Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[CH3:22][C:2]1([CH3:1])[C:10]2[CH:9]=[C:8]3[N:11]([S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=4)(=[O:32])=[O:31])[C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC)nc3cc21
Solvent: O
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC)n3S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.8 %

Procedure:
To a solution of 7,7-dimethyl-2-methylamino-5-pentyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (230 mg) in pyridine (6 ml) is added 4-methyl-benzenesulfonyl chloride (160 mg; 0.84 mmol) at 0° C. After addition the mixture is warmed to RT and stirred for 48 h. The reaction solution is dissolved with water and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with hydrochloric acid (0.5 N) and brine, dried over Na2SO4 and concentrated in vacuo. The compound (135 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (40:1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[CH:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].P(Br)(Br)[Br:22]>C(OCC)C>[C:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[CH:8]([Br:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(=O)OCc1ccc(Cl)cc1C(O)c1ccccc1
Solvent: CCOCC
Product: CC(=O)OCc1ccc(Cl)cc1C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 45 g. of 2-acetoxymethyl-5-chloro-benzhydrol in 270 ml. of ethyl ether, 13.7 g. of phosphorus tribromide in 45 ml. ethyl ether is added and the solution is stirred for 3 hours at room temperature. The organic solution is successively washed with a sodium bicarbonate solution and with water. After drying over sodium sulfate and evaporation of the solvent, 43.1 grams of the crude title compound is obtained which may be used for further reaction steps. B.p. 175°-180° C. 0.5 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39][CH:40](O)[CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:39][CH2:40][CH2:41][N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: CC(O)Br
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCBr)Cc2ccccc2N1c1ccccc1F
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.46 g, 1.7 mmol) in tetrahydrofuran (20 mL) was cool to 0° C. and treated with triphenylphosphine (0.65 g, 2.5 mmol), bromoethanol (0.25 mL, 3.5 mmol) and diisopropyl azodicarboxylate (0.5 mL, 2.6 mmol). After the final addition, the reaction mixture was warmed to room temperature for 2 h, evaporated to a brown oil. The crude product residue was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to afford 3-(2-bromoethyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.44 g, 63%) as a white solid:
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:12]=[C:13]([OH:32])[CH:14]=[CH:15][C:16]=1[CH:17]([CH3:31])[C:18]([OH:30])([C:23]1[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=1)[C:19]([F:22])([F:21])[F:20]>>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:32][C:13]1[CH:14]=[CH:15][C:16]([CH:17]([CH3:31])[C:18]([OH:30])([C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=2)[C:19]([F:20])([F:21])[F:22])=[C:11]([Cl:10])[CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1cnc(C(O)(C(C)c2ccc(OCC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from tert-butyl bromoacetate and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=461.1 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11]2)=[N:6]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:18][O:17][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH2:14])[CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(Cn1cc2ccc([N+](=O)[O-])cc2n1)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(Cn1cc2ccc(N)cc2n1)OC

Procedure:
To a stirred solution of 2-(2,2-dimethoxyethyl)-6-nitro-2H-indazole (1.89 g, 7.52 mmol) and NH4Cl (337 mg, 6.01 mmol) in ethanol/H2O (2:1, 75 mL) at room temperature was added Fe (1.28 g, 23.7 mmol) and the resulting mixture was heated for 2 hours at 70 C. The mixture was allowed to cool and was filtered through celite. The residue was washed with hot Methanol (5×20 mL) and the combined eluent was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and filtered. Concentration of the organic layer under reduced pressure provided 2-(2,2-dimethoxyethyl)-2H-indazol-6-ylamine as an amber oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.25 (m, 6 H), 4.34 (d, J=5.43 Hz, 2 H), 4.81 (t, J=5.59 Hz, 1 H), 5.22 (s, 2 H), 6.52 (m, 2 H), 7.37 (m, 1 H) and 8.02 (s, 1 H); MS (ESI) 222 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH:5]2[OH:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[CH2:7][CH2:6][CH:5]2[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)CCC(O)c2cc(Br)ccc21
Product: CC1(C)CCC(O[Si](C)(C)C(C)(C)C)c2cc(Br)ccc21

Procedure:
Continuing on with the description of Reaction Scheme 6, 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene is reacted in the presence of base with t-butyldimethylsilyl chloride to provide 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldimethylsilyloxy)naphthalene (Compound B15). The starting 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene can be obtained by reduction of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Under conditions similar to the ones described above Compound B15 is converted to the boronic acid derivative (5,5-dimethyl-8-(t-butyldimethylsilyloxy)-5,6,7,8-tetrahydro-naphth-2-yl)boronic acid (Compound B14). Compound B14 is then coupled with ethyl 6-bromo-naphthalene-2-carboxylate to yield ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-2-yl]naphth-2-oate (Compound B3). Compound B3 is then reacted with tetrabutylammonium fluoride to remove the t-butyldimethylsilyl blocking group and to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-2-yl]naphth-2-oate (Compound B4). Compound B4 can be acylated to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-2-yl]naphth-2-oate (Compound B10), or methoxymethylated with methoxymethyl chloride in the presence of base (preferably ethyl N,N-diisopropylamine, Hunig's base) to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-2-yl]naphth-2-oate (Compound B8), and oxidized with N-methyl morpholine N-oxide to provide ethyl-6-[5,5-dimethyl-5,6-dihydro--naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate (Compound B6). Compounds B8 and B10 of the invention are within the scope of Formula 1, whereas Compound B6 is within the scope of Formula 2. Compound B6 can be converted into the O-methyloxime(ethyl 6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate (Compound B11) not shown in the scheme) and into other derivatives such as oximes, imines, hydrazones and the like, as is described above in connection with Reaction Scheme 2. Further derivatives of Compound B6 (and of analogous compounds) wherein the 8-oxo function of the molecule is modified can be obtained in accordance with the general synthetic methodology described in this specification. For example the trifluoromethylsulfonyl (triflate) derivative can be obtained in analogy to the reaction leading to Compound A9 as described in Reaction Scheme 2, and the trifluoromethylsulfonyl (triflate) derivative is reacted with the reagents R14Me to provide compounds of Formula 6.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[C:53](OC(=O)C)(=[O:55])[CH3:54]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:53]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1)(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of 22 mg of (2R)-1-{(2S,4S)-4-amino-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide in 1 ml of chloroform, 0.0089 ml of acetic anhydride and 0.0127 ml of pyridine were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol=8/1), to provide 18 mg of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CC1(O)CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 252 mg, 2.0 mmol), copper(I) iodide (20 mg), and dichlorobis(triphenylphosphine)palladium(II) (40 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-tetrahydropyran-4-yl-ethynyl)-pyrazin-2-yl]-propionamide (474 mg, 89.30%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H30ClN3O4S (M+H)+ 532.1668, found 532.1675.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[N:35][CH:36]=1.[CH2:44]([O:46][C:47](=[O:50])[CH:48]=[CH2:49])[CH3:45]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:44]([O:46][C:47](=[O:50])[CH:48]=[CH:49][C:31]1[CH:36]=[N:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[CH:33][CH:32]=1)[CH3:45]
Reactant: Fc1ccccc1-c1ccc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(-c2ccccc2F)nc1
Temperature: 125 °C
Reaction time: 20 h

Procedure:
Under nitrogen, 0.755 g (3.38 mmol) of palladium acetate, 2.05 g (6.75 mmol) of tri(ortho-tolyl)phosphine and 97.8 ml (0.708 mol) of triethylamine were added to a solution of 34.0 g (0.135 mol) of 5-bromo-2-(2-fluoro-phenyl) -pyridine in 2.2 l of acetonitrile. Then 23.38 ml (0.216 mol) of acrylic acid ethyl ester were added, and the mixture was shaken in an autoclave at 125° C. for 20 h. After cooling, the mixture was poured onto ice/water, the mixture stirred at 5 to 10° C. for 1 h, and the precipitated product was collected by filtration and purified by chromatography (silica gel, n-heptane/ethyl acetate 3:1). Yield: 24.3 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[O-:13][C:14]#[N:15].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[O:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Water (2.5 mL) is added slowly to a mixture of 4-fluoro-3-(trifluoromethyl)aniline (500 mg, 2.79 mmol) in glacial acetic acid (1.5 mL). A solution of sodium cyanate (200 mg, 3.07 mmol) in water (2.5 mL) is added slowly, and the mixture is stirred at room temperature for 4 h. The mixture is extracted twice with dichloromethane, and the combined organic layers are concentrated under reduced pressure. Yield: 588 mg; ESI mass spectrum [M+H]+=223; Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:46]1([C:52](O)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([C:52]([CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[O:53])[CH2:28][CH2:29]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCN(C(=O)C2CCCCC2)CC1
Yield: 69.4 %

Procedure:
The procedure of Example 14 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (4.23 g.), N,N'-dicyclohexylcarbodiimide (3.1 g.) in anhydrous methylene chloride (100 cc.) and cyclohexylcarboxylic acid (1.92 g.). After having filtered off the precipitate, the organic solution is washed with an 8% aqueous solution of sodium bicarbonate (20 cc.) and then dried over anhydrous potassium carbonate (10 g.). After the solution has been filtered and the filtrate concentrated to dryness, the residue is recrystallised from ethanol (300 cc.). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(4-cyclohexylcarbonylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3.7 g.), which melts at 240° C., is thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])NCC3C=CC(Cl)=CC=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)=[CH:45][CH:44]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])[N:49]([C:46]3[CH:45]=[CH:44][C:43]([Cl:42])=[CH:48][CH:47]=3)[CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc(NC2CCCCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)N(c4ccc(Cl)cc4)C4CCCCC4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was prepared as described for Compound 546c using Compound 546b in place of 4-chloro-N-methylaniline. MS: 635.31 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.Cl>C(O)C>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCCC1CCOCC1
Agent: Cl
Solvent: CCO
Product: O=C1CNc2ncc(Br)nc2N1CCC1CCOCC1
Temperature: 100 °C

Procedure:
Ethyl 2-(5-bromo-3-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)pyrazin-2-ylamino)acetate (0.5 g, 1.291 mmol) and hydrochloric acid (6 M in water, 0.215 mL, 1.291 mmol) were combined in ethanol (2 mL) and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 100° C. for 2400 s. The reaction mixture was concentrated and purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (quantitative yield). MS (ESI) m/z 341.1 [M]+, 343.1 [M+2]+.
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](OB=O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[C:2]([C:33]2[CH:34]=[C:29]([CH2:28][OH:27])[CH:30]=[CH:31][CH:32]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Reactant: O=BOc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cccc(CO)c3)c2cc1OC
Temperature: 25 °C
Yield: 101.3 %

Procedure:
4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50 mg), tetrakistriphenylphosphine palladium(0) (14 mg), and (3-hydroxymethylphenyl)boranic acid (55 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassium carbonate solution (1 ml), and the suspension was stirred at 80° C. for 2.5 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (54 mg, yield 97%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:57][N:54]1[CH2:55][CH2:56][N:51]([CH2:50][CH2:49][CH2:48][NH:47][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]3[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[O:7])[CH:14]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:52][CH2:53]1
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCN2CCN(C)CC2)cc1
Yield: 16.7 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), TBTU (60 mg, 0.186 mmol), 1-(3-aminopropyl)-4-methylpiperazine (25 mg, 0.156 mmol) and DIPEA (81 μl, 0.467 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. The DMF was evaporated under vacuum and the residue dissolved in chloroform and filtered through an aminopropyl SPE (3 g). The filtrate was purified by flash chromatography on silica, eluting with DCM/ethanol/ammonia (110:8:1), which after evaporation of the solvents under vacuum gave N-(4′-{[3-(4-methylpiperazin-1-yl)propylamino]carbonyl)-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (12 mg, 17%). NMR; δH [2H6]-DMSO 9.91,(1H, s), 8.55,(1H, t), 8.35,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.29,(2H, m), 2.48-2.20,(10H, m), 2.19,(3H, s), 2.13,(3H, s), 1.68,(2H, m). LCMS: retention time 2.37 min, MH+461.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:20])([CH3:19])[CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[N:32]=[CH:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:19])([CH3:20])[CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[S:35]([C:33]2[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=2)(=[O:37])=[O:36])=[CH:21][CH:22]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC1(C)CNC(=O)c2cc(NCc3ccc(Cl)cc3)ccc21
Solvent: c1ccncc1
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc3c(c2)C(=O)NCC3(C)C)c1
Temperature: 150 °C
Yield: 54.5 %

Procedure:
To a stirred solution of 7-(4-chloro-benzylamino)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (20 mg, 0.06 mmol) and pyridine (12 μl, 0.14 mmol) in anhydrous acetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (25 mg, 0.14 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the crude residue purified by preparative HPLC (Method A) to afford the title compound as a colourless solid (15 mg, 21%). HPLC retention time 4.07 min. Mass spectrum (ES+) m/z 459 (M+H).