Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)[C:42]3(C4C=CC(O)=C[C:51]=4[O:50][CH2:49]3)C2=O)C=CC=CC=1>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([O:25][CH2:42][CH2:49][O:50][CH3:51])[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(O)ccc12
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(O)cc12
Product: COCCOc1ccc2c(c1)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2.68 and making non-critical variations using 1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1′-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.25 (m, 10H), 7.15-7.07 (m, 1H), 7.04 (s, 1H), 7.00-6.90 (m, 2H), 6.58-6.44 (m, 3H), 6.41-6.33 (m, 1H), 4.86 (ABq, 2H), 4.15-3.98 (m, 2H), 3.75-3.66 (m, 2H), 3.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:37]=[C:38]([C@@H:42]([NH2:44])[CH3:43])[CH:39]=[CH:40][CH:41]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[F:33][C:34]([F:45])([F:46])[O:35][C:36]1[CH:37]=[C:38]([C@@H:42]([NH:44][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:22])[CH3:43])[CH:39]=[CH:40][CH:41]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@H](N)c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) and (S)-1-(3-trifluoromethoxy-phenyl)-ethylamine hydrochloride (155 mg, 0.45 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then water and petroleum ether were added. The resulting off-white precipitate was collected by filtration. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 126 mg (89%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide as an off-white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]4)[CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:3][CH:2]=1.CN(C(O[N:37]1N=N[C:39]2C=CC=N[C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)C>CN(C)C=O.C(OCC)(=O)C>[CH2:38]([NH:37][C:26]([C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:9](=[O:10])[NH:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:16]=1)=[CH:25][CH:24]=2)=[O:28])[CH3:39]
Reactant: O=C(NCc1ccncc1)c1cc(-c2ccc3[nH]c(C(=O)O)cc3c2)ccn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc2cc(-c3ccnc(C(=O)NCc4ccncc4)c3)ccc2[nH]1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a mixture of 5-{2-[(Pyridin-4-ylmethyl)-carbamoyl]-pyridin-4-yl}-1H-indole-2-carboxylic acid (40 mg, 0.1 mmol) in N,N dimethylformamide (1 ml) is added HATU (49 mg, 0.13 mmol) followed by N,N-diisopropylethylamine (0.025 ml. 0.12 mmol). The reaction is stirred for ½ hour. The ethylamine (64 uL, 0.13 mmol) is added and the reaction mixture stirred for 24 hours. The reaction mixture is diluted with ethyl acetate and is washed 3× with water, 1× with sodium carbonate and 1× with brine. The organic layer dried over Na2SO4, filtered, and is evaporated in vacuo. The crude product is purified by reverse phase HPLC to give the title compound 8 mg, 19%, LC/MS ESI m/z (M+H)+=400.4.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH2:6].CN1CCOCC1.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:38]([OH:40])=O)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N=C=NCCCN(CC)CC)C>C(Cl)Cl.O>[CH:4]([CH:5]([NH:6][C:38](=[O:40])[C@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:3]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCC(C=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.4 %

Procedure:
In 50 ml of methylene chloride was dissolved 1.8 g of L-norleucine methyl ester hydrochloride, and 1.1 ml of N-methylmorpholine was added to the solution. To the solution were further added 3.0 g of N-benzyloxycarbonyl-L-phenylalanine and 1.9 g of 1-ethyl-3-(3-diethylaminopropyl)carbodiimide, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% citric acid solution, a saturated brine, a saturated sodium bicarbonate solution, and a saturated brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 4.1 g of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.N1C2C=CC=C([C:29]([O:31][CH3:32])=[O:30])C=2C=C1>>[CH3:18][C:13]1([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15][B:11]([C:8]2[NH:9][C:10]3[CH:2]=[CH:3][CH:4]=[C:5]([C:29]([O:31][CH3:32])=[O:30])[C:6]=3[CH:7]=2)[O:12]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COC(=O)c1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 1H-indole-4-carboxylic acid, methyl ester.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:5][CH:4]=1>C(#N)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][S:11](=[O:13])(=[O:12])[NH2:1])=[CH:5][CH:4]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)NC(CS(=O)(=O)Cl)c1ccc(Cl)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(CS(N)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
Ammonia (1.5 mL, 31.50 mmol) was added to a suspension of tert-butyl 1-(4-chlorophenyl)-2-(chlorosulfonyl)ethylcarbamate (Intermediate 78) (0.542 g, 1.53 mmol) in acetonitrile (10 mL). The mixture was stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine. The organic solution was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 30% ethyl acetate/DCM). The desired product, tert-butyl 1-(4-chlorophenyl)-2-sulfamoylethylcarbamate (0.351 g, 68.5%), was thus isolated as a colourless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CS(C)=O>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CC(C)=CCBr
Solvent: CS(C)=O
Product: CC(=O)c1cc2c(cc1OCC=C(C)C)C(C)(C)CCC2(C)C
Yield: 126.1 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-ethanone (0.125 g, 0.507 mmol) in DMSO (1 mL) was alkylated with 4-bromo-2-methyl-2-butene (0.106 g, 0.710 mmol, 0.082 mL) as described in Example 21. Aqueous workup gave 1-[3-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl]ethanone 0.201 g (100% crude) as a clear yellow crystalline solid: 1H-NMR (400 MHz, CDCl3) δ 7.72 (s, 1H, Ar-H), 6.83 (s, 1H, Ar-H), 5,48 (m, 1H, olefinic), 4.59 (d, J=6.6 Hz, 2H, OCH2), 2.60 (s, 3H, CH3), 1.79 (s, 3H, CH3), 1.76 (s, 3H, CH3), 1.67 (appp d, J=2.7 Hz, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[I:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[N:3]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([I:7])=[CH:9][CH:10]=2)[CH:4]=[CH:5][N:6]=1
Reactant: BrCc1ccc(I)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nccn1Cc1ccc(I)cc1
Yield: 44 %

Procedure:
A mixture of 2-methylimidazole (0.66 g, 8.0 mmol), 4-iodobenzyl bromide (J. Am. Chem. Soc, 1949, 71, 3360) (2.38 g, 8.0 mmol) and potassium carbonate (2.21 g, 16 mmol) in acetonitrile (100 ml) was stirred at reflux for 15 hrs. After cooling, precipitates were filtered off and the filtrate was concentrated to dryness. The residue was partitioned between ether (100 ml) and water (100 ml). The ethereal layer was separated, washed with brine (100 ml), dried (magnesium sulfate) and concentrated. Purification by column chromatography (silica-gel, 50 g; methanol in dichloro-methane, increasing the ratio of methanol from 0% to 5%) yielded the titled compound (1.05 g, 44%).
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.S(O[CH2:33][CH2:34][C:35]1C2CCCCCC=2C=CC=1)(=O)(=O)C>>[C:1]1([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:15][CH2:16]2)[C:2]2[CH2:33][CH2:34][CH2:35][CH2:7][CH2:8][C:3]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OCCc1cccc2c1CCCCC2
Reactant: COc1cc2c(cc1N1CCN(CCC3Cc4ccccc43)CC1)OCC2
Product: COc1cc2c(cc1N1CCN(CCc3cccc4c3CCCCC4)CC1)OCC2

Procedure:
Prepared in the same manner as the product of Example 3 but using 2-(benzocycloheptan-1-yl)ethanol mesylate instead of 2-(benzocyclobutan-1-yl)-1-bromoethane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][CH:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.ClC1N=CC=CN=1.CC1OC(C)CNC1>>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:13]2[CH2:14][CH:15]([CH3:17])[CH2:16][CH:11]([CH3:10])[CH2:12]2)[N:3]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC1CNCC(C)C1
Agent: CC1CNCC(C)O1
Agent: Clc1ncccn1
Product: Cc1cc(C)nc(N2CC(C)CC(C)C2)n1

Procedure:
In a similar manner to Synthesis Example 6-1 except that 2-chloro-4,6-dimethylpyrimidine and 3,5-dimethylpiperidine were used instead of 2-chloropyrimidine and 2,6-dimethylmorpholine, respectively, N-(4,6-dimethylpyrimidin-2-yl)-3,5-dimethylpiperidine (Compound 45) was obtained (yield 97%).
Reaction SMILES: [Cl:1][C@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:6]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.[CH2:25](Cl)Cl.Cl.CNC.C=O>C(O)(C)(C)C>[Cl:1][C@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[C:6]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:7](=[CH2:25])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Reactant: ClCCl
Agent: C=O
Agent: CNC
Agent: Cl
Solvent: CC(C)(C)O
Product: C=C1C(COC(C)=O)=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2S1(=O)=O
Temperature: 90 °C
Yield: 81.6 %

Procedure:
A mixture of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4-carboxylate-1,1-dioxide (1.9 g), methylene chloride (3 ml), dimethylamine hydrochloride (0.817 g), t-butanol (80 ml) and formaldehyde solution (I.10 ml, 37% w/v in water) was heated to reflux at 90° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 1.6 g (81.6%) of t-butyl 7α-chloro-2-methylene-3-acetoxymethyl-3-cephem-4-carboxylate-1,1-dioxide, m.p. 148°-149° C. This product without further purification was used in the next step.
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:25]=[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=2)[C:10]=1[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])C.[OH-].[Na+]>>[CH2:29]([O:28][C:26]1[CH:27]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[C:10]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])[CH:23]=[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Yield: 76.3 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(5-benzyloxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (229 mg, 0.34 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[3-[6-(5-benzyloxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (163 mg, 78%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C38H41FO7 (M+Na)+ 651.2728. found 651.2729.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(P(CCCC)CCCC)CCC.[C:25]1([C:31](O)([CH3:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:31]([CH3:33])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:32])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (0.5 g), tri(n-butyl)phosphine (0.72 mL) and 2-phenyl-2-propanol (0.26 g) in tetrahydrofuran (5 mL) was added 1, 1′-azobis (N,N-dimethyl -formamide) (0.5 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=10/1) to give 2-chloro-5-(1-methyl-1-phenylethoxy)-1-nitrobenzene (0.19 g). This material was dissolved in tetrahydrofuran (3.5 mL). To the solution were added methanol (3.5 mL), nickel(II) bromide (11 mg) and sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =3/1) to give the title compound (0.14 g).
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].[O:34]1[CH:38]=[CH:37][C:36]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:35]1.C1COCC1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:39][C:36]2[CH:37]=[CH:38][O:34][CH:35]=2)[C:24]=1[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)OCc2ccoc2)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)n(Cc2ccoc2)c2ncccc12
Reaction time: 0.5 h

Procedure:
BEMP (182 μL, 0.63 mmol) is added to a stirring solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.39 mmol) in DMF (1.2 ml). After 30 minutes, a solution of toluene-4-sulfonic acid furan-3-ylmethyl ester in THF (1.4 ml, 0.45 mmol) is added. After 18 hours, the reaction is partitioned between water and ether. The organic layer is washed with brine then reduced in vacuo. The residue is purified by flash column chromatography (3:1 iso-hexane/EtOAc elution) to furnish (1-furan-3-ylmethyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester; MH+=285.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:16]([O:18]CC)=O)[C:7]2[CH:12]=[N:11][N:10]([CH:13]([CH3:15])[CH3:14])[C:8]=2[N:9]=1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:16]([NH:21][CH2:22][C:23]2[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])=[O:18])[C:7]2[CH:12]=[N:11][N:10]([CH:13]([CH3:14])[CH3:15])[C:8]=2[N:9]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
Aqueous NaOH (0.964 g, 24.11 mmol) was added to a solution of ethyl 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (5 g, 16.07 mmol) in EtOH (50 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The crude acid (3 g, 10.55 mmol) was then dissolved in DMSO (35 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (3.2 g, 21.0 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (8.23 g, 15.82 mmol) was added to it and stirring was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (3 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH2:37]([NH:39][CH3:40])[CH3:38]>ClCCCl>[CH3:36][N:34]([CH3:35])[CH2:33][CH2:32][N:17]1[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=2)[N:20]=[C:16]1[CH:13]1[CH2:12][CH2:11][N:10]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[CH2:8][N:39]([CH2:37][CH3:38])[CH3:40])[CH2:15][CH2:14]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Reactant: CCNC
Solvent: ClCCCl
Product: CCN(C)Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde (90.00 mg; 0.18 mmol; 1.00 eq.) in 1 ml DCE added ethyl-methyl-amine (0.02 ml; 0.19 mmol; 1.05 eq.) and sodium p-triacetoxyborohydride (113.20 mg; 0.53 mmol; 3.00 eq.), stirred for overnight at RT, lc-ms showed desired (<30%, major ms 618/619), purified by prep HPLC, collected title compound. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:16]2[S:15][C:14](=[S:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.CI.[CH3:20]COC(C)=O>CN(C=O)C>[Br:7][C:8]1[C:16]2[S:15][C:14]([S:17][CH3:20])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: S=c1[nH]c2cccc(Br)c2s1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (67 mg, 0.49 mmol) was added to a solution of 7-bromo-1,3-benzothiazole-2(3H)-thione (100 mg, 0.41 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 30 min. Methyl iodide (25 μL, 0.41 mmol) was added and the resulting mixture was stirred at room temperature for 30 min. EtOAc was added the separated organic fraction was washed with water and brine, dried over sodium sulfate, and concentrated. The title compound thus obtained was used without further purification. MS (ESI): 260.34, 262.32 [M+H]+; HPLC tR=1.54 min (HPLC: Anayltical—2 min).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:33][NH:34][CH:35]([CH2:37][CH3:38])[CH3:36]>C(Cl)(Cl)Cl>[CH3:33][N:34]([CH:35]([CH3:36])[CH2:37][CH3:38])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Reactant: CCC(C)NC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 63.5 %

Procedure:
Operations are carried out as for Example 7, starting with 2.96 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.33 g of triethylamine, 1.49 g of ethyl chloroformate and 1.34 g of N-methyl 2-butanamine in 120 ml of chloroform. 2.4 g of N-methyl N(1-methyl propyl) 1-phenyl isoquinoline 3-carboxamide melting at 95°-96° C., are obtained.