Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:22]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:16][C@H:15]2[CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:22]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)N[C@@H]2CCNC[C@@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCN(C(=O)C(C)(C)C)C[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 17 h
Yield: 46.7 %

Procedure:
In a dry flask 1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea (43 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), and then triethylamine (65 μL, 0.47 mmol) and pivaloyl chloride (12 μL, 0.10 mmol) were added. The reaction mixture was stirred for 17 hours. The reaction mixture was concentrated in vacuo then was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (18 mg, 38%). 1H NMR (300 MHz, CD3OD), δ: 8.04 (s, 1H), 7.64 (d, 1H, J=7), 7.58 (dd, 1H, J=7, J′=1), 7.40 (t, 1H, J=8), 7.19 (m, 2H), 6.99 (t, 2H, J=9), 4.27 (d, 1H, J=14), 4.14 (d, 1H, J=15), 3.71 (m, 1H), 3.48 (bm, 3H), 3.25 (m, 2H), 3.07 (m, 1H), 2.95 (m, 2H), 2.66 (m, 2H), 2.57 (s, 3H), 1.98 (m, 4H), 1.76 (m, 2H), 1.62 (m, 1H), 1.28 (s, 9H), 1.20 (m, 1H). HRMS (ESI), C32H44FN4O3 m+/z: calc. 551.3397, found=551.3402.
Reaction SMILES: S(O[C@H:12]1[CH2:36][C@H:35]([O:37]C(=O)C)[C@@:34]2([CH3:41])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:42])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.O.[OH-].[Na+]>C1C=CC=CC=1>[OH:37][C@@H:35]1[C@@:34]2([CH3:41])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:42])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:13][CH2:12][CH2:36]1
Reactant: CC(=O)O[C@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CCC[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 0.900 mg of the tosylate 18 in 50 ml of benzene was stirred and purged with N2. Upon addition of 2.3 ml of Vitride reagent (a solution of 70% Na bis(2-methoxyethoxy aluminum hydride in benzene, Aldrich Chemical Co.), the mixture was refluxed (80°) for 18 hours. The product was isolated in the usual manner: after addition of water and 1.0 ml of 10% NaOH, the inorganic precipitate was removed by filtration and washed with ether, the aqueous phase was further extracted with ether, and the combined organic extracts were washed (10% NaOH), and dried over Na2SO4 and evaporated in vacuo. Chromatography of this residue on silica gel (using 20% ethylacetate in Skellysolve B) gave pure 1α-hydroxycholest-5-ene (19), nmr (CDCl3) δ5.53 (1H, m, C-6), 3.74 (1H, m, C-1); mass spectrum, m/e 386 (M+), 371, 368, 273.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][C:9]=3[C:8]=2[NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18]([OH:24])[CH2:17]2.Cl.[C:26](Cl)(=O)[O:27]C(CCCCC)CC.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]/[C:53]([OH:55])=[O:54]>N1C=CC=CC=1.CCO.O>[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]/[C:53]([OH:55])=[O:54].[C:1]1([C:7]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][C:9]=3[C:8]=2[NH:15][C:26](=[O:27])[O:24][C@@H:18]2[CH:19]3[CH2:22][CH2:23][N:16]([CH2:21][CH2:20]3)[CH2:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC(CC)OC(=O)Cl
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Nc1c(-c2ccccc2)sc2c1CCC2
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(-c2ccccc2)sc2c1CCC2)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-amine (110 mg) in pyridine (2 mL) was added (3R)-quinuclidin-3-ol and (3R)-1-azabicyclo[2.2.2]octa-3-yl chlorocarbonate hydrochloride (231 mg) synthesized from triphosgene, followed by stirring at room temperature for 30 minutes, and then stirring at 80° C. for 15 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, then dried over MgSO4, and concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to obtain a colorless oily substance (135 mg). This was dissolved in EtOH, and fumaric acid (38 mg) was added thereto. The crystal precipitated was collected by filtration to obtain (3R)-1-azabicyclo[2.2.2]oct-3-yl (2-phenyl-5,6-dihydro-4H-cyclopenta[b]thien-3-yl)carbamate fumarate (103 mg) as a white solid.
Reaction SMILES: [C:1]1(C)C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].COP(CC(=O)C)(=O)OC.[C:30]([O:34][C:35](=[O:45])[NH:36][CH:37]1[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>CC#N.CO>[C:30]([O:34][C:35](=[O:45])[NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([C:43]#[CH:1])[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Agent: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C#C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of p-toluenesulfonyl azide (10.57 g, 53.1 mmol) in MeCN (660 ml) were added K2CO3 (18.6 g, 134.5 mmol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (7.3 ml, 53.1 mmol). The slurry was stirred at rt for 2 hours and a solution of (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (8.5 g, 37.4 mmol) in MeOH (100 ml) was added and the reaction proceeded overnight. The solvent was removed in vacuo. The residue was partitioned between water (100 ml) and EA (150 ml). The aq. layer was further extracted twice with EA (2×150 ml). The combined extracts were washed with brine and concentrated to dryness. The residue was chromatographed (Hex-EA 3-1) to afford the title alkyne (4.6 g, 55% yield) as a white solid.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]2[C:9](=[O:10])[C:8](=[O:11])[C:7]=2[NH:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([C:29]([O:31][CH3:32])=[O:30])[NH2:28])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(N(C(C)C)C(C)C)C.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH:2]1([NH:5][C:6]2[C:9](=[O:10])[C:8](=[O:11])[C:7]=2[NH:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([C:29]([O:31][CH3:32])=[O:30])[NH:28][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H](N)COc1ccc(-c2cccc(Nc3c(NC4CC4)c(=O)c3=O)c2)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N[C@@H](COc1ccc(-c2cccc(Nc3c(NC4CC4)c(=O)c3=O)c2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 15 (97.0 mg, 0.2 mmol, 1 equiv) and ethyl chloroformate (29.8 mg, 0.3 mmol, 1.3 equiv) were suspended in THF (2 mL) and cooled to 0° C. Ethyldiisopropyl amine (82.1 mg, 0.6 mmol, 3 equiv) was added dropwise and the reaction mixture was allowed to reach rt. It was stirred for 1 hour at ambient temperature. Ethyl acetate and saturated aqueous NH4Cl solution were added and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were dried over Na2SO4. After removal of the solvents under reduced pressure the crude product was purified by chromatography (SiO2, gradient CH/EtOAc 6:4 to EtOAc 100%). Yield 39.0 mg, 37.3%. 1H NMR (CDCl3, 400 MHz) δ 7.61-7.55 (m, 1H); 7.52-7.49 (m, 2H); 7.31-7.18 (m, 2H); 7.09-6.96 (m, 1H); 6.82 (d, 2H); 5.71 (d, 1H); 4.79-4.64 (m, 1H); 4.34-4.29 (m, 1H); 4.19-4.02 (m, 4H); 3.75 (s, 3H); 3.19-3.06 (m, 1H); 1.23 (t, 3H); 0.89-0.75 (m, 2 H); 0.76-0.68 (m, 2H). MS (EI) 494 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([CH:7]=O)[CH2:2]1.Cl.[NH2:10][OH:11].[OH-].[Na+]>O>[O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH2:2]1
Reactant: O=CC1=CCCOC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ON=CC1=CCCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 5,6-dihydro-2H-pyran-3-carbaldehyde (10 g, 89 mmol) and hydrochloric acid salt of hydroxylamine (12.0 g, 178 mmol) in water (80 mL) was added a solution of sodium hydroxide (6.4 g, 160 mmol) in water (20 mL) dropwise. The cooling bath was removed and the mixture was allowed to stir at ambient temperature for 1 hour, the resulting solution was acidified with 2 N aqueous hydrochloric acid to pH 3-4, and then extracted with ethyl acetate (3×100 mL). All the organic solutions were washed with saturated NaHCO3 aqueous solution (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid, which was used in next step without further purification. 1H NMR (300 MHz, CD3OD) δ 7.76 (s, 1H), 6.15 (br, 1H), 4.35 (d, J=1.8 Hz, 2H), 3.86 (t, J=5.7 Hz, 2H), 2.32-2.31 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:3]1.[Cl:14][C:15]1[C:20]([C:21]2[C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[C:19]([F:30])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([NH:1][C:26]([C:25]2[C:21]([C:20]3[C:19]([F:30])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:14])=[N:22][O:23][C:24]=2[CH3:29])=[O:27])[CH2:3]1
Reactant: COC(=O)CC1CCCCC(N)C1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Yield: 873.9 %

Procedure:
A solution of 4.4 g (24 mmol) of methyl 2-(3-aminocycloheptyl)acetate, 0.03 g (0.46 mmol) of 3-(6-chloro-2-fluorophenyl)-5-methylisoxazole4-carbonyl chloride, and 0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) was stirred for 12 hours. The solvent was removed in vacuo and replaced with ethyl acetate. The organic layer was washed with 1N HCl, then aq. NaHCO3, followed by brine and dried. The solvent was removed in vacuo then chromatographed on silica gel with hexane/EtOAc 3/1 to yield 1.7 g of the title compound. MS(ES+)m/z=423.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][P:9]=[O:10]>CC(C)=O>[PH2:9]([O-:10])=[O:8].[NH3+:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=PO
Reactant: Nc1ccccc1
Solvent: CC(C)=O
Product: O=[PH2][O-]
Product: [NH3+]c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
Aniline (182 g, 1.95 mol) was added over 30 min via an additional funnel to an ice-cold aqueous solution of hypophosphorus acid (50% wt, 258 g, 1.95 mol). The light brown solution turned into thick slurry. Acetone (500 ml) was added and the resulting mixture was stirred for 5 min before filtration. The solid was washed with acetone to provide the product anilinium hypophosphite (134 g, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1I)[N:7]([CH3:12])[CH:6]=[C:5]2[C:13]1[C:14](=[O:30])[NH:15][C:16](=[O:29])[C:17]=1[C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=2[O:20][CH:19]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:10]2[CH:9]=[C:8]3[C:4]([C:5]([C:13]4[C:14](=[O:30])[NH:15][C:16](=[O:29])[C:17]=4[C:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=5[O:20][CH:19]=4)=[CH:6][N:7]3[CH3:12])=[CH:3][C:2]=2[F:1])=[CH:34][CH:33]=1
Reactant: COc1cccc2c(C3=C(c4cn(C)c5cc(I)c(F)cc45)C(=O)NC3=O)coc12
Reactant: OB(O)c1ccc(Cl)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: [K+]
Solvent: COCCOC
Product: COc1cccc2c(C3=C(c4cn(C)c5cc(-c6ccc(Cl)cc6)c(F)cc45)C(=O)NC3=O)coc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
3-(5-Fluoro-6-iodo-1-methyl-1H-indol-3-yl )-4-(7-methoxy benzofuran-3-yl)-pyrrole-2,5-dione (0.020 g, 0.039 mmol), Pd(PPh3)4 (4.5 mg, 0.004 mmol), and 4-chloro-phenylboronic acid (15.1 mg, 0.097 mmol) were dissolved in dimethoxy ethane (DME) (4 mL), and the mixture was degassed for 1 min and stirred for 10 min at room temperature. A solution of K2CO3 (2 M, 0.049 mL, 0.098 mmol) was added. The mixture was degassed again for 1 min, and stirred at 85° C. overnight. The resulting mixture was cooled to ambient temperature and poured into a mixture of 0.1 N HCl/EtOAc (15 mL/15 mL). After partition, the organic layer was washed with water, filtered, and concentrated. The residue was purified by preparative TLC using (ethyl acetate-hexane, 1:1) to afford the product as an orange solid (10 mg, 51%). The sample was purified by HPLC to give 3 mg of pure final compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:31][CH2:30][C:22]4[N:23]=[C:24](S(C)=O)[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH4+:32].[OH-]>O1CCOCC1>[NH2:32][C:24]1[N:25]=[CH:26][C:21]2[CH2:20][N:19]([C:15]3[N:14]=[C:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:18]=[CH:17][CH:16]=3)[CH2:31][CH2:30][C:22]=2[N:23]=1
Reactant: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(S(C)=O)ncc4C3)n2)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)n2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A suspension of 6-(2-Methanesulfinyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyridine-2-carboxylic acid (4-isopropyl-phenyl)-amide (405 mg, 0.930 mmol) in 1,4-dioxane (10 ml) was treated with NH4OH (3 ml, 28-30%) and the reaction mixture was heated in a sealed tube at 100° C. with stirring for 15 hours. Upon cooling to room temperature, the reaction mixture was concentrated and the residue was taken up in water. The aqueous mixture was extracted with ethyl acetate and the organic extract was dried (MgSO4), filtered, and concentrated. Trituration with MeOH gave the title compound as a yellow, amorphous solid (200 mg, 55%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[N:27]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:23]=2[CH:22]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)[nH]c4cc(Cl)ccc43)CC2)ccc1Cl
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)[nH]c4ccc(Cl)cc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-Chloro-1,3-dihydro-benzoimidazol-2-one (117 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (10a) and 6-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (10b) as a 1:1 mixture:HPLC retention time, 2.29 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 435.3, found, 435.4.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][CH2:6][C:5]=2[CH:4]=[N:3]1.[CH3:16][C:17]([CH3:40])([CH3:39])[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=2[CH3:38])[CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.ClCCl.C(N(CC)CC)C>[CH3:16][C:17]([CH3:40])([CH3:39])[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:7]3[CH2:6][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:11]=4[NH:10][C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=4)=[O:34])=[CH:31][C:30]=2[CH3:38])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)O)ccc1OCCN1CCN(CCC(C)(C)C)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCN1CCN(CCC(C)(C)C)CC1
Yield: 4 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (20 mg, 0.15 mmol) were added to a solution of 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (37 mg, 0.20 mmol) and 4-{2-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid from Example E40 (53 mg, 0.15 mmol) in dichloromethane (5 ml) and triethylamine (to pH9). The mixture was heated at re-flux for 2 days then concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% chloroform) to give an off-white solid identified as the title compound (3.5 mg, 4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[F:16][CH:17]([F:21])[C:18](Cl)=[O:19]>O1CCCC1>[OH2:15].[F:16][CH:17]([F:21])[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:19].[F:16][CH:17]([F:21])[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:19]
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: O=C(Cl)C(F)F
Solvent: C1CCOC1
Product: O
Product: O=C(Nc1ccc(C2=NNC(=O)C3CC23)cc1)C(F)F
Reaction time: 20 h
Yield: 94.3 %

Procedure:
3.0 g (14.9 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, 2.0 g (17.5 millimoles) of difluoroacetyl chloride and 100 ml of absolute tetrahydrofuran are kept first for 3 hours at 0°-5° C. and then for 20 hours at room temperature. The product is filtered off at 10° C., washed with water and recrystallized from methanol. 2.7 g (63% of theory) of 2-(p-difluoroacetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one hemihydrate are obtained as colorless crystals, of melting point 223°-224° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1C
Temperature: 130 °C
Yield: 8.5 %

Procedure:
2,4-Dichloro-5-methylpyrimidine (28.1 g, 4172 mmol), ethyl 2-aminobenzoate (26.7 mL, 181 mmol), diisopropylethylamine (33 mL, 190 mmol) and ethanol (200 mL) were mixed together then equally divided and placed in two 350 mL pressure vessels. They were then capped and heated to 130° C. for three days. Upon cooling to room temperature, the precipitated product was collected and washed with ethanol followed by hexanes and then dried to give 4.5 g (9%) of ethyl 2-[(2-chloro-5-methyl-4-pyrimidinyl)amino]benzoate as an off-white solid. MS: M(C14H14ClN3O2)=291.7, (M+H)+=292.2 and 294.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH:12]([CH:14]=[CH2:15])=O.Cl.[OH-].[Na+]>CCOC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=1)[N:5]=[CH:15][CH:14]=[CH:12]2
Reactant: COc1ccc(N)c(OC)c1
Reactant: C=CC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2ncccc2c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
2,4-Dimethoxyaniline (20.0 g, 131 mmol), 8.70 mL (7.30 g, 131 mmol) acrolein and 500 mL 1 N HCl are refluxed for 30 min. The reaction mixture is cooled to 23° C., poured into 200 mL of vigorously stirring EtOAc, and neutralized with 10N NaOH. The resulting bi-phasic solution is stirred for 30 min and filtered through celite. The layers are separated, and the aqueous layer is extracted with 3×300 mL EtOAc. The combined organics are washed with 1×400 mL H2O, 1×400 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2, eluting with 4/1 EtOAc/hexanes containing 10% MeOH, gives 6.40 g (33.8 mmol, a 26% yield) of the title compound as an off-white solid. MS (ES) m/z 190 (MH)+.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:15]=[C:14]([CH:27]=O)[CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.ClCCCl>[CH3:10][O:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[N:15]=[C:14]([CH2:27][NH:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:13]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cc(C=O)nn1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(CN[C@H](C)c2ccccc2)nn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with (R)-1-phenylethanamine 45 (0.135 g, 1.11 mmol), 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 74 (0.200 g, 0.740 mmol), 5 mL of DCE, 3 drops of concentrated AcOH, and sodium triacetoxyborohydride (0.314 g, 1.48 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 10 mL of saturated aqueous NaHCO3 and the mixture was extracted with CH2Cl2. The combined extracts were dried and concentrated. Purification via column chromatography on silica gel (1% to 6% MeOH in DCM) gave (1R)—N-({5-methoxy-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}methyl)-1-phenylethanamine 75. Mass spectrum: calculated for C20H20F3N3O 375.2; found 376.2 (M++1).