Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(OCc3ccccc3)cc2)c1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(O)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.3 %

Procedure:
A round-bottom flask was charged with [4-(4-benzyloxy-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (4.17 g, 9.73 mmol) in ethanol (250 mL). A full spatula scoop of 10% palladium on carbon was added into the reaction flask. The reaction mixture was stirred under hydrogen gas at atmospheric pressure overnight at room temperature. The reaction mixture was then filtered through a bed of celite. The filtrate was concentrated to afford 3.96 g (100%) of [6-fluoro-4-(4-hydroxy-benzyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester, which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.17 (br. s, 1 H), 7.91 (dd, J=8.7, 6.2 Hz, 1 H), 7.74 (s, 1 H), 7.64 (dd, J=12.2, 1.9 Hz, 1 H), 7.33 (td, J=8.7, 1.9 Hz, 1 H), 6.83 (d, J=8.5 Hz, 2 H), 6.62 (d, J=8.5 Hz, 2 H), 4.32 (s, 2 H), 3.93 (s, 2 H), 3.64 (s, 3 H), 2.30 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[N:9]=[CH:10][C:5]2=[C:4]([C:11](=[O:12])[NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[CH:3]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.5 g, 1.33 mmol) in DMF (5 mL), K2CO3 (0.275 g, 1.99 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (0.529 g, 2.01 mmol) was added. Resulting reaction mixture was stirred at 80° C. for 12 h. On completion of reaction, water was added to it and extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.5 g, 67.2%).
Reaction SMILES: N(C(C1CCN(C(OC(C)(C)C)=O)CC1)=[O:4])N.N1C=CC=CC=1C#N.[C:26]1([C:32]2[C:33]([C:44]3[CH:49]=[CH:48][C:47]([CH2:50][N:51]4[CH2:56][CH2:55][CH:54]([C:57]5[N:61]=[C:60]([C:62]6[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=6)[NH:59][N:58]=5)[CH2:53][CH2:52]4)=[CH:46][CH:45]=3)=[N:34][C:35]3[N:36]([N:38]=[C:39]([C:41](N)=[O:42])[CH:40]=3)[CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CN(C=O)C.C(O)(=O)C.C(N(CC)CC)C>[C:26]1([C:32]2[C:33]([C:44]3[CH:45]=[CH:46][C:47]([CH2:50][N:51]4[CH2:52][CH2:53][CH:54]([C:57]5[N:61]=[C:60]([C:62]6[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=6)[NH:59][N:58]=5)[CH2:55][CH2:56]4)=[CH:48][CH:49]=3)=[N:34][C:35]3[N:36]([N:38]=[C:39]([C:41]([OH:42])=[O:4])[CH:40]=3)[CH:37]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: NC(=O)c1cc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C

Procedure:
0.14 ml triethylamine are added to a solution of 101 mg 2-(5-piperidin-4H[1,2,4]triazol-3-yl)-pyridine*2HCl (prepared from tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate and pyridine-2-carbonitrile according to a procedure described in U.S. Pat. No. 4,011,218 or WO2005100344) in 5 ml methanol. To this solution a solution of 150 mg 5-(4-formylphenyl)-6-phenylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (prepared as described under example 78) in 15 ml DMF is added, followed by 0.07 ml glacial acetic acid and 186 mg NaBH(OAc)3. The resulting mixture is stirred at room temperature. Additional portions of 2 equivalents NaBH(OAc)3 are added after 1, 2 and 3 hours. The solvent is removed by evaporation after 20 h and the residue is purified by RP HPLC (water, 10 mM NH4COOH, pH 3.7/ACN) to yield the desired compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69].[BH4-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:34][CH:35]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(N2C(=O)[C@H](SCC(=O)c3ccc4c(c3)OCO4)[C@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(N2C(=O)[C@H](SCC(O)c3ccc4c(c3)OCO4)[C@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CC3CCCCC3)C(=O)O)cc2)cc1
Reaction time: 22 h

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-methylphenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.020 g, 0.040 mmol) and NMM (0.013 ml, 0.116 mmol) in DMF (3 ml) at RT was added TBTU (0.020 g, 0.062 mmol). The reaction mixture was stirred for 30 min after which glycyl-3-cyclohexyl-D-alanine (0.011 g, 0.032 mmol) was added. The mixture was stirred for 22 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with MeOH (2 ml) and added NaBH4 (0.028 g, 0.740 mmol). After 15 min the reaction was quenched by the addition of an aqueous solution of hydrochloric acid (1M, 1 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: [OH:1][CH:2]([C:30]1[O:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:33][N:34]=1)[CH:3]([NH:6][C:7](=[O:29])[CH:8]([CH2:18][S:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:20])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[N:12]1([C:10](=[O:11])[CH2:9][CH:8]([CH2:18][S:19]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:20])=[O:21])[C:7]([NH:6][CH:3]([C:2]([C:30]2[O:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:33][N:34]=2)=[O:1])[CH2:4][CH3:5])=[O:29])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(-c2ccccc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nnc(-c2ccccc2)o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 224 mg of 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; H1 NMR(DMSO-d): 8.9, 8.84 (1H, d, d, NH, diastereomeric), 8.1–8(2H, m), 7.7–7.6(3H, m), 7.4–7.3(5H, m),5.1–4.9(1H, m), 4.5–4.3(2H, m), 3.6–3.3(11H, m), 3.12–3(1H, m), 2.65–2.5(1H, m), 2–1.9(1H, m), 1.8–1.7(1H, m), 0.96(3H, t); MS: 567.6(M−1), 569.4(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.O.Cl>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 gm (10 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C, were dissolved in 15 ml of dimethyl sulfoxide, 2 gm of potassium carbonate and 1.5 ml of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, the mixture was diluted with water, hydrochloric acid was added and the reaction product was extracted with ethyl acetate. After washing, drying and evaporating the extract, the residue was recrystallized from isopropanol (10 ml). Yield: 1.4 gm (44% of theory); m.p. 79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:8]([NH:13][CH3:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].C(O[C:22](=[O:24])[CH3:23])(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:8]([N:13]([CH3:14])[C:22](=[O:24])[CH3:23])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ncccc1C(=O)c1cccc(Cl)c1
Product: CC(=O)N(C)c1ncccc1C(=O)c1cccc(Cl)c1
Yield: 90 %

Procedure:
Acetic anhydride (40 ml) solution containing 3-(3-chlorobenzoyl)-2-methylaminopyridine (3.16 g, 13 mmol) was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (benzene-ethyl acetate) to give N-[3-(3-chlorobenzoyl)-2-pyridyl]-N-methylacetamide (3.34 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1.[NH:21]([C:28]1[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([N:21]([C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=3[C:30]([O:32][CH3:33])=[O:31])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[O:13]2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: COC(=O)c1ccccc1Nc1ccccc1
Product: COC(=O)c1ccccc1N(c1ccccc1)C1(c2ccc(N(C)C)cc2)OC(=O)c2ccccc21
Yield: 28.1 %

Procedure:
Following a procedure similar to that described in Example 4 but employing 2.6 g of 2-[4-(dimethylamino)benzoyl]benzoic acid and 2.3 g of methyl 2-anilinobenzoate there was obtained 1.3 g of 3-[4-(dimethylamino)phenyl]-3-{[2-(methoxycarbonyl)phenyl]phenylamino}phthalide, m.p. 92.5°-102° C. A toluene solution of the product contacted with acidic clay developed a yellow-colored image.
Reaction SMILES: C(OC([NH:6][NH:7][CH2:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)=O)C.[OH-].[Na+].[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17]>>[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17].[CH:10]1([CH2:9][CH2:8][NH:7][NH2:6])[CH2:12][CH2:11]1
Reactant: CCOC(=O)NNCCC1CC1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: NNCCC1CC1
Temperature: 120 °C

Procedure:
N′-(2-Cyclopropylethyl)hydrazinecarboxylic acid ethyl ester (5a) (2.2 g, 12.6 mmol) was suspended in 7 mL of a 40% aqueous NaOH solution. The biphasic mixture was heated for 12 h at 120° C., upon which it was cooled to room temperature and partitioned between brine and CH2Cl2. The organic layer was removed, dried over MgSO4, and filtered. Oxalic acid (1.1 g, 12.6 mmol) was added to the filtrate, which after 12 h was filtered and dried in vacuo to yield 1.7 g (50%) of the oxalate salt (6a) as a white powder. 1H-NMR (400 MHz, D2O): 3.13 (t, 2H, J=7.2 Hz); 1.46 (q, 2H, J=7.2 Hz); 0.61 (m, 1H); 0.1 (d, 2H); 0.39 (m, 2H); 0.01 (m, 2H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:27])=[O:24]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1cccc(OCC(C)=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1cccc(OCC(C)NCC(O)c2cccc(Cl)c2)c1
Yield: 58.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.11 g of methyl 3-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 17), 70 ml of benzene, 60 ml of absolute methanol and 2.45 g of sodium cyanoborohydride, 2.57 g of the title compound were obtained having an Rf=0.38 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[I:15](O)(O)(O)(O)(O)=O.II.S(=O)(=O)(O)O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([I:15])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Brc1ccc2oc3ccccc3c2c1
Reactant: [O-][I+](O)(O)(O)(O)O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2oc3ccc(I)cc3c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-Bromodibenzofuran (2.5 g, 10.1 mmol), orthoperiodic acid (0.49 g, 2.15 mmol), iodine (1.02 g, 4.02 mmol), sulfuric acid, H2O (2 ml) and acetic acid (10 ml) are put into a reaction vessel and the mixture is stirred at 70° C. for 3 hours. After cooling to room temperature the reaction mixture is poured into water and filtered. The white solid is washed by methanol and the desired product is obtained (1.92 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][CH:20]([OH:22])[CH3:21]>>[Br:1][C:2]1[CH:7]=[C:6]([O:22][CH:20]([CH3:21])[CH3:19])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(C)O
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Br
Temperature: 50 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (Step 1, 1.5 g, 6.4 mmol) in 2-propanol (30 mL) was added cesium carbonate (5.3 g, 16 mmol). The mixture was heated at 50° C. overnight. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and the residue was purified with silica gel column chromatography with 5% ethyl acetate in hexanes to afford 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene as a yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:20]([NH2:22])[CH3:21]>C(#N)C>[F:17][C:16]([F:19])([F:18])[S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:22][CH2:20][CH3:21])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CCN
Reactant: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Solvent: CC#N
Product: CCNCC1OCc2ccc(S(=O)(=O)C(F)(F)F)cc2O1
Yield: 56.6 %

Procedure:
Preparation according to Example 9. 2-(bromomethyl)-7-[(trifluoromethyl)sulfonyl]-4H-1,3-benzodioxine (0.28 g, 0.76 mmol), ethanamine (70% in water, 2.0 ml, 25.2 mmol) and ACN (2.0 ml) was heated at 120° C. for 20 min. Purification by flash chromatography using EtOAc/MeOH (4:1) as eluent afforded the title compound (0.14 g, 52%). The amine was converted into hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 169° C. MS m/z (rel. intensity, 70 eV) 325 (M+, 1), 239 (5), 106 (5), 77 (7), 58 (bp).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20][C@@H:21]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48]/[CH:49]=[CH:50]/[C:51](O)=[O:52])[CH2:44][CH2:43]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:29]([C:28]1[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:15][N:16]2[C@H:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:51](=[O:52])/[CH:50]=[CH:49]/[CH2:48][N:45]4[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][NH:39][C:37](=[O:38])[O:36][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:43][CH2:44]4)[CH2:26][CH2:27]3)[CH2:20][CH2:19][NH:18][C:17]=12)(=[O:30])[NH2:31]
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C/C=C/C(=O)O)CC1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC[C@H]2C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CCN(C/C=C/C(=O)N2CCC([C@@H]3CCNc4c(C(N)=O)c(-c5ccc(Oc6ccccc6)cc5)nn43)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
A mixture of (S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (1.26 g, 3.03 mmol), (E)-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)but-2-enoic acid (948.4 mg, 3.03 mmol), HATU (1.21 g, 3.18 mmol), DIEA (782 mg, 6.06 mmol) in 30 mL of DMF was stirred at RT for 15 hr. The mixture was poured into 300 mL of water and extracted with EA (100 mL). The organic phase was washed with water (100 mL×3) and concentrated to give 1.25 g (58%) of product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=8.4 Hz, 2H), 7.42 (t, J=8.4 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.12-7.02 (m, 4H), 6.67 (br s, 1H), 6.64-6.53 (m, 3H), 4.53-4.40 (m, 1H), 4.14-4.05 (m, 1H), 3.32-3.25 (m, 2H), 3.10-2.91 (m, 5H), 2.45-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.96-1.84 (m, 1H), 1.78-1.65 (m, 1H), 1.62-1.50 (m, 1H), 1.37 (s, 9H), 1.31-1.10 (m, 3H). MS (ESI) m/e [M+1]+713.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:22])=[C:16]([F:24])[CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Br)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-2-fluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (15.1 mg) with purity >90%. MS (pos) m/z 423.3, 425.3.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[OH:25][CH2:26][CH2:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:30].C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[OH:25][CH2:26][CH2:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:32]1)=[O:30]
Reactant: O=C(NCCO)C1CCCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCC(C(=O)NCCO)C3)n2n1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), N-(2-hydroxyethyl)piperidine-3-carboxamide (100 mg, 0.580 mmol), and N, N-diisopropylethylamine (112 mg, 0.870 mmol) in DMF (1.0 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (20-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (65.9 mg, 47%). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 8.12 (t, J=5.6 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.22 (s, 1H), 6.21 (s, 1H), 4.16-4.38 (m, 2H), 3.42-3.51 (m, 1H), 3.40 (t, J=6.2 Hz, 2H), 3.04-3.22 (m, 3H), 2.52-2.63 (m, 1H), 2.38 (s, 3H), 1.86-2.00 (m, 1H), 1.61-1.85 (m, 3H), 1.45 (s, 6H); ESI-MS: m/z 481.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:24][CH2:25][CH3:26])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:24][CH2:25][CH3:26])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[C:13]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])=[CH:12][N:11]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCN(C(=O)OC(C)(C)C)c1cc(Nc2ccc(C#N)cc2)ncc1C#CCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCN(C(=O)OC(C)(C)C)c1cc(Nc2ccc(C#N)cc2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of tert-butyl (2-((4-cyanophenyl)amino)-5-(5-hydroxy-1-pentyn-1-yl)pyridin-4-yl)(propyl)carbamate (S11, 17 mg), phthalimide (12 mg) and triphenylphosphine (21 mg) in tetrahydrofuran (1 mL), a 2.2 mol/mL solution of diethyl azodicarboxylate in toluene (36 μL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent, 100 to 40% hexane in ethyl acetate) to obtain tert-butyl (2-((4-cyanophenyl)amino)-5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)pyridin-4-yl)(propyl)carbamate (S12, 20 mg).