Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([OH:34])[CH2:12]1)[C:8](=[O:35])[NH:7]2)=[O:5])[CH3:2].C1N=CN([C:41]([N:43]2[CH:47]=N[CH:45]=[CH:44]2)=[O:42])C=1.C(Cl)Cl.CO.C1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)CCN1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:41]([N:43]3[CH2:44][CH2:45][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[CH2:47]3)=[O:42])[CH2:12]1)[C:8](=[O:35])[NH:7]2)=[O:5])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3CCc4ccccc4C3)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
The macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in DCM (2.2 mL), followed by addition of CDI (45 mg, 0.27 mmol) in one portion. The reaction was stirred at rt overnight. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). 1,2,3,4-tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was added to the reaction drop-wise, and the reaction was stirred at rt for overnight. After 22 h, TLC showed reaction complete. The reaction was diluted with DCM (6 mL) and washed with 1N aq. HCl (2×2 mL), sat. sodium bicarbonate (2 mL), brine (2 mL), dried (Na2SO4), and concentrated down. The crude was purified on silica gel (Biotage 40S, eluent: 2 to 4% MeOH in DCM), giving 11 as a pale yellowish foamy powder (131 mg, 90%).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18](=[O:28])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:8]=1)C.O>CO.O1CCCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:18]([C@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:29])=[O:5])=[O:28])=[CH:25][CH:24]=1)#[N:27]
Reactant: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)Nc2ccc(C#N)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1ccc(NC(=O)[C@H]2CCCN2c2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
Add lithium hydroxide (0.03 g, 1.3 mmol) to the crude 3-[(R)-2-(4-cyano-phenylcarbamoyl)-pyrrolidin-1-yl]-benzoic acid ethyl ester (0.05 g, 0.14 mmol) in a 1:1:1 mixture of water:MeOH/tetrahydrofuran (3 mL). Stir the mixture at room temperature for 15 h then wash with EtOAc. Adjust the pH of the aqueous phase to slightly acidic by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with methylene chloride, dry the combined organic phase over anhydrous sodium sulfate and concentrate under a stream of nitrogen to provide 0.020 g of 3-[(R)-2-(4-cyano-phenylcarbamoyl)-pyrrolidin-1-yl]-benzoic acid as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.C(Cl)Cl.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[F:26][C:23]([F:24])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1)[C:12]([NH:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:9][CH2:8]1)=[O:27]
Reactant: CCOC(=O)Cl
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (66 mg, 0.17 mmol) in a 2:1 mixture of CH2Cl2:DMF (3 mL) and TEA (69 μL, 0.50 mmol) was treated with ethyl chloroformate (27 mg, 0.25 mmol). The reaction mixture was allowed to stir overnight, then the solvent was removed in vacuo and the residue was purified by HiTOPs.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>O1CCOCC1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:29]([C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[N:4][C:3]([C:2]([F:15])([F:16])[F:1])=[N:5]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(OC)cc2)cc1
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (0.92 g, 3.95 mmol) in 10 mL of dioxane, were added pyridine (0.319 mL, 3.95 mmol) and a solution of 4-methoxybenzoyl chloride (673 mg, 3.95 mmol) in 3 mL of dioxane. The mixture was refluxed with stirring for 12 hours. The solvent was removed under reduced pressure. 50 mL of dichloromethane and 20 mL of 0.1 N hydrochloric acid were added to the residue and the organic layer was separated. The aqueous layer was extracted with 50 mL of dichloromethane. A combined organic layer was washed with 0.1 N hydrochloric acid and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (toluene-ethyl acetate 9:1) and then recrystallized with diisopropyl ether-hexane to give pale brown needle of 1,5-bis(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (0.67 g, 48.6% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:18](Br)([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]([CH3:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1oc2ccc(Cl)c(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Cl)c(OC(C)C)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (110 mg) was added 2 mL of isopropylbromide, 150 mg of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 134 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a thick colorless oil (100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.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>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]34[O:16][CH2:15][CH2:14][C@H:13]3[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]4)[CH:7]=2)=[O:34])=[N:31][CH:32]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Yield: 68.8 %

Procedure:
A solution of (±)-tert-butyl (4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (31 mg), 5-bromopicolinic acid (26 mg), HATU (48 mg), and DIEA (44 μL) in DMF (0.41 mL) was stirred at rt for 2 h, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% A/B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a yellow foam (32 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.71 (1H, s),8.21 (1H, dd, J=0.4, 8.0 Hz), 8.07 (1H, dd, J=2.0, 8.0 Hz), 8.03 (1H, m), 7.72 (1H, m), 7.14 (1H, t, J=10.5 Hz), 4.15 (2H, m), 3.32 (1H, m), 3.03 (1H, m), 2.90 (1H, m), 2.40 (1H, m), 2.22 (1H, m), and 1.51 (9H, s). MS (M+H)+: 553.3.
Reaction SMILES: [CH3:1][C:2]1[N:6](C(OCC2C=CC=CC=2)=O)[CH:5]=[N:4][C:3]=1[CH2:17][N:18]1[CH2:31][CH2:30][C:21]2[N:22]([CH3:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:20]=2[C:19]1=[O:32].C(O)C.Cl>CO>[CH3:29][N:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:20]2[C:19](=[O:32])[N:18]([CH2:17][C:3]3[N:4]=[CH:5][NH:6][C:2]=3[CH3:1])[CH2:31][CH2:30][C:21]1=2
Reactant: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Yield: 75 %

Procedure:
A solution of phenylmethyl 5-methyl-4-[(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido[4,3-b]indol-2-yl)methyl]-1H-imidazole-1-carboxylate (134 mg) in a mixture of absolute ethanol and 2N hydrochloric acid (2:1; 30 ml) was heated on a steam bath for 15 min. After cooling, the solution was concentrated in vacuo to ca. 20 ml and diluted with water (40 ml). The mixture was then washed with ethyl acetate (2×40 ml) and the acidic aqueous layer was basified with potassium carbonate solution. The solution was then extracted with ethyl acetate (3×50 ml) and the combined, dried organic extracts, were concentrated onto FCC silica and purified by FCC eluting with System A (150:8:1) to give a solid. This was dissolved in hot methanol and triturated with ether to give the title compound (69 mg). The 1H-n.m.r. and t.l.c. data obtained for this material were consistent with those obtained for the product of Example 20.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[N-:4]=[C:5]=[O:6].[C:7]1([CH2:13]C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N(C=O)C1C=CC=CC=1>>[CH3:13][C:7]1[C:8]([N:4]=[C:5]=[O:6])=[CH:9][C:10]([N:1]=[C:2]=[O:3])=[CH:11][CH:12]=1
Reactant: [N-]=C=O
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: O=CNc1ccccc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
7 g of the addition compound described in Example 22, 1 g of a polysiloxane-polyalkylene glycol of Example 32 (foam stabilizer) and 200 g of a mixture of 70% by weight of crude diphenylmethane diisocyanate which had been prepared by aniline formaldehyde condensation followed by phosgenation, and 30% by weight of the distillation residue obtained from the preparation of tolylene diisocyanate were vigorously stirred together as described in Example 36. The isocyanate mixture has an isocyanate content of 29.1% and a viscosity of 1030 cP/25° C. This mixture was then heated to 150° C. for 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:20].CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][Br:20])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
50.1 g (0.202 mol) of 3,3-bis(4-fluorophenyl)propanol were dissolved in 150 ml of toluene, and a solution of 21.8 g (0.081 mol) of PBr3 in 50 ml of toluene was added dropwise. The mixture was stirred at room temperature for 30 minutes and at 60° C. for 90 minutes and, for hydrolysis, was poured onto 400 ml of ice, 200 ml of ether were added, the organic phase was separated off, washed with NaHCO3 solution and NaCl solution, dried and concentrated and the residue was distilled in vacuo for purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11].Cl[CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:18][S:15]([CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)CCCl
Reactant: OCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)CCn1c(CO)nc2ccccc21

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)methanol (1.0 g, 6.75 mmol) and 1-chloro-2-(methylsulfonyl) ethane (1.05 g, 7.42 mmol) in DMF (3 mL) was stirred in the presence of K2CO3 (0.93 g, 6.75 mmol) at RT for overnight. The mixture was poured into water (20 mL) and extracted with DCM (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude (1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazol-2-yl)methanol which was used for next step directly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:51][O:52][C:53](=[O:67])[CH2:54][O:55][C:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([NH2:66])=[CH:58][CH:57]=1>CN(C)C=O.O>[CH3:51][O:52][C:53](=[O:67])[CH2:54][O:55][C:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([NH:66][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]3)[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:58][CH:57]=1
Reactant: CC1CCN(c2cc(F)cc(C(=O)O)c2)CC1
Reactant: COC(=O)COc1ccc(N)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)c2cc(F)cc(N3CCC(C)CC3)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
A solution of 3-fluoro-5-(4-methylpiperidin-1-yl)-benzoic acid (0.650 g, 2.7 mmol) in dimethylformamide (5 ml) is treated with HBTU (1.7 g, 1.7 eq) and diisopropylethylamine (1.6 ml, 3.5 eq). The mixture is stirred for five minutes at room temperature before a solution of (4-aminonaphthalen-1-yloxy)-acetic acid methyl ester (0.696 g, 1.1 eq) in DMF (2 ml) is added. The mixture is then stirred at room temperature for an additional 15 h before being diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel, eluted with ethyl acetate in hexane (10-30%) to give {4-[3-fluoro-5-(4-methylpiperidin-1-yl)-benzoylamino]-naphthalen-1-yloxy}-acetic acid methyl ester as a solid (1.0 g). Mp: 50-51° C. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.26 (m, 1H), 7.87 (m, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 6.96 (m, 3H), 5.05 (s, 2H), 3.84 (d, J=12.6 Hz, 1H), 3.74 (s, 3H) 2.77 (t, J=11.7 Hz, 2H), 1.68 (brd, 2H), 1.60 (m, 1H), 1.20 (m, 2H), 0.94 (d, J=6.3 Hz, 3H). MS: 451 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].N1C=[CH:15][N:14]=[N:13]1.[Na].[C:18](#[N:20])C>>[N:14]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)=[O:4])[CH:15]=[N:20][CH:18]=[N:13]1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: c1c[nH]nn1
Reactant: CC#N
Agent: [Na]
Product: Cc1ccc(C(=O)Cn2cncn2)cc1

Procedure:
2-Bromo-4'-methylacetophenone (12.78 g; 0.06 mole), sodium triazole (5.46 g; 0.06 mole) in dry acetonitrile solution (100 ml) were stirred at 20° C. for 5 hours. The solvent was evaporated and the residue purified by chromatography using silica gel/chloroform to give 2-(1,2,4-triazol-1- yl)-4'-methylacetophenone as a white solid (mp 118.4° C.). The latter compound (3.0 g; 0.015 mole) together with sodium acetate (1.23 g; 0.015 mole) and acetic acid (30 ml), was stirred at 40° C. during the addition of bromine (2.38 g; 0.015 mole) in acetic acid (2 ml). The mixture was stirred for a further 30 minutes and poured into chloroform (50 ml) and washed with water and sodium bicarbonate solution. The chloroform layer was separated, dried (MgSO4) and evaporated to give crude 2-bromo-2-(1,2,4-triazol-1-yl)-4'-methylacetophenone.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][N:5]=1)[NH2:3].C(O)(C(F)(F)F)=O.[F:21][CH:22]([F:34])[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=O>C(O)C(F)(F)F>[CH:27]1([C:25]2[N:2]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][N:5]=3)[N:3]=[C:23]([CH:22]([F:21])[F:34])[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(CC(=O)C1CCCCC1)C(F)F
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2C2CCCCC2)nc1
Yield: 48.7 %

Procedure:
2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (448 mg, 2 mmol) and TFA (1.38 mL, 18 mmol) were mixed in trifluoroethanol (10 mL) and stirred for 5 minutes 4,4-Difluoro-1-cyclohexyl-1,3-butanedione (408 mg, 2 mmol) was added. The resulting reaction mixture was heated at reflux temperature for 60 hours. The solvent was then removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with brine and concentrated in vacuo. The product was purified by recrystallization from 3:1 of isooctane:methylene chloride to give the title compound (346 mg, 49%).
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][C:15]([OH:19])([CH3:18])[CH2:14][C@@H:13]1[NH:20]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:19][C:15]1([CH3:18])[CH2:16][CH2:17][C@@H:12]([NH2:11])[C@@H:13]([NH2:20])[CH2:14]1
Reactant: [H][H]
Reactant: CC1(O)CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC1(O)CC[C@@H](N)[C@@H](N)C1

Procedure:
10% Palladium on carbon (350 mg) was suspended in a methanol solution (100 ml) of (1R*,2S*)-N1,N2-bis(benzyloxycarbonyl)-4-hydroxy-4-methyl-1,2-cyclohexanediamine (Stereoisomer A) (780 mg), and the suspension was stirred for 5 hours in a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. After the residue was dissolved in dichloromethane (100 ml), and the solution was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain the title compound (Stereoisomer A) (190 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[C:31]4[C:27](=[CH:28][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:30]=4)[CH:26]=[C:25]([C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:44]([Li])(C)(C)C.IC.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:44][C:28]1[N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:30]=[C:31]2[C:27]=1[CH:26]=[C:25]([C:40]([F:41])([F:43])[F:42])[CH:24]=[C:23]2[CH2:22][O:21][CH2:20][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2nn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-phenyl-4-(((5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (97 mg, 0.16 mmol) was dissolved in dry tetrahydrofuran (3 mL) and stirred at room temperature for 15 min. The stirred mixture was cooled to −78° C. and treated with a solution of tert-butyllithium (1.7 M in pentane, 190 μL, 0.33 mmol). The reaction was gradually warmed to −20° C. over 1 h, cooled to −78° C. and treated with iodomethane (10 μL, 0.19 mmol). The reaction was warmed to 0° C. over several hours then treated with saturated ammonium chloride. The reaction was diluted with ethyl acetate. The layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate, filtered and concentrated to afford 100 mg (quant.) as a clear oil. LC/MS (HPLC method 1): tR=3.70 min, 634.26(MH)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]([OH:23])=O)[S:20][C:13]=13)=[CH:6][CH:5]=2.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]([OH:32])([CH3:31])[CH3:30]>>[OH:32][C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:21]([C:19]1[S:20][C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[NH:11][C:7]2[CH:6]=[C:5]3[C:4](=[CH:9][CH:8]=2)[NH:3][C:2]([CH3:10])=[CH:1]3)[CH:18]=1)=[O:23])([CH3:31])[CH3:30]
Reactant: CC(C)(O)[C@@H]1CCCN1
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC[C@H]5C(C)(C)O)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid and (S)-2-pyrrolidin-2-yl-propan-2-ol by a procedure analogous to Example 21B. MS: 435.3; HPLC Rf: 4.134 min.; HPLC purity 95%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].O>CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 35 %

Procedure:
20 g of 2,6-diacetylpyridine (0.123 mol), 19.08 g of 2-chloro-4,6-dimethylaniline (0.123 mol) and 0.5 g of p-toluenesulfonic acid were heated under reflux on a water separator in 500 ml of heptane for 75 min. The insoluble solid was filtered off. The solvent was distilled off from the filtrate down to 150 ml, and the remaining filtrate was cooled to room temperature, while stirring. 25.3 g of a yellow solid precipitated out. This was filtered off and recrystallized from 60 ml of hot isopropanol. A total of 12.9 g (0.043 mol) of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-pyridin-2-yl}ethanone were obtained in a yield of 35%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>>[NH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:26]1[CH:25]=[C:24]([C:23]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]3[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:23][CH2:11][NH2:10])[CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:29]=[CH:28][N:27]=1
Reactant: NCCCN
Reactant: Fc1ccc(-c2nn3c(-c4ccnc(F)c4)cccc3c2-c2ccnc(F)c2)cc1
Product: NCCCNc1cc(-c2c(-c3ccc(F)cc3)nn3c(-c4ccnc(NCCCN)c4)cccc23)ccn1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 2-(4-fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-α]pyridine (34 mg, 0.08 mmol) in 1,3-diaminopropane (1 mL) was heated at 150° C. for 0.25 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and the residue was triturated with hot ethyl acetate. The resulting solids were collected on filter, washed with ethyl ether and dried to provide N-{4-[3-{2-[(3-aminopropyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-yl]pyridin-2-yl}propane-1,3-diamine as a light yellow powder (19 mg, 46%). 1H NMR (CD3OD): δ 8.18 (d, 1H), 8.03 (d, 1H), 7.78 (d, 1H), 7.65 (dd, 2H), 7.45 (dd, 1H), 7.30 (s, 1H), 7.1–7.2 (m, 4H), 6.60 (s, 1H), 6.59 (d, 1H), 3.55 (t, 2H), 3.47 (t, 2H), 3.0 (q, 4H), 1.88–2.04 (m, 4H); MS m/z 511 (M+1).