Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14][CH2:15]Br.CC([O-])(C)C.[K+]>>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: BrCCCBr
Reactant: Oc1cccc2ncccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: BrCCCOc1cccc2ncccc12
Yield: 35.5 %

Procedure:
Following the same procedure as in Example 1-(a), reaction and treatment were carried out using 1.0 g of 5-hydroxyquinoline, 2.1 g of 1,3-dibromopropane and 0.78 g of t-BuOK as a base, in order to obtain 0.65 g of 5-(3-bromopropoxy)quinoline.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]4[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=4)[CH2:26][CH2:25]3)[N:22]=[CH:23][C:16]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:35]([C:32]1[N:31]=[C:30]([C@H:27]2[CH2:28][CH2:29][C@H:24]([N:21]3[C:17]4=[N:18][CH:19]=[N:20][C:15]([O:13][C:10]5[CH:11]=[CH:12][C:7]([N:6]6[C:2]([CH3:1])=[N:3][N:4]=[N:5]6)=[CH:8][CH:9]=5)=[C:16]4[CH:23]=[N:22]3)[CH2:25][CH2:26]2)[O:34][N:33]=1)([CH3:37])[CH3:36]
Reactant: Cc1nnnn1-c1ccc(O)cc1
Reactant: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3[C@H]2CC[C@H](c3nc(C(C)C)no3)CC2)cc1
Temperature: 180 °C

Procedure:
A mixture of 4-(5-methyl-tetrazol-1-yl)-phenol (Chembridge Corporation, San Diego, Calif., USA; 76 mg, 0.43 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 26; 150 mg, 0.43 mmol), and potassium carbonate (72 mg, 0.52 mmol) in dimethylformamide (5 mL) was heated in a microwave at 180° C. for 10 min. The mixture was filtered. The filtrate was concentrated and purified using a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-1H-pyrazolo[3,4-d]pyrimidine (86 mg, 41%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[N:12]=[C:13]=[S:14])[CH3:2].[CH2:15]([NH:17][CH2:18][C:19](O)=[O:20])[CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:15]([N:17]1[CH2:18][C:19](=[O:20])[N:12]([C:4]2[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:13]1=[S:14])[CH3:16]
Reactant: CCNCC(=O)O
Reactant: CCc1cccc(C(C)C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C(C)C)c1N1C(=O)CN(CC)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 28 using 20.5 g of 2-ethyl-6-isopropylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % ethyl acetate in hexane). Crystallization from diethyl ether/hexane afforded pure title compound (7.5 g) as a white solid, m.p. 77°-79° C. Anal. Calcd. for. C16H22N2O S: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.12; H, 7.77; N, 9.69. Mass spectrum i2EI, M.+) m/z 290.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrC(C)C(Br)=[O:48]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:48])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Reactant: CC(Br)C(=O)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 987 mg of trans-6-amino-3 -chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part B) in 50 mL of dry ether was added 0.350 mL of dry pyridine and 1.66 g of α-bromopropionyl bromide. The cooling bath was removed and then after 30 min at ambient temperature, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 50 mL of dry DMF, 2.35 g of lithium iodide and 2.3 g of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 3 days. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product. The title compound was obtained by crystallization from ethyl acetate/hexanes, and recrystallization from ethyl acetate afforded 650 mg of pure title compound: mp 171-172°; HRMS: Calcd. for C16H168NO2F3Cl (M+H)+: 346.082166. Found: 346.080681: mp 147-147.5°; HRMS: Calcd. for C17H18NO2F3Cl (M+H)+: 360.097816. Found: 360.097869
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][CH:7]([CH2:24][O:25][C:26]1[C:31]2[C:32](=[O:39])[CH:33]=[C:34]([C:36]([NH2:38])=O)[O:35][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:8][O:9][C:10]1[C:15]2[C:16](=[O:23])[CH:17]=[C:18]([C:20]([NH2:22])=O)[O:19][C:14]=2[CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[Cl:6][CH:7]([CH2:8][O:9][C:10]1[C:15]2[C:16](=[O:23])[CH:17]=[C:18]([C:20]#[N:22])[O:19][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:24][O:25][C:26]1[C:31]2[C:32](=[O:39])[CH:33]=[C:34]([C:36]#[N:38])[O:35][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)c1cc(=O)c2c(OCC(Cl)COc3cccc4oc(C(N)=O)cc(=O)c34)cccc2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)c2c(OCC(Cl)COc3cccc4oc(C#N)cc(=O)c34)cccc2o1
Temperature: 0 °C

Procedure:
To 120 parts of N,N-dimethylformamide was slowly added 5 parts of phosphorous oxychloride with stirring and ice-cooling. Then 10 parts of 5,5'-[(2-chlorotrimethylene) dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxamide] were added to the solution, in small quantities, and the reaction mixture was stirred at room temperature for 60 hours. The resulting dark solution was poured into 500 parts of ice/water and the precipitated solid was filtered, washed with water and dried to give 6.8 parts of a brown powder. Crystalisation of this product from a mixture of ethanol and N,N-dimethylformamide gave 4.6 parts of 5,5'-[(2-chlorotrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carbonitrile] as white crystals, m.p. 185° C. (decomp.), giving a positive Beilstein's halogen test.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:27])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCCc2ccccc2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)c1ccc(OCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-Butyl 4-(4-(2-(2-Fluorophenyl)ethoxy)phenyl)-4-oxobutyrate (Step 2, 1.2 g, 3.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 4 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:7]=[N:6][CH:5]=1)=[O:3].[ClH:28].CO>>[ClH:28].[CH3:1][S:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[N:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: CS(=O)c1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 79 (138 mg) and 10% hydrogen chloride/methanol solution (3 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (92.2 mg) as brown powdery solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][CH2:22]Br)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH3:2].[N:24]1([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:1]([NH:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][CH2:22][N:27]2[CH2:28][CH2:29][N:24]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:25][CH2:26]2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: CCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(ethyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 42.2 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (54 mg, 0.076 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.42 (d, J=6.96 Hz, 1H), 8.50 (s, 1H), 8.30-8.34 (m, 1H), 8.11 (s, 1H), 7.80-7.86 (m, 1H), 7.77 (d, J=8.06 Hz, 1H), 7.71 (d, J=9.16 Hz, 1H), 7.43-7.48 (m, 1H), 7.32-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.16 (t, J=8.06 Hz, 2H), 7.00 (t, J=6.23 Hz, 2H), 6.67 (d, J=4.94 Hz, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 3.26-3.27 (m, 2H), 2.70 (t, J=7.33 Hz, 2H), 2.34-2.42 (m, 4H), 1.43-1.50 (m, J=4.76 Hz, 4H), 1.32-1.39 (m, 2H). MS (ESI): 708 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][OH:41].C([O-])(O)=O.[Na+]>>[OH:41][N:40]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][C@@H:10]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])=[O:31])=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)N[C@@H](C)C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccc(-c3ccc(C(=O)N[C@@H](C)C(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from (S)-2-({4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-propionic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white solid, MS (ESI+): m/z=522.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:2][CH2:3][CH3:4].[C:22]1([O:28][CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:21])[CH:7]([C:25]1[CH:26]=[CH:27][C:22]([O:28][CH3:29])=[CH:23][CH:24]=1)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)c1ccc(OC)cc1

Procedure:
A solution of 0.91 g. (3.0 mmol.) of N-(β,β,β-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl ester and 0.3 g. (2.8 mmol.) of anisole in 20 ml. of methylene chloride containing two drops of boron trifluoride etherate was maintained at 25° for 5 hours. The solvent was then evaporated in vacuo and 2:1 hexane-methylene chloride was added. Chromatography on silica gel with methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=1.[CH3:23][C:24]([O-:27])([CH3:26])[CH3:25].[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+]>[Br:12][C:10]1[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=[C:2]([O:27][C:24]([CH3:26])([CH3:25])[CH3:23])[CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Br)c2nc(Br)cc(Br)c2c1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (1.0 g, 1.98 mmol, 1.00 equip) in toluene (30 mL), and KOt-Bu (2.18 mL, 1.10 equip). The resulting solution was stirred for 1.5 h at 65° C. The resulting solution was diluted with saturated sodium chloride (50 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5:95) to yield 4,8-dibromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline as a yellow solid. LCMS (ES, m/z) 498 [M+H]+
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
Sodium triacetoxyborohydride (32.0 g, 151.0 mmol) is added to a stirred solution of tert-butyl 4-oxo-1-piperidine carboxylate (20.0 g, 100.4 mmol), isobutylamine (10.5 ml, 105.7 mmol), acetic acid (6.0 ml, 104.8 mmol) and 1,2-dichloroethane (300 ml). The reaction is stirred for 18 hours at room temperature under nitrogen. The reaction is poured into 2N NaOH (300 ml) and extracted with ethyl acetate (200 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield (24.5 g, 95%) of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=257.1 (M+1); 1H NMR (CDCl3): δ=4.01 (2H, br s), 2.78-2.75 (2H, m), 2.60-2.53 (1H, m), 2.42 (2H, d), 1.83-1.64 (3H, m), 1.56 (1H, br s), 1.44 (9H, s), 1.28-1.18 (2H, m), 0.90 (6H, d).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(C)cc2)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-p-tolyl-methanone (Example 354) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-p-tolyl-methanone. MS (M+H)+, 390
Reaction SMILES: [C:1]([Si:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:41][CH2:42][CH2:43][CH3:44]>C1COCC1>[C:1]([Si:5]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:44][CH2:43][CH2:42][CH2:41]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCCCCCCCCCCCCS(=O)(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a stirred solution of tert-butyldiphenyl(12-(phenylsulfonyl)dodecyloxy)silane (0.381 g, 0.675 mmol) in THF (2 mL) was added n-BuLi (2.5 M solution in hexanes, 0.297 mL, 0.742 mmol) at −78° C. under Argon. After stirring the resulting solution for 30 min, the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (2 mL) at −10° C. and the aqueous phase was extracted with DCM (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified by silica gel column chromatography using 5% ethyl acetate/hexane to afford the title product as a clear thick oil (0.16 g, 85%). 1H NMR (CDCl3): δ7.89-7.39 (m, 15H), 5.37 (m, 8H), 3.64 (t, 2H, J=6.5 Hz), 2.78 (m, 7H), 2.08 (m, 4H), 1.82 (m, 2H), 1.37-1.20 (m, 30H), 1.04 (s, 9H), 1.04 (t, 3H, J=6.7 Hz). m/z (ESI) 837.74 (M++1).
Reaction SMILES: ClC1C=C([C:8]2[CH:9]=[C:10]([CH:14]=[C:15](C3C=CC=C(Cl)C=3)[C:16]=2[O:17][CH2:18]CO)[C:11]([OH:13])=[O:12])C=CC=1.COC1C=CC(C(OCCCCCCN)=O)=CC=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: COc1ccc(C(=O)OCCCCCCN)cc1
Product: COc1ccc(C(=O)O)cc1

Procedure:
The product was prepared as a colorless, viscous oil (0.675 g, 71%) from 3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid (0.605 g, 1.5 mmol) and 4-methoxybenzoic acid, 6-aminohexyl ester (0.565 g, 2.25 mmol) using a procedure similar to step 3 of example 164; 1H NMR (400 MHz, DMSO-d6) 1.33-1.46 (m, 4H), 1.50-1.58 (m. 2H),1.65-1.73 (m, 2H), 3.10-3.15 (m, 2H), 3.22-3.30 (m, 4H), 3.80 (s, 3H), 4.21 (t, J=6.6,Hz, 2H), 4.44 (t, J=6.6 Hz, 1H), 6.99-7.03 (m, 2H), 7.45-7.52 (m, 4H), 7.57-7.61 (m, 2H), 7.69 (s, 2H), 7.85-7.91 (m, 4H), 8.56 (t, J=5.5 Hz, 1H); IR (film) 3350, 2940, 1710, 1640, 1605, 1540, 1510, 1275 cm−1; mass spectrum[(+)ESI], m/z 636 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:8][C:9](=[O:18])[N:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:7])[CH3:6].[CH3:22][O-].[Na+].CI>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:8][C:9](=[O:18])[N:10]([O:17][CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(NC(=O)N(O)c1ccccc1)c1cccc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CON(C(=O)NC(C)(C)c1cccc(Cl)c1)c1ccccc1
Yield: 83.3 %

Procedure:
A solution of 2.2 g of N-phenylhydroxylamine in 10 ml of benzene was added to a solution of 0.02 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as in Synthesis Example 1) in 10 ml of benzene. The mixture was stirred well and allowed to stand overnight. The precipitated crystals were filtered off and washed with n-hexane to yield 5.7 g of 3-(m-chloro-α,α-dimethylbenzyl)-1-hydroxy-1-phenylurea. To 3.1 g of the urea was added a solution of 550 mg of sodium methoxide in 10 ml of methanol. The mixture was made homogeneous by stirring and 1.5 g of methyl iodide was added thereto. The mixture was then heated under reflux for 2 hours. The solvent was evaporated off and the residue was extracted with benzene and water was added. The benzene layer was dried over sodium sulfate and the solvent was distilled off to give crystals, which were recrystallized from a mixture of n-hexane and benzene to obtain 2.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:13]=[C:12]([Br:11])[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cccc(Br)c2)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 6.9 grams (0.044 mole) of 4-chlorophenylboronic acid (commercially available), 25.0 grams (0.100 mole) of 1,3-dibromobenzene, 0.2 gram (catalyst) of tetrakis(triphenylphosphine)palladium(O), 75 mL of aqueous 2M sodium carbonate, and 75 mL of toluene, yielding 3-(4-chlorophenyl)phenyl bromide.