Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33][CH2:32]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: N#CC1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (2.5 g, 10.8 mmol), HOBT (4.2 g, 24.9 mmol), EDC (4.77 g, 24.9 mmol) and piperidine-4-carbonitrile (2.98 g, 27.0 mmol). Then added DMF (50 mL) followed by N,N-diisopropylethylamine (10.7 ml, 61.6 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with 10% citric acid and extracted with EtOAc (2×). The combined organic layers were washed twice with 10% citric acid, twice with sat'd LiCl and once with brine then dried over MgSO4, filtered and concentrated to give 3.4 g (97%) of [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a beige foamy solid.
Reaction SMILES: COC(=O)C1C=CC=CC=1[N+]([O-])=O.[CH3:14][O:15][C:16](=[O:38])[C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:18]=1>O1CCOCC1.[Ni]>[CH3:14][O:15][C:16](=[O:38])[C:17]1[CH:22]=[C:21]([NH2:23])[C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[CH:18]=1
Reactant: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: COC(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(N2CCCC2)c1

Procedure:
A solution of 30 g of the nitrobenzoic acid methyl ester obtained according to (b) in 500 ml of dioxane is hydrogenated catalytically in the presence of Raney nickel. After completion of the absorption of hydrogen, the whole is filtered and the filtrate is concentrated. The residue yields, on recrystallization from methanol, the desired compound in the form of colourless crystals melting at 153°-156° C in a very good yield.
Reaction SMILES: C1(C)C=CC(S)=CC=1.[OH:9][C:10]1[C:21]([OH:22])=[CH:20][C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]=1[S:23][C:24]1[CH:29]=[CH:28][C:27](C)=[CH:26][CH:25]=1.[N+:31](C1C=CC(S)=CC=1)([O-:33])=[O:32]>CO>[OH:9][C:10]1[C:21]([OH:22])=[CH:20][C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1ccc(Sc2c(O)c(O)cc3c2CCN(C)CC3)cc1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cc1ccc(S)cc1
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3ccc([N+](=O)[O-])cc3)c2CC1

Procedure:
Similarly, reaction of 1 g. (0.0075 mole) of p-toluenethiol and 2 g. of the dione in 200 ml. of methanol as described above gave 7,8-dihydroxy-3-methyl-6-(p-tolylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 105°-114° C. and reaction of 1.65 g. (0.0011 mole) of p-nitrothiophenol and 2.3 g. of the dione in 200 ml. of methanol gave 7,8-dihydroxy-3-methyl-6-(p-nitrophenylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 165°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:15]2[CH2:18][CH2:17][CH2:16]2)([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:19]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:19][C:3]1[CH:4]=[C:5]([C:8]([CH:15]2[CH2:16][CH2:17][CH2:18]2)([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)CC(C)(c1ccc(Cl)c([N+](=O)[O-])c1)C1CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC(C)(c1ccc(Cl)c(N)c1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.79 g (5.74 mmol) of methyl 3-(4-chloro-3-nitrophenyl)-3-cyclobutylbutanoate were dissolved in 50 ml of ethyl acetate, and about 150 mg of 10% palladium on carbon were added. At RT, the reaction mixture was stirred vigorously under an atmosphere of hydrogen at atmospheric pressure overnight. The mixture was then filtered through Celite, and the filtrate obtained was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 1.36 g of the target product (84% of theory).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=1)(=[O:45])=[O:44].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:49]1[CH:50]=[CH:51][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=1)=[CH:14]/[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(=O)/C(I)=C\CC1CCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A mixture of zinc dust (0.98 g, 15 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.14 g, 0.75 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (82 mg, 0.75 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (1.47 g, 5 mmol) in dry tetrahydrofuran (1.5 mL) over 3 min. After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (0.94 g, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (75 mL), and the organic compound was extracted into diethyl ether (3×50 mL). The combined ether extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/7 hexanes/diethyl ether) afforded (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid methyl ester (1.10 g, 86%) as a colorless oil: EI-HRMS m/e calcd for C17H22O4S (M+) 322.1235, found 322.1239.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: C1CCNCC1
Solvent: CCO
Product: CC#CCOc1ncnc(N2CCCCC2)c1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.38 g of piperidine was added therein, and the mixture was stirred for 7 hours under reflux condition. The reaction mixture was cooled to near room temperature and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.37 g of 4-(2-butynyloxy)-5-fluoro-6-piperidinopyrimidine (hereinafter, referred to as Compound (2)).
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[CH2:18])[CH:11]=[CH:10]2)C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>C(O)C>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[CH2:18])[CH:11]=[CH:10]2
Reactant: C=Cc1ccc2cc(OC(C)OCC)ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1ccc2cc(O)ccc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
18 g of 6-(1-Ethoxy ethoxy)-2-vinylnaphthalene (0.0743 mol) was dissolved in 80 mL of ethanol. To this was added 1.6 g of pyridinium p-toluenesulfonate (0.0064 mol). The reaction mixture was stirred at 50° C. After 3 h, TLC analysis (silica, CH2Cl2) indicated that the reaction was over. The reaction mixture was cooled down to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2) to yield 11.15 g of pure 6-hydroxy-2-vinylnaphthalene (62%).
Reaction SMILES: CC1(C)[C@@H:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5](=[O:11])OO1.[CH2:13]1[CH2:17][O:16]CC1.B.[CH2:19]1COCC1>CO>[OH:11][CH2:5][CH2:6][C@H:7]1[O:16][C:17]([CH3:13])([CH3:19])[O:10][C:8]1=[O:9]
Reactant: C1CCOC1
Reactant: CC1(C)OOC(=O)[C@@H]1CC(=O)O
Agent: B
Solvent: CO
Product: CC1(C)OC(=O)[C@@H](CCO)O1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
To a stirring solution of (R)-(−)-dimethyl-5-oxo-1,2-dioxolane-4-acetic acid (15.8 g, 91 mmol), and THF (90 mL), at 0° C., under N2, was added borane-THF complex (1.0 M in THF, 100 mL, 100 mmol) dropwise over 60 minutes. The mixture was stirred at 0° C. for 2.5 hours and then allowed to warm to 25° C. The mixture was stirred at room temperature for 19 hours. The mixture was poured into MeOH (150 mL) and the solution was evaporated to dryness under reduced pressure at 25° C. The residue was purified via silica gel chromatography using 30% EtOAc in hexanes to obtain the desired alcohol as a clear oil (7.1 g, 44.6 mmol, 49% yield). 1H NMR (400 MHz, CDCl3) δ 4.61-4.51 (m, 1H), 3.89-3.80 (m, 2H), 2.20-2.12 (m, 2H), 2.05-1.98 (m, 1H), 1.64 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>ClCCCl>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([N:11]2[C:22](=[O:23])[NH:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[O:20][CH3:21]
Reactant: COc1cc(NS(=O)(=O)c2cccnc2N)cnc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(N2C(=O)Nc3ncccc3S2(=O)=O)cnc1OC
Yield: 64.6 %

Procedure:
The title compound (1.4 g, 4.16 mmol) was prepared from 2-amino-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide (2.0 g, 6.44 mmol) and 1,1′-carbonyldiimidazole (3.13 g, 19.3 mmol) in 1,2-dichloroethane (15 mL) at 90° C. for 16 h using the methods of (IntA14) step 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH2:31](I)[CH3:32].CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH2:31][CH3:32])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCI
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1nc(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2-(1H)pyrimidone (14.2 g) in N,N-dimethylformamide (1.42 ml) were added potassium hydroxide (5.5 g) and ethyl iodide (6.0 ml) and the mixture was stirred at ambient temperature for 2.5 hours. To the reaction mixture were added additional potassium tert-butoxide (5.0 g) and ethyl iodide (3.0 ml) and the mixture was stirred at ambient temperature for more 2 hours. The mixture was poured into ice-water (150 ml). The resulting precipitates were collected by filtration, air-dried and subjected to column chromatography on silica gel using a mixture of dichloromethane and methanol as an eluent to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.135 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])=[CH:4][CH:3]=1.B([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(O)O>>[CH3:15][O:14][N:12]([CH3:13])[C:10]([CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[O:11]
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CON(C)C(=O)C[C@H](c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C

Procedure:
In analogy to example 74, step 6, from (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) and 4-boronobenzoic acid was prepared the title compound as a light brown foam, MS (ESI+): m/z=404.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][CH:26]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.[I-].[K+].[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CCOCC.O.CN(C)C=O>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:25][CH2:24][CH2:23][N:9]2[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])[CH2:7][CH2:8]2)=[CH:32][CH:31]=1
Reactant: O=C(c1ccccc1F)C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1F)C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 34.6 %

Procedure:
A mixture of 10.0 g of 4-(2-fluorobenzoyl)piperidine, 16.9 g of potassium carbonate, 20.8 g of 4-chloro-1,1-bis(4-fluorophenyl)butane, 250 ml of dimethylformamide and a few crystals of potassium iodide was heated at 90° for 8 hrs with stirring. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield an oil. The oil was dissolved in ether, and oxalic acid was added. Recrystallization of the resultant solid from ethanol gave 10.6 g (34.6%) of 1-[4,4-bis(4-fluorophenyl)-1-butyl]-4-(2-fluorobenzoyl)piperidine oxalate, mp 179°-181° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1(C(N)=O)[NH:9][N:8]=[CH:7][S:6]1)(=[O:4])=[O:3].[CH2:13]([N:15](CC)CC)C.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[S:6][C:7]([C:13]#[N:15])=[N:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)C1(C(N)=O)NN=CS1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1nnc(C#N)s1

Procedure:
A mixture of 20 ml titanium tetrachloride in 50 ml carbon tetrachloride was added dropwise at 0° to 5° C. upon stirring to 350 ml tetrahydrofuran. Subsequently, 2-methylsulfonyl-1,3,4-thiadiazole-2-carboxamide was added in batches at room temperature in an amount of 20.7 g. After continued stirring for 1 hour a solution of 50 ml triethylamine in 50 ml tetrahydrofuran was dropped into the mixture within a period of 60 minutes. The mixture was then reacted with 50 ml water, the total mixture was extracted with chloroform and the organic phase was dried over magnesium sulfate and the solvent was distilled off in a vacuum. The residue was taken up in acetic acid ethylester, subjected to boiling with activated carbon, filtered and concentrated. The residue was crystallized from chloroform/tetrahydrofuran (3:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:30][C:18]3[N:19]=[C:20]([Cl:29])[N:21]=[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)C>[Cl:29][C:20]1[N:21]=[C:22]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:17]2[CH:16]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:30][C:18]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: Cl
Solvent: CCOCC
Product: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Yield: 71.7 %

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.61 g) was treated with an excess of hydrogen chloride in diethyl ether at room temperature overnight. Removal of volatiles and basification with aqueous sodium hydrogen chloride afforded 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (0.90 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH2:17]([NH:16][C:14]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])=[O:15])[CH2:18][CH3:19]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1ccc(F)c(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3OC)c(F)ccc2c1N

Procedure:
The title compound was prepared from 4-amino-7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (200.0 mg, 0.53 mmol) and 2-fluoro-5-methoxyphenyl boronic acid (181.7 mg, 1.07 mmol) according to Method A to afford a yellow crystalline solid (111.0 mg, 56%). 1H NMR (300.132 MHz, CDCl3) δ 8.49 (t, J=5.3 Hz, 1H), 7.91 (dd, J=9.3, 5.2 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.16-7.07 (m, 2H), 6.98 (dd, J=9.1, 4.5 Hz, 1H), 3.70 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=373 (M+H). HPLC 2.66 min.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].NN>C(O)C>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCCCC
Agent: NN
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(N)cc1OCCCCCCCCCCCC
Yield: 94.5 %

Procedure:
1,2-Didodecanoxy-4-nitrobenzene (10 g, 20.4 mmol) was then dissolved in ethanol (100 ml) , followed by addition of hydrazine (4ml) and graphite (8 g). The mixture was then refluxed for 24 hours and filtered. The filtrate was given a hexane/water work-up and the hexane fraction was dried over MgSO4 and evaporated to produce 1,2-didodecanoxy-4-amino benzene as white solid (8.9 g, 95%). 1H NMR (CDCl3) d 7.02(s, Ph, 1H) 6.96 (d, Ph, 1H), 6.69 (d, Ph, 1H), 3.97 (m, OCH2, 4H), 2.0-0.8 (m, alkyl ).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]=[N:3]1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1>>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[N:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1cc(N)nn1
Product: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Yield: 52.5 %

Procedure:
Following the procedure in Example 130c, and starting with 293b (500 mg, 5.10 mmol, 1.0 eq.) and 3,5-dibromo-1-methylpyridin-2(1H)-one (2.04 g, 7.65 mmol, 1.5 eq.) afforded 293c as a yellow solid (760 mg, 52%). MS-ESI: [M+H]+ 283.9.
Reaction SMILES: C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1.Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([F:37])=[CH:29][CH:28]=1.[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:41]([O:40][C:38]([N:45]1[CH2:50][CH2:49][N:48]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([F:37])=[CH:29][CH:28]=2)[CH2:47][CH2:46]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c3ccccc23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A first intermediate compound, 1-(4-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A mixture of dicyclohexylphosphino biphenyl (0.155 g, 0.444 mmol, 0.1 mmol) and palladium acetate (0.099 g, 0.444 mmol, 0.1 equiv) in dry toluene (15 mL) was bubbled with N2 gas for two hours. To the resultant clear solution was added 1-bromo-4-fluoro naphthalene (1.0 g, 4.44 mmol, 1.0 equiv) followed by 1-Boc-piperazine (1.0 g, 5.33 mmol, 1.2 equiv). To this mixture was added NaOtBu (0.600 g, 6.22 mmol, 1.4 equiv) and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was taken up in CH2Cl2, filtered through a celite bed, and then rinsed with CH2Cl2. The combined filtrates were concentrated and purified by column chromatography on silica (20% EtOAc in hexane). 4-(4-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, impure) was obtained as a dark viscous liquid, which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3) δ 8.25 (m, 1H), 8.05 (m, 1H), 7.55 (m, 2H), 7.05–6.80 (m, 2H), 4.00 (br s, 4H), 3.00 (br s, 4H), 1.45(s, 9H). MS: ES+ 331.13 (M+H)+ (Exact mass: 330.17).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:22]C(=O)OC(C)(C)C)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]=2[CH:21]=1.Cl>ClCCl>[NH2:22][C@@H:4]([CH2:3][CH:2]([CH3:30])[CH3:1])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]=2[CH:21]=1
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)[nH]c(=O)c1cnccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c(c1)[nH]c(=O)c1cnccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
(S)-tert-butyl (4-methyl-1-((5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (10 mg, 0.024 mmol) in dichloromethane (1 mL) was cooled to 0° C. To the solution was added hydrogen chloride (0.886 mg, 0.012 mL, 0.024 mmol, 2M in diethyl ether) dropwise. The temperature of the reaction mixture was maintained at 0° C. for 30 min and then the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford (S)-8-((2-amino-4-methylpentyl)oxy)benzo[c][2,7]naphthyridin-5(6H)-one (4 mg, 0.012 mmol, 49% yield) as a pale yellow solid. LC/MS (ESI) m/e 312.2 [(M+H)+, calcd for C18H22N3O2 312.2]; LC/MS retention time (method A): tR=1.1 min; HPLC retention time (method A): tR=6.85 min; HPLC retention time (method B): tR=7.51 min 1H NMR (400 MHz, D2O) δ ppm 9.30 (br. s., 1H), 8.77 (br. s., 1H), 8.36 (br. s., 1H), 8.07 (br. s., 1H), 6.95 (br. s., 1H), 6.72 (br. s., 1H), 4.41 (d, J=9.03 Hz, 1H), 4.26 (br. s., 1H), 3.89 (br. s., 1H), 3.38 (s, 1H), 1.72-1.88 (m, 2H), 1.05 (d, J=2.51 Hz, 6H).