Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:12][CH:13]=2)=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:35]
Reactant: O=C(NC1CNC1)c1cnc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)N1CC(NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of N-azetidin-3-yl-2-(3-fluorophenyl)pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in DMF (1.0 mL) was added DIPEA (0.06 mL, 0.32 mmol) and pivaloyl chloride (30 mg, 0.24 mmol). The mixtures were stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and concentrated to give a solid, which was purified by chromatography (silica, 80% EtOAc/Hex) to give the product, N-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]-2-(3-fluorophenyl)pyrimidine-5-carboxamide (50 mg, 86%). HRMS (M+H)=357.1727 expected, observed=357.1799.
Reaction SMILES: [OH-].[K+].CS(C)=O.[NH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.Br[CH2:13][C:14]([O:16]CC)=[O:15]>O>[N:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: CCOC(=O)CBr
Reactant: c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cn1cccc1
Reaction time: 1 h

Procedure:
To a mixture of potassium hydroxide (16.7 g) and dry DMSO (150 mL), pyrrole (5 g) was added dropwise at 20-25° C., with stirring under nitrogen atmosphere. Stirring was continued for 1 hr at 20-25° C. Ethyl bromoacetate (24.5 g) was added dropwise at 20-25° C. and stirring was continued for 2 hr. In the reaction mixture (150 mL) DM water was added and pH was made acidic (pH=3) with 20% HCI (50 mL). The reaction mixture was extracted with diethyl ether (2×100 mL). The combined organic extract was washed with DM water (100 mL), saturated brine (100 mL) and dried over Na2SO4. The solvent was evaporated to obtain pyrrol-1-yl-acetic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1)=[O:3].[OH-].[Na+].O.Cl[C:16]([CH3:20])([CH3:19])[C:17]#[CH:18]>C1(C)C(C)=CC=CC=1>[C:2]([C:4]1[CH:5]=[C:6]([I:11])[C:7]2[O:10][C:16]([CH3:20])([CH3:19])[CH:17]=[CH:18][C:8]=2[CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)c(I)c1
Reactant: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=O)c1cc(I)c2c(c1)C=CC(C)(C)O2
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 4-hydroxy-3-iodoacetophenone (5.24 g), 40% sodium hydroxide solution (4.8 ml), water (19 ml), xylene (11 ml) and 3-chloro-3-methylbut-1-yne (4.1 g) was heated to 90° C. for 3 hrs. The mixture was cooled and extracted with ether, and the ether extracts were washed with 2N sodium hydroxide solution, water and brine and dried over anhydrous sodium sulphate. The ethereal solution was filtered and evaporated, and the xylene solution that remained was refluxed for 16 hrs. The solution was evaporated and the residue chromatographed on silica gel using 10% ethyl acetate in hexane to give 6-acetyl-8-iodo-2,2-dimethyl-2H-1-benzopyran as a colourless solid (3.07 g), m.p. 102° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.C[N:19](C)C=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)ccc1Br
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 2-bromo-5-fluorobenzoic acid (10.0 g, 45.66 mmol) in dichloromethane (100 ml) was treated at 25° C. with oxalyl chloride (8.0 ml, 91.3 mmol) followed by a drop of N,N-dimethylformamide. The resulting mixture was then stirred for 4 h. The solvent and excess reagent were evaporated in vacuo and the residual oil was dissolved in tetrahydrofuran (100 ml) and added to a mixture of tetrahydrofuran (200 ml), water (100 ml) and concentrated ammonium hydroxide (10 ml). The resulting mixture was then stirred at 25° C. for 20 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 9.51 g (96% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.9-6.3 (2H, broad, NH2), 7.05 (1H, m, aromatic), 7.42 (1H, dd, J=3.2 Hz and J=8.3 Hz, aromatic), 7.61 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][C:16]([O:19][C:20](=[O:23])[CH2:21]Br)([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:21][C:20]([O:19][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:23])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 0.0077 mol) in DMF (25 mL) was added 2-bromoacetic acid 1,1-dimethylethyl ester (1.2 mL, 0.0085 mol) and cesium carbonate (3.8 g, 0.012 mol). The suspension was stirred at 90° C. overnight. The reaction mixture was cooled to RT and partitioned with ethyl acetate and water. The organic layer was washed with water, brine, and dried over MgSO4. The solution was concentrated to afford the desired compound (2.0 g, 84%). Analytical LC/MS: (M+H)+=309.4.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[C:8]([CH2:27][NH2:28])[CH:7]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:44][C:45]1[S:46][C:47]([Cl:53])=[CH:48][C:49]=1[C:50](Cl)=[O:51].CNCCNC>C(Cl)Cl.C(Cl)Cl.CO.CO>[Cl:44][C:45]1[S:46][C:47]([Cl:53])=[CH:48][C:49]=1[C:50]([NH:28][CH2:27][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:29])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])=[O:51]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(CN)c1
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Agent: CNCCNC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)cc1CNC(=O)c1cc(Cl)sc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
General Parallel Synthesis Procedure: 3-{3-Aminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester: trifluoroacetic acid salt (565 mg, 1.1 mmol) was dissolved in CH2Cl2 (25 mL) and washed with saturated NaHCO3 solution (15 mL). The organic layer was dried (NaSO4), filtered, and concentrated to 3-{3-aminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester (368 mg, 0.93 mmol, 84%). A portion of this free base (26 mg, 0.071 mmol) in CH2Cl2 (0.5 mL) was treated with triethylamine (0.075 mL, 0.54 mmol) then 2,5-dichloro-thiophene-3-carbonyl chloride (0.049 mL, 0.22 mmol). The reaction mixture was shaken overnight and dimethylethylenediamine (0.15 mL, 1.4 mmol) was added. The reaction mixture was shaken for 2 h and passed through an SCX column (1 g, equilibrated with 2 mL MeOH then 2 mL MeOH/CH2Cl2 1/1). The methyl ester-amide product was eluted with MeOH/CH2Cl2 (1:1, 10 mL) and concentrated. The residue was dissolved in THF (2 mL) and MeOH (2 mL) and treated with 5N NaOH (1 mL). The solution was heated at 55° C. for 2.5 h, cooled, and acidified with 5N HCl (1.5 mL). The mixture was transferred to a ChemElute cartridge and eluted with CH2Cl2. The solvent was removed under a stream of N2. The crude product was dried under vacuum and purified by mass-directed HPLC to give the title compound as a foam (9.9 mg, 26%).) MS (ESI) m/z 559.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][CH2:7][C@@H:8]2[CH2:13][N:12]([CH3:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)=[CH:4][C:3]=1[CH3:22].C([Li])CCC.[C:28](=[O:30])=[O:29]>O1CCCC1>[CH3:22][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:13][N:12]([CH3:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:19]=[C:20]([CH3:21])[C:2]=1[C:28]([OH:30])=[O:29]
Reactant: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, the compound (219 g) prepared in Example 8 was dissolved in anhydrous tetrahydrofuran (1.7 L) and stirred at −78° C. n-butyl lithium (1.58 M n-hexane solution, 421 mL) was added to the solution and was stirred for 1 hour. After carbon dioxide was blown into the solution, the solution was stirred for 2 hours while heating up to 0° C. After the residue obtained by removing the solvent was diluted with a 1N sodium hydroxide aqueous solution, the solution was washed by tert-butylmethylether. A 5N hydrochloric acid was added to the aqueous phase while stirring to obtain a crystal. The title compound (183 g) having the following physical data was obtained by filtrating and drying the crystal.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:49])=[C:11]([CH:17]([C:19]2[N:20]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[OH:18])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:15]([C:13]1[CH:12]=[C:11]([CH:17]([OH:18])[C:19]2[N:20]([C:30]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[C:10]([F:49])=[C:9]([OH:8])[CH:14]=1)[CH3:16]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 448.1 (1.74 g, 2.60 mmol) in 10 mL THF at rt, was added TBAF (1M in THF, 2.60 mL, 2.60 mmol). The mixture was stirred at rt for 30 min, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was triturated with hexanes (10 mL) to afford after filtration 1.32 g of intermediate 448.2 as a white solid. LCMS (2 min gradient) RT=1.81 min, 555.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:33][C:34]3[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[NH:33][C:34]6[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:35]=6[N:36]=5)[CH2:30][CH2:31]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: N#Cc1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccc(C#N)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 200 mg (0.64 mmol) 2-piperidine-4-yl-3H-benzimidazole-5-carbonitrile hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After five days stirring at room temperature the solvents have been evaporated and the residue was purified via chromatography. 121 mg of the desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][N:22]4[CH:26]([C:5]=3[C:4]=2[CH:3]=1)[CH2:25][CH2:24][CH2:23]4.[C:27](O)(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[O:13][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:6]3[CH2:20][CH2:21][N:22]4[CH:26]([C:5]=3[C:4]=2[CH:3]=1)[CH2:25][CH2:24][CH2:23]4
Reactant: O=C(O)CCC(=O)O
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)CCC(=O)O)c2ccncc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
2-(10-Methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol (350 mg, 1 mmol), succinic acid (118 mg, 1 mmol) and dimethylaminopyridine (122 mg, 1 mmol) in DCM (20 mL) were stirred at RT. Dicyclohexylcarbodiimide (206 mg, 1.6 mmol) in DCM (20 mL) was added dropwise and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated to obtain the crude product that was purified by reverse phase HPLC to yield 4-(2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethoxy)-4-oxobutanoic acid (96 mg). 1H NMR (CD3OD, freebase) δ (ppm): 8.46 (d, 2H), 7.33 (d, 2H), 7.27 (d, 1H), 7.23 (s, 1H), 7.01 (d, 1H), 6.07 (t, 1H), 4.8 (t, 2H), 4.5 (m, 2H), 3.55 (m, 2H), 3.45 (m, 1H), 3.0 (q, 2H), 2.7 (m, 1H), 2.54 (m, 2H), 2.39 (s, 3H), 2.37 (m, 1H), 2.1 (m, 4H). Separation by chiral HPLC provided diastereomers V-18a-d.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH3:37])([CH3:36])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:35])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][C:27]([C:30](OCC)=[O:31])([CH3:29])[CH3:28])[CH:21]=2)[CH:14]=1)C.C(OCC)(=O)C.Cl>CC(OC)(C)C>[OH:35][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:11]([CH3:37])([CH3:36])[CH2:10][OH:9])[CH:14]=1)[C:20]1[CH:21]=[C:22]([CH2:26][C:27]([CH3:29])([CH3:28])[CH2:30][OH:31])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)(CO)Cc1cccc(C(O)c2cccc(CC(C)(C)CO)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
Under Ar atmosphere, to a suspension of LiAlH4 (7.90 g, 208 mmol) in MTBE (200 mL) was added dropwise a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methylpropyl)-benzoyl]phenyl}-2,2-dimethylpropionic acid ethyl ester (25.9 g, 59 mmol) in MTBE (150 mL). The reaction mixture was stirred at room temperature for 16 h and heated to reflux for 3 h. Ethyl acetate (100 mL) was added and the reaction mixture was heated to reflux for 1 h and cooled to room temperature. The reaction mixture was poured into ice (500 g) and acidified with hydrochloric acid solution (2 N, 800 mL). The aqueous solution was extracted with MTBE (4×200 mL). The combined organic layers were washed with saturated NaHCO3 solution (200 mL) and saturated NaCl solution (200 mL), dried over MgSO4, and concentrated under vacuum. The residue (22.6 g) was subjected to column chromatography on silica gel using hexanes/ethyl acetate (3:2) as eluent to afford 3-(3-{hydroxy-[3-(3-hydroxy-2,2-dimethylpropyl)-phenyl]-methyl}-phenyl)-2,2-dimethylpropan-1-ol (19.0 g, 90%) as a white solid. Mp 98-99° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.26-7.19 (m, 6H), 7.06-7.03 (m, 2H), 5.80 (d, 1H, J=3.4 Hz), 3.23 (s, 4H), 3.05 (d, 1H, J=3.4 Hz), 2.56 (s, 4H), 2.07 (br d, 2H, J=4.4 Hz), 0.85 (s, 12H). 13C NMR (75 MHz, CD3OD=49.15 ppm): δ (ppm): 145.5, 140.2, 130.5, 130.1, 128.7, 125.4, 77.1, 71.5, 45.6, 37.4, 24.6, 24.5. HRMS (FAB, gly): Calcd for C23H33O3 (M+H): 357.2430. found: 357.2388. HPLC: 99.8% pure.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.Cl.[NH2:18][C:19]1[N:24]=[C:23]([NH2:25])[C:22]([N:26]=O)=[C:21]([NH2:28])[N:20]=1>C(OCCO)C>[NH2:18][C:19]1[N:24]=[C:23]([NH2:25])[C:22]2[C:21](=[N:28][C:14]([NH2:15])=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH3:16])[CH3:2])=[CH:12][CH:11]=3)[N:26]=2)[N:20]=1
Reactant: CN(C)CCOc1ccc(CC#N)cc1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: Cl
Agent: [Na]
Solvent: CCOCCO
Product: CN(C)CCOc1ccc(-c2nc3c(N)nc(N)nc3nc2N)cc1

Procedure:
0.03 mol of metallic sodium is dissolved with stirring in 150 ml of 2-ethoxyethanol. 3.1 g (0.013 mol) of 4-(β-dimethylamino-ethoxy)-phenyl acetonitrile in the form of the hydrochloride are added with stirring followed by 1.45 g (0.01 mol) of 2,4,6-triamino-5-nitroso-pyrimidine. After stirring for 48 hours at 60°-65° C. excluding access of moisture, the mixture is centrifuged when still hot. Petroleum ether is added to the solution obtained until it becomes cloudy. The solution is kept refrigerated to complete precipitation. The precipitate is filtered off. It can be recrystallized from n-butanol.
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=[O:29])[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][C:14]=3[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:29])[C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: O=C1c2c(-c3ccc(Cl)cc3Cl)cccc2[C@H]2CN(Cc3ccccc3)CC[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1c2c(-c3ccc(Cl)cc3Cl)cccc2[C@H]2CNCC[C@@H]12

Procedure:
The title compound was prepared as a white solid (69 mg, 0.21) by following the procedure step A of example 4 from cis-3-benzyl-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (90 mg, 0.21 mmol) and Pd(OH)2 (18 mg, 20 wt %) in MeOH (3.0 mL): MS (ES) 332.1 (M+H).
Reaction SMILES: Br.[CH2:2]([C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH2:7][CH:6]=1)[CH2:3][CH3:4].C(C1C=CC(C2CCC(=[O:35])CC2)=CC=1)CC.C([Mg]Br)CC>C(Cl)Cl>[CH2:17]([C:14]1([OH:35])[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)[CH2:18][CH3:19]
Reactant: CCCC1=CCC(c2ccc(CCC)cc2)CC1
Reactant: CCCc1ccc(C2CCC(=O)CC2)cc1
Agent: Br
Agent: CCC[Mg]Br
Solvent: ClCCl
Product: CCCc1ccc(C2CCC(O)(CCC)CC2)cc1

Procedure:
HBr is passed, at 0°, into a solution in 50 ml of CH2Cl2 of 2.42 g of 1-propyl-4-p-propylphenylcyclohexene (obtainable by reacting 4-p-propylphenylcyclohexanone with C3H7MgBr, hydrolysing the product to give 1-propyl-4-p-propylphenylcyclohexan-1-ol and dehydrating the latter), the mixture is allowed to stand overnight and is worked up in the customary manner to give r-1-bromo-1-propyl-cis-4-p-propylphenylcyclohexane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH3:11])[C:6]1=[O:12].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[K]>CN(C)C(=O)C>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][N:7]([CH2:10][CH3:11])[C:6]3=[O:12])[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CCN1CCN(CCCCl)C1=O
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN1CCN(CCCN2CC[C@H](NC(=O)c3cc(Cl)c(N)cc3OC)[C@H](OC)C2)C1=O
Temperature: 70 °C
Yield: 36.6 %

Procedure:
A mixture of 6.3 parts of 1-(3-chloropropyl)-3-ethyl-2-imidazolidinone, 4.76 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 2.3 parts of sodium carbonate, 0.1 parts of potassium iode and 90 parts of N,N-dimethylacetamide was stirred over weekend at 70° C. After cooling, the reaction mixture was evaporated. The residue was taken up in dichloromethane and water. The organic layer was separated, washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile and a few drops of water at 0° C. The product was filtered off and dried in vacuo at 40° C., yielding 2.83 parts (36.6%) of cis-4-amino-5-chloro-N-[1-[3-(3-ethyl-2-oxo-1-imidazolidinyl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 112.9° C. (compound 12).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH3:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C@@H:15]([CH3:18])[CH2:16][OH:17])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][CH2:16][C@@H:15]([N:12]2[CH2:13][CH2:14][C@@H:10]([CH3:9])[CH2:11]2)[CH3:18])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C[C@@H]1CCN([C@@H](C)CO)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@@H]1CCN([C@@H](C)COc2ccc(I)cc2)C1
Temperature: 125 °C
Yield: 76.2 %

Procedure:
A mixture of 1,4-diiodobenzene (2.07 g, 6.27 mmol), ((S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (0.6 g, 4.18 mmol), CuI (80 mg, 0.4 mmol), cesium carbonate (1.36 g, 4.18 mmol) in butyronitrile (4 mL) was degassed and then heated at 125° C. overnight. The mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated and purified on a silica gel column using 0-10% methanol in dichloromethane to afford (R)-1-((S)-1-(4-iodophenoxy)propan-2-yl)-3-methylpyrrolidine (1.1 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ: 7.57 (d, 2H), 6.79 (d, 2H), 4.04-3.99 (m, 1H), 3.89-3.78 (m, 1H), 2.94-2.85 (m, 1H), 2.66-2.56 (m, 2H), 2.56 (m, 1H), 2.15-2.05 (m, 2H), 1.90-1.86 (m, 1H), 1.24-1.22 (m, 1H), 1.10 (d, 3H), 0.96 (d, 3H). LCMS: 346 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)=O)(C)(C)C.Br[C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[CH:30]=[C:31]([NH2:32])[CH:33]=[CH:34][CH:35]=3)=[N:25][CH:24]=2)[CH:12]=[N:8]1
Reactant: Nc1cccc(-c2ncc(Br)cn2)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1cccc(-c2ncc(-c3cn[nH]c3)cn2)c1
Temperature: 90 °C
Yield: 83.8 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (20.7 g; 70.4 mmol; 1.0 eq.), 3-(5-Bromo-pyrimidin-2-yl)-phenylamine (intermediate 4, 17.6 g; 70.4 mmol; 1.0 eq.), bis(triphenylphosphine)palladium(II) chloride (4.94 g; 7.04 mmol; 0.10 eq.) and potassium carbonate (14.6 g; 105 mmol; 1.5 eq.) were suspended in dioxane (540 mL) and water (273 mL). The reaction mixture was then heated at 90° C. for 16 h. It was filtered through Celite and the filtrate was extracted with EtOAc. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The gum obtained was then triturated Et2O (100 mL). The resulting solid was filtered off and dried under high vacuum to give the title compound as a beige solid (14 g, 87%). 1H NMR (300 MHz, DMSO-d6) δ 13.21 (brs, 1H), 9.12 (s, 2H), 8.44 (m, 1H), 8.14 (m, 1H), 7.67 (t, J=2.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.14 (t, J=7.8 Hz, 1H), 5.25 (s, 2H), 6.68 (ddd, J=7.8 Hz, 2.0 Hz, 1.0 Hz, 1H). HPLC (Condition A): Rt 1.24 min (purity 72.1%). MS (ESI+): 238.2.