Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([CH:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=1)[C:31]([OH:33])=O)[CH2:26][CH3:27])[CH3:24].[Cl:39][C:40]1[CH:41]=[C:42]([CH:47]=[C:48]([CH3:55])[C:49]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C:43]([NH:45]O)=[NH:44]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:39][C:40]1[CH:41]=[C:42]([C:43]2[N:45]=[C:31]([C:30]3[CH:34]=[C:35]([O:37][CH3:38])[N:36]=[C:28]([CH:25]([CH2:23][CH3:24])[CH2:26][CH3:27])[CH:29]=3)[O:33][N:44]=2)[CH:47]=[C:48]([CH3:55])[C:49]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(-c2nc(-c3cc(C)c(NS(C)(=O)=O)c(Cl)c3)no2)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
HOBt (20 mg, 148 μmol) and EDC HCl (28 mg, 148 μmol) are added to a solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (30 mg, 134 μmol) in DMF (5 mL). The mixture is stirred at rt for 5 min before 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (38 mg, 136 μmol) is added. The mixture is stirred at rt for 18 h before it is diluted with sat. aq. NaHCO3 solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The resulting orange oil (65 mg) is dissolved in dioxane (5 mL) and heated to 80° C. for 3 h. The solvent is removed in vacuo and the crude product is purified on prep. TLC plates using heptane:EA 3:2 to give the title compound (36 mg) as a white solid; LC-MS**: tR=0.88 min, [M+H]+=465.06; 1H NMR (CDCl3): δ0.84 (t, J=7.5 Hz, 6H), 1.69-1.88 (m, 4H), 2.56-2.63 (m, 1H), 2.65 (s, 3H), 3.17 (s, 3H), 4.02 (s, 3H), 6.26 (s, 1H), 7.32 (d, J=1.0 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H), 8.17 (d, J=1.5 Hz, 1H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[CH:23]([CH2:26]O)[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:52]I>C(Cl)Cl>[I:52][CH2:26][CH:23]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[C:25](=[C:14]([O:13][CH:10]4[CH2:11][CH2:12][CH:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH2:8][CH2:9]4)[N:15]=[CH:16][N:17]=3)[C:24]1=2
Reactant: II
Reactant: OCC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of (12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl)methanol (260 mg, 0.67 mmol, 1.00 equiv) in DCM (20 mL). Imidazole (91 mg, 1.34 mmol, 2.00 equiv) and PPh3 (264 mg, 1.01 mmol, 1.50 equiv) were added successively, followed by the addition of I2 (255 mg, 1.00 mmol, 1.50 equiv) at room temperature. The resulting solution was stirred overnight at ambient temperature and diluted with DCM and washed with Na2SO3 (sat.) and brine. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by a silica gel column with EtOAc/petroleum ether (1:1-3:1) to provide the desired 3-(iodomethyl)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (287 mg, 86%) as a light yellow solid. MS (ES): m/z 500 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:17])([F:16])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:6]([F:17])([F:16])[F:5]
Reactant: O=S(Cl)Cl
Reactant: Oc1ccccc1C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Oc1ccccc1C(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.28 ml) was added to a solution of 2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (3.0 g) and pyridine (1.23 ml) in toluene (50 ml). The reaction was stirred at room temperature for 1 hr, after which time the toluene was removed in vacuuo and the residue partitioned between ethyl acetate (100 ml) and 1 n HCl (100 ml). The organics were separated and dried over magnesium sulfate, filtered and solvent removed in vacuuo to afford the title compound as a clear oil (3.0 g). 1H NMR (CDCl3): δ 5.93 (m, 1H), 6.90 (d, J=4.52 Hz, 1H), 7.10 (m, 1H), 7.35 (m, 1H), 7.69 (m, 1H).
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Product: CCCCOc1ocnc1C

Procedure:
Example 3 is repeated, except that a mixture of 13.14% by weight of n-butyl α-isocyanopropionate and 86.86% by weight of tris(2-ethylhexyl)amine is continuously added via inlet (A).
Reaction SMILES: [N+](C1C=COC2C=1S(=O)(=O)NCC2)([O-])=O.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[S:26]([NH:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27].[H][H]>CO.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]2[O:32][CH2:31][CH2:30][NH:29][S:26](=[O:28])(=[O:27])[C:18]=2[CH:19]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCO)c1
Agent: [Ni]
Agent: O=[N+]([O-])C1=C2C(CCNS2(=O)=O)OC=C1
Solvent: CO
Product: Nc1ccc2c(c1)S(=O)(=O)NCCO2
Temperature: 0 °C

Procedure:
244 g of 8-nitro-3,4-dihydro-(2H)-5,1,2-benzoxathiazine 1,1-dioxide, which is accessible by an intramolecular condensation reaction from 2-chloro-5-nitro-N-(2-hydroxyethyl)-benzenesulphonamide (DOS (German Published Specification) 1,670,759), are suspended in 600 ml of methanol and are reduced in the presence of 3 g of freshly prepared Raney nickel as catalyst by injecting three times the equimolar amount of hydrogen in an autoclave at 50° C. When the reduction is complete, the catalyst is removed from the hot reaction solution, from which the amino compound crystallizes out in fine flakes after cooling to 0° C. 205 g of 8-amino-3,4-dihydro-(2H)-5,1,2-benzoxathiazepine 1,1-dioxide of the formula ##STR17## melting point 179° C. are obtained after filtering off with suction and drying.
Reaction SMILES: C([C:5]1[N:10]2[C:11]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:12]=3[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:14][CH2:15][C:9]2=[N:8][C:7](=[O:30])[CH:6]=1)(OC)=O.[I-].[Li+]>N1C=CC=CC=1>[N+:27]([C:24]1[CH:25]=[CH:26][C:11]2[N:10]3[CH:5]=[CH:6][C:7](=[O:30])[N:8]=[C:9]3[CH2:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:12]=2[CH:23]=1)([O-:29])=[O:28]
Reactant: COC(=O)c1cc(=O)nc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-2

Procedure:
In the manner given in Example 32, 1-carbomethoxy-9-nitro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin3(5H)-one was heated in pyridine with lithium iodide to give 9-nitro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].I[CH3:21]>C1COCC1>[Cl:3][C:4]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH3:21])=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1cc(CCO)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(Cl)c(C(=O)OC(C)(C)C)c1

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in oil, 2 eq.) in anhydrous THF (0.23 M) was added tert-butyl 2-chloro-5-(2-hydroxyethyl)benzoate from the previous step (1 eq.). The reaction mixture was heated at reflux for 30 min before iodomethane (7.9 eq.) was added. After carefully quenching with sat. aq. NaHCO3, the resulting mixture was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→85:15 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([NH:34][C@@H:32]([C:29]2[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[CH3:33])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: NCCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCCc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 140 °C
Yield: 15.3 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.64 mmol), (3-phenylpropyl)amine (500 mg, 3.70 mmol), and Hunig's base (2 mL) in 1-1-methyl-2-pyrrolidinone (NMP) (3 mL) was heated for 4 hours at 140° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 10% CH3CN/H2O to 30% CH3CN/H2O) to afford the title compound (90 mg) as a yellow solid. LC-MS (ES) m/z=360 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.80-1.87 (m, 2H), 2.64-2.68 (m, 2H), 3.28-3.30 (m, 2H), 5.37 (s, 2H), 5.97 (s, 2H), 6.27 (s, 1H), 6.93 (s, 1H), 7.17-7.31 (m, 5H), 7.40 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]([C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:49]=1[OH:50])[C:44](O)=[O:45])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:51]([C:48]1[CH:47]=[C:43]([CH:42]=[C:41]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:49]=1[OH:50])[C:44]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[O:45])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and 3,5-di-t-butyl-4-hydroxybenzoic acid (204 mg) in anhydrous N,N-dimethylformamide (8 ml) were added triethylamine (0.32 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (153 mg). The mixture was stirred at room temperature for 1 hour and then allowed to stand at room temperature overnight. To the reaction mixture was further added triethylamine (0.10 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (134 mg) and this mixture was stirred at room temperature for 8 hours and allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→3:1 as the eluant to afford the title compound (176 mg, mp 160-162° C.).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][N:6]([CH3:9])[CH:5]=1)(=O)[CH3:2].[CH2:10]([NH2:13])[CH2:11][NH2:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1.CO>[CH3:9][N:6]1[CH:7]=[CH:8][C:4]([CH:1]([NH:12][CH2:11][CH2:10][NH2:13])[CH3:2])=[CH:5]1
Reactant: CC(=O)c1ccn(C)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(NCCN)c1ccn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
3-Acetyl-1-methylpyrrole (1.0 g) and ethylenediamine (1.46 g) were dissolved in toluene (10 ml), the solution was added with p-toluenesulfonic acid monohydrate (154 mg), and the mixture was refluxed for 2 hours by heating. The reaction mixture was added to a suspension of sodium borohydride (307 mg) in tetrahydrofuran, then the mixture was added with methanol, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was made acidic with 1 N hydrochloric acid, and then the solvent was evaporated under reduced pressure. The mixture was added with distilled water and potassium carbonate, and thereby neutralized, and then the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (1.14 g).
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34]>C(O)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:15]1[N:16]([CH3:17])[C:12]2[C:11]3[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=3[CH:28]=[CH:27][C:13]=2[N:14]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C#N
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A 25 mL round bottom flask was charged with 2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.258 g, 0.562 mmol) and a stir bar. Water (3 mL), glacial acetic acid (3 mL) and concentrated sulfuric acid (3 mL) were combined and added to the round bottom flask while still hot (60° C.). The flask was sealed with a plastic stopper and heated in an oil bath at 100° C. After 2 hours, the flask was removed from the oil bath and stirred at room temperature overnight. The clear solution was then poured onto ice and neutralized with concentrated ammonium hydroxide. The resulting precipitate was recovered by filtration, resuspended in methanol and filtered. The resulting solid was washed with methanol until the filtrate was colorless to provide 2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.106 g, 46%) as a light gray solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.47 (s, 1H), 7.78-7.68 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 4.28 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H); ESMS (m/z): found, 387.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH2:19]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:26]([C:25]3[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=3[O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:8]1[C:9]2[C:5]3[C:4](=[CH:15][CH:14]=[CH:13][C:6]=3[C:7]1=[O:12])[C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)(=[O:18])[CH3:17]
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Reactant: CC(=O)OC(C)=O
Product: CSc1ccc2c3c(cccc13)C(=O)N2C(C)=O

Procedure:
A mixture of 1 g of 6-(methylthio)-benz[cd]-indol-2(1H)-one (Example 2) and 10 ml of acetic anhydride is stirred and heated at reflux for 2 hours, cooled and filtered. The cake is washed with ethanol and ether then dried. The dried cake is suspended in 15 ml of hot ethanol, filtered and the cake crystallized from 150 ml of ethanol to afford the desired product as a solid.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C1(C)C=CC=CC=1>CN(C)C=O.[Zn]>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise in a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mg-atoms) of zinc (powder) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at room temperature for one hour. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 551 mg (2.96 mmol) of diphenylphosphine in 63% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[S:43](Cl)(=[O:45])=[O:44])[CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[N:33]=[CH:34][CH:35]=[CH:36]2)(=[O:44])=[O:45])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3cccnc23)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 8-quinolinesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 67 mg. MS (ES+): m/e=542.2 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(I)cc2)CC1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
4-Iodobenzoic acid (500 mg, 2.02 mmol) and DMF (50 uL) were dissolved in DCM (24 mL), oxalyl chloride (0.18 mL, 2.12 mmol) was added drop-wise and the reaction mixture was stirred for 30 min. DIPEA (0.42 mL, 2.42 mmol) and a solution of N-methylpiperazine (222 mg, 2.22 mmol) in DCM (1 mL) were added and the reaction mixture was stirred for 30 min, washed with sat aq NaHCO3 (2×75 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (660 mg, 99.2%) as a yellow solid. LCMS (ES+): 331.0 [MH]+. HPLC: Rt 4.05 min, 99.6% purity.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:22][C:23]1[CH:39]=[CH:38][C:26]([CH:27]=[C:28]2[C:33](=[O:34])[O:32][C:31]([CH3:36])([CH3:35])[O:30][C:29]2=[O:37])=[CH:25][CH:24]=1>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([C@H:27]([CH:28]2[C:29](=[O:37])[O:30][C:31]([CH3:36])([CH3:35])[O:32][C:33]2=[O:34])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:38][CH:39]=1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(Br)cc2)C(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(=O)C([C@H](C#Cc2ccccc2)c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Yield: 51.3 %

Procedure:
A solution of copper (II) acetate monohydrate (10 mg, 0.050 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (20 mg, 0.10 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 33.1 mg, 0.050 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(4-bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (77.7 mg, 0.25 mmol). The reaction mixture was stirred vigorously at 0° C. for 42 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1→1:1) to give 53 mg of the pure title compound as a white solid. (Yield: 39%)