Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C@H:29]([NH:33]C(=O)OCC5C=CC=CC=5)[C:30](=[O:32])[NH2:31])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>ClCCl>[NH2:33][C@@H:29]([CH2:28][C@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([NH:8][CH3:6])[CH2:14][CH2:13]4)[C:27]=3[C:26]1=2)[C:30]([NH2:31])=[O:32]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](N)C(N)=O)CC4)CC1
Temperature: 30 °C
Reaction time: 5 h

Procedure:
To a solution of benzyl N-[(1S)-2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-1-carbamoylethyl]carbamate (70 mg, 0.11 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrogen chloride (12 M, 2 mL). The resulting solution was stirred for 5 h at 30° C. and then concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC under the following conditions: Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 50 mL NH4HCO3) and CH3CN (5.0% CH3CN up to 43.0% in 12 min, up to 95.0% in 2 min, down to 5.0% in 2 min); UV detection at 254/220 nm. This resulted in 28 mg (64%) of (2S)-2-amino-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide as a white solid. MS (ES): m/z 390 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 1.39-1.55 (m, 3H), 1.72-1.85 (m, 2H), 2.17-2.28 (m, 3H), 2.29-2.39 (m, 3H), 2.56 (s, 3H), 2.63-2.72 (m, 1H), 2.81-3.97 (m, 2H), 3.05-3.15 (m, 1H), 3.35-3.45 (m, 2H), 5.20-5.35 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>O1CCCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (1.00 g, 8.06 mmol) and pyridine (1.96 ml, 24.2 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.67 ml, 12.1 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (2.30 g, 95.4%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:13][O:14]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH:13]=[O:14]
Reactant: COc1ccc(C)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methylanisole (12.2 g., 0.1 mole) in 300 ml. of methylene chloride was cooled to 0° C. Titanium tetrachloride (3.8 g., 0.2 mole) was added followed by the dropwise addition of 1,1-dichloromethyl methyl ether (13.8 g., 0.12 mole) over 3 minutes. After stirring for 30 minutes at 0° C., the reaction mixture was poured into 600 ml. of water. The aqueous phase was extracted with two further portions of methylene chloride. The combined organic phase/extracts was washed with brine, dried over anhydrous magnesium sulfate and evaporated to yield 2-methoxy-5-methylbenzaldehyde as an oil [15 g., 100%; ir (CH2Cl2) 1678, 1608, 1488 cm-1 ].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:24])=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:24][C:9]1[C:8]([NH2:7])=[CH:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=2)[N:10]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N

Procedure:
In analog to the procedure described in example 5F], [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester was reacted with trifluoroacetic acid to yield the title compound as colorless solid.
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([CH3:24])([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:18])[N:13]=[C:12](Cl)[N:11]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[CH3:26][C:27]([NH2:34])([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:28].C1C=CNC(=O)C=1.[OH-].[Na+]>>[CH3:1][C:2]([NH:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([CH3:24])([CH3:18])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:13]=[C:12]([NH:34][C:27]([CH3:28])([CH3:26])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:11]=1)([CH3:3])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(NC(C)(C)CC(C)(C)C)n1
Agent: O=c1cccc[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)CC(C)(C)Nc1nc(NC(C)(C)CC(C)(C)C)nc(NC(C)(C)CC(C)(C)C)n1

Procedure:
A mixture of 3.7 g. (0.01 mole) of 2,4-bis(2,4,4-trimethyl-2-pentylamino)-6-chloro-s-triazine, 2.6 g. (0.02 mole) of 2,4,4-trimethyl-2-pentylamine and 2,85 g. (0.03 mole) of α-pyridone are fused and heated at the boiling point for 21/2 hours during which time the mixture turns a brown color. At the end of this period the mixture is cooled yielding a solid mass which is treated with about 10 ml. of 10% sodium hydroxide. On filtration, 4.52 g. of a beige solid is obtained m.p. 151°-156° C. Recrystallization of the beige solid from 75 ml. of hot ethanol yields 3.09 g. of colorless needles, m.p. 156°-157.5° C.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:29][C:27]3[S:28][C:24]([CH3:23])=[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Cc1sc(N)nc1-c1ccccc1
Product: Cc1sc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)nc1-c1ccccc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 5-methyl-4-phenylthiazol-2-amine (46 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(5-methyl-4-phenylthiazol-2-yl)benzamide as an off-white solid. Yield: 54 mg (46%). 1H-NMR: 8.19 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.68 (d, J=7.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 1H) 7.50-7.34 (m, 3H), 7.24-7.08 (m, 3H), 3.84-3.78 (m, 2H), 2.52 (s, 3H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.57 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1)#[N:23].NC1C=C(C#N)C=CC=1NC1N=CC(CC(N)=O)=C(NCC2C=C(F)C=C(F)C=2)C=1>>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][C:26]=1[NH:31][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Agent: N#Cc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c(N)c1
Product: N#Cc1ccc(N)c(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c1

Procedure:
From 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) and 4-cyano-1,2-phenylenediamine in a manner similar to step 1 of Example 365, a mixture of 6-[(2-amino-4-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide and 6-[(2-amino-5-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (1H-NMR integral ratio 1:6) was obtained as a light yellow oil (yield 7%).
Reaction SMILES: C([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1>CO.[H][H]>[C:19]1([CH2:18][CH2:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:26])=[O:8])=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Yield: 90.4 %

Procedure:
To N-(4-phenylbutyryl)-L-proline benzyl ester (9.31 g) in 99% methanol (100 ml) was added 10% Pd--C (0.90 g), and the mixture was stirred at room temperature in hydrogen stream for 2 hours. The catalyst was filtered off with celite, and the filtrate was concentrated to give 6.26 g of N-(4-phenylbutyryl)-L-proline.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH2:37][NH:36][CH2:35][CH2:34][C:10]=3[N:11]=[C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[CH:17][N:18]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[N:13]=2)[CH2:6][CH2:5][N:4]([C:38](=[O:40])[CH3:39])[CH2:3]1.FC(F)(F)S(O[C:47]1[CH:52]=[C:51]([C:53]2([CH3:57])[CH2:56][O:55][CH2:54]2)[CH:50]=[CH:49][C:48]=1[CH3:58])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH2:37][N:36]([C:49]4[CH:50]=[C:51]([C:53]5([CH3:57])[CH2:56][O:55][CH2:54]5)[CH:52]=[CH:47][C:48]=4[CH3:58])[CH2:35][CH2:34][C:10]=3[N:11]=[C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[CH:17][N:18]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[N:13]=2)[CH2:6][CH2:5][N:4]([C:38](=[O:40])[CH3:39])[CH2:3]1
Reactant: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CNCC3)[C@H](C)C1
Reactant: Cc1ccc(C2(C)COC2)cc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C4(C)COC4)ccc2C)CC3)[C@H](C)C1
Temperature: 140 °C

Procedure:
A mixture of (R)-1-(3-methyl-4-(2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone (0.155 g, 0.278 mmol), 2-methyl-5-(3-methyloxetan-3-yl)phenyl trifluoromethanesulfonate (0.086 g, 0.278 mmol) prepared as described in Example 13, cesium carbonate (0.272 g, 0.834 mmol) and chloro(2-dicyclohexylphosphino-2′-4′-6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butylether adduct (CAS#1028276-56-5) (0.031 g, 0.042 mmol) in THF (4 mL) was heated in a microwave reactor at 140° C. for 3 h. The reaction was then filtered and concentrated, the resulting residue was purified by FCC (60-100% EtOAc/DCM) to provide (R)-1-(3-methyl-4-(2-(3-methyl-1-tosyl-1H-indol-4-yl)-6-(2-methyl-5-(3-methyloxetan-3-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone. MS (ESI+) m/z 719.3 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH2:20][CH3:21])[CH:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH2:20]([C:11]1[CH:10]=[C:9]([OH:8])[CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:21]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1CC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(O)cc1CC
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 51.8 %

Procedure:
To a solution of ethyl 4-benzyloxy-2-ethylbenzoate (0.633 g) in ethanol (6.2 mL) was added 10% palladium-carbon (0.227 g), and the mixture was stirred at room temperature for 1.2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to afford the title compound (0.224 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][O-].[K+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CC(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:9]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Cc1cnc(N)c(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(Br)cc(C)cn12
Temperature: 90 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
A mixture of 3-bromo-5-methylpyridin-2-amine (3 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (7.6 g), sulfuric acid (0.86 mL) and 2-propanol (60 mL) was stirred at 90° C. for 24 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[CH2:19][C:20]3[CH:36]=[CH:35][C:23]4[N:24]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[CH3:34])[O:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C>[C:29]1([CH3:34])[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH:27][C:25]1[O:26][C:22]2[CH:21]=[C:20]([CH2:19][C:18]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]4([CH2:4][C:3]([OH:38])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[CH:12][CH:13]=3)=[O:37])[CH:36]=[CH:35][C:23]=2[N:24]=1
Reactant: COC(=O)CC1(c2ccc(NC(=O)Cc3ccc4nc(Nc5ccccc5C)oc4c3)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)CCOCC4)cc3)cc2o1
Yield: 51.4 %

Procedure:
A solution of (4-(4-{2-[2-o-tolylamino-benzoxazol-6-yl]-acetylamino}-phenyl)-tetrahydro-pyran-4-yl)-acetic acid methyl ester [0.2 g, Reference Example 17(b)] in ethanol (25 mL) was treated with sodium hydroxide solution (2 mL, 1N) and the mixture was stirred under argon and at reflux temperature for 3 hours. The reaction mixture was evaporated and the residue was dissolved in water (25 mL). This solution was washed with diethyl ether (10 mL) and then acidified to pH 1 by addition of hydrochloric acid (3 mL, 1N). The resulting precipitate was filtered, then washed four times with water (5 mL) and then dried at 60° C. under high vacuum to give the title compound (0.1 g) as an off-white solid. LC-MS: RT=3.10 minutes, MS(ES+): 500(M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][CH2:8][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:18][CH2:19]3)[CH:25]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Temperature: 150 °C
Yield: 83.7 %

Procedure:
To a solution of [(3-bromophenyl)methyl]amine hydrochloric salt (0.556 g, 2.5 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.041 g, 3.25 mmol), Pd(PPh3)4 (0.144 g, 0.125 mmol), K2CO3 (1.382 g, 10 mmol) and was heated in a microwave at 150° C. for 15 min. The organic layer was separated, dried with a Glas-Col evaporator, then was purified by CombiFlash chromatograph to afford 0.798 g (84%) of the title compound. LC-MS m/z 382 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([Mg]Cl)=[CH2:22]>C1COCC1.[Cu]I>[C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]([OH:19])[CH2:20][CH:21]=[CH2:22])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Mg]Cl
Reactant: c1ccc(-c2nc([C@@H]3CO3)oc2-c2ccccc2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-(4,5-diphenyloxazol-2-yl)oxirane (12 g) and CuI (0.19 g) in THF (240 ml) was dropwise added a solution of vinylmagnesium chloride in THF (1.0 M solution, 101 ml) at -78° C. under N2. The mixture was stirred for 1 hour at room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (4S)-4-(4,5-diphenyloxazol-2-yl)-4-hydroxy-1-butene (9.2 g). MS (m/z): 292 (M+ +1) IR (Nujol): 3300, 1600 cm-1NMR (CDCl3, δ): 2.7-2.9 (2H, m), 3.17 (1H, d, J=5.8 Hz), 4.8-5.0 (1H, m), 5.1-5.3 (2H, m), 5.8-6.0 (1H, m), 7.2-7.8 (10H, m)
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCc1ccc(O)cc1
Reactant: CC(C)CCOCCCCOCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCc1ccc(OCCCCCCOCCCCOCCC(C)C)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
2.60 g (0.010 mol) of 6-(4-Isopentyloxybutyloxy)-hexanol are mixed with 1.22 g (0.010 mol) of 4-ethylphenol and 2.06 g (0.010 mol) of dicyclohexyl carbodiimide and the mixture is stirred at 100° C. over the course of 3 days. After cooling the residue is chromatographed with hexane/ethyl acetate (97:3) on silica gel, whereupon 1-ethyl-4-[6-(4-isopentyloxybutyloxy)-hexyloxy]-benzene is obtained, which according to thin layer chromatography and gas-chromatography is a pure oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:8]([CH3:12])=[N:9]2)=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C2C=1C(C)=C(CC1C=CC(Cl)=CC=1)C(C)=N2.C([Si]([O:66][C:67]([O:69][CH3:70])=[CH2:68])(C)C)(C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:70][O:69][C:67](=[O:66])[CH2:68][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[C:6]([CH3:21])=[C:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]([CH3:12])=[N:9]2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: Cc1nc2cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Cl)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 7-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yl ester and trifluoromethanesulfonic acid 5-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-7-yl ester (0.86 g), tert-butyl-(1-methoxyvinyloxy)-dimethyl silane (2.0 mL), sodium acetate (0.18 g), bis(dibenzylideneacetone) palladium (0.05 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.05 g) in N,N-dimethylformamide (11.0 mL) was heated by microwave irradiation at 120° C. for 15 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and then dried over-magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and pentane (4:0:1 to 1:0:0 to 50:1:0 to 25:1:0 to 12.5:1:0 by volume) gave title compound as a honey coloured gum, 0.25 g.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[OH-:29].[Na+]>O>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[C:10](=[O:29])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: [OH-]
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCc1c2n(c(=O)c3c(OC)c(OC)ccc13)CCc1cc3c(cc1-2)OCO3
Yield: 12 %

Procedure:
A mixture of 13-ethyl-9,10-dimethoxy-5,6-dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (1.1 g, 2.2 mmol) and 30% sodium hydroxide in water (150 mL) was refluxed for 56 h. The precipitate formed was collected and treated with hot 3% hydrochloric acid. The precipitate was collected and re-crystallized from ethanol to afford 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-one (100 mg. 12%).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([O:19][CH3:20])=[CH:10][C:4]=1[O:5][CH2:6][C:7]([NH2:9])=[O:8])=O.[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:7]([CH2:6][O:5][C:4]1[CH:10]=[C:11]([O:19][CH3:20])[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:13][C:3]=1/[CH:1]=[CH:22]/[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[O:23])(=[O:8])[NH2:9]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OCC(N)=O)c(C=O)cc1-c1cccs1
Product: COc1cc(OCC(N)=O)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 70 %

Procedure:
The title compound was prepared by condensing 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetamide (Ex-71A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 70% yield, mp 235° C. (dec.). 1H-NMR (300 MHz, DMSO-d6) δ 8.26–8.30 (m, 3H), 8.08–8.11 (m, 4H), 7.67 (d, 1H, J=2.7 Hz), 7.65 (brs, 1H), 7.53 (d, 1H, J=4.0 Hz), 7.49 (brs, 1H), 7.13 (m, 1H), 6.77 (s, 1H), 4.75 (s, 2H), 3.97 (s, 3H). MS (EI) m/z=437 ([M]+, 100%). HRMS (EI) Calcd. for C23H19NO6S: 437.0933. Found: 437.0924.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:11][C:9]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C=CN(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C
Yield: 76.2 %

Procedure:
To a solution of 2-acetylamino-4-methyl-5-nitropyridine (33.8 g, 0.173 mol) in dry DMF (300 mL) was added dimethylformamide dimethyl acetal (50.7 mL, 0.381 mol) and the mixture heated at 90° C. for 90 min. The solvent was evaporated in vacuo using toluene as an azeotrope. The residue was triturated with ether and the solid collected by filtration to give the title compound (33 g, 76%) as an orange solid. mp 193°-196° C. 1H NMR (250 MHz, CDCl3) δ 2.23 (3H, s), 3.04 (6H, s), 6.12 (1H, d, J=13.1Hz), 7.43 (1H, d, J=13.1Hz), 8.17 (1H, br s), 8.27 (1H, s) and 8.83 (1H, s).