Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)(=[O:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: c1c[nH]cn1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)n1ccnc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
2.36 g of 5-nitro-2-methyl-phenylsulfonyl chloride (0.01 mol) and 1.36 g of imidazole (0.02 mol) were dissolved in 15 ml of pyridine, and the mixture was stirred at 50° C. for 3 hours to react. After the reaction, the reaction mixture was poured into water, and extracted with chloroform. The chloroform layer was washed with water and dehydrated. Evaporation of chloroform gave 1.70 g of 1-(5-nitro-2-methyl-phenylsulfonyl)-imidazole of the m.p. 119°-120° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH2:26][CH3:27])=[CH:23][CH:24]=4)[N:19]([CH3:28])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2[C:11](=[N:16][CH:15]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH2:26][CH3:27])=[CH:23][CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:13]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)nn(C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: CCc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)nn(C)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
N-tert-Butyl-2-(6-ethyl-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.03 g, 0.059 mmol), ethylenediamine (1 mL, 15.0 mmol) and TBAF (1 mL, 3.45 mmol) were combined with DMF (3.0 mL) and the reaction mixture warmed to 60° C. After 3 h, the mixture was concentrated to dryness and partitioned between ethyl acetate and water. The organic phase was concentrated in vacuo then purified by chromatography to give 2-(6-ethyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (5 mg, 22%). MS: (M+H)+=377; 1H NMR (DMSO-d6) δ: 12.79 (br. s., 1H), 8.96-9.28 (m, 1H), 8.19-8.49 (m, 2H), 7.97 (s, 1H), 7.57 (s, 1H), 6.98-7.25 (m, 1H), 4.16 (s, 3H), 2.81 (q, J=7.4 Hz, 2H), 1.41-1.66 (m, 9H), 1.21-1.35 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:14][C:9]1[C:8]2[C:7]3[C:6](=[N:31][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:29]=2)[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[C:13]=3[CH2:12][S:11][N:10]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CCO)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cnc(Cn2nc3cc(CCO)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture composed of the above di-tert-butyl {8-(2-hydroxyethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (16 mg), dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was placed into the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel chromatography (chloroform-methanol). The resulting oil was dissolved in dioxane, followed by lyophilization to obtain the title compound (8.3 mg, 78%) as an amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([O:12]C)=[O:11])=[N:6][CH:7]=1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C@H:9]([C:10]([OH:12])=[O:11])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:4][CH:3]=1
Reactant: COC(=O)C(CC(C)C)Nc1ncc(Br)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](Nc1ncc(Br)cn1)C(=O)O
Reaction time: 5 h

Procedure:
To methyl 2-[(5-bromo-2-pyrimidinyl)amino]-4-methylpentanoate (1.27 g, 4.2 mmol) in MeOH (50 mL) was added an aqueous solution of LiOH (2 M, 21 mL, 42 mmol) and the reaction was stirred for 5 hours. The reaction was neutralized with aqueous 10% HCl (pH of 6–7) and concentrated to a minimum volume in vacuo. Brine was added and the product was extracted with EtOAc (3×), dried on Na2SO4, concentrated in vacuo, and stripped with MePh (3×) to afford N-(5-bromo-2-pyrimidinyl)leucine which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[C:5]([C:18]2[S:19][C:20]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]3)=[O:24])=[N:21][N:22]=2)=[CH:4][N:3]=1.C[CH2:32][N:33](C(C)C)C(C)C.Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:33][CH3:32])=[O:14])=[CH:16][CH:17]=2)[C:5]([C:18]2[S:19][C:20]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]3)=[O:24])=[N:21][N:22]=2)=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(Nc2cc(Cl)ncc2-c2nnc(C(=O)N3CC[C@@H](O)C3)s2)cc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(Nc2cc(Cl)ncc2-c2nnc(C(=O)N3CC[C@@H](O)C3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)benzoic acid (15) (150 mg, 0.336 mmol) in DMF (10 mL), DIPEA (1.682 mmol, 5 equiv.), methanamine HCl (3.36 mmol, 10 equiv.) and HATU (0.673 mmol, 2 equiv.) were added at room temperature. The reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was evaporated to remove excess of DMF. The residue obtained was then diluted with water and extracted using EtOAc. The organic layer was dried over Na2SO4, filtered and evaporated to get crude compound. The crude compound was purified by column chromatography through silica gel and MeOH:DCM as eluent to isolate the desired compound, (R)-4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)-N-methylbenzamide (16). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.71 min; LCMS (ES-API), m/z 459.63 (M+H).
Reaction SMILES: CCN(CC)CC.[CH2:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>O1CCOCC1>[C:30]1([N:29]2[C:25]([N:14]3[CH2:15][CH2:16][C:12]4([CH2:8][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11]4)[CH2:13]3)=[N:26][N:27]=[N:28]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3nnnn3-c3ccccc3)C2)C1
Temperature: 115 °C

Procedure:
Et3N (5 mL) was added into a solution of tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g) and 5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 7-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@H:16]([CH:21]4[CH2:23][CH2:22]4)[C:17]([F:20])([F:19])[F:18])=[N:13][CH:12]=[C:11]([C:24]([NH2:26])=[O:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:14]([NH:15][C@H:16]([CH:21]5[CH2:22][CH2:23]5)[C:17]([F:19])([F:18])[F:20])=[N:13][CH:12]=[C:11]([C:24]([NH2:26])=[O:25])[C:7]=4[NH:8][C:9]=3[CH:10]=2)=[CH:30][N:29]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(Cl)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)ccc12
Temperature: 100 °C

Procedure:
7-Chloro-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (8.36 g, 21.8 mmol) and 2-aminopyrimidine-5-boronic acid pinacol ester (7.73 g, 34.9 mmol) were placed in a flask. Pd2(dba)3 (2.0 g, 2.184 mmol), tricyclohexylphosphine (1.53 g, 5.46 mmol), dioxane (437 ml) and K3PO4 (1.25 M in water, 59.2 ml, 74.0 mmol) were added and the flask purged with N2 for 15 min. The reaction mixture was heated at 100° C. for 4 h, and cooled to room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (magnesium sulfate), and concentrated. Flash chromatography gave the title compound as a white solid. 1H NMR (600 MHz, CD3SOCD3) δ 11.64 (s, 1H); 8.62 (s, 2H); 8.54 (d, 1H); 8.52 (s, 1H); 7.97 (br s, 1H); 7.95 (d, 1H); 7.53 (dd, 1H); 7.30 (br s, 1H); 7.01 (d, 1H); 6.79 (s, 2H); 4.87 (m, 1H); 1.62 (m, 1H); 0.76 (m, 1H); 0.64 (m, 1H); 0.55 (m, 1H); 0.35 (m, 1H). LRMS (APCI) calc'd for (C21H18F3N7O) [M+H]+, 442.2. found 442.1.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C@@H:15]2[CH2:19][C:18](=[N:20][O:21][CH3:22])[CH2:17][N:16]2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:24])[N:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH3:53][N:54]([CH3:60])[CH2:55][CH2:56]C(O)=O.C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:30][C:25]([C:23]([N:16]2[CH2:17][C:18](=[N:20][O:21][CH3:22])[CH2:19][C@H:15]2[C:12]2[N:11]=[C:10]([CH2:9][NH:8][C:6](=[O:5])[CH2:56][CH2:55][N:54]([CH3:60])[CH3:53])[O:14][N:13]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: CN(C)CCC(=O)O
Reactant: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1C[C@@H](c2noc(CNC(=O)CCN(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (Example 50) was treated with a 25% TFA/DCM solution at 0° C. The reaction was monitored by LC/MS and stopped after completion. The reaction was then made basic with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. Solvent removal afforded a crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and N,N-dimethyl-β-alanine (1 equivalent) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 equivalent) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, gave the title compound as a mixture of E- and Z-isomers in 52% yield (82% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10](I)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4].[CH2:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10]([C:33]3[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[CH:31][CH:32]=3)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1ccc(C2=CCC(c3ccccc3)C3(C(=O)OC)CN(Cc4ccccc4)CC23)cc1
Yield: 72 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1.35 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 20 cm3 of toluene, from 340 mg of tetrakis(triphenylphosphine)palladium, from 0.38 g of trimer anhydride of 4-ethylphenylboronic acid in 10 cm3 of methanol and from 15 cm3 of a 2N aqueous sodium carbonate solution at reflux for eighteen hours, 0.92 g (72%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-(4-ethylphenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a viscous yellow oil, the characteristic of which was as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([O:20][CH3:21])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:29][S:30]([O:6][CH:4]([CH3:5])[C:3]([O:20][CH3:21])([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1)(=[O:32])=[O:31]
Reactant: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(OC)(c1cccc(Oc2ccccc2)c1)C(C)OS(C)(=O)=O

Procedure:
The oil, 1,1-dimethoxy-1-(3-phenoxyphenyl)propan-2-ol, from Example 26 and 11.3 g of triethylamine are dissolved in 65 ml of toluene. Then the solution is cooled to 10°-12° C. and 9.7 g of methanesulfonyl chloride in 35 ml of toluene is added over 30 minutes. After the addition is completed, the mixture is poured into 100 ml of saturated sodium bicarbonate solution, and 100 ml of toluene is added. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 23.25 g of 1,1-dimethoxy-1-(3-phenoxyphenyl)prop-2-yl methanesulfonate, as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:22]3[NH:23][C:19]([CH:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=4)[CH2:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[CH:20][CH:21]=3)[CH:29]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(Cc2ccnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(C)(=O)=O)cc4)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-4-carbaldehyde (170 mg) in 1,2-dichloroethane (5 mL) was added 1-acetylpiperazine (115 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (250 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (180 mg, yield 85%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (19:1, volume ratio). MS: 551 (MH+).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Br:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1/[CH:8]=[N:9]/[C@@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][OH:12]>O1CCCC1.[Zn]>[Br:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[C@@H:8]([NH:9][C@@H:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][OH:12])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: OC[C@@H](/N=C/c1ccccc1Br)c1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC[C@H](N[C@H](CO)c1ccccc1)c1ccccc1Br
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a stirred suspension of zinc (70.8 mmol, 4.63 g, <10 micron) in tetrahydrofuran (35 mL) under nitrogen was added allyl bromide (70.8 mmol, 6.16 mL, 8.57 g) over 1 minute at room temperature. There was a moderate exotherm and the resultant grey suspension was stirred for 1.5 h then cooled in an ice/brine bath. A solution of (S,E)-2-(2-bromobenzylideneamino)-2-phenylethanol (compound 1; 23.60 mmol, 7.18 g) in tetra-hydrofuran (20 mL) was added dropwise over 30 minutes and stirred 10 minutes at 0° C. The bath was replaced with a 25° C. water bath and the grey suspension was stirred for 30 minutes at room temperature then quenched by addition of water, in one portion (50 mL). Methylene chloride (100 mL) was added and the mixture stirred for 1 h then to this mixture was added saturated sodium hydrogen carbonate (50 mL). The mixture was filtered through dicalite and layers separated. The separated aqueous layer was extracted further with methylene chloride and the organic extracts dried over sodium sulfate and evaporated to a pale yellow oil which was purified on 200 g silica pad using ethyl acetate/heptane (10-30%) to give pure (S)-2-((S)-1-(2-bromophenyl)but-3-enylamino)-2-phenylethanol (4.52 g), MS (ES): m/z [M+H]+ 346 and 348.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[CH2:46]([O:48][C:49](Cl)=[O:50])[CH3:47]>O1CCCC1>[CH2:46]([O:48][C:49]([N:13]([CH2:12][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:50])[CH3:47]
Reactant: CCOC(=O)Cl
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.43 g, 0.85 mmole) and triethylamine (130 μl, 0.93 mmole) in 5 ml of anhydrous tetrahydrofuran, was added dropwise ethylchloroformate (89 μl, 0.93 mmole). The resulting mixture was stirred for about 16 hours at room temperature. The tetrahydrofuran was removed under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH:28]=[O:29])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1.S([CH2:51][N+:52]#[C-:53])(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([C:28]3[O:29][CH:53]=[N:52][CH:51]=3)[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3cnco3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate (235 mg) and tosylmethyl isocyanide (125 mg) were dissolved in methanol (4 ml), sodium methoxide (28% methanol solution, 325 mg) was added and the mixture was heated under reflux with stirring for 2 hr. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-100:0) was concentrated under reduced pressure to give the object product (98.5 mg).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>CCOCC.C(OCC)(=O)C>[ClH:1].[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:29][CH3:30])[CH2:18][N:17]([C:15]([CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:16])[CH2:26][CH2:25]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 5 N hydrochloric acid in Et2O (15 ml) was added to a solution of 4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (3 g, 7.43 mmol) in ethyl acetate and the mixture was stirred for 2 hours at room temperature. The precipitate formed was collected by filtration and the white solid obtained was identified as (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(piperidin-4-yl)-methanone hydrochloride (2.1 g, 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10]([N:12]([CH2:20][CH3:21])[C:13]1[S:14][C:15]([CH:18]=O)=[CH:16][N:17]=1)[CH3:11]>CN1C(=O)CCC1.[N+](C1C=CC=CC=1)([O-])=O.CC#N.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:18]([C:15]3[S:14][C:13]([N:12]([CH2:10][CH3:11])[CH2:20][CH3:21])=[N:17][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN(CC)c1ncc(C=O)s1
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CN1CCCC1=O
Product: CCN(CC)c1ncc(-c2nc3cc(Br)cnc3[nH]2)s1
Temperature: 170 °C
Reaction time: 2 h
Yield: 5.4 %

Procedure:
5-Bromopyridine-2,3-diamine (0.1 g, 0.53 mmol) was dissolved in NMP (0.5 ml) and heated to 170° C. 2-(Diethylamino)-1,3-thiazole-5-carbaldehyde (0.098 g, 0.53 mmol) dissolved in nitrobenzene (1.0 ml) was added slowly (20 min). After 2 h, the reaction mixture was diluted with CH3CN/water and purified by HPLC-C18, giving the title product (0.01 g, 6%).