Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1cc2cc(Cl)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a mixture of methyl 4-{[1-(5-chloro-1-methyl-1H-indol-2-yl)heptyl]amino}benzoate (1.15 g) synthesized above, tetrahydrofuran (15 mL) and ethanol (15 mL) was added 1N is aqueous sodium hydroxide solution (15 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (30 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.09 g, 98%) as a white solid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH:8]([CH:20]1[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCC.O>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:24](=[O:26])[CH2:25][CH:20]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:21]([OH:23])=[O:22]
Reactant: OCCNCCO
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC=CC(CC(=O)N(CCO)CCO)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 500 ml, two-neck flask was charged with 52.6 g (500 mmol) diethanolamine and 50 ml toluene. A temperature probe was placed into this solution through one of the necks of the flask and the flask was immersed into a water bath. A solution of 105.2 g (500 mmol) dodecenylsuccinic anhydride dissolved in 200 ml toluene was dripped into the magnetically stirred solution diethanolamine solution over a 40-minute period. Ice was added to the water bath as required to prevent temperature of the reaction mixture from getting above 25° C. The mixture was then stirred for another 2.5 hours at room temperature. The complete disappearance of the anhydride functional group was confirmed by infrared spectroscopy. The FTIR trace on this compound had significant absorptions at 2957, 2924, 2858, 1733, 1616, 1560, 1415, 1160, 1069, 969, and 728 wavenumbers. The solution was concentrated down to 50% solids in toluene and was then set aside for later use.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][NH:19][CH2:18][CH2:17][N:16]3[CH3:21])[O:12][N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:19]2[CH2:18][CH2:17][N:16]([CH3:21])[CH:15]([C:13]3[O:12][N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[N:14]=3)[CH2:20]2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCNCC1c1nc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(F)cc2)CC1c1nc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-piperazine dihydrochloride (0.285 g, 0.86 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (374 mL, 2.7 mmol) and 4-fluorobenzoyl chloride (102 mL, 0.86 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred for 2 h. NaOH 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with NaOH 1N (6 mL) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. Purification of the crude by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 99/1/0.1) afforded (4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazine-1-yl}-methanone (0.12 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C(C1[C:25]2[C:20](=C[CH:22]=[CH:23][CH:24]=2)[C:19]([N:26]=[C:27]=[S:28])=CC=1)#N.Cl.NC1(CCl)CCCC1>>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:1]=[C:27]2[NH:26][CH2:19][C:20]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[S:28]2)=[CH:3][CH:4]=1)#[N:13]
Reactant: N#Cc1ccc(N=C=S)c2ccccc12
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: Cl
Agent: NC1(CCl)CCCC1
Product: N#Cc1ccc(N=C2NCC3(CCCC3)S2)c2ccccc12

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. 1-Amino-4-cyanonaphthalene was converted into 4-cyano-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate to Method C1a to give 2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH3:16])=[CH:14][C:9]=2[C:8](=[O:17])[NH:7][C:6]2[CH:18]=[CH:19][CH:20]=[N:21][C:5]1=2)=[O:3].[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:25][CH3:26])[CH3:23].C(OC(C)C)(C)C>>[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH3:16])=[CH:14][C:9]=2[C:8](=[O:17])[NH:7][C:6]2[CH:18]=[CH:19][CH:20]=[N:21][C:5]1=2)=[O:3])[CH2:25][CH3:26])[CH3:23]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: CCc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)Cl
Solvent: CC(C)OC(C)C
Product: CCc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)NCCN1CCCCC1CN(CC)CC
Yield: 70 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 70% of theory. Colourless crystals, m.p. 124°-126° C. (diisopropylether).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.CCO[CH2:18][CH3:19].O=O>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:18][CH3:19]
Reactant: CCOCC
Reactant: C#CCCCCCCCCCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: c1ccncc1
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCCC
Reaction time: 72 h

Procedure:
Dodec-1-yne (EGA 24,440-6) (1.2 g) was heated in the presence of copper acetate (4 g) in a mixture of pyridine (100 cm3) , methanol 300 cm3) and ether (400 cm3), for 72 h, at 30°-32° C., in the presence of a gentle stream of pure oxygen. The ether and methanol were then evaporated off under reduced pressure after the excess dissolved oxygen had been removed by the passage of argon, in the presence of 1 g of CuCl. The solution was taken up by fresh anhydrous pyridine (400 cm3) for 72 h at 47° C. (reflux). Part of the pyridine was then evaporated off under reduced pressure, after which the mixture was acidified with a 10% aqueous solution of HCl. After extraction with ether and evaporation, an oily liquid was obtained which crystallized in the cold. The oil was chromatographed in CHCl3 on SiO2 to give an oil which was transparent at room temperature (0.877 g, y=73%). The product was checked by NMR, gas chromatography (purity 97%) and mass spectroscopy (peak 330).
Reaction SMILES: [CH:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)=[CH2:2].[N+](=C[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-].[CH3:18]COCC>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[O:3][CH:1]1[CH2:18][CH:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCOCC
Reactant: C=COC1CCCCO1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CCOC(=O)C1CC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.75 mol of the compound obtained in Step 1 in 200 ml of ether there are added 1.5 g of rhodium acetate and then, over 6 hours, a solution of 93 g of ethyl diazoacetate in 50 ml of ether. After stirring at ambient temperature for 16 hours, the reaction mixture is filtered and is then distilled at 50-90° C. and 0.5 torr. The residue obtained is redistilled at 80-84° C. and 0.2 torr, allowing the expected product to be isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].CS[C:10](=[N:14][C:15]1C=CC=CN=1)[NH:11][C:12]#[N:13].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C.CCOCC>N1C=CC=CC=1>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:10]([NH:11][C:12]#[N:13])=[N:14][C:15]1[CH:25]=[CH:24][N:23]=[CH:26][CH:27]=1
Reactant: NCCOCCO
Reactant: CSC(=Nc1ccccn1)NC#N
Reactant: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CNC(=Nc1ccncc1)NCCOCCO
Temperature: 55 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a reaction flask, 2-(2-aminoethoxy)ethanol (5.78 g, 55 mmol) and S-methyl-N-cyano-N′-pyridylisothiourea (9.60 g, 50 mmol) were suspended in pyridine (40 mL). Triethylamine (7 mL, 50 mmol) was added followed by (4-dimethylamino)pyridine (cat., 100 mg). The reaction mixture became clear solution, which was stirred at 50-60° C. for 10 hours. The reaction mixture was then cooled to room temperature. Ether (200 mL) was added and the resulting solid was collected to give N-[2-(2-hydroxyethoxy)-ethyl]-N′-cyano-N″-pyridin-4-yl-guanidine (12.0 g, 48 mmol, 96%) as a white solid which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[Cl:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C(N(CC)CC)C>C(O)C>[ClH:13].[Cl:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:2][S:21][C:19]1[N:18]=[C:17]([OH:22])[CH:16]=[C:15]([CH3:14])[N:20]=1
Reactant: Clc1c(CBr)cnc2ccccc12
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cnc3ccccc3c2Cl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.3 %

Procedure:
A mixture of 3-(bromomethyl)-4-chloroquinoline (982 mg, 3.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (450 mg, 3.2 mmol), and triethylamine (1.3 mL, 9.5 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The solvent was evaporated to dryness and co-evaporated with EtOAc (20 mL). The product was suspended in water (200 mL). The product was recovered by filtration and washed with water (3×200 mL), diethyl ether (1×50 mL), and hexanes (2×50 mL). The solid material was dried in vacuo, affording the title compound (951 mg, 79% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.65 (s, 2H), 6.02 (s (br), 1H), 7.75 (td, 1H, J=1.4 Hz, 6.8 Hz), 7.83 (td, 1H, J=1.4 Hz, 6.8 Hz), 8.05 (dd, 1H, J=0.6 Hz, 7.6 Hz), 8.20 (dd, 1H, J=0.6 Hz, 8.4 Hz), 9.10 (s, 1H); M+318.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: N#CCC(N)=O
Reactant: CCC/C=C/C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of DMSO (300 mL) containing t-BuOK (20 g, 178 mmol) and cyanoacetamide (16.5 g, 196 mmol) was added (3E)-3-hepten-2-one (20 g, 178 mmol), and the contents were stirred at room temperature for 30 min. Additional t-BuOK (60 g, 534 mmol) was added and the reaction mixture was placed under an atmosphere of oxygen for an additional 1 h. The reaction mixture was purged with argon, diluted with 4 volumes of H2O, and then 5 volumes of 4N HCl, which were added slowly. The reaction mixture was filtered, washed with water, and dried to give 6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile (10 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.25-12.40 (br s, 1H), 6.18 (s, 1H), 2.53 (t, 2H), 2.22 (s, 3H), 1.57-1.64 (m, 2H), 0.84 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(O)CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:17]3[CH2:16][CH2:15][N:14]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=4)[CH2:19][CH2:18]3)[N:10]=2)[CH:7]=1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Cl)cc(Cl)c2n1
Solvent: OCCO
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A mixture of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 19, Step 1; 0.301 g), 4-(piperazin-1-yl)benzamide (Example 3, Step 1; 0.2916 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 1 h at 80-85° C. The mixture is then allowed to cool and water is added. The solids are collected, washed with water and hexane, and dried under reduced pressure. The solid is then adsorbed onto silica gel and chromatographed using methanol/dichloromethane (8/92). The appropriate fractions are combined and concentrated and the residue is crystallized from dichloromethane/methanol to give 0.2938 g of the title compound; mp 234-235° C.; MS m/z 403,405; IR (mineral oil) 1606, 1668, 1392, 1522, 1241 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.35, 3.83, 6.89, 7.27, 7.63, 7.72, 8.10.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.C([O:26]C(=O)CCCOC1C=CC=C(C2C=CC=CC=2)C=1)C.[NH3:45]>>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([NH:45][OH:26])=[O:3])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: N
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CCCOc1cccc(-c2ccccc2)c1
Product: COc1ccc(-c2ccc(OCCCC(=O)NO)cc2)cc1

Procedure:
The desired compound was prepared according to the method of Example 2, steps 2 and 3, except substituting 4-[4-(4-methoxyphenyl)phenoxy]butanoic acid ethyl ester, prepared as in step 1, for 4-(3-phenylphenoxy)butanoic acid ethyl ester. 1H NMR (CD3OD) δ 2.08 (dt, 2H, J=6.8, 13.6 Hz), 2.30 (t, 2H, J=7.4 Hz), 3.80 (s, 3H), 4.01 (t, 2H, J=6.0 Hz), 6.94 (d, 4H, J=8.8 Hz),7.46 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.8 Hz). MS (DCI/NH3) 302 (M+H)+, 319 (M+NH4)+. Anal. Calcd for C17H19NO4 ·0.40H2O·0.60NH4Cl: C, 59.94; H, 6.57; N, 6.58. Found: C, 60.28; H, 6.50; N, 6.60.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].[CH:23]1(I)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(C=O)C>[CH:23]1([O:20][C:4]2[CH:5]=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[B:15]([OH:16])[O:14][CH2:13][C:12]=4[CH:17]=3)[CH:18]=[CH:19][C:3]=2[C:1]#[N:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (200 mg, 0.75 mmol) in THF (50 mL) and DMF (20 mL) was added NaH (47 mg, 95%, 1.87 mmol) portion-wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of cyclopentyl iodide (0.26 mL, 2.25 mmol). The reaction was stirred at room temperature for 24 hours. After the reaction, all volatile components were evaporated under vacuum. The residue was purified using silica gel column chromatography, eluting with 25% EtOAc/hexane, afforded 36 mg of the title compound in 12.6% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.23 (s, 1H), 7.78 (d, J=7.8 Hz, 1H) 7.69 (d, J=8.6 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J=2.0, 8.2 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.56 (dd, J=1.9, 8.6 Hz, 1H), 4.96 (s, 2H), 4.95 (t, J=5.8 Hz, 1H), 1.95-1.55 (m, 8H); MS (ES) m/z: 336 (M+H)+; HPLC purity: 99.15% (220 nm), 99.62% (MaxPlot).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]>O1CCCC1>[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH2:30][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16](=[O:18])[CH:17]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:8]=[C:9]12
Reactant: COc1ccccc1CCBr
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1CCC1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.2 %

Procedure:
To a solution of 0.500 g (2.06 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one in dry tetrahydrofuran (20 mL) under argon at −30° C. was added 3.10 mL (3.10 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at room temperature for 10 min and 1.31 mL of 1-(2-bromo-ethyl)-2-methoxy-benzene (8.25 mmol) was added. The reaction was stirred at 70° C. for 6 hours. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 3% of methanol and 0.3% of ammonia) to afford 0.087 g of a solid (11%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([CH:18]2[CH2:23][CH2:22][C:21](=[C:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(Cl)Cl.[CH3:33][OH:34].[C:35]([O-:38])(O)=O.[Na+]>C(Cl)Cl.CO>[CH3:33][O:34][C:27]1([O:38][CH3:35])[CH2:28][CH2:29][C:24](=[C:21]2[CH2:20][CH2:19][CH:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:23][CH2:22]2)[CH2:25][CH2:26]1
Reactant: CO
Reactant: C1CCC(=C2CCC(C3CCCCC3)CC2)CC1
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Product: COC1(OC)CCC(=C2CCC(C3CCCCC3)CC2)CC1
Reaction time: 3 h

Procedure:
A catalytic mount of p-toluenesulfonic acid (26 mg) was added to a solution of 4-(4'-cyclohexylcyclohexylidene)cyclohexane (2", 2"-dimethyltrimethylene)ketal (5.56 g) in 1:1 methylene chloride-methanol (400 ml). TLC after three hours indicated the reaction to be about 50% complete. Additional methanol (200 ml) was added and the reaction checked by TLC after another two hours. About 10% of starting material remained. The reaction was worked up at this time by the addition of more CH2Cl2 followed by saturated aqueous NaHCO3 solution. The mixture was shaken and the layers were separated. The aqueous layer was extracted two more times with CH2Cl2, the pooled CH2Cl2 extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to a solid. This dimethyl ketal was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4F)nc23)CC1
Yield: 73.6 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.053 mMol) 2,4-difluorobenzoyl chloride, 0.012 gm (77%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]1[CH3:47])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]3[CH3:47])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1Br
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (S)-tert-butyl 4-((2-bromophenyl)sulfonyl)-3-methylpiperazine-1-carboxylate. MS (ESI): mass calcd. for C26H30FN5O4S, 527.20; m/z found, 528.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(N(C)C2CCOCC2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-[methyl(oxan-4-yl)amino]benzoate (413 mg, 1.32 mmol) in THF (13 ml) and MeOH (2 ml) was added 4M NaOH (13.16 ml). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 385 mg (98%) of the title compound as a thick yellow oil. LC-MS 94%, m/z=300.0/302.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.74 (d, J=2.0 Hz, 1H), 7.30-7.12 (m, 1H), 4.11-4.02 (m, 2H), 4.01 (s, 3H), 3.54 (t, J=11.6 Hz, 1H), 3.40 (t, J=11.3 Hz, 2H), 2.76 (s, 3H), 1.97-1.78 (m, 2H), 1.63 (d, J=11.8 Hz, 2H).