Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)([CH3:3])=[CH2:2].[Cl:11]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:11][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(C)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A mixture of 4.7 g of 2-isopropenyl-6-methylpyridine, 4.7 g of N-chlorosuccinimide and 10 ml of carbon tetrachloride was stirred at 150° to 160° C. for 30 minutes. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1). to obtain 2.0 g of the objective compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][C:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:34])[C:31](O)=[O:32].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:31](=[O:32])[C:30]([CH3:29])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:34])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)C(C)(C)c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4′-(4-Aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.038 g, 0.1 mmol), α,α-dimethylphenylacetic acid (0.020 g, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.023 g, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (0.016 g, 0.12 mmol), and triethylamine (0.56 mL, 0.4 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[N:4]=[C:19]=[O:20]
Reactant: COc1cc(N)c(Br)cc1OC
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(Br)c(N=C=O)cc1OC
Temperature: 90 °C

Procedure:
2-Bromo-4,5-dimethoxyaniline (464 mg, 2.0 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 245 mg), pyridine (1.3 eq, 0.22 ml) were added followed by phosgene (1.33 eq, 1.33 ml of a 20% solution in toluene). The mixture was heated to 90° C. for 4 hours. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuo to give 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (542 mg, quantitative) as a light brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH2:23])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1)=O>>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH:23][CH2:26][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: NCCc1ccccc1OCc1ccc(CCc2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(CCc3ccccc3)cc2)cc1

Procedure:
This compound was prepared analogously to Ex. I.1 from 2-(2-{[4-(2-phenylethyl)-benzyl]oxy}phenyl)ethylamine and tert-butyl 4-formylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[CH:12]1([NH:15][C:16]2[NH:10][C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=3[N:11]=2)[CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Reactant: S=C=NC1CC1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Cl)c1Cl
Yield: 83.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.02 g, 14.28 mmol), cyclopropyl isothiocyanate (1.53 g, 15.42 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.24 g, 19.45 mmol) and pyridine (55 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 3.29 g (83%) of a white solid. MS (CI): m/z 274. Anal. Calcd for C10H8Cl3N3-(0.6 C4H8O2): C, 45.21; H, 3.92; N, 12.76. Found: C, 45.37; H, 3.91; N, 12.76.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 106 using tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (1.50 g, 4.10 mmol) and ethyl bromoacetate (460 μl, 4.10 mmol) as starting materials.
Reaction SMILES: O=C1NC2C=C(CN3CCN(C4C=CC(C(O)=O)=CC=4)CC3)C=NC=2N2CCCC[C@@H]12.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:60]=[CH:59][C:53]([C:54]([O:56]CC)=[O:55])=[CH:52][N:51]=4)[CH2:46][CH2:45]3)[CH:41]=[N:42][C:36]=2[N:35]2[CH2:61][CH2:62][CH2:63][CH2:64][C@@H:34]12>>[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([CH2:43][N:44]3[CH2:45][CH2:46][N:47]([C:50]4[CH:60]=[CH:59][C:53]([C:54]([OH:56])=[O:55])=[CH:52][N:51]=4)[CH2:48][CH2:49]3)[CH:41]=[N:42][C:36]=2[N:35]2[CH2:61][CH2:62][CH2:63][CH2:64][C@@H:34]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1

Procedure:
Compound 76B was prepared using a procedure analogous to that described in connection with Compound 73B except that (S)-ethyl 6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate was used instead of (S)-ethyl 4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate to yield the title compound as a white solid. [M+H] calc'd for C, 22; H, 26; N, 6; O, 3, 423; found, 423.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].BrCCF>CC(C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([CH2:2][CH2:4][F:5])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(CCF)CC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (50 mg, 0.080 mmol) and K2CO3 (44.4 mg, 0.322 mmol) in acetone (2.0 mL) was added 1-bromo-2-fluoroethane (5.4 μL, 0.072 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 1 h and then at 50° C. for 3 days. The reaction mixture was cooled to 23° C., an additional portion of 1-bromo-2-fluoroethane (2.7 μL, 0.036 mmol) was added, and the reaction mixture was heated for an additional 1.5 hr at 50° C., cooled to 23° C., and concentrated via rotary evaporation. The resulting crude material was reconstituted in DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (10.7 mg, 23.6%) as a yellow film. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.19 (d, J=6.8 Hz, 6H), 1.83-1.92 (m, 2H), 2.02-2.13 (m, 2H), 2.79-2.96 (m, 3H), 2.96-3.11 (m, 0.9H), 3.24-3.36 (m, 2H), 3.38-3.55 (m, 1.1H) 3.65 (br s, 1.1H), 3.71 (m, 0.9H), 3.73-3.84 (m, 1H), 4.12-4.19 (m, 1H), 4.28 (br s, 0.9H), 4.30 (br s, 1.1H), 4.54 (ddd, J=11.7, 7.8, 3.9 Hz, 1H), 4.87 (t, J=4.4 Hz, 0.9H), 4.88-4.95 (m, 1H), 4.97 (t, J=4.4 Hz, 1.1H), 5.86 (d, J=8.3 Hz, 1H), 6.97-7.08 (m, 1H), 7.25-7.37 (m, 2H); ESI-MS m/z [M+H]+ 450.5.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].C[O-].[Na+].CO>CCOCC>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 64.4 h
Yield: 95.3 %

Procedure:
A solution of 4-benzyloxyacetophenone (6.50 g, 29 mmol) in ether (70 mL) was cooled to 0° C. and treated with ethyl trifluoroacetate (4.12 g, 29 mmol) and 25% sodium methoxide in methanol (6.39 g, 30 mmol). The reaction was warmed to room temperature and stirred for 64.4 hours. The reaction was quenched with 3 N HCl (15 mL), extracted with ethyl acetate, washed with brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (8.91 g, 96%): mp 92.4-96.5° C. 1H NMR (CDCl3) 15.30 (br s, 1 H), 8.86 (d, 2 H, J=8.9 Hz), 7.43 (m, 5 H), 7.08 (d, 2 H, J=8.9 Hz), 6.50 (s, 1 H) 5.16 (s, 2 H).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]([CH2:10][CH2:11][CH:12]1[CH2:18][N:17](CC2C=CC=CC=2)[C:16](=[O:26])[C:15]2[CH:27]=[CH:28][CH:29]=[N:30][C:14]=2[O:13]1)[CH3:9].[OH-].[Na+].CN(C)C=O>O>[CH3:9][N:8]([CH3:7])[CH2:10][CH2:11][CH:12]1[CH2:18][NH:17][C:16](=[O:26])[C:15]2[CH:27]=[CH:28][CH:29]=[N:30][C:14]=2[O:13]1
Reactant: CN(C)CCC1CN(Cc2ccccc2)C(=O)c2cccnc2O1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCC1CNC(=O)c2cccnc2O1
Reaction time: 0.33 h

Procedure:
A solution of 3.0 g (0.006 mole) of 2-[2-(dimethylamino ethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f][1,4]oxazepin-5(4H)-one oxalate[1:1.5]-hemihydrate in about 50 ml of water was made basic with dilute aqueous sodium hydroxide solution and then extracted with three 50 ml portions of benzene. The combined benzene extract was dried over anhydrous sodium sulfate and concentrated on the rotary evaporator (steam bath/50 mm). The residue was dried further by azeotroping 2 times with about 50 ml of dry benzene, evaporating to dryness each time. The final residue was dissolved in 40 ml of liquid ammonia and small spheres of sodium were added with stirring to the solution until a blue color persisted for 20 minutes. (Addition time was about 1 hr). Three grams of ammonium chloride was added slowly and the ammonia was allowed to evaporate. The residue was suspended in chloroform and the mixture was filtered. The filtrate was concentrated and the residue chromatographed on preparative high pressure liquid chromatograph using a silica gel column and eluting with 75% ethyl acetate/25% dimethylformamide. The yield of product was 0.1 g (7%). The chemical ionization mass spectrophotometer gave a peak at 236 corresponding to a molecular weight of 235. The 1H NMR spectrum of the subject compound was obtained in CDCl3 containing 1% tetramethylsilane (TMS) and is consistent with the proposed structure and dimethylformamide (DMF) and mineral oil as minor impurities. The chemical shifts, multiplicities, and assignments are given below:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1cn2c(=O)[nH]nc2c2cc(Cl)ccc12

Procedure:
To a solution of tert-butyl[(2E)-3-(9-chloro-3-oxo-2,3-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-6-yl)prop-2-en-1-yl]carbamate (3-10)(14 mg, 0.037 mmol, 1.0 equiv.) in EtOH (4 mL), was added Pd(OH)2/C (20% Pd, 1.3 mg, 0.002 mmol, 0.05 equiv.). The reaction mixture was stirred at room temperature for 1.5 hours under atmospheric pressure of hydrogen. The catalyst was then filtered off, and the filtrate was concentrated to dryness. The resulting crude product was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA) to afford the titled product (3-12). LRMS m/z (M+H) 377.1 found, 377.1 required.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:23][CH:22]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Solvent: CO
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of the product of Example 9 (4.0 g, 8.0 mmol) stirring in 1,2-dichloroethane (50 mL) at 0° C. was added boron trichloride (10 mL, 117.0 mmol). The resulting dark purple solution was stirred at room temperature overnight in a sealed tube then cooled to 0° C. Methanol (50 mL) was carefully added dropwise over a 30 minute period (caution: gas evolution). The resulting solution was concentrated and dissolved in ethyl acetate. The organic extract was washed with saturated aqueous, sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated. The resulting brown foam was purified by flash chromatography (silica gel, methanol/chloroform gradient) to give 2.7 g (63%) of desired product as a white foam: 1H-NMR (300 MHz, DMSO) δ9.72 (br s, 1H), 7.62-7.80 (m, 2H), 7.22-7.50 (m, 6H), 7.10-7.22 (m, 2H), 7.00 (m, 1H), 6.80-6.90 (m, 2H), 6.78 (m, 1H), 4.23 (s, 2H), 3.85-4.10 (m, 2H), 2.50-2.75 (m, 2H), 2.25-2.50 (m, 4H), 1.25-1.56 (m, 6H); Anal. Calc'd. for: C, 82.35; H, 7.14; N, 3.20. Found: C, 82.17; H, 7.11; N, 3.35; MS (FD) m/e 437 (M+); IR (KBr) 2935.07, 2855.01, 1621.38, 1597.26 cm−1.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH2:23][OH:24])=[CH:10][CH:9]=1)[CH3:2]>[O-2].[Mn+2].C1(C)C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH:23]=[O:24])=[CH:10][CH:9]=1)[CH3:26]
Reactant: CCN(CC)CCCNc1ccc(CO)c2sc3ccccc3c(=O)c12
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCN(CC)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of 1-[[3-(diethylamino)propyl]amino]-4-(hydroxymethyl)thioxanthen-9-one (3.82 g), toluene (60 mL) and manganese oxide (7.5 g) was refluxed for 6.5 hours. The mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated in vacuo to afford 3.3 g (87%) of 1-[[3-(diethylamino)propyl]amino]-9-oxothioxanthen-4 -carboxaldehyde as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:13]=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClCCl.[OH-].[NH4+:24].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:24][C:8]1[C:7]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CC(C)(O)Cn1cnc2cnc3cc(Br)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1-liter round bottom flask was charged with 1-(7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (25.0 g, 78.0 mmol), dichloromethane (400 mL) and chloroform (100 mL). To this solution was slowly added in small portions 3-chloroperoxybenxzoic acid (34.0 g of 60% purity, 117 mmol, 1.5 eq). The reaction was maintained at room temperature for 2 hours and then concentrated ammonium hydroxide solution (200 mL) was added. The mixture was vigorously stirred as p-toluenesulfonyl chloride (22.4 g, 117 mmol) was slowly added in small portions. The reaction was complete within 1 hour but was left to stir at room temperature overnight. The reaction mixture was filtered to collect a pale yellow solid. The product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform). The resulting pale yellow solid was slurried in cold acetonitrile, isolated by filtration, and air-dried on the vacuum filter to provide 17.2 g of 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with chloroform (3×100 mL). The chloroform fractions were combined, washed with brine (100 mL), dried over magnesium sulfate and concentrated to dryness to provide an additional 0.8 g of 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH2:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:24][C:18]1([CH2:17][NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: NCC1(O)CCCCC1
Product: O=C(NCC1(O)CCCCC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-(aminomethyl)-cyclohexanol (CAN 4000-72-0) as starting materials and isolated (19.2 mg, 57%) as white solid; MS (ESI, m/z): 339.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4](F)[CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1F
Reactant: NC1CCOCC1
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a suspension of 2-(4-chloro-2-fluoronitrobenzen-5-yl)benzoxazole (see Working Example 112-1) (0.38 g, 1.3 mmol) in acetonitrile (8 mL) was added 4-aminotetrahydropyran (0.30 g, 2.9 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered. The crystals obtained were purified by silica gel column chromatography to yield the title compound (0.10 g, 21% yield) as brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH2:14][OH:15])[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]3)=[CH:4][CH:3]=1.BrC1C=CC(C23C(COC)C2CN(C(OC(C)(C)C)=O)C3)=CC=1.[Cl:46][C:47]1[CH:48]=[C:49](O)[CH:50]=[CH:51][C:52]=1[Cl:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:46][C:47]1[CH:48]=[C:49]([CH:50]=[CH:51][C:52]=1[Cl:53])[O:15][CH2:14][CH:13]1[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH:12]1[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]2
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC2C(CO)C2(c2ccc(Br)cc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2C(COc3ccc(Cl)c(Cl)c3)C2(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl 1-(4-bromophenyl)-6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.31 mmol) obtained in Step 4 of Intermediate IX, in dry THF (10 mL), were sequentially added 3,4-dichlorophenol (428.0 mg, 2.62 mmol), triphenylphosphine (688.4 mg, 2.62 mmol) and diethyl azodicarboxylate (0.414 mL, 2.62 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at r.t. overnight. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with 1N NaOH (3 mL). The compound was extracted with ethylacetate. The organic layer was washed with water, separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford the title compound (500 mg, 74%) as a viscous oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1.[NH3:20]>O1CCCC1.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([NH2:20])=[O:19])=[CH:11][CH:10]=1
Reactant: N
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(N)=O)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
44.5 ml (351 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. to a suspension of 50.0 g (281 mmol) 3-(4-Methoxyphenyl)-acrylic acid in 300 ml tetrahydrofuran and 3.0 ml N,N-dimethyl formamide. Stirring was continued at 0–5° C. for 30 min. and thereafter for 2 h at room temperature. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 48.8 g (98%) 3-(4-Methoxyphenyl)-acrylamide were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][CH2:27]O)[CH2:21]1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:27][CH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][O:20][CH2:21]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCC1CCCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCC1CCCOC1

Procedure:
A solution of triphenylphosphine (725 mg, 2.77 mmol) in DCM (4 ml) was added dropwise with water-bath cooling to a solution of 2-(tetrahydro-2H-pyran-3-yl)ethanol (300 mg, 2.304 mmol) and carbon tetrabromide (917 mg, 2.77 mmol) in DCM (6 ml).