Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH3:25][C:26]1[O:27][C:28]([C:34]2[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=2)=[C:29]([C:31](Cl)=[O:32])[N:30]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:31]([C:29]1[N:30]=[C:26]([CH3:25])[O:27][C:28]=1[C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)=[O:32])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=1.10 min, [M+H]+=482.06.
Reaction SMILES: [SH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:26](I)([CH3:28])[CH3:27]>>[CH:26]([S:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)([CH3:28])[CH3:27]
Reactant: CC(C)I
Reactant: SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Product: CC(C)SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 1, 4-mercapto-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran was reacted with isopropyl iodide to give 4-isopropylthio-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran in 67% yield, as an oil.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1)[C:3](=[O:12])[NH:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH3:1][N:2]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=1)[C:3](=[O:12])[NH:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCc1ccc(N(C)C(=O)NCCC(=O)OCC)cc1
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCCCCCCCc1ccc(N(C)C(=O)NCCC(=O)O)cc1
Yield: 84 %

Procedure:
When the product of Step C is substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 84% yield, as a colourless solid. 1H-NMR (CDCl3) 7.19 (d, 2H, J=8.3 Hz); 7.09 (d, 2H, J=8.3 Hz); 4.83 (m, 1H); 3.54 (m, 2H); 3.4 (m, 2H); 3.22 (s, 3H); 2.6-2.5 (m, 4H); 1.59 (m, 2H); 1.27 (m, 10H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1c(F)c(NCCO)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 35.5 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid, 100 mg of 4-aminoisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 97 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH:13]([O:15]CCCC)=[CH2:14].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)(=[O:15])[CH3:14]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(C)=O)cc1F
Temperature: 80 °C
Reaction time: 24 h
Yield: 27.9 %

Procedure:
A mixture of methyl 4-bromo-2-fluorobenzoate (7.0 g, 0.030 mol), 1-(ethenyloxy)butane (13 mL, 0.099 mol), palladium acetate (200 mg, 0.0009 mol), 1,3-bis(diphenylphosphino)propane (700 mg, 0.002 mol), and potassium carbonate (4.29 g, 0.0310 mol) in DMF (50 mL) and water (3 mL) was heated at 80° C. with stirring for 24 h. After cooling to RT, to the solution was added 1N HCl solution (31 ml). The mixture was stirred at RT for 1 h, and then extracted with ethyl ether. The combined extracts were washed with brine; dried over Na2SO4, filtered concentrated. The residue was flash chromatographed on a silica gel column to give the desired product (1.64 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.B#B.CO>O1CCCC1>[CH2:3]([C:4]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]2[C:11]([CH2:12][OH:14])=[CH:15][CH:16]=[CH:17][C:18]=2[N:19]=1)[CH2:2][CH2:7][CH3:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NCc1ccccc1Cl
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.2 %

Procedure:
A suspension of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole-7-carboxylic acid (Example 3) (9.06 g, 26.4 mmol) in dry tetrahydrofuran (950 mL) under an argon atmosphere was treated dropwise with a solution of diborane in tetrahydrofuran (105.2 mL of 1M diborane). The mixture was stirred at ambient temperature overnight. The reaction was cooled, treated with excess methanol continuously and the solvents were evaporated. The residue was dissolved in methylene chloride, and the solution was washed well with water, dried and concentrated. The crude product was chromatographed over 500 g of silica gel with a gradient of methanol in methylene chloride to give about 5 g of product. This was boiled in 10% hydrochloric acid (100 mL) and then chilled. The yellow crystals were filtered to provide 4.78 g of 2-n-butyl-1-(2-chlorophenyl)methyl-7-hydroxymethyl-1H-benzimidazole hydrochloride; mp 223°-233.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:27][CH2:26][CH2:25][O:24][CH3:23])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: COCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCCOc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo [1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. EI-MS m/e (%): 314 (M+, 54), 256 ([M—MeOCH═CH2]+, 100), 214 (59).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:52]=[CH:51][C:41]([O:42][CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:38]6[CH:52]=[CH:51][C:41]([O:42][CH2:43][CH2:44][N:45]7[CH2:46][CH2:47][O:48][CH2:49][CH2:50]7)=[CH:40][CH:39]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(OCCN7CCOCC7)cc6)cn5)CCO4)c3n2)cn1
Temperature: 105 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 15 mg (0.03 mmol) was dissolved in dioxane 1 ml, and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)ethyl)morpholine 16.5 mg (0.05 mmol), 1M Na2CO3 98 μl (0.09 mmol), and Pd(pph3)4 2 mg (0.001 mmol) were added and then charged with nitrogen, followed by stirring at 105° C. for 18 hours. After the reaction, the reaction mixture was extracted with EA and brine, and the organic layer was dried over MgSO4. Column chromatography (methylene chloride methanol=20:1) gave a product 6 mg (31%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.BrCCCN(C)C1C=CC=CC=1>CN(C=O)C>[Br:11][CH2:12][CH2:13][CH2:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: BrCCCBr
Reactant: CNc1cccc(OC)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(CCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cccc(N(C)CCCBr)c1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
N-methyl-3-methoxyaniline (1.0 g, 7.294 mmol) was dissolved in anhydrous DMF (20 mL), to which 1,3-dibromopropane (1.48 mL, 14.589 mmol), K2CO3 (3.018 g, 21.884 mmol) and 18-crown-6 (0.24 g, 1.458 mmol) were added at room temperature, and reaction mixture stirred at 35° C. for 24 hours. The remaining procedure was followed as described for compound 14 to obtain compound 15. Yield: 0.760 g (75%). 1H NMR (500 MHz, CDCl3): δ 2.16 (tt, 2H, J=6.5, 13.5 Hz, Hc), 2.98 (s, 3H, NCH3, Ha), 3.46-3.54 (m, 4H, Hb and Hd), 3.83 (s, 3H, OMe), 6.32-6.66 (m, 2H, Hg and Hi), 6.38-6.42 (m, 1H, Ha), 7.16-7.21 (m, 1H, Hf); 13C NMR (125 MHz, CDCl3): δ 29.90 (Cc), 31.34 (Cd), 38.65 (Ca), 50.79 (Cb), 55.02 (OCH3), 98.77 (Ci), 101.26 (Ce), 105.31 (Cg), 129.81 (Cf), 150.32 (Cj), 160.72 (Ch). EI-MS: [M+H]+ C11H7BrNO calcd 258.05, obsd 258.04.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.N1CCCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:32]1([C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH2:7][CH2:8]2)=[O:13])=[CH:22][CH:21]=3)=[O:24])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:35][CH2:36]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: C1CCCNCC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCCCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), azepane (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [O:1]=[C:2]([C:22]1[S:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)[CH2:3][CH2:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH:10]([CH2:18][CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>>[O:1]=[C:2]([C:22]1[S:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)=[CH:25][CH:26]=1)[CH2:3][CH2:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH:10]([CH2:18][CH3:19])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)C(=O)O

Procedure:
2-(4-(3-Oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoic acid is prepared from tert-butyl 2-(4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)butanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([NH2:15])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2].[C:16](Cl)(Cl)=[O:17]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([N:15]=[C:16]=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)OC12CC3CC(CC(N)(C3)C1)C2
Solvent: Cc1ccccc1
Product: CC(=O)OC12CC3CC(CC(N=C=O)(C3)C1)C2
Reaction time: 6 h
Yield: 85 %

Procedure:
In toluene (100 mL) was dissolved 10 mmole of 1-acetyloxy-3-aminoadamantane obtained by the method of Example 15. To the resultant solution was added 12 mmole of phosgene at room temperature and the mixture was stirred for 6 hours. As a result, the conversion of 1-acetyloxy-3-aminoadamantane was 95% and 1-acetyloxy-3-isocyanatoadamantane (yield 85%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([S:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH3:26])[CH:29]=2)(=[O:36])=[O:35])[CH2:9][CH2:8][N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(S(=O)(=O)c2cccc(OC)c2)CCN1Cc1ccccc1
Yield: 82.5 %

Procedure:
A solution of 1-benzyl-piperazine-2-carboxylic acid ethyl ester (300 mg) in DMF (13 mL) was treated with triethylamine (0.5 mL) and 3-methoxybenzene sulfonyl chloride (274.6 mg) at RT for 2 hours. Water was added, and the inorganic layer was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and evaporated to yield 1-benzyl-4-(3-methoxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester as a colorless oil (417 mg), MS: 419.3 ([M+H]+).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C[N+]([O-])=O>[OH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:2]([NH2:5])(=[O:3])=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: NS(=O)(=O)c1ccccc1O
Temperature: 45 °C

Procedure:
To a solution of chlorosulfonylisocyanate (Aldrich; 2 mL) in 76 mL MeNO2 at 0° C. was added phenol (2 g) in 10 mL MeNO2. The solution was heated at 45° C. for 30 minutes then AlCl3 (3.46 g) was added and the temperature raised to 100° C. for 30 minutes. The reaction mixture was poured onto ice/H2O, extracted (2× Et2O), and washed with H2O. The organic layer was extracted with K2CO3 (saturated solution) and the aqueous phase then acidified with 1N HCl. Extraction of the aqueous phase with Et2O followed by drying (MgSO4) and evaporation yielded a black oil. Purification of this oil by chromatography (hexane/EtOAc 1:1) gave the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])[CH2:3]1.[ClH:26].[N:27]1([C:32](N)=[NH:33])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:26].[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:32](=[NH:27])[NH2:33])[CH2:14][CH2:13]2)=[O:9])[CH2:3]1
Reactant: O=C(OCC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCC(COC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.3 %

Procedure:
To a solution of 14 mg of piperidin-4-ylmethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 0.020 ml of anhydrous dimethylformamide, 6.3 mg of 1H-pyrazole-1-carboxamidine hydrochloride and 0.008 ml of diisopropylethylamine were added, followed by stirring at room temperature for 12 hours. The reaction liquid was condensed and dried to solid. Thus obtained crude product was purified on silica gel column chromatography (eluent: chloroform/methanol=10/1), to provide 11 mg of the title compound in the form of a colorless solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][Si](C)(C)C)[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:32].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH2:47][CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CN(C=O)C.[Cl-].[NH4+]>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[CH:27])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:32][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH2:47][CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: C[Si](C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (0.91 ml) in tetrahydrofuran (1.0M, 0.91 mmol) was added over 5 min. to a stirred mixture of {5-chloro-7-[(trimethylsilyl)ethynyl]-1,3-benzodioxol-4-yl}amine (0.122 g) and 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (0.140 g) in DMF (4 ml) cooled to 0° C. under a nitrogen atmosphere and the mixture was stirred for 1 hr at ambient temperature. The mixture was diluted with saturated aqueous ammonium chloride (40 ml) and extracted with ethyl acetate (3×20 ml). The organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methanol and dichloromethane as eluent. There was thus obtained the title compound as a solid (0.120 g). NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.37 (m, 4H), 2.45 (t, 2H), 3.57 (m, 4H), 3.92 (s, 3H), 4.17 (t, 2H), 4.50 (s, 1H), 6.15 (s, 2H), 7.15 (s, 1H), 7.17 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 497 and 499.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].ClC1C2C(=CC=CC=2)N=CC=1NC=O.Cl.[C:33]1([O:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(ON)C>C(O)(C)C>[O:39]([N:40]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][CH2:15][CH3:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOc1ccccc1
Agent: CCON
Agent: Cl
Agent: O=CNc1cnc2ccccc2c1Cl
Solvent: CC(C)O
Product: CCCc1nc2cnc3ccccc3c2n1Oc1ccccc1
Yield: 37.2 %

Procedure:
The method of Part B of Example 20 was followed using N-(4-chloroquinolin-3-yl)butyramide (3.5 g, 14 mmol) in lieu of 4-chloroquinolin-3-ylformamide and O-phenylhydroxylamine hydrochloride (2.3 g, 16 mmol) in lieu of O-ethylhydroxylamine hydrochloride in isopropanol (100 mL). Chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent to provide 1.58 g of 1-phenoxy-2-propyl-1H-imidazo[4,5-c]quinoline as a brown, foamy solid.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:8]([NH2:10])=[O:9])[C:5]([NH2:7])=[O:6].C(O[CH:14]=[CH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])C.Cl>CO>[O:6]=[C:5]1[C:4]([C:8]([NH2:10])=[O:9])=[CH:14][CH:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[NH:7]1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: NC(=O)CC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 45 °C
Yield: 82.8 %

Procedure:
Sodium methoxide (74 g, 1.37 mol) was dissolved in methanol (1,000 mL), and malon diamide (100 g, 0.979 mol) was added to this solution at room temperature. To this mixture, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (191 g, 1.14 mol) was added dropwise at a temperature between 25 and 30° C., and the resultant mixture was refluxed under heating for 2 hours. After cooling to 45° C., concentrated hydrochloric acid was added to the mixed solution to give a pH of 3 to 4, and 500 mL of methanol was distilled off at normal pressure. To the residue, water (500 mL) was added, and the mixture was stirred for a day at room temperature. The resultant product was precipitated while cooling with ice. Thus obtained crystal was collected by filtration, washed with water, and then dried under reduced pressure, to obtain 167 g of a subject compound (yield: 83%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)([CH3:14])[CH2:12][OH:13].C[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:25]1([S:28]([O:13][CH2:12][C:11]([CH3:10])([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH3:14])(=[O:30])=[O:29])[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(CO)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(COS(=O)(=O)c1ccccc1)c1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
710 μl (4.07 mmol) of N,N-diisopropylethylamine and 33.13 mg (0.27 mmol) of 4-dimethyl amino pyridine are added to a solution of 410 mg (2.71 mmol) of 2-methyl-2-pyrid-4-ylpropan-1-ol in 10 mL of dichloromethane. The mixture is cooled to 0° C. and a solution of 775.42 mg (4.07 mmol) of 4-methylbenzene-1-sulfonyl chloride in 2 mL of dichloromethane is then added. After allowing the reaction medium to warm to room temperature and stirring overnight, it is washed with water and with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 660 mg of 2-methyl-2-pyrid-4-ylpropyl benzenesulfonate, corresponding to the following characteristics: