Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 3-(1,1′-biphenyl-4-yloxy)azetidine hydrochloride (100 mg, 382 μmol) in dichloromethane (2.5 mL) was added triethylamine (63 μL, 48 mg, 478 μmol) followed by phenyl isocyanate (35 μL, 38 mg, 320 μmol) and the reaction stirred at room temperature for 2.5 hours. The mixture was loaded directly onto a 2 g pre-packed SCX-2 cartridge and the product eluted with 1:1 dichloromethane:methanol (15 mL). The solvents were evaporated to give the urea (113 mg, 100%) as a white powder; LCMS retention time 2.57 minutes, m/z 345.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 8.54 (s, 1H), 7.62 (d, 4H, J=7.6 Hz), 7.50 (d, 2H, J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (t, 1H, J=7.2 Hz), 7.23 (t, 2H, J=7.8 Hz), 7.98-7.91 (m, 3H), 5.09 (m, 1H), 4.46-4.42 (m, 2H) and 3.95-3.91 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc(Cl)c(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 3-bromo-4-chloroaniline (200 mg, 0.969 mmol) in dichloromethane (5 mL) was added triethylamine (0.374 mL, 2.91 mmol). The solution was cooled to 0° C. and benzenesulfonyl chloride (188 mg, 1.066 mmol) was added dropwise. After stirring at room temperature for 12 hours, the mixture was extracted with dichloromethane and the organic layer washed with water and brine (25 mL each). Drying over sodium sulfate, filtration and concentration afforded the title compound. LCMS: 346.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([NH2:26])=[O:9])=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(N)=O)c1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (0.400 g, 1.39 mmol), THF (25 mL), oxalyl chloride (0.14 mL, 1.67 mmol) and ammonia gas to afford 0.220 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.25 (d, J=5.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.12 (br s, 2H); MS (m/z): 287.01 (M+H+).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:35]([CH:32]6[CH2:34][CH2:33]6)(=[O:37])=[O:36])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
A round bottom flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.40 g, 0.92 mmol), TEA (0.51 mL, 3.7 mmol) in DCM (3 mL) and DMF (6 mL). Cyclopropanesulfonyl chloride (0.16 g, 1.1 mmol) was added drop-wise and the resulting suspension was stirred at ambient temperature for about 18 h. The solvent was removed under reduced pressure and DCM (10 mL) was added. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 55%): LC/MS (Table 2, Method a) Rt=2.14 min; MS m/z 541 (M+H)+.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=[O:23].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:22]([C:13]3[CH:14]=[CH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=3)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.94-2.03 (m, 3H), 2.29-2.40 (m, 4H), 3.40 (s, 2H), 3.51 (s, 4H), 4.43 (s, 1H), 7.54-7.62 (m, 2H), 7.86-8.02 (m, 4H), 8.40 (d, J=1 Hz, 1H); MS (APCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1
Reactant: C1COCCN1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccccc3)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
657 mg of 6-[[2-chloro-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 13 ml of morpholine, and the mixture was stirred for 6 hours at 120° C. It was concentrated by evaporation to a very large extent in a vacuum, mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 271 mg was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and 1-(methylsulfonyl)piperazine for 96 hours. The residue was purified by silica gel column chromatography eluting with 50-100% DCM in cyclohexanes.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:15][CH3:16])=[C:4]([F:14])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (60 g, 229.01 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). To the resulting mixture was then added ethylmagnesium bromide (2M) (185 mL, 1.60 equiv) dropwise with stirring at −20° C. The resulting solution was stirred for 2 h at room temperature, then cooled to 0° C. with a water/ice bath. The reaction was then quenched by the addition of NH4Cl/H2O (500 mL). The resulting solution was extracted with ethyl acetate (3×300 mL) and the organic layers combined. The resulting mixture was washed with water (1×300 mL) and brine (1×300 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield 1-(4-bromo-2-fluorophenyl)propan-1-one as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1.C([Li])CCC.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>>[CH3:12][O:11][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:2]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:3][N:4]([CH3:13])[C:5]=12
Reactant: COc1nccc2c(I)cn(C)c12
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: COc1nccc2c(B3OC(C)(C)C(C)(C)O3)cn(C)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
3-Iodo-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (3.89 g, 13.50 mmol) was flow purged with nitrogen for 30 minutes, then treated with tetrahydrofuran (135 mL). The reaction mixture was cooled to −78° C. Butyllithium (5.40 mL, 13.50 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.75 mL, 13.50 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2.5 hours. The reaction mixture was poured onto water and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 100% heptane to 30% ethyl acetate/heptane) to provide the title compound (2.75 g, 70% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Br.[NH2:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][C:11]([Br:16])=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:7][C:8]1[C:13]([CH2:14][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:12][C:11]([Br:16])=[CH:10][N:9]=1
Reactant: COCCN
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNCc1cc(Br)cnc1N
Reaction time: 8 h
Yield: 89.6 %

Procedure:
2-Methoxyethylamine (1.49 mL, 17.16 mmole) was added to a solution of 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (1.49 g, 4.29 mmole) and DIEA (2.24 mL, 12.87 mmole) in CH2Cl2 (10 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the solution was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to afford the title compound (1.00 g, 90%) as a light brown liquid after drying in vacuo: MS (ES) m/e 260/262 (M+H)+.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH2:29][CH3:30]>C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[C:9]([CH2:29][CH3:30])[CH:10]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26][CH:25]=1)#[N:28]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(N)c(CC)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(NC(=O)NC(C)C)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of isopropyl isocyanate (130 mg, 1.55 mmol) in THF (2 ml) was added to a solution of the ethyl (RS)-(4-amino-3-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (500 mg, 1.55 mmol) described in Example 186.1 in THF (10 ml). The mixture was stirred overnight at room temperature. Thereafter, further isopropyl isocyanate (260 mg, 3.1 mmol) was added and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated. The residue was suspended in CH2Cl2/MeOH (98:2) and the colorless solid was filtered off. The solid was washed with EtOH and dried under a high vacuum. Ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-4-(3-isopropylureido)-phenyl]-acetate (395 mg, 62%) was obtained as a colorless solid; MS: 409 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:30])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:30])[CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CON(C)C(=O)C(C)c1ccccc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C(C)c2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-2-phenylpropionamide. It is used in crude form in the following reaction.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].[C:15]1(=[O:24])[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17][O:16]1>C1COCC1>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH2:17][C:18]2([C:15]([OH:24])=[O:16])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:12][CH:13]=1)[C:4]#[C:5][CH3:6]
Reactant: O=C1OCC12CCOCC2
Reactant: CC#CCOc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(SCC2(C(=O)O)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 0.112 g (2.81 mmol) of 60% sodium hydride in 2 mL of THF, cooled to 0° C., was added a solution of 0.500 g (2.81 mmol) of 4-but-2-ynyloxy-benzenethiol, dissolved in 3 mL of THF. The resulting mixture was stirred for 0.5 h at room temperature, then cooled to 5° C., followed by the addition of 0.518 g (3.65 mmol) of neat 2,7-dioxaspiro[3,5]nonane-1-one while keeping the reaction temperature below 10° C. The reaction was allowed to warm to room temperature and stirred for an additional 0.5 h and then quenched with 3 mL of 3N HCl solution and 3 mL of water. The resulting mixture was extracted with dichloromethane and the combined organics were washed with water and brine, dried over Na2SO4, filtered through a plug of silica gel and concentrated in vacuo. The residue was triturated with hexanes and acetonitrile and filtered to give 0.72 g of the carboxylic acid as a semi-solid. Electrospray Mass Spec: 319 (M−H)−.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(Cl)cc1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 41.3 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,4-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.98 g, 6.13 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.5 g, 8.18 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (1.57 g, 41%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]2[CH:25]=[CH:11][CH:12]=[C:13]([C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:23]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a 250-mL three-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 5.00 g (0.04 Mol) of 1-ethynyl-4-fluorobenzene, 11.16 g (0.04 Mol) of 3-bromo-4′-fluorobenzophenone (from the first step), 0.1 g of triphenylphosphine, 0.05 g of cuprous iodide, 0.05 g of dichlorobis(triphenylphosphine)palladium[II], and 200 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 4 hr and then cooled to ambient with stirring for an additional 16 hr (overnight). The reaction slurry was filtered to remove the white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solid was dissolved in dichloromethane. The resulting solution was washed with water (2×100 mL), 2% HCl (2×100 mL), brine and then dried over sodium sulfate. After filtration and removal of the solvent, the product was purified by crystallization from acetone yielding 23 g (75%)of white crystals having a melting point of 130-131° C. In an alternative experiment, during which recrystallization was carried out in toluene, the recovered pure rhombic needles of the product had a melting point of 135-136° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:23])(=[O:22])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15]>C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([OH:23])=[O:22])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=C(C(=O)O)c1ccccc1
Solvent: CCO
Product: O=C(O)C(CN1CCN(c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
1-Phenylpiperazine and atropic acid in ethanol is heated under reflux for 18 h, cooled to room temperature, and evaporated in vacuo. The solid is triturated with acetone to give the title product.
Reaction SMILES: [C:1]([C:3]1[NH:17][C:16]2[C:18]3[C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:8][N:7]1[CH3:27])#[CH:2]>C(O)C.[Ni]>[CH2:1]([C:3]1[NH:17][C:16]2[C:18]3[C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:8][N:7]1[CH3:27])[CH3:2]
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Agent: [Ni]
Solvent: CCO
Product: CCc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Yield: 384.4 %

Procedure:
At room temperature and under normal pressure, 140 mg (0.084 mmol) of 3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea is hydrogenated in 20 ml of ethanol after addition of 0.1 g of Raney nickel within 45 minutes. After the catalyst has been removed by filtration and the solution has been concentrated, the product is recrystallized from ehtanol/hexane, yielding 119 mg of 3-(2-ethyl-6-methyl-8α-ergolinyl)-1,1-diethylurea (84%), mp 165°-168° C., [α]D =+25° (c=0.22 in pyridine).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1([CH3:28])[C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:27])[O:15]1>>[CH3:13][C:14]1([CH3:28])[C:19]2[CH:20]=[C:21]([C:2]3[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=3)[CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:27])[O:15]1
Reactant: CC(=O)Nc1ccc(Br)cc1F
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)cc1F

Procedure:
Prepared according to procedure B from 4′-bromo-2′-fluoroacetanilide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off white solid; mp 245-247° C. 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 9.79 (s, 1H), 7.95 (t, 1H; J=8.4 Hz), 7.56-7.63 (m, 3H), 7.47 (dd, 1H, J=1.64, 8.47 Hz), 6.95 (d, 1H; J=8.9 Hz), 2.1 (s, 3H), 1.67 (s, 6H); MS +APCI [M+H]+ m/z 329. Anal. Calc. For C18H17N2 FO3: C, 65.85; H, 5.22; N, 8.53. Found: C, 65.46; H, 5.24; N, 8.12.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCNCCCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 67.7 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 2 g (12.7 mmol) of dipentylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.01 g (68%) of (S)-8-chloro-1-(5-dipentylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)O1.[Cl:29][C:30]1[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.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:29][C:30]1[N:31]=[CH:32][N:33]=[C:34]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:10]=2)[CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Reactant: Clc1cc(Cl)ncn1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(Cl)ncn3)c3cccnc32)cc1
Yield: 33 %

Procedure:
A solution of boronate 4 (0.11 g, 0.276 mmol), 4,6-dichloropyrimidine (0.049 g, 0.331 mmol), catalytic Pd(PPh3)4 and excess potassium carbonate in DMF was heated in the microwave at 160° C. for 5 minutes resulting in conversion to product by TLC (20% EtOAc:hexanes). The reaction was partitioned between EtOAc/H2O, extracted, stripped down in vacuo and purified by silica column (eluent:5% EtOAc:hexanes) giving 8 (0.035 g) as a white solid in 33% yield.