Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:31]#[N:32])[C:11]([CH3:30])=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=3)[C:13]=2[N:14]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15]2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:31]#[N:32])[C:11]([CH3:30])=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:13]=2[N:14]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:20])[CH3:21])[CH2:15]2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-c2c(C)c(C#N)c3nc(C(C)(C)C)oc3c2N2CC[C@H](N(C)C)C2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1c(-c2cccc(O)c2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)C)nc2c1C#N

Procedure:
2-tert-Butyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-(3-methoxyphenyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-23) (10 mg, 23.1 μmol) was dissolved (partially suspended) in benzene (2.0 ml), and dropwise added to a benzene (2.0 ml) suspension reflux liquid of aluminium chloride (9.2 mg, 69.0 μmol). The benzene wash (8.0 ml) of the eggplant-type flask with the starting material adhering thereto was also added, followed by refluxing for 0.5 hours. After cooling, aluminium chloride (61.7 mg, 462 μmol) was further added, followed by further stirring under reflux for 15 minutes. After cooling, saturated sodium bicarbonate water (50 ml) was added to the reaction liquid, the product was extracted with chloroform (50 ml×2), ethyl acetate (50 ml).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Yield: 64.7 %

Procedure:
Using 6-chloropyridazine-3-carboxylic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.37 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.46 g) was obtained.
Reaction SMILES: C1(C)C(S(O[CH2:11][CH2:12][CH2:13][C@H:14]([C@@H:16]2[C@:33]3([CH3:34])[C:19]([C:20]4[CH2:21][CH2:22][C@@H:23]5[C@:28]([C:30]=4[CH2:31][CH2:32]3)([CH3:29])[CH2:27][CH2:26][CH:25]([OH:35])[C:24]5([CH3:37])[CH3:36])=[CH:18][CH2:17]2)[CH3:15])(=O)=O)=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:36][C:24]1([CH3:37])[C@@H:25]([OH:35])[CH2:26][CH2:27][C@@:28]2([CH3:29])[CH:23]1[CH2:22][CH2:21][C:20]1[C:19]3[C@@:33]([CH2:32][CH2:31][C:30]=12)([CH3:34])[C@@H:16]([C@H:14]([CH3:15])[CH2:13][CH2:12][CH3:11])[CH2:17][CH:18]=3
Reactant: Cc1ccccc1S(=O)(=O)OCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(O)C(C)(C)[C@@H]1CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of 24-toluenesulphonyloxy-4,4-dimethyl-5α-chola-8,14-diene-3-ol (100 mg, 0.18 mmol) in diethyl ether (25 mL) was added lithium aluminium hydride (40 mg, 1.1 mmol) and the reaction was stirred 16 hours at room temperature. The reaction was then poured into water and extracted with diethyl ether. Drying over magnesium sulphate, concentration under reduced pressure and purification by flash chromatography gave the title compound (41 mg).
Reaction SMILES: [I:1]Cl.Cl.Cl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=[CH:9][C:8]=1[OH:17].[OH-].[NH4+]>Cl.O>[I:1][C:9]1[C:8]([OH:17])=[C:7]([CH2:6][NH2:5])[CH:12]=[C:11]([C:13]([CH3:14])([CH3:16])[CH3:15])[N:10]=1
Reactant: ClI
Reactant: CC(C)(C)c1cc(CN)c(O)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(CN)c(O)c(I)n1
Reaction time: 18 h
Yield: 78.4 %

Procedure:
A solution of iodine monochloride (2.68 g., 0.02 mole) in 4N hydrochloric acid (15 ml.) is added to a solution of 4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol . dihydrochloride (5.06 g., 0.02 mole) in water (30 ml.). The resulting solution is kept at 20°-25° C. for 18 hours, diluted with water to a volume of 100 ml. and basicified with concentrated ammonium hydroxide (12 ml.) whereupon a solid is deposited. The solid is collected, washed with water and air-dried to give 2-iodo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol (4.8g., 78%), m.p. 162°-165° C. Recrystallization of the latter from 50% ethanol provides an analytical sample of 2-iodo-4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol as pale beige crystals, m.p. 170°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Temperature: 160 °C
Yield: 32.7 %

Procedure:
A mixture of C-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (620 mg, 3.0 mmol), methyl 6-chloronicotinate (516 mg, 3.0 mmol), N,N-diisopropyl ethyl amine (1.0 mL, 6.0 mmol) and DMSO (6 mL) was heated in the microwave to 160° C. for 2 h. The mixture was then diluted with ice-water and extracted with ethyl acetate. The combined organic extracts were then washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 then dichloromethane:methanol 97:3) afforded the title compound (335 mg, 33%) as a white foam. MS: m/e=342.1 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:14][CH2:15]1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N[C@H]2CC[C@H](O)CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 3-bromobenzoate (0.43 g, 2.00 mmol), trans-4-aminocyclohexanol (0.35 g, 3.00 mmol), cesium carbonate (1.63 g, 5.00 mmol), Xantphos (0.024 g, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.010 g, 0.01 mmol) in 1,4-dioxane (25 mL) was stirred at 80° C. under N2 atmosphere for 18 hours. After cooling to room temperature the reaction mixture was filtered through a pad of Celite and was washed with ethyl acetate (200 mL), and the combined filtrate was partitioned with water. The organic layer was separated and washed with 1 M aqueous hydrochloric acid and brine, dried over sodium sulfate, filtered, and the solution was concentrated. The residue was purified by column chromatography (hexane:ethyl acetate 4:1 to 3:2) to give methyl 3-[(trans-4-hydroxycyclohexyl)amino]benzoate. (0.28 g, 56%). 1H NMR (400 MHz, DMSO-d6): 7.18 (m, 2H), 7.08 (m, 1H), 6.82 (m, 1H), 5.82 (d, 1H), 3.84 (s, 3H), 3.34 (m, 1H), 2.57 (m, 1H), 1.85 (m, 2H), 1.71 (m, 2H), 1.58 (m, 2H), 1.46 (m, 2H). MS (EI) for C14H19NO3: 250 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](ON2C3=NC=CC=C3N=N2)=[O:20])[C:14]=1[CH3:31].[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C=O)C>[CH3:33][CH2:32][N:34]([CH2:35][CH2:36][NH:37][C:19]([C:15]1[C:14]([CH3:31])=[C:13](/[CH:12]=[C:5]2/[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]/2=[O:11])[NH:17][C:16]=1[CH3:18])=[O:20])[CH2:38][CH3:39]
Reactant: CCN(CC)CCN
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Yield: 88 %

Procedure:
15 (10 g, 33.3 mmol) was suspended in DMF (50 ml, 5 P.) and stirred for 5 minutes. DIPEA (9.0 mL, 54.5 mmol) was then added and the mixture was stirred for 10 minutes. HATU (13.95 g, 36.7 mmol) was added and the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight. The intermediate (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (15b) (12 g, 86.5 percent yield) with 86.8% HPLC purity as a yellow powder was got. 1H NMR (300 MHz, DMSO-d6): δ 2.61 (s, 3H, H-31), 2.68 (s, 3H, H-16), 6.87 (m, 1H, H-2), 7.01 (m, 1H, H-6), 7.64 (m, 1H, H-10), 7.85 (m, 1H, H-3), 8.73 (dd, J=1.5, 1.2 Hz, 1H, H-28), 8.83 (dd, J=1.2, 1.5 Hz, 1H, H-27), 13.11 (s, 1H, NH). To a 15b (10.0 g, 23.9 mmol) DMF solution was added N,N-diethylethane-1,2-diamine (7; 3.33 g, 28.7 mmol), the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight to give Sunitinib (8.38 g, 88% yield) with 77.6% HPLC purity.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[OH-].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO>[C:12]1([N:8]2[C:9]([NH:11][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:10][C:6]([C:4]([OH:3])=[O:5])=[N:7]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccccn1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1cc(Nc2ccccn2)n(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
200 mg (0.865 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester were dissolved in 5 ml DMF and 108 mg (0.95 mmol, 1.1 eq) of 2-Chloropyridine, 620 mg (1.9 mmol, 2.2 eq) of Cs2CO3, 20 mg (0.1 eq) of palladium(II)acetate and 60 mg of xantphos (0.12 eq) were added and the resulting mixture heated to 100° C. for 6 hours. The mixture was filtered over a pad of Celite and 2 ml of 1N NaOH (2 mmol, 2.3 eq) were added together with 2 ml of EtOH. After stirring overnight at RT the crude reaction mixture was subjected to HPLC chromatography delivering 60 mg of product. (Yield: 25%)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]2[S:14][CH:15]=[C:16]([CH3:17])[C:5]=12.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](OC)=[O:26].[Cl-].[NH4+]>CN1CCCC1=O>[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25]([NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]2[S:14][CH:15]=[C:16]([CH3:17])[C:5]=12)=[O:26]
Reactant: COC(=O)CN1CCCC1=O
Reactant: Cc1csc2nc3c(c(N)c12)CCCC3
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: Cc1csc2nc3c(c(NC(=O)CN4CCCC4=O)c12)CCCC3
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml of N-methylpyrrolidone, was added 3.28 g of 4-amino-3-methyl -5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. The mixture was heated to 50° C. and stirred for 40 minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture at 50° C. over a period of 30 minutes. After the stirring at 50° C. for 20 minutes, the mixture was cooled to 15° C. and poured into 130 ml aqueous solution containing 13.5 g of ammonium chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:20])[CH3:12])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CN(C)c1ccccc1
Agent: Cl
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 189.9 %

Procedure:
A mixture consisting of 44.76 g (0.3 mole) of the 4-dimethylaminobenzaldehyde thus obtained, 76.3 g (0.63 mole) of dimethylaniline and 247 g of a 20% aqueous HCl solution was condensed by stirring it at 100° C. for 8 hours to obtain 106.4 g of tris(4-dimethylaminophenyl)methane.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11](=O)[CH2:12][C@@H:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C@@H:13]([CH3:14])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1
Temperature: -10 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
A clean, dry flask was charged with (S)-(3-phenylamino-butyryl)-carbamic acid benzyl ester (0.821 g, 2.63 mmol) followed by reagent grade ethanol (20 mL) and cooled to −10° C. Sodium borohydride (0.070 g, 1.84 mmol) was added to the solution in one portion. Nitrogen gas purging is maintained for 5 minutes. A solution of 3.3 M aqueous magnesium chloride solution (0.561 g MgCl2 6H2O in 1.5 mL water) was added at such a rate that the internal temperature did not exceed −5° C. Once addition was completed, the reaction solution was warmed to 0° C. for 30 min. The reaction was quenched with methylene chloride (10 mL), and 1 M hydrochloric acid/citric acid solution (10.52 mL 1 N HCl, and 1.38 g citric acid). This bilayer was stirred at room temperature for six hours. The reaction mixture was diluted with ethyl acetate (200 mL) and neutralized with sat. aqueous NaHCO3 solution (pH=10). The organics were collected together and washed with sat. NaCl solution and dried over Na2SO4, filtered and concentrated. Flash chromatography using an Isco system (100% hexane to 50% EtOAc/50% hexane gradient) afforded the title compound (0.733 g). (91%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.C1O[C:19]2([CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[O:18]C1>O1CCCC1>[C:22]12([CH2:23][CH2:24][C:19](=[O:18])[CH2:20][CH2:21]1)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](=[O:5])[O:6]2
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)OC(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of 2-bromobenzoic acid (4.77 g) in anhydrous tetrahydrofuran (100 mL) was cooled to −78° C. under an atmosphere of nitrogen, to which n-butyllithium (1.53M solution in hexane, 31 mL) was dropwise added while being kept the internal temperature below −55° C. After being stirred for 1 hour, a solution of 1,4-cyclohexanedione monoethylene ketal (5.18 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the mixture while being kept the internal temperature below −67° C. After the temperature was raised to room temperature, the reaction solution was partitioned between water (150 mL) and hexane (100 mL). The aqueous layer was acidified with concentrated hydrochloric acid and refluxed together with acetone (10 mL) for 2 hours. After cooling, thus obtained mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over anhydrous Na2SO4 and evaporated. The residue was crystallized from ethyl acetate-hexane to give the subject compound (2.42 g).
Reaction SMILES: [NH:1]([C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])[C:2]([CH3:4])=[O:3].[H][H]>C(O)C>[C:2]([NH:1][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 58 %

Procedure:
With the catalyst prepared as in example 7 there have been reduced 0.725 g of 3-acetoxy, 4-methoxy, alpha-acetaminocinnamic acid dissolved in 25 mls of anhydrous ethanol. The reaction has been carried out in an autoclave (glass) with a hydrogen pressure of 2 atm at room temperature. There has been obtained 3-acetoxy, 4-methoxy, N-acetylphenylalanine with an optical yield of 58%. [α]D22 =+12.8 (c=1, acetone) the [α]D22 (c=1, acetone) of enantiomerically pure 3-acetoxy, 4-methoxy N-acetylphenylalanine=22.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:13].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>CN(C=O)C.O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(I)cc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A solution of 4-iodobenzoic acid (2.0 g, 8.0 mmol), HATU (4.6 g, 12.0 mmol) and DIPEA (1.6 g, 12.0 mmol) in DMF (30 mL) was stirred for 1 h. Then, dimethylamine hydrochloride (0.98 mg, 12.0 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 2:1). The reaction mixture was poured into water (30 mL) and extracted with EtOAc (40 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified by silica gel column chromatography using petroleum ether/EtOAc (4:1) to afford the desired compound (1.5 g, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, 2H), 7.16 (d, 2H), 3.15-2.97 (d, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[C:14]([C:15]([O:17]C)=O)=[CH:13][S:12][CH:11]=1)=[O:8].Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.NC1C(C(OC)=O)=CSC=1.BrCCCCN=C=O>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:17])[C:14]4=[CH:13][S:12][CH:11]=[C:10]4[NH:9][C:7]3=[O:8])[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: COC(=O)c1cscc1N
Agent: Cl
Agent: O=C=NCCCCBr
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cscc3c2=O)CC1

Procedure:
The title compound was prepared by the procedure of Example 10 using N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl)urea (6.92 g, 21 mmol) and 4-(4-fluorobenzoyl)piperidine hydrochloride (10.16 g, 42 mmol). The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce the urea as a tan solid, mp 85°-86° C. There was obtained 3.62 g (40.8% yield) of the title compound as a brown solid. This material was recrystallized from CH2Cl2 /ether, mp 190°-192° C.
Reaction SMILES: Br[C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]#[N:16])=[CH:8][C:7]=3[N:6]=[C:5]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:4]=2[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][NH:17][C:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:14][C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([C:15]#[N:16])=[CH:8][C:7]=2[N:6]=1
Reactant: OB(O)c1ccccc1
Reactant: CN(C)CCNc1nc2cc(C#N)ccc2c2sc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNc1nc2cc(C#N)ccc2c2sc(-c3ccccc3)cc12
Temperature: 120 °C

Procedure:
2-bromo-4-(2-(dimethylamino)ethylamino)thieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 55 mg, 0.146 mmol), benzene boronic acid (2.0 eq, 36 mg, 0.295 mmol), cesium carbonate (2.0 eq, 95 mg, 0.292 mmol) and PdCl2(dppf) (0.05 eq, 5 mg, 0.068 mmol) were mixed in dioxane (0.5 ml) containing 5% of water. The mixture was heated under microwave for 10 min at 120° C. After addition of water and filtration, 4-(2-(dimethylamino)ethylamino)-2-phenylthieno[3,2-c]quinoline-7-carbonitrile was isolated as a solid. LCMS (ES) m/z 373 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[C:13](CCC(O)=O)[CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.BrC1C=CC([NH2:26])=CC=1.O=P(Cl)(Cl)Cl>>[NH2:26][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:2]([NH2:1])[C:3]3[C:8]([N:9]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:14]=1
Reactant: Nc1c2ccccc2nc2ccc(CCC(=O)O)cc12
Reactant: Nc1ccc(Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc2nc3ccccc3c(N)c2c1

Procedure:
Ullmann reaction (Step 1) of 2-chlorobenzoic acid 1 and 4-bromoaniline 2 afforded 4′-bromodiphenylamine-2-carboxylic acid 3. Cyclisation with POCl3 followed by amination gave the expected 3-bromo-9-aminoacridine 5 in good yield and purity.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>O>[Cl:15][CH2:16][CH2:17][C:18]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][C:2]([C:18](=[O:19])[CH2:17][CH2:16][Cl:15])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Solvent: O
Product: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2

Procedure:
Prepared from xanthene 16 and 3-chloropropionyl chloride as described in Scheme 5 to give a solid. Mp 179-181° C. 1H NMR (CDCl3, 400 MHz) δ7.86-7.84 (m, 4H), 7.13 (d, J=10 Hz, 2H), 4.18 (s, 2H), 3.94 (t, J=8 Hz, 4H), 3.44 (t, J=8 Hz, 4H). Anal. (C19H16Cl2O3. 0.1 H2O).