Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]1([CH3:12])[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][CH:6]=1.BrBr>CO>[OH:11][C:10]1[CH:9]=[CH:8][C:7]([S:1][C:2]#[N:3])=[CH:6][C:5]=1[CH3:12]
Reactant: N#C[S-]
Reactant: Cc1ccccc1O
Agent: BrBr
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SC#N)ccc1O

Procedure:
Sodium thiocyanate (23.5 g, 0.29 mole) was added to a solution of ortho-cresol (31.4 g, 0.29 mole) in methyl alcohol (225 ml) and cooled by an ice bath. A solution of bromine (46.4 g, 0.29 mole) in methyl alcohol (50 ml) was added dropwise over 45 minutes. The reaction was filtered and poured into water (400 ml). Sodium thiosulfate was added to eliminate the color (yellow). The product was extracted into ethyl ether (2×200 ml). The ethyl ether extracts were washed with water (100 ml), 1N hydrochloric acid (200 ml) and saturated sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated. The product was purified by chromatography on silica. The structure was confirmed by NMR and IR spectroscopy.
Reaction SMILES: [CH3:1][C:2]12[CH2:25][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:27])([CH3:26])[CH2:3]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[N:58]1([C:22]([CH:19]2[CH2:20][CH2:21][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([N:7]4[CH2:27][C:4]5([CH3:26])[CH2:5][CH:6]4[CH2:25][C:2]([CH3:1])([CH3:8])[CH2:3]5)=[O:10])=[CH:16][CH:15]=3)[CH2:18]2)=[O:23])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N3CCC(C(=O)O)C3)cc2)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N3CCC(C(=O)N4CCOCC4)C3)cc2)C1
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of 1-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid (300 mg, 0.81 mmol, prepared as described in ex-ample 1) and HOBT (131 mg, 0.97 mmol) in dry THF (20 ml) was added EDAC (186 mg, 0.97 mmol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (219 μl, 1.22 mmol) and morpholine (85 μl, 0.97 mmol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. The resulting residue was purified by preparative HPLC (Gilson) and pure fractions were collected and evaporated to dryness and dried in vacuo at 50° C. affording 250 mg (70%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[S:24][C:23]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([NH:43][C:44]4[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[CH:54](I)([CH3:56])[CH3:55].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:54]([N:43]([S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:32](=[O:33])[NH:31][C:23]2[S:24][C:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[C:22]=2[C:20](=[O:21])[NH:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:18][CH:17]=2)[CH:35]=1)(=[O:41])=[O:42])[C:44]1[CH:45]=[CH:46][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=1)([CH3:56])[CH3:55]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Nc5ccc(C(=O)OC)cc5)c4)sc4c3CCCC4)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(c5ccc(C(=O)OC)cc5)C(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 350 mg of methyl 4-({[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate, 0.070 mL of isopropyl iodide, 193 mg of potassium carbonate, and 3.5 mL of DMF was stirred at 80° C. overnight. Further, 0.14 mL of isopropyl iodide was added thereto, followed by further stirring at 80° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 264 mg of methyl 4-(isopropyl {[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36](=[O:41])[NH:37][CH:38]([CH3:40])[CH3:39])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([C:36](=[O:41])[NH:37][CH:38]([CH3:39])[CH3:40])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CC(C)NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: Cl
Agent: [Li+]
Product: CC(C)NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[(N-isopropyl)carbamoyl]piperazine hydrochloride
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1([CH3:20])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10][CH2:9]O1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]2[C:3]([CH2:2][Cl:1])=[N:5][CH:6]=[C:7]([CH3:20])[C:12]=12
Reactant: CC1(CNC(=O)CCl)OCCc2c1[nH]c1ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(CCl)n2c1c(CCCl)c1ccccc12

Procedure:
A mixture of 2-chloro-N-[(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide (9.0 g, described in Example 8) and phosphorus oxychloride (200 ml) is refluxed for 60 minutes and evaporated slowly to dryness under reduced pressure (10 mm Hg, the final bath temperature 140° C.). The residue is dissolved in chloroform and the solution is washed quickly with ice-cold 5% solution of sodium hydroxide, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed through a column of silica gel (300 g) using chloroform. The eluates are evaporated and the residue is crystallized from ethyl acetate to obtain the title compound (5.5 g); mp 160°-161° C., nmr(CDCl3) δ2.53(s), 3.62(m), 4.94(s) and 7.10-8.20(m).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:5][C:4]=2[N:3]=1.Cl.[OH-].[Na+]>C(O)C.O>[NH2:27][CH2:26][CH2:25][CH2:24][O:23][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([NH:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][O:20][CH2:21][CH3:22])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCNC(=O)OC(C)(C)C)ccc3c2n1NC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1NC(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of tert-butyl [3-(4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-yloxy)propyl]carbamate (1.24 g, 2.62 mmol) in 5 mL of ethanol (EtOH) was treated with 5 mL of 4.3 M HCl in EtOH. The reaction was heated to 100° C. After 1 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown solid. The solid was dissolved in a minimum amount of H2O and treated with 10% NaOH solution until the pH of the liquid was 13. The basic aqueous mixture was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 7-(3-aminopropoxy)-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.84 g) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12](C1NC=CN=1)(C1NC=CN=1)=[S:13]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2)=[C:12]=[S:13]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cn1ccc2cc(N)ccc21
Solvent: CCOC(C)=O
Product: Cn1ccc2cc(N=C=S)ccc21
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A flask was charged with 5-amino-1-methyl-1H-indole (8.8 g; 60 mmol), thiocarbonyl diimidazole (10.7 g; 60 mmol) and ethyl acetate (200 mL). The reaction was heated at 50° C. for five minutes, and after cooling, the solvent was evaporated. The crude material was dissolved in dichloromethane (100 mL) and filtered through a short plug of silica gel, which was washed with another bolus of dichloromethane (100 mL). The organic eluent was evaporated to give 5-isothiocyanato-1-methyl-1H-indole (8.9 g; 47 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:38]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][C:14]3[N:15]=[CH:16][N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=3)[C:6]=2[CH:58]=1.CC(O)C.[ClH:63]>C(Cl)Cl>[ClH:1].[ClH:63].[NH2:38][CH:12]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:11][O:10][C:7]1[C:6]2[CH:58]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: Clc1ccc2onc(OCC(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: NC(COc1noc2ccc(Cl)cc12)Cc1c[nH]cn1

Procedure:
To a solution of 0.91 g of 5-chloro-3-[2-tritylamino-3-(1-trityl-4-imidazolyl)propoxy]-1,2-benzoisoxazole in 2 ml of methylene chloride is added 2.2 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for 24 hours, after which the solvent is removed by distillation under reduced pressure. Diisopropyl ether is added to the residue obtained and the crystals precipitated are collected by filtration, to obtain 0.4 g of colorless, crystalline 3-[2-amino-3-(4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole dihydrochloride having a melting point of 246.0°-248.4° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[C:24]([F:32])[CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:35][CH:34]=[CH:33][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[C:24]([F:32])[CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=4)=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NCc3ccc(F)cc3)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.4 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added [(4-fluorophenyl)methyl]amine (1.01 mL, 8.89 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure and purified via SiO2. This lead to a yellow solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a 10% ammonium chloride solution, saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide (67 mg, 0.104 mmol) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 3.06-3.18 (m, 4 H), 3.76 (s, 3 H), 4.16 (t, J=8.29 Hz, 2 H), 4.51 (d, J=5.86 Hz, 2 H), 6.17 (d, J=1.19 Hz, 1 H), 6.81-7.01 (m, 3 H), 7.13 (t, J=8.84 Hz, 2 H), 7.38 (dd, J=8.29, 5.72 Hz, 2 H), 7.78 (s, 1 H), 8.43 (d, J=11.90 Hz, 1 H), 8.51 (s, 1 H), 9.14-9.25 (m, 1 H), 10.38 (s, 1 H), 11.32 (br. s., 1 H). (ESIMS (M+H)+=645)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:20]([N:22]([CH2:32][CH3:33])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:32]([N:22]([CH2:20][CH3:21])[C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:25][CH:24]=1)[CH3:33]
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CCN(CC)c1ccc(B(O)O)cc1
Product: CCN(CC)c1ccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc1

Procedure:
[2-(4-Diethylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-(diethylamino)phenylboronic acid following general procedures as described in these Examples. MP 211-213° C., M+H=391.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C>C1COCC1>[CH2:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]1[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCc2ccccc2C1=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O[C@@H]1c2ccccc2CC[C@H]1NCc1ccccc1
Temperature: 25 °C
Yield: 897.1 %

Procedure:
A solution of 2-benzamido-3,4-dihydronaphthalen-1(2H)-one (3.0 g, 1.1 mmole) in THF (150 ml) was added dropwise to a suspension of LiAlH4 (2.0 g) in THF (50 ml). The reaction was heated at reflux for 2 hr and then cooled to room temperature. Enough ethanol was added to destroy excess LiAlH4 followed by 150 ml of Rochell's salt solution (20%). The resulting mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with brine and dried over Na2SO4. Evaporation of the solvent afforded 2.5 g (88%) of the product, m.p. 110°-114° C. After recrystallization from cyclohexane it had m.p. 112°-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[C:5](/[N+:10]#[C-:11])=[CH:6]/[N:7]([CH3:9])C)[CH3:2].[Br:13][C:14]1[CH:15]=C([CH:18]=[CH:19][CH:20]=1)N>C(O)CCC>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[CH:11][N:7]([C:9]2[CH:18]=[CH:19][CH:20]=[C:14]([Br:13])[CH:15]=2)[CH:6]=1)=[O:12])[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Solvent: CCCCO
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)cn1
Yield: 13 %

Procedure:
A solution of compound (Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester (11.8 g, 79 mmol) and 3-bromo aniline (11.3 g, 65 mmol) in n-butanol (90 mL) was heated to reflux for 72 h [reaction was monitored by TLC]. Reaction mixture was concentrated under reduced pressure to remove n-butanol and the residue was passed through silica gel column, eluated with a mixture of ethyl acetate and hexane to give a mixture of ethyl and n-butyl ester compounds which was then separated by flash column chromatography over silica gel using 3:7 mixture ethyl acetate and hexane as eluant. Finally the ethyl ester was further purified by crystallization to furnish 3 (2.5 g, 13%) as a brown solid. HRMS (ESI+): m/z=295.1349 [M+H]
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:12]=[C:13]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:32]([O:31][C:25]1[CH:24]=[C:23]([C:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([N:10]3[CH:3]=[CH:7][CH:6]=[CH:5]3)[CH:12]=2)=[CH:20][C:21]#[N:22])[CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH3:33]
Reactant: COC1CCC(OC)O1
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(-n3cccc3)c2)ccc1OC
Temperature: 25 °C

Procedure:
2,5-Dimethoxytetrahydrofuran (0.2 g, 1.7 mmol) was added to a stirred solution of 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.5 g, 1.5 mmol) in acetic acid (10 mL). The reaction mixture was heated to reflux under nitrogen for one hour. The mixture was cooled down to room temperature. The mixture was stirred with EtOAc (100 mL) and saturated NaHCO3 (40 mL) was added slowly. The EtOAc solution was washed with water (60 mL), brine (60 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, Hexane:EtOAc 6:4) to afford mixture of isomers of 3-(3-ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-pyrrol-1-yl-phenyl)-acronitrile (0.4 g, 60%) as a white solid: mp 109-111° C.; 1H NMR (CDCl3) δ 7.00 (m, 2H), 7.47-6.81 (m, 6H), 6.30 (m, 2H), 5.59 (5.57) (s, 1H), 4.05 (m, 2H), 3.91 (m, 6H), 1.45 (m, 3H); 13C NMR (CDCl3) δ 161.67(161.61), 153.93(154.35), 151.56(151.00), 148.27(148.00), 131.40(132.10), 129.83(130.06), 129.03(127.16), 125.93(127.93), 123.07, 122.21, 122.05(121.93), 118.52(118.43), 114.00, 112.01(112.06), 111.09(112.70), 109.15(109.28), 92.45, 64.56, 56.05(56.00), 14.69; Anal. Calcd for C23H22N2O3. Theoretical: C, 73.78; H, 5.92, N, 7.48. Found: C, 73.46; H, 5.71; N, 7.35.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: CC(=O)O
Product: Brc1ccc2oc3ccccc3c2c1
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, 150 g of dibenzofuran and 1 l of acetic acid were loaded into a 300-ml three-necked flask, and then the contents were dissolved under heat. 188 Grams of bromine were added dropwise to the solution. After that, the mixture was stirred for 20 hours under air cooling. The precipitated crystal was separated by filtration, and was then sequentially washed with acetic acid and water. The washed crystal was dried under reduced pressure. The resultant crystal was purified by distillation under reduced pressure, and was then repeatedly recrystallized with methanol several times. Thus, 66.8 g of 2-bromodibenzofuran were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[N:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:38]=[N:37][C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Clc1cc(Oc2cnc3ccccc3n2)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cnc5ccccc5n4)ncn3)CC1)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
24 mg (0.087 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 20 mg (0.077 mmol) 2-(6-chloro-pyrimidin-4-yloxy)-quinoxaline and 0.050 mL (0.29 mmol) DIPEA were combined in 1.0 mL DMF and stirred overnight at 90° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[CH3:16]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1OC
Temperature: 70 °C
Yield: 96.8 %

Procedure:
A mixture of methyl vanillate (6.376 g, 35 mmol), bromoethane (4.359 g, 40 mmol), and K2CO3 (5.528 g, 40 mmol) in DMF (40 mL) was heated at 70° C. for 2 hours. The reaction mixture was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to give methyl 4-ethoxy-3-methoxybenzoate as white solid (7.123 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, 1H), 7.55 (d, 1H), 6.88 (d, 1H), 4.17 (q, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.50 (t, 3H); LC-MS (ESI) m/z 211 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19]CC3C=CC(OC)=CC=3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:19])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N
Reaction time: 26 h

Procedure:
To a stirred solution of 7-fluoro-N-(4-methoxybenzyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.486 g, 1.30 mmol) in dichloromethane (13.0 mL) was added TFA (0.5 mL, 6.49 mmol). Stirring continued at 23° C. for 26 hours. After which, the reaction was concentrated in vacuo, dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The combined organic layers were concentrated in vacuo and purified on silica gel eluting with 0-10% methanol in dichloromethane to give the desired product 7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=254.1 (M+1).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[N:10]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.[Cl-].[NH4+]>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:19]([C:18]2[CH:17]=[CH:16][C:15]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:22][CH:21]=2)[OH:20])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A Grignard reagent which is prepared by reacting 1.9 g of magnesium with 15 g of p-chlorobromobenzene in 40 ml of ether is added to a suspension of 6.2 g of 4-(1-imidazolyl)benzaldehyde in 70 ml of ether at 0° C. After the mixture is stirred at room temperature for an hour, the reaction mixture is poured into an aqueous ammonium chloride solution with caution. The mixture is extracted with chloroform and the chloroform is distilled off. The residue is purified column-chromatographically and recrystallized from toluene to give 8.6 g of α-(4-chlorophenyl)-4-(1-imidazolyl)benzenemethanol as white crystals, melting at 148.5°-149.5° C.