 (m, 6H), 7.67 (d, 2H, J=15.9 Hz); 13C NMR: δ 114.4, 117.5, 124.4, 126.3, 130.4, 136.9, 142.0, 162.9, 188.1; Anal. Calcd for C17H12OF2: C, 75.55; H, 4.48. Found: C, 75.26; H, 4.65.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(OCC)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]1)[N:6]=[CH:5][N:4]=[C:3]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCCN(C)C1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Agent: Cl
Solvent: CCOCC
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCC1CCCN(C)C1
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 26 except that 3 equivalents of the 1M solution of hydrogen chloride in diethyl ether were used, 4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide. The reaction product was purified by column chromatography on silica using an 89:10:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 34% yield; NMR: 1.12 (m, 1H), 1.52 (m, 1H), 1.65-2.05 (broad, 3H), 2.15 (s, 3H), 2.2 (s, 3H), 2.7 (m, 2H), 2.90 (m, 2H), 3.53 (m, 4H), 3.73 (m, 4H), 3.95 (s, 3H), 4.04 (d, 2H), 7.1 (m, 1H), 7.16 (s, 1H), 7.24 (m, 1H), 7.31 (m, 1H), 7.59 (m, 1H), 7.78 (m, 1H), 7.84 (s, 1H), 8.27 (m, 2H), 9.4 (s, 1H), 10.3 (s, 1H); m/s: M+H+ 598.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:28]=[CH:27][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39](=O)[O-:40])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:18]3[N:17]=[C:15]4[N:14]([CH:19]=3)[C:13]3[CH:27]=[CH:28][C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:11][C:12]=3[S:16]4)=[CH:25][CH:24]=2)=[O:40])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Reactant: CC(C)(C)c1cc(NC(=O)[O-])no1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1

Procedure:
reacting 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl)imidazo[2,1-b]benzothiazole (VIII) with a 5-tert-butylisoxazol-3-ylcarbamate derivative (X) to yield N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzo-thiazol-2-yl]phenyl}urea (I); and
Reaction SMILES: [Br:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([C:25]([F:28])([F:26])[F:27])[C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2N)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
A stirred suspension of 1,1-dimethylethyl 4-{[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]amino}-1-piperidinecarboxylate (D66, 1.10 g, 2.3 mmol) in ethanol (50 ml) at room temperature under argon was treated with Raney Nickel (30 mg) followed by dropwise addition over 10 minutes of hydrazine hydrate (0.50 ml, 16 mmol). The mixture was stirred well at room temperature for 20 minutes, then heated at 45° C. for 1 hr, before cooling to 20° C. and filtering through Kieselguhr. The filtrate was concentrated under vacuum to afford the title compound as a white solid (0.98 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([N:18]1[CH2:22][CH2:21][CH:20](O)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[CH2:11]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A chilled solution of 4-nitrophenol (3.9 g, 28 mmol) and 1-benzyl-3-pyrrolidinol (7.5 g, 42 mmol) in THF was treated with diisopropyl azodicarboxylate (8.3 mL, 42 mmol), stirred at ambient temperatures, under nitrogen, for 45 minutes, poured into excess water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was twice purified by flash chromatography with 40% ethyl acetate in hexane to give 1-benzyl-3-(4-nitro-phenoxy)-pyrrolidine as a dark yellow gum, 7.2 g (86% yield), Mass spectrum (+APPI, [M+H]+) m/z 299. 1HNMR (500 MHz, DMSO-d6): δ8.11-8.15 (m, 2H), 7.23-7.29 (m, 4H), 7.17-7.21 (m, 1H), 7.02-7.07 (m, 2H), 4.97-5.02 (m, 1H), 3.56 (s, 1H), 2.80-2.84 (m, 1H), 2.61-2.71 (m, 2H), 2.28-2.41 (m, 2H), 1.73-1.79 ppm (m, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:29](=[O:30])[C:28]#[C:27][C:18]3[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=3[Cl:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(OCCn2cccn2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCn2cccn2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-(2-pyrazol-1-ylethoxy)phenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 56 mg (43% of theory); melting point: 120° C.-125° C.; C21H15ClF3N3O2 (M=433.82); calc.: molecular ion peak (M+H)+: 434/436; found: molecular ion peak (M+H)+: 434/436; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[O:7][CH3:8].[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:8][O:7][C:6]1[S:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:18]1[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(OC)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Temperature: 85 °C
Yield: 143 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-bromo-5-(methyloxy)-2-thiophenecarboxylate (772 mg, 3.07 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (773 mg, 3.72 mmol) [prepared according to the procedure of Preparation 7], K2CO3 (1.419 g, 10.27 mmol) and Pd(Pt—Bu3)2 (103 mg, 0.20 mmol) in 1,4-Dioxane (12 mL) and Water (3 mL). The reaction was heated at 85° C. for 2 hours. The mixture was partitioned between CHCl3/H2O and the aqueous layer made acidic with 6N HCl. The separated organic layer was dried over Na2SO4 and evaporated. The resulting material was adsorbed onto silica and purified via column chromatography (0-50% EtOAc/Hexane) affording the title compound (967 mg, 4.39 mmol, 85%): LC-MS (ES) m/z=253 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4]>[Pd]>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:3]=1[NH2:4]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Product: Cc1cccc(N)c1N

Procedure:
The 5,6-dihydro-N,N-dipropyl-4H-imidazo(4,5,1-j)quinolin-5-amines of the invention, compounds of Formula I where D is nitrogen, A is CH, n is 0 and D and A are joined by a double bond, may be prepared as illustrated in Scheme 2 for the preparation of compound 6. Catalytic hydrogenation of 2-methyl-6-nitroaniline (XVI) using a palladium catalyst afforded 3-methyl-1,2-benzenediamine (XVIII) which was heated with formic acid to give 4-methylbenzimidazole (XVIII). This was heated in dioxane with di-t-butyl dicarbonate and the t-butyl 4-methylbenzimidazole-1-carboxylate (XIXa, R is OC(CH3)3) thus obtained was brominated with N-bromosuccinimide in carbon tetrachloride to give t-butyl 4-(bromomethyl)benzimidazole-1-carboxylate (XXa). Alkylation of XXa with the potassium salt of diethyl (dipropylamino)-malonate (VIb) in refluxing THF afforded XXIa which was hydrolyzed to XXII using sodium ethoxide in ethanol containing limited amounts of water. Compound XXII was reduced to the alcohol XXIII using lithium aluminum hydride. When XXIII was treated with carbon tetrabromide and triphenylphosphine in methylene chloride compound 6 was obtained directly.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27]CN(CC4C=NC=CC=4)CC3)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].N1C2C(=CC=CC=2)C=[C:39](C(O)=O)[CH:38]=1>>[CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:15]([C:16]2[CH:27]=[N:22][C:19]3[C:20]([CH:21]=2)=[CH:39][CH:38]=[CH:17][CH:18]=3)=[O:35])=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1
Product: CCOC(=O)C=Cc1ccc(CNC(=O)c2cnc3ccccc3c2)cc1
Yield: 89 %

Procedure:
The titled compound was prepared as described in the process (1-2) by using 3-quinolinecarboxylic acid.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[N+:6]([C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[C:14]2[CH:19]3[C:20]([CH3:22])([CH3:21])[C:16]([CH3:23])([CH2:17][CH2:18]3)[C:15]2=[O:24])=[CH:11][CH:10]=1)([O-])=O>[Zn].O>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[C:14]2[CH:19]3[C:20]([CH3:22])([CH3:21])[C:16]([CH3:23])([CH2:17][CH2:18]3)[C:15]2=[O:24])=[CH:25][CH:26]=1
Reactant: CC12CCC(C(=Cc3ccc([N+](=O)[O-])cc3)C1=O)C2(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CC12CCC(C(=Cc3ccc(N)cc3)C1=O)C2(C)C
Yield: 99 %

Procedure:
A mixture of fine zinc powder (60 g), ethanol (250 ml), ammonium chloride (2 g) and water (20 ml) is heated to the reflux temperature and the paranitrobenzylidenecamphor (20 g, 0.07 mol) is added in portions with stirring. The mixture is allowed to reflux for half an hour, the zinc is filtered and the mixture is rinsed with alcohol. The filtrate is poured in ice (500 g). The precipitate obtained is filtered, washed with water and dried under vacuum. A quantitative yield of para-aminobenzylidenecamphor (17.7 g) is obtained. It is recrystallised in ethanol to give the expected derivative:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:22]4[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:13]=2)[N:22]2[C:17]=1[C:18]([NH2:23])=[N:19][CH:20]=[N:21]2
Reactant: CN1CCN(c2cc(-c3ccc4c(N)ncnn34)ccn2)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CN1CCN(c2cc(-c3cc(Br)c4c(N)ncnn34)ccn2)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
To a cooled (−20° C.) solution 7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (250 mg, 0.81 mmol) in tetrahydrofuran (5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (115 mg, 0.40 mmol) in four portions over 15 min. The mixture was allowed to stir (−20° C.) for 4 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (10 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×20 mL). The combined organics were filtered to remove a fine precipitate and the filtrate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 0% to 25% acetonitrile in water to obtain 60 mg (19%) of the desired product as a yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, 1 H), 8.14 (dd, 1 H), 7.89 (s, 1 H), 7.14 (s, 1 H), 6.90 (d, 1 H), 3.55-3.50 (m, 4 H), 2.40-2.34 (m, 4 H), 2.20 (s, 3 H); ES-MS m/z 388.12 [M+H]+, HPLC RT (min) 1.38.
Reaction SMILES: [NH3:1].O1CCOCC1.[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[S:26][C:27]([S:30]([OH:33])(=O)=[O:31])=[CH:28][N:29]=2)[CH2:21][CH2:20]1)=[O:17]>>[NH2:1][S:30]([C:27]1[S:26][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16]([C:10]3[NH:11][C:12]([CH3:15])=[C:13]([Cl:14])[C:9]=3[Cl:8])=[O:17])[CH2:20][CH2:21]2)=[N:29][CH:28]=1)(=[O:33])=[O:31]
Reactant: N
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(S(=O)(=O)O)s3)CC2)c(Cl)c1Cl
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(S(N)(=O)=O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
0.5 M ammonia/dioxane (10 ml, 5 mmol) was added to 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-sulfonic acid (Example 254; 100 mg, 0.226 mmol) in a pressure bottle. The mixture was stirred at room temperature for 4 h. Excess solvent was removed in vacuo and the brown solid was dried in vacuo to give the title compound (56 mg).