Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:25]([N:1]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (5 g, 19.30 mmol), potassium carbonate (10.70 g, 77.20 mmol) and benzyl bromide (7.90 g, 46.30 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=5:1). The reaction solution was heated to 60° C. and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, added with 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, yield: 43.0%) as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccs1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(-c3cccs3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
Step A - 15.4 g of 4-nitro-o-aminophenol and 11.2 g of thiophenecarboxaldehyde are dissolved in glacial acetic acid (450 ml) and heated to 85°. 44.4 g of lead tetraacetate is dissolved in 400 ml glacial acetic acid by warming and added to the above solution. Heating is continued for 0.5 hr and the solution is cooled to room temperature, diluted with an equal volume of water and the dark precipitate is collected and washed with additional water. The crude product is dissolved in CH2Cl2 (800 ml) and heated with 2.0 g of "Darco" G-60, followed by evaporation of the CH2Cl2. The resulting material is recrystallized from ethanol-chloroform (3:1) to yield 12.4 g of 5-nitro-2-(2-thienyl)benzoxazol, mp 186°-188°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]1=[O:21]
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.35 g of NaH (80% suspension in mineral oil), 12.2 g of 1-(4-chlorophenyl)-5-phenyl-4-imidazolin-2-one, 90 cc. of DMF, 11.3 g of 9-bromo-nonanic acid methyl ester and 1.35 g of NaJ.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>C1COCC1.O1CCOCCOCCOCCOCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH:11]=[C:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Diethyl 3-(4-(trifluoromethyl)phenoxy)benzylphosphonate (1.7 g, 4.4 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.02 mL, 0.10 mmol) were combined in THF (10 mL). Sodium hydride (195 mg, 60% dispersion in mineral oil, 4.9 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (875 mg, 4.9 mmol) in THF (5 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10%, EtOAc:heptane) to afford the title compound (1.75 g, 92% yield) as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 14.9 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 3,4,5-trichloropyridine (216 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (35 mg), a white solid, in 15% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:65])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:62]=[CH:61][C:34]([C:35]([O:37][CH:38]([O:40][C:41]([O:43][C@@H:44]3[C@H:48]4[O:49]C(C)(C)[O:51][C@H:47]4[O:46][C@@H:45]3[C@H:54]3[CH2:58][O:57]C(C)(C)[O:55]3)=[O:42])[CH3:39])=[O:36])=[CH:33][C:32]=2[O:63][CH3:64])=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.O>>[OH:55][C@@H:54]([C@@H:45]1[C@H:44]([O:43][C:41]([O:40][CH:38]([O:37][C:35](=[O:36])[C:34]2[CH:61]=[CH:62][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:65])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:63][CH3:64])[CH:33]=2)[CH3:39])=[O:42])[C@@H:48]([OH:49])[C@@H:47]([OH:51])[O:46]1)[CH2:58][OH:57]
Reactant: COc1cc(C(=O)OC(C)OC(=O)O[C@@H]2[C@H]3OC(C)(C)O[C@H]3O[C@@H]2[C@H]2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(=O)OC(C)OC(=O)O[C@@H]2[C@@H](O)[C@@H](O)O[C@@H]2[C@H](O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 15 mL round-bottomed flask was charged with 1-(((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yloxy)carbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (111 mg, 117 μmol). The mix of trifluoroacetic acid (1.48 g, 1 mL, 13.0 mmol) and water (375 mg, 375 μl, 20.8 mmol) was added. LC-MS indicated the completion of the reaction after stirring at room temperature for 1 h.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:31]=[N:32]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline(4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 10 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 1 gave 3-acetylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline (infra red spectrum identical with that of authentic material). Similar results were obtained when the 2,6-lutidine was replaced by 2,4-lutidine (2.15 parts) and 2,4,6-collidine (2.4 parts).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33](=[O:53])[CH2:34][C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:53])[CH2:34][C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(CCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(CCc4ccccc4)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-diphenyl-propyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:20]3[C:19]([Cl:18])=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([F:28])[CH:21]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (12.90 g, 81.50 mmol) in dimethylsulfoxide (800 mL) was added potassium tert-butoxide (21.00 g, 187.00 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes under nitrogen. To this mixture was added 5-chloro-2,4-difluorobenzoic acid (15.70 g, 81.70 mmol). The mixture was stirred at ambient temperature for 3 days, after which it was split into two equal portions. Each portion was diluted with ethyl acetate (700 mL), washed with 1 M hydrochloric acid (700 mL), a 1:1 mixture of 1 M hydrochloric acid and brine (700 mL), and brine (700 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50%, to afford the title compound as a light yellow solid (5.66 g, 21%): 1H NMR (300 MHz, CDCl3) δ 9.24 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 6.69 (d, J=12.4 Hz, 1H), 4.54-4.51 (m, 1H), 3.97-3.95 (m, 4H), 2.06-1.93 (m, 4H), 1.81-1.74 (m, 1H), 1.70-1.51 (m, 3H); MS (ES−) m/z 329.1, 331.1 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J41) (347 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (430 mg, 77%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:27][CH2:28][CH3:29])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:26]=1)[CH3:2].ClC(Cl)(Cl)C([N:34]=C=O)=O>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:27][CH2:28][CH3:29])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:34])[C:8]=2[N:26]=1)[CH3:2]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCc4cccnc4)cc3c21
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCc4cccnc4)cc3c21
Reaction time: 0.5 h

Procedure:
The crude 2-ethoxymethyl-5-oxido-1-propyl-8-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinoline from Part A was dissolved in 50 mL of dichloromethane and trichloroacetyl isocyanate (540 mg, 2.85 mmol) was added dropwise. The reaction was monitored by thin layer chromatography and once the starting material was consumed, 2 mL of concentrated ammonium hydroxide was added. The reaction was stirred for 30 minutes and then passed through a column containing cation-exchange resin. The column was washed with methanol to remove impurities followed by elution of the desired product from the column with 2M ammonia in methanol. The volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane and purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-8% methanol in dichloromethane. The solid was further purified by recrystallization from acetonitrile to give 2-ethoxymethyl-1-propyl-8-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-4-amine as light amber crystals, mp 190.0-191.0° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCN1CCCCC1)\c1nc2ccccc2o1
Yield: 42 %

Procedure:
The title compound was prepared as described in Example 18 starting with (D) of Example 18 (2.5 g, 7.6 mmmol) and using piperidine in place of dibutylamine to produce 1.2 g (42% yield) of the title compound as the HCl salt, mp 230°-232° C. IR(KBr): 1600 cm-1. MS: 377(MH+). 1H NMR (DMSO): δ 7.91-6.95 (m, 10H), 3.99 (t, J=5.2 Hz, 2H), 3.10 (m, 6H), 1.75 (m, 10H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][CH2:18][CH2:19][OH:20].[OH-].[Na+]>C(O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: OCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(CCCO)cc2)cc1
Reaction time: 40 h

Procedure:
4'-Cyano-4-hydroxybiphenyl (6 g, 0.02 mol) and 3-bromo-1-propanol (5.6 g, 0.04 mol) were dissolved in ethanol (300 ml), followed by gradually dropwise adding an aqueous solution of sodium hydroxide (10 g) in water (20 ml) over 30 minutes, continuing, as it was, stirring for 40 hours, thereafter distilling off ethanol (about 200 ml) under reduced pressure, then adding water (500 ml), extracting the resulting deposited crystals three times with toluene (100 ml), removing insoluble matter by filtration, washing the toluene layer twice with a 2N aqueous solution of NaOH, further 3 times with water, drying over anhydrous sodium sulfate, completely distilling off toluene and recrystallizing the residual crystals from methanol to prepare 3-(4'-cyano-4-biphenylyl)-1-propanol. Yield: 2 g (28%). This product exhibited liquid crystal phases and its C-N point was 109.0°~110.7° C. and its N-I point was 113.6° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[C:7]1=[O:21].[NH3:37]>CO>[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:22]([N:5]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]3)[C:7]1=[O:21])[CH2:4][C:3]([NH2:37])=[O:2])(=[O:23])=[O:24])[CH:34]=[CH:33]2
Reactant: COC(=O)CN([C@H]1CCCN(C2CCN(C(C)C)CC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: N
Solvent: CO
Product: CC(C)N1CCC(N2CCC[C@H](N(CC(N)=O)S(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(S)-[(6-Chloro-naphthalene-2-sulfonyl)-(1′-isopropyl-2-oxo-[1,4′]bipiperidinyl-3-yl)-amino]-acetic acid methyl ester (the product obtained in Example 8) was dissolved in 2.0M NH3 in methanol (5.0 mL), and the mixture was stirred at room temperature for 48 hr. The solvent was removed. HPLC purification (10% to 100% acetonitrile/water) provided the title compound as a white solid. LC-MS found: (M+1)+=521.31.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.C(O)(=O)C1C=CC=CC=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: O=C(O)c1ccccc1
Solvent: CCCCCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Brc1cn2cncc2s1
Temperature: 180 °C
Reaction time: 24 h
Yield: 49.2 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (32 mg, 0.13 mmol) and benzoic acid (16 mg, 0.13 mmol) dissolved in 1,2,4-trichlorobenzene (1 ml) was stirred at 180° C. for 24 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 2 M hydrochloric acid (3 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under the reduced pressure, and the residue was thoroughly dried to give 2-bromoimidazo[5,1-b]thiazole (13 mg, 49%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=2)=[O:56])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)cc1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 60% yield. LCMS for C31H29ClN9O2 (M+H)+: m/z=594.0.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].N1C=CC=CC=1.[NH2:13][C:14]1[C:15]([F:38])=[CH:16][C:17]([F:37])=[C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:19]=1>C(OCC)C>[NH2:13][C:14]1[C:15]([F:38])=[CH:16][C:17]([F:37])=[C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:19]=1
Reactant: NCC(F)(F)F
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: CCOCC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(F)(F)F)c(Cl)c32)c(F)cc1F
Temperature: 40 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
2,2,2-Trifluoroethylamine (50 mg) and pyridine (300 ml) were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was stirred at 40° C. for 2 days. Additional 2,2,2-trifluoroethylamine (50 mg) was added, and the mixture was stirred at 40° C. for 2 days. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and solids deposited were collected by filtration and washed with ethanol to obtain the title compound (90 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[C:18]([C:35]([O:37]CC)=[O:36])[N:19]3[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+:41].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[C:18]([C:35]([O-:37])=[O:36])[N:19]3[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:41]
Reactant: CCOC(=O)c1cc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)c(OC)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(cc(C(=O)[O-])n2S(=O)(=O)c2ccccc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 83 %

Procedure:
Ethyl 4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate (330 mg, 0.6 mmol, Intermediate 56) was dissolved in THF (10 mL) before lithium hydroxide (17 mg, 0.7 mmol) was added followed by 4 mL water. The reaction mixture was heated to 70° C. for 24 h before the reaction was completed. The reaction mixture was evaporated. This gave 3 g of a white solid which was washed with several portions of hot DCM and then hot THF. The combined wash phases were evaporated. This gave 270 mg of a slightly brown solid. Yield 83%. MS (ESI+) for C26H30N3O7SLi m/z 530 (M+H)+.