Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][O:4][CH2:5][CH:6](O)[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:17][CH:6]([CH2:5][O:4][CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)COCC(O)CN1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)COCC(Cl)CN1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
Dry hydrogen chloride gas was bubbled into an ice-cooled solution of 107.7 g (0.5 mole) of α-[(2,2-dimethylpropoxy)methyl]-1-pyrrolidineethanol (the product of Example 3a) in 110 ml of dry toluene until 20.05 g (0.55 mole) was taken up. This solution was added to a stirred ice-cooled suspension of 109.4 g (0.525 mole) of phosphorous pentachloride in 60ml of dry toluene (argon atmosphere) at a rate to keep the reaction temperature between 10°-15° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 1.5 hr. The reaction mixture was added to a stirred ice-cooled solution of 385 ml (4.5 mole) of 45% potassium hydroxide and 700 ml of ice at a rate to keep the reaction temperature between 25°-35° C. The reaction mixture was stirred for 0.5 hr then extracted with toluene. An immiscible oil formed between the layers. The oil was partitioned between dichloromethane and water. The dichloromethane layer and the toluene layer above were combined, dried and concentrated to dryness to give 84.3 g of oil. The oil was distilled (65°-86° C. at 0.35 mm) to give 76.63 g of oily product.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9]([CH3:28])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O-:25])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:26]=1[CH3:27])=[O:5].[C:32](OCC)(=O)[CH3:33].CCCCCC>>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9]([CH3:28])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:32][CH3:33])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:26]=1[CH3:27])=[O:5]
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(/C=C/C(=O)[O-])cc1)CO2
Solvent: CCCCCC
Product: CCOC(=O)CCc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 84 %

Procedure:
Using (2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate obtained in Example 178, the title compound was synthesized in the same manner as in Example 180. Yield: 84%. Melting point: 103-105° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.I[C:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=2)=[CH:6][CH:5]=1)[CH3:12]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccc(CN(C)C)cc1
Product: CN(C)Cc1ccc(/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)cc1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A22A, utilizing N,N-dimethyl-1-(4-vinylphenyl)methanamine (42 mg, 0.26 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol) with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange gum (33.4 mg, 44%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1 H), 8.27 (m, 2 H), 7.81 (d, J=9.29 Hz, 1 H), 7.69 (d, J=8.28 Hz, 2 H), 7.61 (d, J=16.6 Hz, 1 H), 7.50 (d, J=16.6 Hz, 1 H), 7.43 (d, J=8.28 Hz, 2 H), 5.86 (s, 2 H), 3.82 (s, 2 H), 3.62 (t, J=8.03 Hz, 1 H), 2.50 (s, 6 H), 0.87 (t, J=8.03 Hz, 2 H), −0.09 (s, 9 H); MS ESI 436.3 [M+H]+, calcd for [C25H33N3O2Si+H]+ 436.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.C([S:39][C:40]([CH3:48])([CH3:47])[C@@H:41]([C:43]([O:45][CH3:46])=[O:44])[NH2:42])C1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:42][C@H:41]([C:43]([O:45][CH3:46])=[O:44])[C:40]([SH:39])([CH3:48])[CH3:47])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)(C)SCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)S
Temperature: -70 °C

Procedure:
146 g of t-butoxycarbonyl proline are dissolved in 1500 ml of methylene chloride. 150 ml of N-methylmorpholine are added to the solution. The solution is cooled to -70° C. 89 ml of isobutylchloroformate are added. The reaction mixture is warmed to -15° C. and then cooled to -70° C. 197 g of methyl S-benzylpenicillaminate hydrochloride are added to the reaction mixture. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is extracted three times with 1.0 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in a minimum of diethyl ether. The ether solution is added to cold rapidly stirring hexane. The white precipitate is filtered and dried to afford the product, methyl t-butoxycarbonylprolylpenicillaminate.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(N(C)C)=O>[C:25]([N:4]1[C:3](=[O:17])[C:2]([F:1])=[CH:15][N:6]([C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:5]1=[O:16])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15 Grams of 2'-deoxy-5-fluoro uridine (FudR) was dissolved in 45 ml of dimethylacetamide. Thereto was added 9 ml of triethylamine. To the mixture being cooled with ice-water was added 8.6 g of benzoyl chloride and the whole mixture was stirred overnight. The reaction mixture was subjected to filtration. The resulting filtrate was subjected to evaporation to obtain the residue, and water was added to the residue. The aqueous solution was extracted with ethyl acetate, and the organic layer was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was concentrated and the residue was recrystallized from ethanol to obtain the desired compound. The yield was 10.5 g. M.p. 126° to 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of p-chlorophenyl isocyanate (15.3 g, 0.10 mol) in toluene (50 ml) is metered at room temperature into a solution of methyl anthranilate (15.1 g, 0.10 mol) in toluene (100 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. Triethylamine (1.4 ml, 1.0 g, 0.010 mol) is metered in and the mixture is stirred at 90° C. for a further 3 hours. After cooling, the product is filtered off with suction and washed with 3×20 ml of toluene and dried. 21.0 g of 3-(4-chlorophenyl)-2,4(1H,3H)-quinazolinedione (yield: 77.0% of theory) of melting point 288° to 290° C. are obtained. According to thin-layer chromatography, the product is contaminated with the intermediate ethyl N-(4-chlorophenylcarbamoyl)anthranilate.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[CH2:16][NH:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:23][S:20]([CH2:19][CH2:18][NH:17][CH2:16][C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([N:31]5[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]5)=[CH:39][CH:38]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(CNCCS(C)(=O)=O)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1

Procedure:
Into a microwave vial, [3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-(2-methanesulfonyl-ethyl)-amine (0.100 g, 0.000255 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.214 g, 0.00112 mol), 1-Methoxy-2-propanol (0.613 mL) and N,N-Diisopropylethylamine (0.133 mL, 0.000764 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 15% methanol). The collected fractions afforded (7-{3-[(2-Methanesulfonyl-ethylamino)-methyl]-phenyl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine a yellow solid (41 mg, 31%). LCMS (E/I+) 520.16 (M+H). NMR 1H (DMSO-d6)-9.76 (ns, 1H), 9.37 (s, 1H), 9.20 (bs, 2H), 8.99 (s, 1H), 8.42 (d, 2H, J=7.45 Hz), 8.16 (s, 1H), 7.61-7.72 (m, 3H), 7.51 (d, 1H, J=7.45 Hz), 7.15 (d, 1H, J=4.47 Hz), 6.91-7.04 (m, 4H), 4.31 (s, 2H), 3.76 (d, 2H, J=12.66 Hz), 3.34-3.63 (m, 6H0, 3.08-3.24 (m, 5H), 2.82-3.00 (m, 5H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Cl:16])=[C:11]([OH:17])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:5]3[S:1][C:2]4[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=4[CH:4]=3)[CH:7]=2)[C:12]=1[Cl:16])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
A mixture of 6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-ol (3.19 g, 10.2 mmol) and cesium carbonate (6.8 g, 21 mmol) in acetone (100 mL) was stirred at ambient temperature for one hour and 15 minutes. Ethyl bromoacetate (1.4 mL, 12 mmol) was added, and the reaction mixture was stirred for 3.5 hours at ambient temperature. The insoluble solids were then filtered, and the filtrate was solvent evaporated. The residue was dissolved in hot chloroform and washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was then stirred in hexane for about ten minutes and filtered and rinsed with hexane. Drying at 65° C. in vacuo for two hours yielded (6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-yloxy)-acetic acid ethyl ester as a light yellow solid (2.7 g, 67%): MP: 187–8° C.; Mass spectrum (+ES, [M+H]+) m/z 397/399. 1HNMR (500 MHz, DMSO-d6): δ8.34 (d, 1H, J=1.68 Hz), 8.21 (d, 1H, J=8.85 Hz), 8.13 (dd, 1H, J=8.93 and 1.76 Hz), 8.01–8.07 (m, 3H), 7.89–7.90 (m, 1H), 7.52 (d, 1H, J=9.15 Hz), 7.37–7.44 (m, 2H), 5.11 (s, 2H), 4.20 (q, 2H, J=7.12 Hz), 1.23 ppm (t, 3H, J=7.10 Hz). Elemental Analysis for C22H17ClO3S: Calcd: C, 66.58; H, 4.32; N, 0.00; Found: C, 66.43; H, 4.27; N, 0.00.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)[CH2:29][CH2:30]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-pyridin-2-yl-piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=449.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH:15]1([NH:1][C@@H:2]2[CH2:7][C:6]3[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=3[O:4][CH2:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c2c1C[C@@H](NC1CCCCC1)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-8fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.45 g, 2.2 mmol), cyclohexanone (0.7 g, 7.2 mmol) and HOAc (0.14 g, 2.3 mmol) in methanol (25 mL) was NaCNBH3 (0.5 g, 8 mmol) added in portions at room temperature. The solution was stirred at room temperature overnight to give a quantitative yield of the title compound. GC/MS (70 eV) M=279 (30%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[OH-:13].[K+].Cl>>[Cl:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cn1ccc2c(Cl)nc(Cl)nc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: Cn1ccc2c(=O)[nH]c(Cl)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (2.39 g, 11.8 mmol) was treated with a 2M aqueous potassium hydroxide solution (70 mL, 140 mmol). The reaction was warmed to 100° C., where it was stirred overnight. The reaction was allowed to cool down to room temperature gradually, where it stirred for an additional 2 nights. The reaction was brought to pH ˜7-8 with a 3N aqueous hydrochloric acid solution. The resulting light yellow mixture was cooled in an ice/water bath and filtered, rinsing twice with a small amount of water. The filtrate was brought to pH ˜2-3 with additional 3N aqueous hydrochloric acid solution. The resulting opaque light yellow mixture was filtered through the original filter cake. The solids were dried in vacuo to afford 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (2.18 g, 100%). NMR (300 MHz, DMSO-d6) δ ppm 3.67 (s, 3H) 6.46 (d, J=3.39 Hz, 1H) 7.11 (d, J=3.39 Hz, 1H) 12.83 (br. s., 1H). LC-MS calcd. for C7H7ClN3O [(M+H)+] 184, obsd, 183.9.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH3:17].Cl>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[CH2:16][CH3:17]
Reactant: CCCBr
Reactant: OB1OCc2ccc(O)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
H181 (110 mg, 0.73 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 117 mg, 2.93 mmol) and 1-bromopropane (0.26 mL, 2.93 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (89 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.1 & 2.4 Hz, 1H), 4.91 (s, 2H), 3.92 (t, J=6.8 Hz, 2H), 1.78-1.68 (m, 2H) and 0.98 (t, J=7.2 Hz, 3H) ppm; Mp: 80-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH2:60]([N:67]1[CH2:71][CH2:70][CH:69]([CH2:72][NH2:73])[O:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C(#N)C.C(N(CC)CC)C>[CH2:60]([N:67]1[CH2:71][CH2:70][CH:69]([CH2:72][NH:73][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=3)=[CH:15][C:16]=2[CH3:23])[O:68]1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: NCC1CCN(Cc2ccccc2)O1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CCN(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (1.75 g) (prepared according to WO 2009/080250) in acetonitrile (35 ml) and triethylamine (2.04 ml) were added under nitrogen atmosphere TBTU (1.61 g), AZA.HOBT (0.68 g) and C-(2-Benzyl-isoxazolidin-5-yl)-methylamine (Step B, 1.61 g) were added. The resulting solution was stirred at room temperature for 4 hours, then quenched by addition of aqueous saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate, dried over sodium sulfate, filtered then concentrated in vacuo. The residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a white solid (60 mg, (mixture of diasteroisomers). LCMS (Method F) 2.20 min, M+H 636/638.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:12]=2[O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.Cl.[CH:32](I)([CH3:34])[CH3:33]>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[CH:32]([N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:11]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:12]=1[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(COc2ccc(Cl)cc2NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(Cl)cc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
To a solution of methyl 4-(2-phenylsulfonylamino-4-chlorophenoxy-methyl)benzoate (402 mg; prepared in Example 7(a)) in DMF (4 ml), potassium carbonate 256 (mg) and isopropyl iodide (185 μl) were added. The mixture was stirred overnight at room temperature and for 9 hours at 50° C. To the reaction solution, iced water and 2N HCl were added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over, concentrated after filtration, solidified with ethanol and washed to give the title compound (411 mg) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:24][C:25]#[CH:26])[C:13]([NH:15][CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([NH3+:64])[C:60]([O:62][CH3:63])=[O:61])=[N+:50]=[N-:51].CCN(C(C)C)C(C)C>CN(C=O)C>[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([C:60]([O:62][CH3:63])=[O:61])[NH:64][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:15][C:13](=[O:14])[CH:12]([CH2:24][C:25]#[CH:26])[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:50]=[N-:51]
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)O
Reactant: COC(=O)C([NH3+])CCC(=O)NCCCN=[N+]=[N-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)NCCCN=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of compound 4 (11.7 g; 31 mmol) in dry DMF (100 mL) was added EDCI (7.25 g; 37.82 mmol), HOBt (5.79 g; 37.82 mmol), and the reaction mixture was stirred at room temperature for 30 min (solution A). In the meantime, to a solution of compound 9 (8.67 g: 31 mmol) in dry DMF (100 mL) kept at 0° C. was added DIEA (10.01 g; 77.7 mmol) and stirred for 30 min (solution B). Solution B was mixed with solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (300 mL) and washed sequentially with saturated sodium bicarbonate (2×75 mL), 5% HCl (2×75 mL) and brine (75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, yielding a crude product which was purified using recrystallization to yield 9 as an off white solid (8.3 g; 46% yield). NMR (CDCl3) δ 8.1 (s, 1H), 7.9 (s, 1H), 7.8 (s, 1H), 7.5 (s, 1H) 7.3 (m, 5H), 5.0 (s, 2H), 4.3 (m, 1H), 4.1 (m, 1H), 3.3 (t, 1H), 2.8 (s, 1H), 2.4 (d, 2H), 2.2 (d, 2H), 2.1 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H), 1.4 (m, 1H), 0.8 (d, 6H)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CN(C)C(=O)CN1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide (Example 80) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine via General Procedure A. Purification on silica yielded 172. (400 MHz CDCl3): 2.61 (8H, s, CH2), 2.94 (3H, s, CH3), 3.07 (3H, s, CH3), 3.19 (2H, s, CH2), 3.82 (2H, s, CH2), 3.87 (4H, m, CH2), 4.01 (4H, m, CH2), 5.19 (2H, s, NH), 7.26 (1H, s, ar), 9.28 (2H, s, ar). MH+498.37
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(S(=O)(=O)Cl)oc2ccc(C(C)C)cc12
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)oc2ccc(C(C)C)cc12
Yield: 21.5 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-isopropyl-3-methylbenzofuran-2-sulfonyl chloride (Intermediate 16) (24 mg, 0.09 mmol) and 5-(3-amino-phenyl)tetrazole (28 mg, 0.17 mmol) giving 7.7 mg (21%) of the title compound. MS (ESI+) calcd for C19H19N5O3S 397.12086, found 397.12046.