Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[C:6]([CH3:15])[CH:5]=1)(=O)[CH3:2].[BH4-].[Na+].O.[NH3:19]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:19][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[C:6]([CH3:15])[CH:5]=1)[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(C(C)(C)C#N)c(C)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a stirred solution of 2-(4-acetyl-2-methylphenyl)-2-methylpropanenitrile (1.77 g, 8.80 mmol) in 7 M ammonia in MeOH (45 mL) is added freshly distilled titanium (IV) isopropoxide (5.20 mL, 17.6 mmol). The reaction mixture is left stirring 18 h at room temperature. After cooling to 0° C., sodium borohydride (500 mg, 13.2 mmol) is added and the reaction mixture stirred at 0° C. until no more gas evolved and then at room temperature 3 h. Water (25 mL) is then added and the titanium oxide removed by filtration on a Buchner funnel. The filtrate is extracted with EtOAc (3×100 mL) (brine (10 mL) is added to help separation between both layers) and the combined organic layers are concentrated under reduced pressure. The resulting crude product (which contained water) is dissolved in Et2O (75 mL), washed with brine, dried over MgSO4 and filtered. 5-6 N HCl in 2-propanol (2.2 mL) is slowly added to the well-stirred filtrate. The resulting white precipitate is filtered on a Buchner funnel and dried in vacuo to provide the expected product 2-[4-(1-aminoethyl)-2-methylphenyl]-2-methylpropanenitrile (1.58 g, 75%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.55 (1H, d, J=8.0 Hz), 7.44-7.37 (2H, m), 4.97 (3H, s), 4.52 (1H, q, J=6.9 Hz), 2.75 (3H, s), 1.86 (6H, s), 1.69 (3H, d, J=6.9 Hz).
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[N:3]=1.[NH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=2)=[CH:23][CH:22]=1>>[OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)=[CH:25][CH:26]=2)[N:3]=1
Reactant: OC1=Nc2cccc(OCC3CO3)c2CC1
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Product: CC1CC(=O)NN=C1c1ccc(OCCNCC(O)COc2cccc3c2CCC(O)=N3)cc1

Procedure:
Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1O>>[OH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: OCCc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCO)cc1

Procedure:
Analogously to Method G, 5.00 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.99 g of 2-(2-hydroxyethyl)phenol are reacted. The title compound is obtained as a colourless oil. Rf=0.08 (1:2 EtOAc-heptane); Rt=5.81.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]([CH2:17][C:18](OCC)=[O:19])[NH:13][C:12]=2[CH:23]=1.C(=O)=O.[OH-].[Na+]>O1CCCC1.O.CC(C)=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]([CH2:17][CH2:18][OH:19])[NH:13][C:12]=2[CH:23]=1
Reactant: CCOC(=O)CC1COc2ccc(F)cc2N1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCCC1COc2ccc(F)cc2N1
Reaction time: 2.5 h

Procedure:
145 ml of tetrahydrofuran are introduced into a 1 l reactor which is cooled with a mixture of ice and salt, and, under an argon atmosphere, 5.9 g (0.153 mol) of lithium aluminium hydride are added, followed by dropwise addition of 23.22 g (0.097 mol) of ethyl (±)-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-3-acetate dissolved in 145 ml of tetrahydrofuran, and the mixture is stirred for 2.5 h. The reactor is cooled with a mixture of cardice and acetone, 45 ml of water and 23 ml of 1N sodium hydroxide are added dropwise and stirring is continued for 0.5 h.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CS(=O)(=O)NCc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(CNS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20.1 g (0.10 mol) of N-(4-hydroxybenzyl)methanesulfonamide, 10.1 g (0.10 mol) of triethylamine and 100 ml of methylene chloride cooled to approximately 0° C. was added a solution of 9.0 g (0.10 mol) of acryloyl chloride in 50 ml of methylene chloride over a 10-minute period. Stirring was continued for 30 minutes, and the mixture was filtered. The filtrate was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator. The residue was recrystallized from 100 ml of 1:1 hexane:1,2-dichloroethane. The yield of N-(4-acryloyloxybenzyl)methanesulfonamide was 8.2 g (32.1 percent of theory), m.p.=112° to 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]4[NH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][C:18]=3[Cl:29])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:14]C)[N:11]=[CH:10][CH:9]=3.B(Br)(Br)Br>ClC(Cl)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([NH:16][C:17]3[C:18]([Cl:29])=[CH:19][C:20]([C:24]4[NH:28][N:27]=[CH:26][CH:25]=4)=[CH:21][C:22]=3[Cl:23])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: COc1nccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Temperature: 85 °C

Procedure:
To a slurry of 9-bromo-N-[2,6-dichloro-4-(1H-pyrazol-5-yl)phenyl]-1-methoxybenzo[c]-2,6-naphthyridin-5-amine (800 mg, 1.55 mmol) in dichloroethane (15 mL) was added boron tribromide (10.9 mL, 10.87 mmol, 1M in dichloromethane). The reaction mixture was heated at 85° C. for 45 min. After cooling to room temperature, the reaction was diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with THF in hexanes (0-50%) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4Cl)[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][CH2:41][C@H:42]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)[OH:43]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[NH:40][CH2:41][C@H:42]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=4)[OH:43])[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chlorophenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59–7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H, 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1[CH:16]([S:20](=[O:35])(=[O:34])[NH:21][C:22]1[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:31]([CH3:33])[CH3:32])[C:17]([O-])=[O:18])(C)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1O)(C)C.[CH3:52][O:53][C:54]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([O:62][CH3:63])[C:55]=1[OH:64]>>[CH3:63][O:62][C:56]1[CH:57]=[C:58]([O:60][CH3:61])[CH:59]=[C:54]([O:53][CH3:52])[C:55]=1[O:64][C:17](=[O:18])[CH2:16][S:20](=[O:34])(=[O:35])[NH:21][C:22]1[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:31]([CH3:32])[CH3:33]
Reactant: COc1cc(OC)c(O)c(OC)c1
Reactant: CC(C)c1cc(C(C)C)c(C(C(=O)[O-])S(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)c(C(C)C)c1
Agent: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Product: COc1cc(OC)c(OC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)c(OC)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,4,6-triisopropylphenol was replaced with 2,4,6-trimethoxyphenol, mp 167°-170° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH:15]([OH:17])[CH3:16]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH:7]=1
Reactant: CC(O)CN
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Product: CC(O)CNc1cc(Cl)cc(NCC(C)O)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added in small portions to 180 ml of 3-amino-2-propanol heated to 80° C., with stirring. The reaction is exothermic. After heating for 3 hours 30 minutes, the reaction mixture is poured into 180 ml of ice-cold water. The product expected precipitates. It is drained, washed to neutrality with water and then dried under vacuum in the presence of phosphorous pentoxide. After recrystallization from 96° ethanol, it melts at 170° C.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C:15]1[CH:23]=[C:19]([C:20]([OH:22])=[O:21])[C:18]([NH2:24])=[CH:17][CH:16]=1>CN(C)C=O>[NH2:24][C:18]1[CH:17]=[CH:16][C:15]([O:14][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Imidazole (1.8 g, 26.1 mmol) and tert-butyldimethylsilyl chloride (3.95 g, 26.1 mmol) were added to a solution of the commercially available 5-hydroxyanthranilic acid (1.0 g, 6.54 mmol) in dimethylformamide (40 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 18 hours. Aqueous work-up afforded an impure sample of 2-amino-5-(tert-butyl-dimethyl-silanyloxy)-benzoic acid (1.74 g) that was used in Step (ii) without further purification.
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:21][CH2:22]O)[CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:17]1[C:12]([Cl:11])=[CH:13][C:14]([CH2:21][CH2:22][Br:2])=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: COc1cc(CCO)cc(Cl)c1Cl
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(CCBr)cc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
In a four-necked flask fitted with a stirrer, internal thermometer, dropping funnel and calcium chloride tube is placed freshly distilled phosphorous tribromide (9.6 g., 0.036 mole) and dry toluene (50 ml.). To this is added dry pyridine (1.5 g.). The mixture is stirred for 15 minutes and then cooled to -5° C. A mixture of 2-(3,4-dichloro-5-methoxyphenyl)ethanol (22.1 g., 0.1 mole) and dry pyridine (0.5 g.) in toluene (50 ml.) is added dropwise with stirring at -5° to -3° C. over a one hour period. The reaction mixture is stirred at -5° to -3° C. for an additional hour and then allowed to warm up to 20°-25° C. The mixture is kept for 48 hours and then added to ice water (ca. 500 ml.). The toluene layer is separated and washed with water, dilute hydrochloric acid, sodium bicarbonate solution and again with water. After drying over Na2SO4 and evaporation of the toluene under reduced pressure there is obtained 2,3-dichloro-5-(2-bromoethyl)anisole.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:15][NH:16][CH:17]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[CH2:18][NH2:19].C[O-].[Na+].[CH3:32][O:33][C:34]([NH:36][C:37](=NC(OC)=O)SC)=[O:35].Cl>C(Cl)(Cl)Cl.C(O)(C)C.O>[CH3:15][N:16]1[CH:17]([C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[CH2:18][N:19]=[C:37]1[NH:36][C:34]([O:33][CH3:32])=[O:35]
Reactant: CNC(CN)c1ccc2c(c1)OCO2
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)NC1=NCC(c2ccc3c(c2)OCO3)N1C

Procedure:
This example illustrates methods according to the invention of preparing the methylenedioxy substituted phenyl compounds of the invention. In this example 9.0 g. of the dihydrochloride salt of β-methylamino-β-(3,4-methylenedioxyphenyl)-ethylamine is dissolved in 40 ml. of water. This solution is stirred and added successively to it is 150 ml. of isopropanol, 4.1 g. of sodium methoxide and finally 8 g. of a mixture of 1-mono and 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 100 ml. of chloroform. The mixture is then stirred for 12 days at room temperature. It is then concentrated under vacuum affording a gummy residue which is then incompletely dissolved in 100 ml. of approximately 1N aqueous hydrochloric acid. The resulting mixture is first filtered and then washed with ethyl ether, heated with charcoal and filtered again. The crude product is then precipitated from the filtrate by addition of aqueous sodium bicarbonate. The precipitate is collected by filtration, stirred with distilled water, collected again and then dried under vacuum affording crude of 1-methyl-4,5-dihydro-5-(3,4-methylenedioxyphenyl)-2-methoxycarbonylaminoimidazole which is recrystallized from isopropanol yielding the purified product. A hydrogen-ion addition salt may be prepared according to the methods set forth in part A of Examples 1-3.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:35][CH:36](Cl)[CH3:37]>>[Cl:35][CH2:36][CH2:37][O:25][C:21]1[C:22]([I:24])=[CH:23][C:18]([O:17][C:13]2[C:14]([I:16])=[CH:15][C:10]([CH2:9][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:28])=[CH:11][C:12]=2[I:27])=[CH:19][C:20]=1[I:26]
Reactant: CC(Cl)Cl
Reactant: O=C(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Cc1cc(I)c(Oc2cc(I)c(OCCCl)c(I)c2)c(I)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
Compound 4 (2.0 g, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous dichloroethane (30 mL) and then Cs2CO3 (1.7 g, 5.2 mmol, 2.5 eq.) was added. The reaction medium was then slowly heated to reflux. The mixture was stirred for 12 hrs. upon reflux then cooled to room temperature, filtered and the solvent was removed under vacuum. The residual oil then was purified by column chromatography (DCM/hexanes 80/20). The product was further recrystallized to give 2-(4-(4-(2-chloroethoxy)-3,5-diiodophenoxy)-3,5-diiodophenyl)-N-cyclohexylacetamide, compound 15, (94 mg, 0.1 mmol) as a powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:33])[N:5]2[C:10]=1[C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:8][C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=1)=[N:6]2>[Pd]>[NH2:30][C:26]1[CH:25]=[C:24]([C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=3)[C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[N:5]3[N:6]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(Nc2nc(-c3cccc([N+](=O)[O-])c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: [Pd]
Product: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
340 mg (0.76 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-4-amine from example 18A are hydrogenated in the presence of 110 mg of palladium on carbon (10% strength) analogously to example 1.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@H:7]([CH2:26][S:27][C:28](=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[NH:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(C)(C)C.FC(F)(F)C(O)=O>>[C:9]([NH:8][C@H:7]([C:6]([OH:45])=[O:5])[CH2:26][S:27][C:28](=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC(=O)CCCCCCCCCCCCCCC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC(=O)CCCCCCCCCCCCCCC)C(=O)O

Procedure:
N,S-Dipalmitoylcysteine tert.-butyl ester (1 g, 1.5 mmol) is treated with anhydrous trifluoroacetic acid for 1 h. The latter is then removed in a rotary evaporator under high vacuum, and the residue is taken up in tert.-butanol and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:6]=2[CH:5]=[C:4]([O:24]C)[CH:3]=1.Br>C(O)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:6]=2[CH:5]=[C:4]([OH:24])[CH:3]=1
Reactant: COc1cc(Br)c2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(-n2c(-c3ccccc3)nc3c(Br)cc(O)cc32)cc1

Procedure:
1.2 g of 4-bromo-6-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazole, 6 ml of acetic acid and 6 ml of aqueous hydrobromic acid (62%) are boiled for 5.5 hours. Then, it is precipitated with waters and the precipitate is suctioned off. The latter was then dispersed between ethyl acetate and 2N sodium hydroxide solution. After the organic phase was washed with water, it was concentrated by evaporation.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][C:22]([NH2:24])=[O:23]>>[C:9]1([C@H:21]2[C@H:21]([C:15]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[Cl:13])[C:22](=[O:23])[NH:24][C:22]2=[O:23])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(Cl)cc1Cl
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(Cl)cc1Cl

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2,4-dichlorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2,4-dichlorophenylacetamide. Yield 20.9 mg, 5.2%. 1H NMR (DMSO-d6) 400 MHz δ: 11.65 (s, 1H), 7.69 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz), 7.34 (s, 1H), 7.12 (m, 1H), 6.87 (m, 2H), 4.65 (d, 1H, J=7.6 Hz), 4.55 (d, 1H, J=7.6 Hz), 4.10 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0), 2.12 (t, 2H, J=6.0 Hz).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:27]3[NH:28][CH2:29][CH2:30][N:31]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>CO.O>[NH:28]1[CH2:29][CH2:30][N:31]=[C:27]1[NH:26][O:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][C:4]([OH:32])=[O:3])[CH:14]=[CH:15]2
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC3=NCCN3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(OCCONC3=NCCN3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
3-(5-{2-[N-(4,5-dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid ethyl ester (0.24 g, 0.55 mmol) was dissolved in 70% methanol/water (4 mL). Lithium hydroxide monohydratate (0.70 g, 4.67 mmol) was added and the reaction was stirred for 16 h at room temperature under an argon atmosphere. The solution was neutralized with 1.0 N HCl (4.67 mL) and the solvent was evaporated under vacuum. The crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (74% yield). 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=3.2 Hz), 7.42 (d, 1H, J=9.0 Hz), 7.20–7.34 (m, 5H), 7.05 (d, 1H, J=2.5 Hz), 6.75 (dd, 1H, J=2.5, 9.0 Hz), 6.40 (d, 1H, J=3.0 Hz), 5.96 (m, 1H), 4.16 (m, 4H), 3.59 (br s, 4H), 3.36 (m, 2H). Mass Spectrum (LCMS, ESI) calculate for C22H25N4O4 409.2 (M+H); found 409.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[C@H:18]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=2[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH:18]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN([C@@H]2c3ccccc3OCC[C@H]2O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2C(=O)CCOc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At −78° C., 0.88 ml of oxalyl chloride (10 mmol) is poured into 25 ml of dichloromethane and then, at the same temperature, there are slowly added 1.02 ml of dimethyl sulphoxide (14.3 mmol). Stirring is carried out for 10 minutes at −78° C. 2.5 g (7.17 mmol) of the compound obtained in Step B of Example 8, dissolved in 15 ml of dichloromethane, are poured into the reaction mixture. Stirring is carried out for 15 minutes at −78° C. and there are then added, over 20 minutes, 5 ml (35.9 mmol) of triethylamine. The mixture is then allowed to return to 0° C. and the reaction mixture is then poured into 100 ml of ice-cold water. Extraction with dichloromethane, drying, filtration and evaporation to dryness are carried out to yield the expected product in the form of an oil.