Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH2:31][N:32]4[C:40](=[O:41])[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]4=[O:42])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(CCCN5C(=O)c6ccccc6C5=O)CC4)c4cc(Cl)ccc43)c21
Temperature: 150 °C
Yield: 63.2 %

Procedure:
A mixture of (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (15 mg, 0.035 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (13 mg, 0.049 mmol), DIEA (0.018 mL, 0.11 mmol) and DMF (0.5 mL) was heated at about 150° C. in microwave for about 30 min. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give (R)-2-(3-(5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-yl)propyl)isoindoline-1,3-dione (12 mg, 63%). LCMS (APCI+) m/z 542, 544 [M+H]+; Rt=3.79 min.
Reaction SMILES: [CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3](=[O:7])[C:4]([O-])=[O:5].[NH2:15][NH2:16]>CCO>[NH:15]([C:4](=[O:5])[C:3]([N:2]([CH3:1])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:7])[NH2:16]
Reactant: CN(Cc1ccncc1)C(=O)C(=O)[O-]
Reactant: NN
Solvent: CCO
Product: CN(Cc1ccncc1)C(=O)C(=O)NN
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoacetate (77) (0.96 g, 4.61 mmol) and hydrazine (0.21 mL, 5.82 mmol) in EtOH (15 mL) was stirred at 80° C. for 18 h. The solvent was removed in vacuo to provide 2-hydrazinyl-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (78) as a pale yellow solid. This product was directly used in the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([OH:40])=O)[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38]([C:34]2[CH:33]=[C:32]([C:31]([F:30])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)=[O:40])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(C(F)(F)F)ccn1
Product: CN(C(=O)c1cc(C(F)(F)F)ccn1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 4-trifluoromethyl-pyridine-2-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-(trifluoromethyl)pyridine-2-carboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 611.2 [M]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](OCC)=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)(C)C.C1COCC1>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:3][C:2]([NH2:4])=[NH:1])=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC(=N)N)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A solution of 3.64 g (61.69 mmol) of guanidine in 150 ml of tert-butanol was added to a solution of 20 g (41.23 mmol) of (1.1) in THF and the mixture was stirred at room temperature for 18 h. A further 4.5 g of guanidine in 150 ml of tert-butanol were then added, and the reaction solution was stirred at room temperature for 7 h, concentrated to about a half and stirred at room temperature for a further 18 h. The solvent was removed in vacuo and the residue was first filtered through basic Al2O3 using CH2Cl2/MeOH/H2O (95/5/0.5) and then chromatographed on silica gel by means of MPLC using CH2Cl2/MeOH/acetic acid (90/10/0.5). 8.6 g (42%) of (1.2) were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:7]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:26]([NH:33][C:11]([C:9]1[NH:8][C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cc2ccnc(Cl)c2[nH]1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 1) (0.10 g, 0.51 mmol) and 1,1′-carbonyldiimidazole (0.09 g, 0.53 mmol) in N,N-dimethylformamide (3.4 mL) was stirred at 50° C. for 1 h. To the stirring solution was added benzylamine (0.11 mL, 1.02 mmol) and the reaction mixture was stirred at 65° C. until the reaction was complete by TLC analysis. The crude reaction mixture was poured into rapidly stirring water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×) and saturated NH4Cl, and dried over Na2SO4. The organic extract was filtered and concentrated to provide N-benzyl-7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.04 g, 0.14 mmol, 27%) as an off-white solid: mp 217-220° C.; 1H NMR (300 MHz, CDCl3) δ4.70 (2H, d, J=5.7 Hz), 6.45-6.61 (1H, m), 6.85 (1H, s), 7.31-7.39 (5H, m), 7.47 (1H, d, J=5.7 Hz), 8.06 (1H, d, J=5.7 Hz), 9.55 (1H, br s); APCI MS m/z 286 [C15H12ClN3O+H]+; HPLC (Method A) >99% (AUC), tR=16.3 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH2:13].CCO>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(Br)c1
Yield: 88 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2M solution of methylamine in EtOH (10.8 mL, 22 mmol) to give the title compound (4.3 g, 88%) as a white solid. MS (ISP) 250.0[(M+H)+].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:16]2=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]2[CH:14]=[CH:13][CH:12]=1>C1COCC1.CO.[Pt](=O)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[C:16]2=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]2[CH2:14][CH2:13][CH2:12]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4ccccc4c3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc4ccccc4c3)C2=N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.9 %

Procedure:
To a solution of 9-naphthalen-2-yl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF/methanol (30 mL/30 mL) was added platinum (IV) oxide (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by recrystallization (methanol-THF/diisopropyl ether) to give the title compound (104.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.N1C=CC=CC=1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:35][O:36][CH2:37][C:38]([O:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:18]3[CH2:22][CH:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:17])=[O:39]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)OCC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
The (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (263 mg, 0.67 mmol) was slurried in dry CH2Cl2 (10 mL) and cooled to 0° C. in an ice bath. The soluton became homogeneous after the addition of the pyridine (0.216 mL, 2.67 mmol). Next, the methoxyacetyl chloride (0.064 mL, 0.69 mmol) was added drop wise. The reaction was stirred at 0° C. for 30 minutes and then the ice bath was removed. After one hour, the reaction was found to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with CH2Cl2 (100 mL) and then washed with 1N HCl/brine (50 mL each), saturated NaHCO3 /brine (50 mL each), and brine (100 mL). Each aqueous portion was back-extracted with more CH2Cl2 (2×25 mL). The organic layers were combined, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to give an orange solid. This solid was chromatographed on silica gel (35 g,) eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give an orange solid. The latter solid was recrystallized by dissolving it in a minimal amount of CH2Cl2 /MeOH and then triturating with ether to yield 158 mg (51%) of the title compound as an off-white solid with a melting point of 147°-148° C. Aqueous solubility (pH 7, phosphate buffer) was 6.4 mg/ml.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.P(=O)(O)(O)O>O.CCOCC>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: c1cc2sccc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1cc2cnccc2s1
Temperature: -44 °C
Reaction time: 1 h

Procedure:
A three neck flask fitted with an internal thermometer containing thieno[3,2-c]pyridine (5.0 g, 37 mmol, 1 equivalent) was evacuated and then filled with a nitrogen gas atmosphere. THF (60 mL) was added and the solution was cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 25 mL, 41 mmol, 1.1 equivalents) was added over 10 minutes, while maintaining the internal temperature at or below −33° C. The reaction was stirred at −33 to −45° C. for 60 minutes. Triisopropyl borate (10.2 mL, 44 mmol, 1.2 equivalents) was added and the cooling bath removed. The reaction was allowed to proceed for 105 minutes. Then 3.0 mL phosphoric acid (85% aqueous, 3.0 mL, 44 mmol, 1.2 equivalents) was added. A yellow solid formed, which was diluted with water and Et2O (about 150 mL each). A yellow solid was collected by filtration and was dried by suction overnight (5.05 g). Analytical Data: 1H NMR (400 MHz, METHANOL-d4) β ppm 7.95 (1H, s), 8.09 (1H, d, J=5.9 Hz), 8.34 (1H, d, J=6.1 Hz), 9.09 (1H, s). MS (APCI, M+1) 180.1. Microanalysis for C7H6BNSO2.H3PO4: calculated C, 30.35; H, 3.27; N, 5.06; P, 11.18. Found: C, 41.12; H, 3.19; N, 6.53; P, 0.68%.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:24][C:20]1([CH3:23])[CH2:21][CH2:22][CH:18]([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)CCC(n2nc3c(c2OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC3)C1
Product: CC1(C)CCC(n2nc3c(c2-c2ccc(F)cc2)CCNCC3)C1
Yield: 38.4 %

Procedure:
The title compound (52.6 mg) was prepared as in Example 177, Steps C and D, using 201.7 mg of 2-(3,3-dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 221, Step A) and 180 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C20H26FN3, 327.44; found, m/z 328.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 2H), 7.33-7.28 (m, 2H), 4.62-4.53 (m, 1H), 3.44-3.39 (m, 2H), 3.31-3.29 (m, 2H), 3.21-3.17 (m, 2H), 2.80-2.75 (m, 2H), 2.20-2.03 (m, 2H), 2.00-1.94 (m, 1H), 1.80-1.73 (m, 2H), 1.49-1.41 (m, 1H), 1.16 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8].C(N(CC)CC)C.C(#N)C>>[CH2:6]([N:9]([C:2]([O:4][CH3:5])=[O:3])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8]
Reactant: COC(=O)Cl
Reactant: C=CCNc1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCN(C(=O)OC)c1ccc(C2(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (34 μL, 0.00044 mol) was added to a mixture of tert-butyl 1-[4-(allylamino)phenyl]cyclopropanecarboxylate (6.0×10−1 mg, 0.00022 mol) and triethylamine (92 μL, 0.00066 mol) in acetonitrile (1.0 mL, 0.019 mol) at rt. The reaction mixture was stirred at rt for 30 minutes, then was washed with water, and then extracted with EtOAc (3×). The organic layers were combined and concentrated. To the residue was added 4.0M HCl in dioxane and the reaction was stirred at rt for 2 h. The solvent was removed in-vacuo and used in the following step. LC/MS: 276.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([OH:20])=O)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28](C=O)C.CN>C1COCC1.ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([NH:28][CH3:27])=[O:20])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Reaction time: 0.08 h
Yield: 76 %

Procedure:
6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (250 mg, 0.746 mmol) was slurried into DCE (8 mL) and then oxalyl chloride (0.30 mL, 3.4 mmol) was added and the slurry was stirred for 5 min. Then DMF (50 μL, 0.65 mmol) was added (foaming) and the slurry was stirred 1 h before methanamine (5 mL, 10 mmol) 2M in THF (exothermic) and TEA (˜3 mL) (exothermic) were added. The reaction was stirred at rt overnight. The reaction was partitioned between water (˜30 mL) and DCM/MeOH (9/1, 3×30 mL). The combined organics were concentrated to dryness and the residue was slurried in MeOH/EtOAc (1:1 ˜40 mL) and filtered to collect 6-bromo-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (172 mg, 0.494 mmol, 66% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.92 (s, 1H), 8.25 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 2.79 (d, J=4.0 Hz, 3H). LC-MS retention time 1.73 min; m/z 348, 350 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(C=O)c(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (12.3 g, 33.7 mmol) in anhydrous THF (40 ml) was added n-butyl lithium (1.60 mol/l, hexane solution) (33.7 mmol, 21.1 ml) at 0° C. After 30 minutes at 0° C., to this was added 2-bromo-4-tert-butylbenzaldehyde (4.06 g, 16.8 mmol) (prepared according to J. Med. Chem. 2005, 48, 71-90) in anhydrous THF (10 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel, eluting with hexane, to afford the title compound (3.27 g, 81%) as a colorless oil.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]([C:17]12[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23][C:22](=[O:32])[CH:21]1[CH2:20][N:19]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:18]2)=[O:16].[Cl-].[NH4+]>C(OCC)C>[CH3:13][O:14][C:15]([C:17]12[CH:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:23][C:22]([OH:32])([C:7]3[CH:8]=[CH:9][C:4]([C:3]([F:12])([F:11])[F:2])=[CH:5][CH:6]=3)[CH:21]1[CH2:20][N:19]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:18]2)=[O:16]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C(F)(F)F)cc1)CCC2c1ccccc1
Temperature: 10 °C
Yield: 66.2 %

Procedure:
0.8 g of magnesium turnings was added to a solution of 7.2 g of 4-(trifluoromethyl)bromobenzene in 40 cm3 of dry diethyl ether. The reaction mixture was spontaneously brought to reflux for ten minutes and was then heated at reflux for twenty minutes. The reaction mixture was subsequently cooled and a solution of 5.6 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 40 cm3 of dry diethyl ether was added over fifteen minutes at a temperature in the region of 10° C. The reaction mixture was stirred for ten minutes at a temperature in the region of 10° C. and then poured into 150 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with three times 75 cm3 of diethyl ether. The organic phases were combined, washed successively with three times 75 cm3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. After crystallization from 25 cm3 of pentane, 5.2 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-[4-(trifluoromethyl)phenyl]-4-phenyloctahydroisoindole-3a-carboxylate were obtained in the form of a beige solid, the characteristic of which was as follows:
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@:16](C)([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].C([C@H]1[C@]2(O)[C@H](CCC(=O)C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)C#C>CC(C)=O.CCCCCC>[CH2:1]([C@H:4]1[C:21]2[C@H:16]([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Agent: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C[C@]12O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C=C12

Procedure:
Using a procedure similar to that described at Example 1 except replacing the 6β-propargyl-5α-hydroxyandrostane-3,17-dione (10) used therein with 6β-propargyl-5α-hydroxyestrane-3,17-dione (11), the title compound was prepared; 60%; m.p. 194°-195° C. (from acetone/hexane); 1H-NMR (CDCl3) δ 0.94 (s, 3H, 18-CH3), 2.73 (m, 1H), 5.94 (s, 1H, 4-H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH:20]1([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=2[F:30])[NH2:26])[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:26][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[CH:27]=[CH:28][C:29]=2[F:30])[CH2:22][CH2:21]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(C2CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(C3CC3)c2)nc(N2CCOCC2)cc1=O
Yield: 24.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 220 mg of 3-cyclopropyl-4-fluoroaniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. After extractions with ethyl acetate and silica column purification, eluent 90/10 CH2Cl2/MeOH, the residue is taken up with ml of diisopropyl ether, and the precipitate is spin-filter-dried and dried under vacuum, so as to obtain 69 mg of N-(3-cyclopropyl-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH:8]1([C:14]#[C:15][CH2:16]O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(O)(=O)CC>>[CH:8]1([CH:14]=[C:15]=[CH:16][CH2:2][C:1]([O:3][CH2:4][CH3:5])=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(C)([O-])[O-]
Reactant: OCC#CC1CCCCC1
Solvent: CCC(=O)O
Product: CCOC(=O)CC=C=CC1CCCCC1
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 66 g of ethyl ortho-acetate, 25 g of cyclohexylethynylcarbinol and 2.5 g of propionic acid was agitated at 130 to 135°C. for 8 hours while distilling off ethanol. The resulting liquid mixture was directly subjected to distillation under reduced pressure and a fraction boiling at 107° to 108°C. under 5 mm Hg was collected. Ethyl 5-cyclohexyl-3,4-pentadienoate was obtained in a yield of 93%.