Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33](OC)=[O:34])=[CH:31][CH:30]=3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].O1CCCC1.Cl>CO>[OH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)=[CH:38][CH:37]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(=O)OC)cc2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CO)cc2)c2ncnn12
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of methyl 4-({6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}methyl)benzoate (2.8 g), 1N aqueous sodium hydroxide solution (30 mL), tetrahydrofuran (30 mL) and methanol (30 mL) was stirred at 50° C. for 3 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (50 mL), N-methylmorpholine (0.67 mL) and ethyl chlorocarbonate (0.58 mL) was added at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was cooled to −15° C., sodium borohydride (0.57 g) and methanol (10 mL) were added, and the mixture was allowed to gradually warm to room temperature. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.86 g, 70%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[C:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.C1COCC1>[C:28]1([NH:38][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc2ccccc12
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 18.7 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]-pyrimidine (0.0376 mmol) and 1-naphthylamine (0.169 mmol) were mixed in CH2Cl2 (2 mL) and then triethylamine (0.187 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.172 mmol), and 4-dimethylaminopyridine (˜1 mg) were added in that order. Poor overall solubility was observed so THF (1 mL) was then added to the mixture, which became more homogeneous. The mixture was stirred at room temperature for 22 h then concentrated under reduced pressure. Purified by silica gel chromatography (1-2% MeOH in CH2Cl2) to yield 3.4 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.49 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.17 (br s, 1H); 8.12 (br s, 1H); 8.02 (br s, 1H); 7.85-7.92 (m, 3H); 7.81 (m, 1H); 7.77 (d, J=8.2 Hz, 1H); 7.69 (d, J=7.5 Hz, 1H); 7.51-7.58 (m, 4H); 7.33 (br s, 2H); 6.82 (d, J=5.5 Hz, 1H); 5.78 (br s, 1H); 5.32 (br s, 1H); 1.71 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 485.2 (M+1).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13])=O)C1C=CC=CC=1.C(OCC)C.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 1.4 g of 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture at room temperature for 2 hours. Add the mixture dropwise to diethyl ether at 0°-5° C. to give 7-[(S)-alanyl]- 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid hydrobromide which is used immediately in the process described in paragraph F below.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:14]([C:16]([O:20]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C[C@@H]1CC[C@H](C2C=CC=CC=2)N1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:16]([NH2:14])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C[C@@H]1CC[C@H](c2ccccc2)N1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 10 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of N,N-dimethyl-1-((2S,5R)-5-phenylpyrrolidin-2-yl)methanamine 250 (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM, 0.1% Et3N) to afford 23 mg of biphenyl amide 247. Yield 45%.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][CH:41]([CH3:43])[CH3:42])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH:16]1[CH3:44])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH:16]([CH3:44])[C:17]3=[N:18][C:19]=2[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:30][CH2:29]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2C
Reaction time: 3 h

Procedure:
A 50 mL round-bottomed flask containing 6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (175 mg, 0.282 mmol) and Pd(OH)2 (20 wt %, 39.5 mg, 0.056 mmol) in THF (2.82 mL) was purged and placed under hydrogen (balloon) for 3 h. Filtration through Celite™ (washed with EtOAc) and concentration in vacuo gave the title compound as a TFA salt (150 mg) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14](Cl)=[O:15].[Cl:17][C:18]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25].ClCCl.CO.N>>[Cl:17][C:18]1[CH:31]=[C:30]([NH:32][C:14](=[O:15])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[Cl:1])[CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(Cl)C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 4.1.d. from (2-chloro-4-trifluoromethylphenyl)propynoic acid chloride and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.26 g (27.5% of theory); C22H21Cl2F3N2O2 (M=473.32); calc.: molecular ion peak (M+H)+: 473/475; found: molecular ion peak (M+H)+: 473/475; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: C(C1C2(CCO)CC(C=1)CC2)(OC)=[O:2].[C:15]([O:25]C)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH:29]=[CH:28]1.C([Sn](=O)CCCC)CCC>CO>[C:15]([O-:25])(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21].[C:27]([O-:32])(=[O:33])/[CH:28]=[CH:29]\[C:30]([O-:2])=[O:31]
Reactant: COC(=O)C1=CC2CCC1(CCO)C2
Reactant: COC(=O)CCCCC(=O)OC
Reactant: O=C1C=CC(=O)O1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Product: O=C([O-])/C=C\C(=O)[O-]
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
A resin cook apparatus is charged with carbomethoxy-(2-hydroxyethyl)norbornene (50 grams, 0.26 mole), dimethyl adipate (13.3 grams, 0.076 mole), maleic anhydride (17.5 grams, 0.18 mole), NPG (29.2 grams, 0.28 mole), and dibutyltin oxide (0.22 grams). The mixture is heated at 180° to 190° C. for 7 hours. A conversion of 72 percent is obtained based on the methanol taken overhead.
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(O)(=O)C>C1COCC1.O>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
CH3MgBr (3.2M in 2-methyltetrahydrofuran, 3.37 mL, 10.79 mmol) was added dropwise over 10 minutes to a solution of indole (1.28 g, 10.79 mmol) in THF (6 mL) at 0° C. The solution was then stirred at 0-2° C. for 0.5 h. 2,4,5-Trichloropyrimidine (1 g, 5.40 mmol) was then added dropwise, resulting in a yellow solution. The ice bath was removed, then the solution was stirred at r.t. for 1 h, resulting in a red solution. The mixture was heated to 60° C. and then stirred at 60° C. for 1.5 h. The mixture was then cooled to r.t. and acetic acid (634 μL, 11.06 mmol) was added dropwise. Water (9.90 mL) and THF (2 mL) were added, then the mixture was stirred for 20 minutes at 60° C., resulting in a bi-phasic solution. The layers were separated and heptane (11 mL) was added to the organic solution, resulting in the crystallisation of a solid. The solid was collected by filtration, washed with heptane (2 mL), and dried in a vacuum oven to give the title compound (1.015 g, 66%) as a yellow solid; 1H NMR: 7.24-7.32 (2H, m), 7.55-7.58 (1H, m), 8.52-8.55 (1H, m), 8.71-8.73 (2H, m), 12.24 (1H, s); m/z: ES+ MH+ 264, 266.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25](Cl)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][CH:34]=1>O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:36]5[O:37][C:33]([CH:29]6[O:30][CH2:31][CH2:32][O:28]6)=[CH:34][CH:35]=5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(-c4ccc(C5OCCO5)o4)cc23)cc1
Yield: 56 %

Procedure:
(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (3.67 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (6.9 g) were reacted together in dioxan (100 ml) as in Procedure B. Purification by column chromatography gave a cream solid (2.59 g); □□ [2H6]DMSO 10.6 (1H,s) 9.26 (1H,s) 8.82 (1H,s) 8.78 (1H,s) 8.25 (2H,d) 8.0–8.3 (4H,d+m) 7.65–7.8 (3H,m) 7.21 (1H,d) 6.82 (1H,d) 6.09 (1H,s) 4.0–4.2 (4H,m); m/z 501 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:17][CH2:16][C:13]1[CH:12]=[C:11]([C:18]([OH:20])=[O:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1)=[O:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)O)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)O)c1
Temperature: 12.5 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a 0° C. mixture of 29.1 (2.2 g, 7.9 mmol) in THF (20 mL) was added pyridine (1.56 g, 19.8 mmol) followed by pivaloyl chloride (0.96 g, 7.9 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting solution was stirred at 0-25° C. overnight and was then quenched with water and treated with 2.0 N HCl (15 mL). The mixture was extracted with EtOAc (3×30 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-65% EtOAc/hexanes for elution gave 29.2 as white solid (1.60 g, 56%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[H][H].[N:10]1([CH2:15][C@@:16]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=2[F:32])([OH:24])[C@H:17]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH3:18])[CH:14]=[N:13][CH:12]=[N:11]1>CN(C)C=O>[N:10]1([CH2:15][C@@:16]([C:25]2[CH:30]=[CH:29][C:28]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:27][C:26]=2[F:32])([OH:24])[C@H:17]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH3:18])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: [H][H]
Reactant: C[C@@H](n1cncn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](n1cncn1)[C@](O)(Cn1cncn1)c1ccc(-n2cncn2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5734.3 %

Procedure:
1H-1,2,4-Triazole (0.3 mg) was added portionwise to a stirred dispersion of 60% sodium hydride in oil (0.16 g) in dimethylformamide (15 ml) under ice-cooling in a stream of nitrogen, followed by further stirring for 15 minutes. When the evolution of hydrogen (ceased), (2R,3R)-1,3-bis (1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-2-butanol (0.64 g) was added to the mixture. The mixture was stirred for 3 hours at 150° C. After cooling, the reaction mixture was added into ice-water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 30 g, eluent: ethyl acetate/acetone/methanol=5:4:1) to give the title compound (Compound 11, 92 mg) as colorless needles.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.80 mmol) in DCE (5 mL) was slowly added to a solution of ethyl (3R)-piperidine-3-carboxylate (140 mg, 0.88 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DCE (25 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 265 mg (66%); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.33 (td, J=12.55, 4.00 Hz, 1 H), 1.50-1.57 (m, 3 H), 1.59 (s, 9 H), 1.62-1.71 (m, 2 H), 1.72-1.84 (m, 1 H), 1.90-2.02 (m, 1 H), 2.22-2.38 (m, 2 H), 2.44 (t, J=11.03 Hz, 1 H), 2.57-2.69 (m, 1 H), 3.28-3.41 (m, 2 H), 3.70 (d, J=11.33 Hz, 1 H), 3.91 (dd, J=11.43, 3.81 Hz, 1 H), 4.01 (dd, J=11.23, 2.83 Hz, 2 H), 4.13 (q, J=7.16 Hz, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.43 (d, J=8.59 Hz, 1 H), 7.64 (dd, J=8.40, 1.76 Hz, 1 H), 8.18 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=492.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[S:16][C:10]=3[C:9]2=[O:25])=[CH:4][C:3]=1[O:26][CH3:27].Cl.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[H-].[Na+].Cl.CCOC(C)=O>CN(C=O)C.CO>[ClH:29].[CH3:27][O:26][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[S:16][C:10]=3[C:9]2=[O:25])[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(O)c(OC)c2)CC3)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OCCN4CCOCC4)c(OC)c2)CC3)cc1
Yield: 20 %

Procedure:
Treat 6-(4-hydroxy-3-methoxy-phenyl)-2-(4-methoxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (0.12 g, 0.31 mmol) in DMF (5 mL) with 4-(2-chloro-ethyl)-morpholine hydrochloride salt (59 mg, 0.31 mmol) and 60% NaH (38 mg, 0.94 mmol). Stir the reaction at 85° C. overnight. Quench with water (5 mL) and dilute with EtOAc (150 mL). Separate the phases and wash the organic phase with water (3×50 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 1% NH3—H2O, 10% CH3OH and 90% EtOAc to give 31 mg. Dissolve the material in CH3OH (2 mL), and treat with 1.0 M HCl in EtOAc (65 μL, 0.065 mmol), with stirring at RT for 5 min. Remove the solvent in vacuo to give 33 mg (20%) of the title compound. LC-MS/ES m/z 495.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[N:7]([CH:18]=1)[C@@H:8]1[O:17][C@H:12]([CH2:13][CH2:14][CH2:15]O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:40]=[N+:41]=[N-:42].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O>[N:40]([CH2:15][CH2:14][CH2:13][C@H:12]1[O:17][C@@H:8]([N:7]2[CH:18]=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:9][C@@H:10]1[OH:11])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 1.25 g of 2',5'-dideoxy-5-ethyl-5'-(2-hydroxyethyl)uridine, 1.18 g of triphenylphosphine, 1.49 g of sodium azide and 1.55 g of carbon tetrabromide in 30 ml of dimethylformamide was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was evaporated to dryness and the residue was subjected to flash chromatography on a column of silica gel using 1% methanol/dichloromethane for the elution to give 0.28 g of 5'-(2-azidoethyl)-2',5'-dideoxy-5-ethyluridine in the form of a colorless oil which crystallized upon standing.
Reaction SMILES: [Cl:1]C1C=CC2N(C)C(=O)C[N:8]3[C:14](C)=NN=[C:7]3[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:29]([CH3:30])[C:28](=[O:31])[CH2:27][N:26]3[C:32]([C:35](F)(F)F)=[N:33][N:34]=[C:25]3[C:24]=2[CH:39]=1>>[ClH:1].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:29][CH3:30])=[C:24]([C:25]2[N:26]([CH2:27][C:28](=[O:31])[N:8]3[CH2:7][CH2:6][CH2:18][CH2:14]3)[C:32]([CH3:35])=[N:33][N:34]=2)[CH:39]=1
Reactant: CN1C(=O)Cn2c(nnc2C(F)(F)F)-c2cc(Cl)ccc21
Reactant: Cc1nnc2n1CC(=O)N(C)c1ccc(Cl)cc1-2
Product: CNc1ccc(Cl)cc1-c1nnc(C)n1CC(=O)N1CCCC1
Product: Cl

Procedure:
Following the procedure of Example 1b but substituting an equivalent amount of 10-chloro-3,7-dimethyl-5H-s-triazolo-[4,3-d][1,4]benzodiazepin-6(7H)-one for the 10-chloro-7-methyl-3-(trifluoromethyl)-5H-s-triazolo[4,3-d][1,4]benzodiazepin-6(7H)-one, one obtains the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[NH3:24]>O1CCOCC1.CO>[NH2:24][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1ccc2nc(Cl)c(C(=O)c3ccccc3OC)cc2c1
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(N)c(C(=O)c3ccccc3OC)cc2c1

Procedure:
(2-Chloro-6-methoxyquinolin-3-yl)(2-methoxyphenyl)methanone (3.4 g, 10.4 mmol) was dissolved in dioxane (25 mL), mixed with 25% aqueous ammonia solution (15 mL) and heated for 30 hours to 150° C. under intrinsic pressure in the pressurized reactor. After cooling, the reaction mixture was diluted with methanol, prepurified with activated carbon and concentrated after filtration. The crude product was dissolved in dichloromethane and washed with water. The dichloromethane solution was dried (sodium sulfate) and concentrated. The crude product was purified chromatographically (silica gel, dichloromethane, 0-2% methanol). Yield: 1.4 g (4.5 mmol, 44%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:4][C@H:3]1[OH:17].ClC(Cl)Cl.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(N(CC)CC)C>[OH:17][C@H:3]1[C@H:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:4]1
Reactant: N[C@@H]1CCN(CCNc2ncccn2)C[C@H]1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(CCNc2ncccn2)C[C@H]1O)c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a stirred solution of 2.37 parts of trans-4-amino-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol in 120 parts of trichloromethane were added 2.08 parts of 3-(trifluoromethyl)benzoyl chloride. The whole was stirred for 15 minutes in an ice bath. After the addition of 1.26 parts of N,N-diethylethanamine, stirring was continued for 18 hours and the temperature was allowed to reach room temperature. The reaction mixture was washed with a sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.07 parts (50.5%) of trans-N-[3-hydroxy-1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-3-(trifluoromethyl)benzamide; mp. 148.3° C. (compound 65).