Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH:10]1[CH2:13][C:12]([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:26][CH2:25][CH2:24][N:23]4[CH:27]=[C:28]([C:30](=[O:32])[NH2:31])[N:29]=[C:22]4[C:21]=3[CH:33]=2)([OH:14])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Li+]>CO.O.ClCCl>[OH:14][C:12]1([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:26][CH2:25][CH2:24][N:23]4[CH:27]=[C:28]([C:30]([NH2:31])=[O:32])[N:29]=[C:22]4[C:21]=3[CH:33]=2)[CH2:11][CH:10]([OH:9])[CH2:13]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(OC(=O)c4ccccc4)C3)c(F)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(O)C3)c(F)cc1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
A suspension of 3-((2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)ethynyl)-3-hydroxycyclobutyl benzoate (190 mg, crude product), lithium hydroxide (96 mg, 4.01 mmol) in methanol (0.5 mL) and water (1 mL) was stirred at room temperature overnight. The resulting solution was diluted with 20 mL of dichloromethane and 10 mL water. The organic layer was washed with 10 mL of brine. The organic was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:10). This resulted in 7 mg of the titled compound as a light yellow solid. This compound was isolated as a single unassigned diasteromer.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][N:10]1[C:23]2[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2.[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30].C(=O)(O)[O-].[Na+]>O>[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:32][CH2:33][N:34]([CH2:7][CH2:8][CH2:9][N:10]2[C:23]3[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:35][CH2:36]1)=[O:30]
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)N(CCCN1CCC(C(=O)c3ccc(Cl)cc3Cl)CC1)c1ccccc1S2
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To 75 ml of dry dimethylformamide was added 2.0 g of 10-(3-chloropropyl)-2-methylthiophenothiazine, 1.7 g of 4-(2,4-dichlorobenzoyl)piperidine, and 5.0 g of sodium bicarbonate. The reaction mixture was stirred at 90° for five hours, poured into 200 ml of water, and extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. This oil was purified by high pressure liquid chromatography on a silica gel column, utilizing ethyl acetate/dichloromethane (1:2 by volume) as the eluent. Concentration of the appropriate fractions yielded 2.7 g of 4-(2,4-dichlorobenzoyl)-1-[3-(2-methylthio-10H-phenothiazin-10-yl)propyl]piperidine as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19]([O:21][CH3:22])=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=3)[C:17]2=[O:34])=[CH:12][CH:11]=1)=[NH:9])=[O:6])[CH:2]=[CH2:3].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].[I-].[K+].C(=O)([O-])O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:4][C:5]([NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C:19]([O:21][CH3:22])=[C:18]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])=[CH:27][CH:28]=3)[C:17]2=[O:34])=[CH:14][CH:15]=1)=[NH:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C=CCOC(=O)NC(=N)c1ccc(N2CC(OC)=C(c3ccc(CCC(=O)O)cc3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC(=N)c1ccc(N2CC(OC)=C(c3ccc(CCC(=O)OCOC(=O)C(C)(C)C)cc3)C2=O)cc1

Procedure:
Prepared by stirring a suspension of 1-[4-(allyloxycarbonyl-amidino)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-4-methoxy-3-pyrrolin-2-one, 2 equivalents of chloromethyl pivalate, 2 equivalents of potassium iodide, 2 equivalents of potassium hydrogen carbonate and 2 equivalents of potassium carbonate in dimethylformamide at ambient temperature for three days.
Reaction SMILES: C([NH:8][C:9]1[C:10]([Cl:37])=[C:11]([N:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@@H:20]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:19]2)[CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)CCl>[NH2:8][C:9]1[C:10]([Cl:37])=[C:11]([N:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:28])[O:26][CH3:27])[C@@H:20]([O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32])[CH2:19]2)[CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1
Reactant: COC(=O)N[C@H]1CCN(c2cc(C(N)=O)cc(NC(=O)OC(C)(C)C)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H]1CCN(c2cc(C(N)=O)cc(N)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
methyl ((3S,4S)-1-(3-(N-BOC-amino)-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (125 mg, 0.168 mmol) was dissolved in ClCH2CH2Cl (10 ml). Trifluoroacetic acid (3 ml, 38.9 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours, then evaporated to dryness. The crude was purified by column chromatography on silica (40 g cartridge, gradient from 100% DCM to 100% EtOAc, then hold at 100% EtOAc) to give methyl ((3S,4S)-1-(3-amino-5-carbamoyl-2-chlorophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (67 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([C:25]#[N:26])[CH2:22][CH:21]1[C:27](O)=[O:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([C:25]#[N:26])[CH2:22][CH:21]1[C:27](=[O:28])[NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)O
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl salt (664 mg, 2.65 mmol) was dissolved in DMF (10 mL) and to this solution was added 4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester crude from the previous step, diisopropyl ethylamine (0.93 mL, 5.3 mmol), followed by HATU (1 g, 2.65 mmol). Reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[N:23]=[N:24][C:25]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:26][C:27]=4[C:28]([OH:30])=[O:29])=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH:39]1(N=C=NC2CCCCC2)CCCCC1.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[N:23]=[N:24][C:25]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][C:27]=4[C:28]([O:30][CH3:39])=[O:29])=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)cc3C(=O)O)cc2)n1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)nnc1Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A RBF was charged with 4-(dimethylamino)pyridine (5.4 mg, 44 μmol), 3-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-6-phenylpyridazine-4-carboxylic acid (210 mg, 440 μmol), methanol (53 μl, 1319 μmol) and 1.3 mL DCM. The mixture was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (100 mg, 484 μmol) dissolved in 1.3 mL DCM was added. The heterogeneous mixture was allowed to warm to RT and stirred for 4 h. 1.3 mL of DMF was added and the reaction was stirred at RT for 72 h. The mixture was filtered through a pad of Celite, washing with DCM. The filtrate was concentrated twice from toluene to remove excess DMF. The crude material was purified by silica gel chromatography, 0-10% MeOH/dDCM. Further purification was done by reverse phase chromatography, Gilson, 5-75% acetonitrile/0.1% TFA over 14 min to provide methyl 3-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-6-phenylpyridazine-4-carboxylate cleanly as a bright yellow solid. MS m/z=492 [M+H]+. Calc'd for C27H21N7O3: 491.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cnc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1=Cc2cc(Cl)cnc2NC1C(F)(F)F
Temperature: 50 °C
Yield: 22.5 %

Procedure:
The ester from Step 4 (1.3 g, 4.4 mmol) and 2.5 N sodium hydroxide solution (3.5 mL, 9 mmol) were mixed in tetrahydrofuran (25 mL), methanol (10 mL), and water (25 mL). The mixture was heated at 50° C. for 4 hours, allowed to cool to room temperature, and was concentrated in vacuo to remove the tetrahydrofuran and methanol. The resulting aqueous solution was washed with diethyl ether (2×100 mL). The aqueous phase was acidified with 3 N HCl causing the precipitation of a yellow solid (1.1 g). The solid was triturated with ethanol-acetone and collected by vacuum filtration providing the title compound as a yellow solid (276 mg, 23%): mp 287.4–288.4° C. 1H NMR (acetone-d6/300 MHz) 11.50 (br s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.28 (br s, 1H), 5.42–5.30 (m, 1H). Anal. Calc'd for C10H6N2O2F3Cl: C, 43.11; H, 2.17; N, 10.05 Found: C, 42.88; H, 2.03; N, 10.06.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:13][C:12]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:15][Si](C)(C)C)=[N:11][CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:26][CH2:27][CH2:28][N:29]1[C:33]([CH3:35])([CH3:34])[C:32](=[O:36])[NH:31][C:30]1=[O:37].C(N(CC)C(C)C)(C)C.C(Cl)(Cl)Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(O)C.C1COCC1>[Br:1][C:2]1[C:3]([C:9]2[S:13][C:12]([CH:14]([OH:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[N:4][C:5]([NH:26][CH2:27][CH2:28][N:29]2[C:33]([CH3:34])([CH3:35])[C:32](=[O:36])[NH:31][C:30]2=[O:37])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: C[Si](C)(C)OC(c1ccccc1)c1ncc(-c2nc(Cl)ncc2Br)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cnc(C(O)c3ccccc3)s2)n1

Procedure:
A solution of 150 mg (0.33 mmol) of 5-bromo-2-chloro-4-{2-[phenyl(trimethylsilyloxy)-methyl]-thiazol-5-yl}pyrimidine, 85 mg (0.50 mmol) of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione and N,N-diisopropylethylamine (0.17 mL, 0.99 mmol) in 4 mL of iPrOH and 1 mol of CHCl3 was heated in a microwave to 170° C. for 20 min and then treated with 0.75 mL of a 1 M solution of tetra-n-butylammonium fluoride in THF for 10 min at rt. The reaction solution was concentrated in vacuo and the crude solid product was purified by flash chromatography eluting with a linear gradient of 75% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 519.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:39][C:40]1[CH:41]=[CH:42][C:43](F)=[N:44][CH:45]=1>CN(C)C=O.O>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[N:44][CH:45]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cn3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 77.5 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (400 mg, 1.00 mmol) in dimethylformamide (5 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.5 mL, 1.50 mmol). After 1 hour 5-bromo-2-fluoropyridine (350 mg, 2.00 mmol) was added and stirring was maintained at 80° C. for 16 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by column chromatography to afford 6-(N-(5-bromopyridin-2-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (430 mg, 0.775 mmol, 77.5% yield) as a yellow solid. LCMS (m/z, ES+)=559 (M+H+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH:18]2[CH:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH:13](SC2C=CC=CC=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2C(COC(=O)c3ccccc3)OC(Sc3ccccc3)C2O1
Agent: [Ni]
Solvent: CCO
Product: O=C1C[C@H]2[C@H](CO[C@@H]2COC(=O)c2ccccc2)O1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A 3-neck, 1000 mL round-bottom flask, equipped for overhead mechanical stirring, was charged with 29.6 g of 8 (80 mmol), 500 mL of ethanol and approximately 30 g of Raney-Ni (Aldrich, which had been washed to neutrality with distilled water). The resulting slurry was heated at reflux for 5 h while stirring vigorously. The reaction mixture was then cooled to room temperature, and the solids were carefully filtered off through a pad of celite. The residue was washed thoroughly with ethanol, and the combined filtrates were concentrated to afford a yellow solid which was purified by chromatography on silica gel to afford 7.63 g (36% yield) of 9 as a white solid. A small sample was recrystallized from acetone/hexane to afford colorless needles: mp 89.5-90.0° C.; [α]D22+3.18 (c=0.8 in CHCl3); Rƒ0.36 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ 8.01 (m, 2H), 7.40-7.65 (m, 3H), 5.15 (m, 1H), 4.41 (m, 2H), 4.05-4.32 (m, 3H), 2.80-3.05 (m, 2H), 2.56 (d, 1H, J=15.7 Hz); MS m/z at 263 for (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[CH:48][C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[N:50][CH:51]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:52]1([C:49]2[N:50]=[CH:51][C:46]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:21]=[CH:22][C:23]([C:26]4([NH2:30])[CH2:29][CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[CH:47][CH:48]=2)[CH2:53][CH2:54][O:55][CH2:56][CH2:57]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1(c2ccc(-c3c(-c4ccc(N5CCOCC5)nc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 49.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (52 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. To the fraction, conc. HCl (3 ml) and methanol (3 ml) were added and the residue was evaporated after 24 h. The residue was purified by HPLC to give the titled compound as a white solid (24 mg, 39%). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.26 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.07 (dd, J=4.9, 1.4 Hz, 1H), 7.93 (dd, J=7.7, 1.4 Hz, 1H), 7.70 (dd, J=8.9, 2.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.11 (t, J=7.4 Hz, 1H), 6.86 (dd, J=8.0, 1.1 Hz, 1H), 6.81 (d, J=9.2 Hz, 1H), 6.73 (dd, J=7.7, 4.9 Hz, 1H), 3.68 (t, J=4.9 Hz, 4H), 3.43 (t, J=5.2 Hz, 4H), 2.45-2.38 (m, 2H), 2.22-2.15 (m, 2H), 2.10-2.01 (m, 1H), 1.75-1.67 (m, 1H); LCMS: 542 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](C(OCC)=O)=[C:9]([Cl:17])[CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[O:18]1CCC[CH2:19]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:19][OH:18]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(Cl)ccc2nccc(Cl)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCc1cnc2ccc(Cl)cc2c1Cl
Reaction time: 5 h

Procedure:
27 g. of 4,6-dichloroquinoline-5-carboxylic acid, ethyl ester (0.1 mol.) are dissolved in 600 ml. of anhydrous tetrahydrofuran. Nitrogen is passed through the flask and while stirring and cooling to 0°, 2.4 g. of lithium aluminum hydride are added a bit at a time in order to keep the reaction temperature at 0° to +5°. Stirring is continued for an additional five hours. Then 2.5 ml. of water, 2.0 ml. of aqueous sodium hydroxide (20%) and again 9 ml. of water are added. The precipitated inorganic salts are filtered off and the solvent is removed by a rotary evaporator. The resulting oil is dissolved in a small quantity of benzene and kept in the refrigerator. The crystallized 4,6-dichloroquinoline-3-methanol is filtered off and recrystallized from ethyl acetate; yield: 12.5 g. (55%); m.p 182°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].Cl>O.N1C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH:10][C:26]([C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)=[O:27])([O-:3])=[O:2]
Reactant: Nc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)c3ccco3)c([N+](=O)[O-])c2)cc1[N+](=O)[O-])c1ccco1
Temperature: 8.5 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
In a 500 ml separable flask equipped with a stirrer, a reflux condenser cooled with water, a thermometer and a dropping funnel, 10.96 g of 3,3′-dinitro-4,4′-diaminobiphenyl was dissolved into 200 ml of N,N-dimethylformamide and then 20 ml of pyridine was added to the solution. While the prepared solution was cooled at 3 to 14° C., 12.53 g of 2-furoyl chloride was added dropwise to the solution. After the addition was completed, the reaction solution was warmed to the room temperature and stirred for further 5 hours. Then, 80 ml of 2N hydrochloric acid and 100 ml of water were added to the solution and the solid substance was separated by filtration. The obtained solid substance was washed well with water and dried in a reduced pressure to obtain 15.0 g of 3,3′-dinitro-4,4′-di-2-furoylamino-biphenyl. The yield was 81%.
Reaction SMILES: O.C(=O)(O)[O-].[Na+].[N:7]1([CH:13]=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Br:15][CH2:16][CH2:17][C:18]([N:10]1[CH2:11][CH2:12][N:7]([CH:13]=[O:14])[CH2:8][CH2:9]1)=[O:19]
Reactant: O=C(Cl)CCBr
Reactant: O=CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=CN1CCN(C(=O)CCBr)CC1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
A mixture of 15 ml of water and 25 ml of methylene chloride containing 3.0 g (36 mmole) of sodium bicarbonate and 2.82 g (24.7 mmole) of 1-piperazinecarboxaldehyde is stirred and treated with 5.0 g (30.9 mmole) of 3-bromopropionyl chloride in 10 ml of methylene chloride over a 15 minute period while maintaining a temperature of about 20° C. After stirring for an additional 20 minutes, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are drive (Na2SO4), filtered and concentrated under high vacuum to yield 4.35 g (70.2%) of product as a colorless solid: mp 96°-98° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:23]([CH3:26])[CH2:24][OH:25])[C:18]1[CH:17]=[C:16]([C:27]#[N:28])[CH:15]=[CH:14][C:13]=1[S:12]2.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:29][S:30]([O:25][CH2:24][CH:23]([N:19]1[C:18]2[CH:17]=[C:16]([C:27]#[N:28])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:20]1=[CH:21][CH:22]=[C:9]([Cl:8])[CH:10]=2)[CH3:26])(=[O:32])=[O:31]
Reactant: CC(CO)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (30 cc) is added to a solution of 7-chloro-10-[(2RS)-1-hydroxy-2-propyl]-2-phenothiazinecarbonitrile (40 g) in methylene chloride (400 cc). The mixture is cooled to 0° C. and then treated dropwise in the course of 1 hour with methanesulphonyl chloride (16.6 cc). Distilled water (1 liter) is then added, after which the constituents of the mixture are allowed to settle and the organic phase is separated and washed with distilled water (500 cc). The organic phase is then dried over magnesium sulphate, filtered and concentrated under reduced pressure (30 mm Hg; 4 kPa) to a residual volume of 100 cc. Isopropyl ether (150 cc) is then introduced slowly and the mixture is left stirred for 30 minutes. Isopropyl ether (300 cc) is then added slowly and the suspension is stirred for 48 hours. The precipitate is filtered off, washed with isopropyl ether (2×50 cc) and dried at 40° C. under reduced pressure (5 mm Hg; 0.67 kPa) to give (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propyl methanesulphonate (34.53 g), m.p. 132° C.