Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:32][C:33]1[C:38]([CH:39]=O)=[CH:37][CH:36]=[CH:35][N:34]=1.CC(O)=O>ClCCCl>[NH2:32][C:33]1[C:38]([CH2:39][N:29]2[CH2:30][CH2:31][N:26]([C:24]([C:22]3[N:23]=[C:19]([CH2:18][N:4]([CH:1]4[CH2:2][CH2:3]4)[S:5]([C:8]4[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=4[CH3:14])(=[O:6])=[O:7])[O:20][CH:21]=3)=[O:25])[CH2:27][CH2:28]2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: Nc1ncccc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cccnc4N)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-amino-3-pyridinecarboxaldehyde (10 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)cccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichlorobenzene and isolated as white solid (5.2 mg, 29%). MS (m/e): 441.3 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:6]([C:32]([OH:34])=O)[CH2:5]1)(=[O:3])[CH3:2].[NH2:35][OH:36]>>[C:1]([N:4]1[CH2:8][C@H:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C@H:6]([C:32]([NH:35][OH:36])=[O:34])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)O)C1
Product: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)NO)C1
Yield: 41 %

Procedure:
According to the procedure of example 17, Step 5, the reaction of 113.5 mg of cis-1-acetyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid with hydroxylamine provided 39 mg (41% yield) of cis-1-acetyl-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxamide. MS: 499.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH3:12])[CH:5]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:19]=[C:16]([CH3:17])[S:18][C:11]=2[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Reactant: CC(N)=S
Product: COC(=O)c1cccc(-c2nc(C)sc2C)c1
Temperature: 130 °C
Yield: 80.4 %

Procedure:
A mixture of rac-3-(2-bromo-propionyl)-benzoic acid methyl ester (6.78 g) and thioacetamide (5.63 g) was heated to 130° C. for 20 min. The mixture was partitioned between AcOEt and H2O, the organic layer was dried and evaporated and the residual oil was chromatographed on silica gel using AcOEt/hexane (1:4) as eluent to give 3-(2,5-dimethyl-thiazol-4-yl)-benzoic acid methyl ester (4.97 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: FC(F)(F)CCBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(F)(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Reaction time: 8 h

Procedure:
The mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol), 3-bromo-1,1,1-trifluoropropane (85.0 uL, 0.60 mmol) and triethylamine (102.0 uL, 0.60 mmol) in 2 mL of DMF was stirred overnight. The reaction mixture was purified by preparative RP-HPLC to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 512.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([F:37])[C:34](O)=[C:33]([Cl:39])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([F:37])[C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([Cl:39])[CH:32]=1
Reactant: COC(=O)c1cc(F)c(O)c(Cl)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1
Yield: 74 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), and 3-chloro-5-fluoro-4-hydroxy-benzoic acid methyl ester (CAS RN 369-15-3) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless foam (74%). MS (Turbo Spray): 577.1 [M+H].
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34]>C(O)C>[OH:34][CH2:33][CH2:32][NH:31][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: NCCO
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(NCCO)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 412 mg (6.74 mmol) of 2-aminoethanol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 82.2 mg (52% of theory)
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].C[N+]1([O-])CC[O:22]CC1>C(#N)C>[Cl:17][C:4]1[C:3]([CH:2]=[O:22])=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 41.0 g (0.12 mol) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate in 250 ml of acetonitrile was treated with 42.1 g (0.36 mol) of N-methylmorphline N-oxide. The batch was stirred for 12 hours at room temperature and subsequently concentrated, and the residue was taken up in ethyl acetate. The solution was extracted with water, dried with sodium sulfate and concentrated. This gave 31.2 g (94% of theory) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 3. Quantities: compound 1 (4.03 g, 21.1 mmol), 1-bromotetradecane (6.41 g, 23.1 mmol), potassium carbonate (5.59 g, 40.5 mmol) and butanone (115 ml).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:17]3[CH:18]=[CH:5][C:4]4[C:16](=[CH:17][CH:18]=[CH:2][CH:3]=4)[CH:15]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(-c2nc(-c3ccc4ccccc4c3)c[nH]2)cc1

Procedure:
Benzamidine hydrochloride and an equimolar amount of sodium methylate were heated under reflux in tetrahydrofuran for 1 hour. After cooling, a tetrahydrofuran solution of an equimolar amount of ω-bromo-2-acetonaphthone was added dropwise thereto so that the temperature did not exceed 30° C., and then an equimolar amount of sodium methylate was further added, followed by heating under reflux for 1 hour. After removal of the solvent by distillation under reduced pressure, the residue was washed with water and subjected to recrystallization from acetonitrile to obtain grayish blue crystals.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[C:43]([S:42][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:44]=2)=[O:21])[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 40 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 167B (0.186 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea as solid (95 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.23-7.80 (m, 10H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.31 (s, 3H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[F:11].C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[F:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([F:8])=[CH:7][C:2]=1[CH:20]=[O:21]
Reactant: COc1cc(F)c(Br)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C=O)cc1F
Temperature: -78 °C
Yield: 99.4 %

Procedure:
To a 250 mL three RB flask fitted with magnetic stirrer was charged 1-Bromo-2,5-difluoro-4-methoxybenzene (1.0 g, 4.5 mmol) in 10 mL of THF, cooled −78° C. To the stirred solvent was added n-butyl lithium (3.09 mL, 1.6M solution, 4.95 mmol) drop wise and stirred at same temperature, was added DMF (0.375 g, 5.13 mmol), once the temperature to reached room temperature and stirred about 16 h. Then reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4. The removal of solvent under reduced pressure to obtain liquid product (0.77 g, yield: 100.0%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])(=[O:15])=[O:14]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CS(=O)(=O)c1cccc(Nc2cc(F)ccc2[N+](=O)[O-])c1

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (0.571 mL, 5.20 mmol) and 3-(methylsulfonyl)aniline (0.891 g, 5.20 mmol) to give 5-fluoro-N-(3-(methylsulfonyl)phenyl)-2-nitroaniline as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (1H, s), 8.25 (1H, dd, J=9.6, 6.1 Hz), 7.85-7.89 (1H, m), 7.64-7.75 (3H, m), 6.98 (1H, dd, J=11.4, 2.6 Hz), 6.79-6.87 (1H, m), 3.24 (3H, s); LC-MS (ESI) m/z 311.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH2:7][CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:9]([CH:8]1[O:16][C:29](=[O:31])[N:6]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC(CNc1ccc(Br)cc1)Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC(Cc2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 121.6 %

Procedure:
A solution containing 1-(4-bromoanilino)-3-phenyl-2-propanol (1.90 g, 0.00621 mol), N,N-diisopropylethylamine (2.48 g, 0.0193 mol) and N,N-dimethylaminopyridine (0.152 g, 0.00124 mol) in anhydrous dichloromethane (64 mL) was cooled to 0° C. and the solution of triphosgene (0.92 g, 0.0031 mol) in anhydrous dichloromethane (16 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for 18 hours. The organic phase was washed with saturated solution of sodium bicarbonate in water (70 mL), brine (60 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 5-benzyl-3-(4-bromophenyl)-1,3-oxazolan-2-one (1.25 g, 0.00377 mol) as a white solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: NCCOCCO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCOCCO)cn2)CC1
Yield: 79 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-(2-aminoethoxy)ethanol. And then, the product was recrystallized with acetone and hexane to give a desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[C:25]2[N:32]=[CH:31][S:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)CC)C>CCCCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH:22][C:24]1[C:25]3[N:32]=[CH:31][S:30][C:26]=3[N:27]=[CH:28][N:29]=1)[CH3:21])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Reactant: Clc1ncnc2scnc12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2scnc12)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Temperature: 25 °C

Procedure:
A mixture of (S)-1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethanamine 71 (100 mg, 0.31 mmol, 1 eq), 7-chlorothiazolo[5,4-d]pyrimidine (E-4) (108 mg, 0.63 mmol, 2 eq) and triethylamine (130 mg, 1.25 mmol, 4.0 eq) in n-BuOH (40 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)thiazolo[5,4-d]pyrimidin-7-amine 72. ESI-MS m/z: 455.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12][C:11]3=O)=[O:7])=[CH:4][CH:3]=1.P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:22][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]([C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]ccc(=O)c2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(4-chlorobenzoyl)quinolin-4(1H)-one (1.26 g, 4.45 mmol) in DMF (8 mL) at room temperature was added slowly phosphorous tribromide. The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until pH was greater than 10, diluted with water and filtered. The product was washed with several portion of water and dried to yield (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone. (M+H)+: 346, 348.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:37]([CH3:39])[CH3:38]>>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]1[N:31]=[CH:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cn(C(C)C)cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 20 %

Procedure:
Prepared using the same procedure described in Example 336 using 1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-(1H-imidazol-4-yl)-ethanone and 2-bromopropane to afford the title compound as an orange solid (67 mg, 20% overall). LC/MS (Method B) 2.88 min, [M+1]+ 517.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cn(CCC)nn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cn(CCC)nn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-4-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.55 g) was dissolved in methylene chloride (16.5 ml), and a solution of m-chloroperbenzoic acid (213 mg) in methylene chloride (11 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-4-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 280) (0.39 g).
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O>[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Yield: 89.6 %

Procedure:
A solution (1 ml) of 2N sodium hydroxide was added to an ethanol solution (5 ml) of 0.22 g (0.69 mmol) of methyl 4-tetradecylpyrrole-2-carboxylate prepared in Example 9 and heated under reflux for 13 hours. Water was added to the resulting mixture, and then washed with ether. After acidifying the aqueous layer with hydrochloric acid, the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The removal of the solvent afforded 0.19 g (95% yield) of 4-tetradecylpyrrole-2-carboxylic acid, m.p. 148°-150° C.