Azzindani/Open_Reaction_Data huggingface dataset:
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][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(propylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 96) (371 mg, 0.84 mmol) in hydrogen chloride in 1,4-dioxan (4M) (4 ml) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The solid was dissolved in fresh hydrogen chloride in 1,4-dioxan (4M) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a yellow oil (313 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].FC(F)(F)C([O-])=O.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25]=1[CH:38]1[CH2:42][CH2:41][NH2+:40][CH2:39]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:5]([O:4][C:2]([N:40]1[CH2:41][CH2:42][CH:38]([C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:24]=2[O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:39]1)=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: c1ccc(COc2ccc(C3CC[NH2+]C3)c(OCc3ccccc3)c2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)COC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is dissolved in 5 ml of tetrahydrofuran in the presence of 0.25 ml of N,N-diisopropylethylamine. 0.108 g of isobutyl chloroformate is added and the reaction mixture is stirred for 30 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.22 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid isobutyl ester is obtained. Yield=66%.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([OH:14])[CH:13]=1)[CH:9]=[O:10].[OH:19][C:20]1C=C(C=C(O)C=1)C(O)=O>>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:9]([O:19][CH3:20])=[O:10]
Reactant: O=Cc1cc(O)cc(OCc2ccccc2F)c1
Reactant: O=C(O)c1cc(O)cc(O)c1
Product: COC(=O)c1cc(O)cc(OCc2ccccc2F)c1

Procedure:
The same experimental conditions were used as described previously for the synthesis of 3-(2-fluorobenzyloxy)-5-hydroxybenzaldehyde (217a) except that the reaction began with 3,5-dihydroxy benzoic acid. The LC/MS gave a calculated and found (M+H+)=277.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]CBr>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=1
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCBr)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl]-N′-propylurea 50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: CN1CCNCC1
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 32.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.265 g, 0.495 mmol), N-methylpiperazine (0.065 mL, 0.58 mmol), and triethylamine (0.10 mL, 0.74 mmol) in DMF (5 mL) was heated at 70° C. for 20 h. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. Water (25 mL) was added and the resulting precipitate was collected by filtration, washed with water (25 mL) and ether (50 mL), and dried in vacuo to afford a brown solid which was purified by silica gel column chromatography. The appropriate fractions were combined and concentrated to afford N2-(4-{4-amino-1-[2-(4-methylpiperazino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide as a beige solid (0.084 g, 0.16 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.11 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=8.4 Hz), 7.29-7.35 (4H, m), 7.15 (1H, t, J=7.4 Hz), 4.46 (2H, t, J=6.8 Hz), 4.04 (3H, s), 3.96 (3H, s), 2.80 (2H, t, J=6.6 Hz), 2.49-2.50 (2H, obscured by DMSO peak), 2.23-2.26 (4H, m), 2.12 (3H, s), and 0.97-0.99 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.24. MS: MH+540.3.
Reaction SMILES: [C:1]([C:12]1[CH:20]=[C:16]([C:17]([OH:19])=O)[C:15]([OH:21])=[CH:14][CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].P(Cl)(Cl)Cl.[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClC1C=CC=CC=1>[C:1]([C:12]1[CH:20]=[C:16]([C:17]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[O:19])[C:15]([OH:21])=[CH:14][CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCC(=O)c1ccc(O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 60 °C
Yield: 23.2 %

Procedure:
In a 100 ml round-bottom flask fitted with a condenser and drying tube is placed 5-n-decanoylsalicylic acid (1.85 g., 6.7 mmoles), dry chlorobenzene (50 ml), and phosphorous trichloride (0.47 g., 3.4 mmoles). The mixture is then stirred by means of a magnetic stirring bar while the mixture is heated to 60° C. for three hours. The resulting solution is cooled to room temperature and 0.93 g. (6.7 mmoles) of p-nitroaniline is added. The mixture is then heated to 60° C. for three hours, with stirring, and then refluxed for 24 hours. The solvent is removed by vacuum vaporization and the residue is recrystallized from ethanol-water. The crystalline product is triturated with concentrated hydrochloric acid, collected and washed with water. Recrystallization from ethanol-water gives 0.64 grams of 5-n-decanoyl-4'-nitrosalicylanilide, mp 142°-143° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CCN(CC)CC>C(Cl)Cl>[CH:25]1([NH:30][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.5 g, 2.301 mmol), HATU (1.05 g, 2.76 mmol) and cyclopentanamine (0.455 mL, 4.60 mmol) in DCM (20 mL) was added Et3N (0.642 mL, 4.60 mmol). The reaction mixture was stirred at room temperature for 5 h, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound (0.61 g, 94%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=23)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCN(Cc2ccccc2)CC1
Yield: 58.3 %

Procedure:
1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (400 mg, 1.23 mmol) and 1-benzylpiperidin-4-amine (1.70 mL, 8.93 mmol) was stirred with N,N-diisopropylethylamine (251 μL. 1.47 mmol) at 140° C. for one day. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (343 mg, yield 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.ClCCCN1CCCCC1>CC(N(C)C)=O.C1(C)C=CC=CC=1.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(=O)N(CCCN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 8.52 g (39.75 mmol) of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 200 ml of DMA was treated at 0° C. with 2.60 g (59.6 mmol) of NaH (55% dispersion in oil) in small portions. The reaction was stirred 1 h at this temperature, then the free 1-(3-chloropropyl)piperidine in 200 ml toluene was dropped in [49.62 g (250.42 mmol, 6.3 eq.) 1-(3-chloropropyl)piperidine hydrochloride were dissolved in 262 ml of 1 M aq. NaOH solution and extracted with toluene (200 ml). The organic phase was dried over Na2SO4]. The reaction was warmed up to RT and stirred overnight. After 2 h at 50° C. and cooling to RT, the reaction was neutralized with water (50 ml), evaporated and then dissolved in sat. aq. NaHCO3/Et2O. After reextraction with Et2O, the organic phase was dried (Na2SO4), evaporated and crystallized from pentane to yield 12.08 g (90%) of the title compound as white crystals. MS: 340.2 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[C:15]([CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16].CC(C)([O-])C.[K+]>O1CCCC1>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:19]/[CH2:18][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C/C=C/c1ccc(-n2ccnc2)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
5.45 g of 4-(1H-imidazol-1-yl)benzaldehyde and 12.93 g of β-carboxyethyltriphenylphosphonium chloride were suspended in 70 ml of tetrahydrofuran. The obtained suspension was cooled to -50° C. and vigorously stirred. 30 ml of a solution of 7.83 g of potassium t-butoxide in tetrahydrofuran was gradually added dropwise to the resulting suspension. The temperature of the obtained mixture was gradually raised to 0° C. After one hour, ice-water was added to the mixture. The obtained mixture was washed with ether. The pH of the aqueous layer was adjusted with concentrated hydrochloric acid to about 4 to precipitate a solid. This solid was recovered by filtration and washed with water and methanol to obtain 5.44 g of the title compound as a pale yellow powder (yield: 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:7]=[CH:6]1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32].[OH-].[Na+]>C(Cl)Cl.C(Cl)Cl.CO>[CH3:30][S:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:7]=[CH:6]1)(=[O:33])=[O:32]
Reactant: NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
To the compound of Example 4, described above (79 mg, 0.26 mmol) in CH2Cl2 (0.5 mL) was added Et3N (72 uL, 0.52 mmol), and then methanesulfonyl chloride (25 uL, 0.31 mmol). The reaction exothermed to CH2Cl2 reflux briefly. The reaction was over within 1 min based on tlc (19:1 CH2Cl2 /MeOH) and was poured into 10% NaOH (5 mL) and extracted with EtOAc (3×20 mL). The extracts were washed with H2O (10 mL) and satd aq Nacl (10 mL), dried (Na2 SO4), concentrated and flash chromatographed (1×10 cm silica) with 0-8% MeOH in CH2Cl2 to afford 63 mg (65%). mp=186°-187°.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[CH3:19][O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([SH:34])=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2>>[CH3:19][O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([S:34][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2
Reactant: COC(=O)COc1c(C)cc(S)c2c1CCC2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Product: COC(=O)COc1c(C)cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCC2

Procedure:
The title compound was prepared from 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole and (7-mercapto-5-methyl-indan-4-yloxy)-acetic acid methyl ester (prepared in a similar manner as described for Example 1D) in a manner analogous to Example 1E. MS m/z 508 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=1)[C:35](O)=[O:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:35](=[O:36])[C:34]3[CH:38]=[C:30]([CH3:29])[CH:31]=[N:32][CH:33]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: Cc1cncc(C(=O)N(Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)C(C)C)c1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 5-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.2 (s, 1H)) 8.7 (s, 1H) 8.4 (s, 1H) 8.3 (m, 2H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 7.0 (d, 1H) 5.6 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 2.4 (s, 3H) 1.2 (d, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[C:8]([CH3:17])([CH3:16])[C:7]1=[O:18].[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:16])([CH3:17])[C:7](=[O:18])[N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: COCCCN1C(=O)C(C)(C)c2ccc(C)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COCCCN1C(=O)C(C)(C)c2ccc(CBr)cc21
Temperature: 25 °C

Procedure:
The mixture of 1.08 g of 1-(3-methoxypropyl)-3,3,6-trimethyl-1,3-dihydroindol-2-one, 0.801 g of N-bromosuccinimide, 0.014 g of 2,2′-azobis(2-methylpropionitrile) and 0.021 g of dibenzoyl peroxide in 50 ml of carbon tetrachloride is heated to reflux with stirring. The reaction mixture is stirred at reflux over 1 hour (succinimide crystallizes out) and subsequently cooled to room temperature. The succinimide is filtered off and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.40 (dichloromethane-diethyl ether); Rt=17.22 (II).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.O[C:45]1[CH:46]=[CH:47][CH:48]=[C:49]2[C:54]=1[N:53]=[C:52]([NH:55][C:56]1[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=1)[N:51]=[CH:50]2>C1COCC1>[CH3:43][N:40]1[CH2:41][CH2:42][CH:37]([O:36][C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:54]=2[N:53]=[C:52]([NH:55][C:56]2[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=2)[N:51]=[CH:50]3)[CH2:38][CH2:39]1
Reactant: CN1CCC(O)CC1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3cccc(O)c3n2)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a 0.3M solution of triphenylphosphine (1.5 eq) in THF was added di-tert-butylazodicarboxylate (1.5 eq). The mixture was stirred 15 minutes at ambient temperature. 4-Hydroxy-1-methylpiperidine (4.5 eq) was added. The mixture was stirred 15 minutes at ambient temperature. 3-(8-Hydroxyquinazolin-2-ylamino)benzenesulfonamide (1.0 eq) was added. The mixture was stirred an additional 1 hour. The crude mixture was concentrated, purified by RPHPLC, and lyophilized to give the desired product in 24.2% yield ES/MS m/z 414 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]3[S:24](=[O:25])[CH2:23][CH2:22][N:21]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)(=[O:28])=[O:27])[C:20]=3[CH:36]=2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C.O>C(O)=O>[Cl:35][C:31]1[CH:30]=[C:29]([S:26]([N:21]2[C:20]3[CH:36]=[C:16]([C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([OH:37])=[O:5])=[CH:8][CH:9]=4)=[O:15])[CH:17]=[CH:18][C:19]=3[S:24](=[O:25])[CH2:23][CH2:22]2)(=[O:27])=[O:28])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCS3=O)cc1
Solvent: O
Solvent: O=CO
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCS3=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A suspension of 4-{[4-(3-chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic acid tert-butyl ester (153 mg, 0.273 mmol) in formic acid (4 mL) was stirred for 16 h at room temperature, then the solution obtained was treated with water, and the suspension was stirred for another 90 min. The precipitate was collected by filtration and dried to produce the title compound (126 mg, 92%). White solid, 505.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:3]1.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:38])([CH3:37])[C:34](=[O:39])[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:32]=2[CH:45]=1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:3][CH:2]2[O:1][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][C:35]([CH3:38])([CH3:37])[C:34](=[O:39])[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:32]=3[CH:45]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(CCl)cc21
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC)cc3)cc21

Procedure:
Analogously to Method D, 0.500 g of benzyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate and 0.505 g of 6-chloromethyl-(3-methoxypropyl)-2,2-dimethyl-4H-benz[1,4]oxazin-3-one are reacted. The title compound is obtained as an orange oil. Rf=0.17 (1:1 EtOAc-heptane); Rt=5.51.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)CC(N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)CC(C)(C)C

Procedure:
2-Amino-4,4-dimethyl-pentanoic acid (1.00 g, 6.84 mmol) was suspended in 50 mL of methanol and cooled in an ice bath. Thionyl chloride (1.82 g, 15.0 mmol) was added dropwise, at which time all the acid went into solution. The reaction was then removed from the ice bath and heated to reflux for 3.5 h. The reaction mixture was concentrated in vacuo and the resulting solid (1.10 g) was used in the next step without further purification. MS, m/z 159.9=M+1