Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22].[NH4+].[Cl-]>C(#N)C.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>[C:8]1([C:3]2[N:4]=[C:5]([NH2:7])[S:6][C:2]=2[C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1nc(-c2ccccc2)c(I)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1sc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a stream of Ar the above prepared 5-iodo-4-phenyl-thiazol-2-ylamine (1.60 g, 5.29 mmol) was dissolved in 30 mL of acetonitrile and treated successively with triethylamine (2.09 mL, 3 eq.), Cul (0.096 g, 0.1 eq.), (Ph3P)2PdCl2 (0.353 g, 0.1 eq. and ethynyltrimethylsilane (2.09 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 15 h at ambient temperature. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=8/2) yielded finally 1.075 g of the title compound as brown foam. MS (ISP): 273.3 [M+H]+.
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])([OH:3])=[O:2]>C(O)CC=C>[CH2:7]([O:22][C:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:1]([O:3][CH2:12][CH2:11][CH:10]=[CH2:9])=[O:2])=[O:24])=[O:23])[CH2:8][CH:4]=[CH2:1]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Agent: C=CCCO
Product: C=CCCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCCC=C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
A mixture of 1.02 g (3 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid and 3 g Amberlite® IR120 in 25 ml 3-buten-1-ol were stirred at room temperature for 72 hours. After filtration the solvent was distilled off, the residue was taken up in dichloromethane and extracted with 2% aqueous sodium bicarbonate. The organic extract was dried with sodium sulfate and the solvent was distilled off to yield 490 mg (37%) (R)-1-[6-[(R)-2-but-3-enyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid but-3-enyl ester as alight yellow oil, MS m/e (%): 449 (M+H+, 100).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([Cl:33])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:33][C:25]1[CH:24]=[C:23]([C@@H:16]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][C:6]([OH:35])=[O:5])[N:10]=2)=[O:34])[CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Temperature: 60 °C
Yield: 97.1 %

Procedure:
3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (prepared in example 8, 3.00 g, 5.72 mmol) was dissolved in 20% trifluoroacetic acid/methylene chloride (100 mL) and stirred under reflux at 60° C. for 2 h, after which time the solvent was removed in vacuo. The crude material was the purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 0% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) to afford 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (2.60 g, 97%) as a white solid: ESI-LRMS m/e calcd for C21H26ClN3O5S [M+] 509.18, found 510.0 [M+H+], 1019.7 [2M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.42-1.91 (m, 8H, 4×CH2), 2.12-2.29 (m, 1H, CH), 2.83 (t, J=6.4 Hz, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.57 (t, J=7.5 Hz, 1H, CH), 4.36 (t, J=6.4 Hz, 2H, NCH2), 6.77 (d, J=2.5 Hz, 1H, Ar), 7.41 (d, J=2.5 Hz, 1 H, Ar), 7.48 (dd, Jo=8.1, Jm=1.5 Hz. 1H, Ar), 7.62 (d, Jm=1.5 Hz, 1H, Ar), 8.06 (d, Jo=8.1 Hz, 1H, Ar), 9.85 (br.s., 1H, CO2H), 10.38 (s, 1H, NH).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2cccs2)CC1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=C(CC1CCN(Cc2ccc[nH]c2=O)CC1)c1cccs1
Yield: 97.9 %

Procedure:
9.6 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-thienyl)ethyl]piperidine obtained in Example 54 and 8.5 ml of thionyl chloride were dissolved in 60 ml of ethanol, and the mixture was heated under reflux for 3 hours. The solvent was evaporated, and then the residue was dissolved in chloroform and a 1N aqueous sodium hydroxide. The organic layer was separated, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was recrystallized from ethanol, to give 9.0 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:17][N:18]([CH2:20][CH2:21][CH2:22]Cl)[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][N:9]([N:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:14]
Reactant: CN(C)CCCCl
Reactant: O=C1NCCN1N=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A near solution of 9.46 g (0.050 mole) of 1-[(phenyl methylene)amino]-2-imidazolidinone in 125 ml of dimethylformamide is treated portionwise with 2.0 g (0.050 mole) of NaH (60% dispersion in mineral oil) with the temperature rising to 30° C. The reaction is stirred at ambient temperature for 15 minutes with a solid forming. A 100 ml portion of dimethylformamide is added, to aid in stirring, and the mixture is stirred at 80° to 90° C. for 30 minutes. The mixture is cooled to ambient temperature and treated all at once with 12.2 g (0.100 mole) of dimethylaminopropyl chloride (prepared as described in Part I above). The resulting mixture is heated at 80° to 90° C. for 3 hours with near dissolution. The solvent is removed in vacuo. The residual semi-solid is dissolved in H2O (150 ml), and extracted with ethyl acetate (2×200 ml). The combined extracts are dried over MgSO4 and the solvent is removed in vacuo. The residual solid is washed with ether and air-dried to yield 4.8 g of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]=[C:30]=[S:31])[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.O1CCN(CCCN=C=S)CC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][NH:11][C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[S:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reactant: S=C=NCCCN1CCOCC1
Solvent: ClC(Cl)Cl
Product: S=C(NCCCN1CCOCC1)NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reaction time: 20 h
Yield: 75.9 %

Procedure:
To a solution of N-(4-bromobenzyl)-N-(pyridin-2-yl)pro-pane-1,3-diamine (1.0 g, 3.123 mmol) in chloroform (40 ml) was added 3-morpholinopropyl isothiocyanate (593 mg, 3.123 mmol) and the reaction mixture was stirred for 20 h at reflux temperature. To the reaction mixture was added 10 drops of 3-morpholinopropyl isothiocyanate and the reaction mixture was stirred for an additional 4 h at reflux temperature. The volatiles were evaporated in vacuo and the residue (2.05 g) was dissolved in ethyl acetate (20 ml) and left over night at room temperature. The precipitate was filtered off and washed with ethyl acetate and dried affording 1.20 g (76%) of the title compound as a solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2.I[CH3:32]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH:23]([CH3:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2
Reactant: CI
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame-dry 100 ml 3-neck round-bottomed flask was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5 ml, 5 mmol) and THF (20 mL). The mixture was cooled to −78° C. followed by adding tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.88 g, 3 mmol) in THF (10 mL) dropwise via addition funnel. After stirring at −78° C. for 30 min, iodomethane (0.4 ml, 6 mmol) was added. The reaction mixture was stirred for 30 min at −78° C. then allowed to warm to rt and stir for 1 h. The mixture was then quenched with sat. NH4Cl (3 mL). Solvent was removed. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and removed solvent. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, solvent system: hexane:acetone=90%:10%, Flow=30 mL/min) to afford a final product as yellowish liquid. MS m/z: 288.4 (M+H). Calc'd. for C17H21NO3—287.3.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]([OH:20])[CH2:14][C:13]#[N:15]
Reactant: CC#N
Reactant: O=Cc1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCC(O)c1ccc(F)cc1F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a stirring solution of diisopropylamine (0.97 mL, 6.89 mmol) in tetrahydrofuran (15 mL) at −70° C. under nitrogen was added a solution of n-butyllithium (2.88 mL, 7.20 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −70° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −70° C., acetonitrile (0.33 mL, 6.26 mmol) was added and the reaction mixture was then stirred at −70° C. for 30 minutes. 2,4-difluoro-benzaldehyde (1.09 g, 7.52 mmol) was added and the resulting solution was allowed to warm to ambient temperature. After 4 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (25 mL), washed with water (10 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was concentrated and purified by column chromatography (40 g silica gel cartridge) eluting with ethyl acetate/hexane (0%-10%) to give the product as light yellow oil (960 mg, 70%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8].I[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[CH2:7]([O:9][C:10](=[O:26])[C@H:11]([CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[NH2:12])[CH3:8]
Reactant: ICC1CCOCC1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N)CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of potassium tert-butoxide (25.7 g) in tetrahydrofuran (800 mL) was added N-(diphenylmethylidene)glycine ethyl ester (45.20 g) over 20 min at 0 to 8° C. The reaction mixture was stirred at 0° C. for 30 min, and 4-(iodomethyl)tetrahydro-2H-pyran (42.0 g) was added thereto. The reaction mixture was stirred overnight at room temperature, and the precipitate solid was filtrated. The filtrate was concentrated, the obtained residue was dissolved in ethanol (200 mL), and 2M hydrochloric acid (200 mL) was added thereto. The reaction mixture was stirred overnight at room temperature, and concentrated. The residue was diluted with water, and the mixture was washed with ethyl acetate (×4). The aqueous layer was adjusted to pH 11 with 8M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (23.00 g, yield 67%) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([CH:25]([OH:27])[CH3:26])=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH2:30](I)[CH3:31]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([CH:25]([O:27][CH2:30][CH3:31])[CH3:26])=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[O:3][CH2:2]1
Reactant: CCI
Reactant: CC(O)c1ccc2c(c1)ncn2-c1cccc(-c2cccc3c2OCO3)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccc3c2OCO3)c1

Procedure:
This was prepared from compound 17 by deprotonisation with sodium hydride followed by alkylation with ethyliodide using standard conditions. LC-ESI-HRMS of [M+H]+ shows 387.1705 Da. Calc. 387.170868 Da, dev. −1 ppm
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:11]2[CH:10]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:24]([O:26]C)=[O:25])[CH:18]=[CH:17]4)=[O:13])[CH:8]=[CH:7][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:35])[C:11]2[CH:10]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]4)=[O:13])[CH:8]=[CH:7][C:6]=2[C:5]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc2cc(C(=O)c3ccc4c(c3)C(C)(C)CC=C4c3ccc(C)cc3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)c4ccc5cc(C(=O)O)ccc5c4)ccc32)cc1
Yield: 98 %

Procedure:
In a manner similar to that of Example 22e, by reacting 0.5 g (1 mmol) of methyl 6-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylcarbonyl)-2-naphthalenecarboxylate (described in Example 22c) with 0.126 g (3 mmol) of lithium hydroxide hydrate, a solid is obtained (0.48 g; yield=98%; m.p.=267° C.).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19]O)[CH:16]=[N:15][CH:14]=2)=[N:8]1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH:44]1[CH2:50][NH:49][CH2:48][CH2:47][NH:46][CH2:45]1>C(Cl)(Cl)Cl>[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH:44]1[CH2:50][N:49]([CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:22])([CH3:21])[CH3:1])[N:8]=3)[CH:14]=[N:15][CH:16]=2)[CH2:48][CH2:47][NH:46][CH2:45]1
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CO)n2)n1
Reactant: C1CCC(OC2CNCCNC2)OC1
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3CCNCC(OC4CCCCO4)C3)n2)n1
Reaction time: 1 h

Procedure:
To a mixture of 44.9 mg of (6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazin-2-yl)methanol, 73 μl of N,N-diisopropylethylamine and 4 ml of chloroform was added 16 μl of methanesulfonyl chloride at room temperature followed by stirring for 1 hour. The reaction mixture was dropped into a solution of 6-(tetrahydro-2H-pyran-2-yloxy)-1,4-diazepane obtained in Reference Example 5 in 2 ml of chloroform, and the reaction mixture was stirred at room temperature for 15 hours. The resulting reaction mixture was washed with water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a basic thin-layer chromatography (eluent: chloroform/methanol=30/1) to give the title compound.
Reaction SMILES: C(N1CCN(CC2C=CC(N[C:17]3[N:22]=[C:21]([C:23]4[CH:35]=[C:34]([F:36])[C:26]5[N:27]=[C:28]([CH3:33])[N:29]([CH:30]([CH3:32])[CH3:31])[C:25]=5[CH:24]=4)[C:20]([F:37])=[CH:19][N:18]=3)=NC=2)CC1)C.[Cl:38]C1N=CC=CN=1>>[Cl:38][C:17]1[N:22]=[C:21]([C:23]2[CH:35]=[C:34]([F:36])[C:26]3[N:27]=[C:28]([CH3:33])[N:29]([CH:30]([CH3:32])[CH3:31])[C:25]=3[CH:24]=2)[C:20]([F:37])=[CH:19][N:18]=1
Reactant: CCN1CCN(Cc2ccc(Nc3ncc(F)c(-c4cc(F)c5nc(C)n(C(C)C)c5c4)n3)nc2)CC1
Reactant: Clc1ncccn1
Product: Cc1nc2c(F)cc(-c3nc(Cl)ncc3F)cc2n1C(C)C

Procedure:
Prepare the following intermediates essentially as described for [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine below using the corresponding amine and chloro-pyrimidine derivatives:
Reaction SMILES: [Br-:1].C([O:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([NH:16][CH2:17][CH2:18][N+:19]23[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]2)[C@@H:21]([O:27][C:28](=[O:43])[C:29]([OH:42])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20]3)=[O:15])=[CH:12][CH:11]=1)C1C=CC=CC=1>CN(C=O)C.[Pd]>[Br-:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH2:17][CH2:18][N+:19]23[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]2)[C@@H:21]([O:27][C:28](=[O:43])[C:29]([OH:42])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20]3)=[O:15])=[CH:44][CH:45]=1
Reactant: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
To a solution of (R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (0.075 g, 0.11 mmol) in DMF (1 ml) under an argon atmosphere is added 10% Pd on carbon (40 mg) and the resulting solution hydrogenated for 3 hours. The catalyst is then removed by filtration and concentration in vacuo yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13](=[O:21])[CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:25][N:26]([CH2:28][CH2:29][CH2:30]Cl)[CH3:27].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH:28]([N:26]([CH3:27])[CH3:25])[CH2:29][CH3:30])[CH:11]=[C:10]([C:13](=[O:21])[CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:9]=2)=[O:7])=[CH:22][CH:23]=1
Reactant: O=C(CN1CCCCC1)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(N(C)C)n1cc(C(=O)CN2CCCCC2)cc1C(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 29.2 %

Procedure:
A solution of 2 g (0.006 mole) of 1-[5-(4-chlorobenzoyl)-1H-pyrrol-3-yl]-2-(1-piperidinyl)ethanone, 1.4 g (0.0078 mole) of dimethylaminopropyl chloride hydrochloride, 5.2 g (0.042 mole) of K2CO3, and 1 g (0.006 mole) of potassium iodide in 40 mL of DMF was stirred overnight then heated to 70° C. for 5 h. After cooling the reaction mixture was poured into water, and extracted with Et2O. The organics were washed with water, brine and dried (K2CO3). The solvent was evaporated in vacuo and treated with ethereal HCl in 2-PrOH to give 0.73 g (29%) of Compound 14. mp 138-141° C. CIMS m/z416 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.35 (Ar, 1H); 7.8 (Ar, 2H); 7.7 (Ar, 2H); 7.2 (Ar, 1H); 4.8 (m, 2H); 4.6 (t, 2H); 3.4 (m, 3H); 3.15-2.9 (m, 4H); 2.75 (d, 6H); 2.2 (m, 2H); 1.9-1.65 (m, 4H); 1.4 (m, 1H). Anal calc'd for: C23H30CIN3O2. 2HCl.1.3H2O: C, 54.00; H, 6.80; N, 8.21. Found: C, 53.69; H, 6.89; N, 7.93 KF 4.04.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13].OS(O)(=O)=O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(O)c(O)c1
Yield: 69 %

Procedure:
A mixture which contained 43 g (0.28 mole) of 3,4-dihydroxybenzoic acid, 300 ml of ethanol and 0.5 ml of concentrated H2SO4 was refluxed for 48 hours. Water was trapped with 3 Å molecular sieves. The reaction mixture was evaporated to dryness in vacuo, and partitioned between ether and 5% NaHCO3 solution. The ether layer was evaporated to give 39 g (69% ) of solid; m.p. 128°-130° C. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:5][C:3]#[N:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% wt in mineral oil) (0.780 g, 32.5 mmol) in THF (100 mL) at room temperature was added diethyl cyanomethylphosphonate (4.50 g, 25.4 mmol) (4 mL). The mixture was stirred for 30 min and benzophenone (4.22 g, 23.2 mmol) was added. The reaction mixture was stirred at room temperature for 1d, and partially concentrated, diluted with Et2O, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 5% to 20% EtOAc in hexanes) gave 3,3-diphenylacrylonitrile.