Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=2)[CH2:17][CH2:16][CH2:15]1)C(=O)OC1C=CC=CC=1.O.[OH-].[Na+]>C(O)C.C(Cl)Cl>[CH3:1][NH:2][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CN(CCN1CCCc2ccc(NC(=N)c3cccs3)cc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CNCCN1CCCc2ccc(NC(=N)c3cccs3)cc21
Yield: 63.8 %

Procedure:
A solution of compound 5 (1.30 g, 2.991 mmol) in ethanol:H2O (30 mL, 3:1) was treated with NaOH (1.19 g, 29.916 mmol) at room temperature and the resulting solution was refluxed for 6 h. The reaction was brought to room temperature, diluted with CH2Cl2 (25 mL) and washed with brine (15 mL). The aqueous layer was extracted with more CH2Cl2 (2×20 mL) and combined CH2Cl2 layer was dried (Na2SO4). The solvent was evaporated and crude product was purified by column chromatography on silica gel (2 M NH3 in MeOH:CH2Cl2, 5:95 to 1:9) to obtain compound 44 (0.6 g, 64%) as a solid. 1H NMR (DMSO-d6) δ 7.69 (d, 1H, J=3.0 Hz), 7.57 (dd, 1H, J=0.9, 5.1 Hz), 7.07 (dd, 1H, J=3.6, 5.1 Hz), 6.78 (d, 1H, J=7.5 Hz), 6.22 (brs, 2H), 6.08 (d, 1H, J=1.2 Hz), 5.99 (dd, 1H, J=1.5, 7.6 Hz), 3.27-3.23 (m, 4H), 2.68-2.61 (m, 4H), 2.31 (s, 3H), 1.87-1.80 (m, 2H); ESI-MS (m/z, %): 315 (MH+, 100); ESI-HRMS calculated for C17H23N4S (MH+), calculated: 315.1637; observed: 315.1652; HPLC purity 98.67% by area.
Reaction SMILES: C([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:35](=[O:36])[C:34]1[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:42])[CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)CCCN2C(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A solution of methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [500 mg, Reference Example 19(a)] in tetrahydrofuran (20 ml) was treated successively with triethylamine (360 mg) and 2,6-dichlorobenzoyl chloride (380 mg). The mixture was stirred at 40° C. for 2 hours and then partitioned between ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml). The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was dissolved in trifluoroacetic acid (2 ml) and the clear solution was left at room temperature for 30 minutes then evaporated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated to give the title compound (200 mg) as a colourless oil.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](NC(=O)CC4C=CC(F)=CC=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[C:41](C(O)=O)[C:40]2=[O:48])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:41]4[C:40](=[O:48])[N:39]([C:36]5[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=5)[CH:44]=[CH:43][CH:42]=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1nccc2c1ccn2-c1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2c1ccn2-c1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 8 h
Yield: 14.7 %

Procedure:
Bis-tert-butyl 1-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl-dicarbamate (Compound B of Example 3, 0.18 g, 0.043 mmol, 1.0 eq) was added to a solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.011 g, 0.047 mmol, 1.1 eq) and TBTU (0.018, 0.047 mmol, 1.1 eq) in DMF (0.50 mL) at room temperature. Diisopropylethylamine (0.008 mL, 0.047 mmol, 1.1 eq) was added to the reaction mixture and stirring was continued for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (YMC C-18 column, 30 min. gradient 25-90% aq. MeOH with 0.1% TFA). The appropriate fractions were concentrated in vacuo and the residue treated with anhydrous HCl (4 N in dioxane) at 0° C. The solution was concentrated in vacuo and the later procedure repeated three times. The residue was triturated with Et2O, discarding the filtrate and the solid was dried in vacuo to afford the title compound (0.003 g, 17%) as a white solid. 1H NMR (CD3OD) δ 7.85-7.87 (m, 2H), 7.56-7.63 (m, 3H), 7.24-7.46 (m, 6H), 7.03-7.09 (m, 3H), 6.94 (br m, 1H); MS(ESI+) m/z 440 (M+H)+, calc: 440.1523, found: 440.1517.
Reaction SMILES: C(C1C=CC=CC=1C=C)=C.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:18]([C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:21])[CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: c1ccccc1
Agent: C=Cc1ccccc1C=C
Agent: [Al+3]
Agent: [Cl-]
Product: CCCC(=O)c1ccccc1

Procedure:
About 50 grams of resin beads of polystyrene that has been copolymerized with about 1% divinylbenzene are stirred at room temperature for about 2 hours in butyryl chloride with aluminum chloride as a catalyst, namely Friedel-Crafts conditions. Reaction occurs with the benzene moieties on the resin to form butyrophenone or propylphenylketone. These resulting ketone moieties are then subjected to the Leukardt-Wallach reduction amination reaction using N-propyl formamide to produce N-propyl α-aminobenzyl moieties. The step-by-step synthesis of the nonapeptide as set forth in Example I is repeated. Cleavage, deprotection and purification are carried out under the same conditions and are found to produce the nonapeptide amide having the following formula:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[N:13][N+:14]([O-:16])=[O:15])[CH2:2]1.[H-].[Na+].[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C(#N)C>[CH2:20]([C:19]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:8]1=[N:13][N+:14]([O-:16])=[O:15])=[O:22])[CH3:21]
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])N=C1NCCCN1CC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N1CCCN(CC2CCOC2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
A mixture of 0.33 g of 1-[(tetrahydro-3-furanyl) methyl]-2-(nitroimino)hexahydropyrimidine, 0.07 g of sodium hydride (60%) and 10 ml of acetonitrile was stirred at 50° C. for 30 minutes. After this mixture was cooled on ice, 0.16 g of propionyl chloride was added dropwise thereto over 30 minutes, and the mixture was then stirred at room temperature for 2 hours. After the completion of reaction, insolubles were removed by filtration, and the filtrate was then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (2:1 ethyl acetate/acetone) to obtain 0.08 g of 1-(ethylcarbonyl)-2-(nitroimino)-3-[(tetrahydro-3-furanyl)methyl]hexahydropyrimidine.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:23])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:24][CH3:25]>C(#N)C>[I-:24].[CH3:25][N+:8]1([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: O=C1c2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Reactant: CI
Solvent: CC#N
Product: C[N+]1(Cc2ccccc2)CCC(N2Cc3ccccc3C2=O)CC1
Product: [I-]
Reaction time: 18 h

Procedure:
A solution of 2 [-1 (phenylmethyl) 4 piperidinyl]2,3-dihydro-lH isoindol-1-one (I, R1 =phenylmethyl. Example 7) was dissolved in 5 mL acetonitrile treated with 0.5 mL of iodomethane. The reaction mixture was allowed to stir for 18 h and the white crystalline precipitate (277 mg) was filtered off to afford I (R1 =phenylmethyl, R2 =CH3): mp 247-250° C. Anal. calcd for C20H23IN2O: C, 55.31; H, 5.34; N, 6.45. Found: 55.64; H, 5.69; N, 6.52.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCCl>[C:8]1([CH:5]2[CH2:6][CH2:7][N:2]([C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[CH2:3][CH2:4]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCC(c2cccc3ccccc23)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc3ccccc23)CC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 1-methyl-4-(1-naphthyl)piperidine (0.5 g, 2.2 mmol) in 1,2-dichloroethane (30 mL) was added a proton sponge (2.1 g, 9.9 mmol) and trichloroethyl chloroformate (0.93 mL, 6.6 mmol), and the resulting mixture was stirred at 115° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid and subsequently with a saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the ethyl acetate layer was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (eluent; hexane:ethyl acetate=6:1) to afford the title compound (0.85 g, yield: 100%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]([NH2:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].C1C(Cl)=CC=C(Cl)C=1>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:21]([NH:22][S:33]([C:29]3[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(=O)Nc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Solvent: Clc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(C)=O)c2)cc(OC)c1
Temperature: 25 °C
Yield: 24 %

Procedure:
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.168 mmol), 3-Acetylaminobenzene sulfonylchloride (59 mg, 0.5 mmol, commercially available from INTERCHIM) are dissolved in a 1 to 2 mixture of pyridine: dichlorobenzene (0.3 ml) and the reaction mixture is heated to 150° C. overnight in an orbital shaker. When TLC confirms the total consumption of the starting material, the reaction mixture is cooled down to rt. The precipitate formed is filtered and purified by column chromatography, using Pet.Ether: EtOAc as eluent, to afford 20 mg (24%) of the title compound as a yellow solid. HPLC (max plot) 89%, rt. 4.08 min. LC/MS: (ES+): 494.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[F:14][C:15]1[N:16]=[CH:17][C:18]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:19][CH:20]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1csc(Nc2ncc(-c3ccc(F)nc3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=352.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 2-fluoropyridine-5-boronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [C:1]([O:9]CC)([O:6][CH2:7][CH3:8])(OCC)[CH3:2].[CH2:12]([CH:14](CCCC)C(O)=O)[CH3:13].[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:22]1(/[CH:28]=[C:12](\[CH3:14])/[CH2:13][CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCC(CC)C(=O)O
Reactant: Cc1ccccc1
Product: CCOC(=O)CC/C(C)=C/C1CC=CCC1
Temperature: 200 °C

Procedure:
The following reagents were charged in a stainless steel autoclave: above-obtained alcohol (9.5 g; 62.4 mmol); triethyl orthoacetate (23.14 g; 140 mmol); 2-ethylhexanoic acid (0.24 g; 1.7 mmol) and toluene (18 ml). The autoclave was purged with nitrogen and heated in an oil bath at 200° C. overnight. After cooling to room temperature, the reaction was poured onto water. A few drops of 5% aq. HCl were added. The mixture was extracted twice with diethyl ether. Each organic phase was washed with water, aqueous saturated NaHCO3 and brine (3×). Combined extracts were dried over sodium sulfate. The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 9:1) followed by bulb-to-bulb distillation (120° C./0.01 mbar). The product was obtained (yield: 79%) as a 98:2 mixture of E and Z isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4]=1[C:19](=O)/[CH:20]=[C:21](\[NH:24][C:25]1[N:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=1)/SC.O.[NH2:35][NH2:36].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4]=1[C:19]1[NH:36][N:35]=[C:21]([NH:24][C:25]2[N:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=2)[CH:20]=1
Reactant: COc1ccc(COc2cccc(OC)c2C(=O)/C=C(\Nc2cnc(C#N)cn2)SC)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(COc2cccc(OC)c2-c2cc(Nc3cnc(C#N)cn3)n[nH]2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A 10 L flange-neck flask, equipped with an air stirrer rod and paddle, thermometer, water condenser, and nitrogen bubbler, is charged with (E)-5-(3-(2-methoxy-6-(4-methoxybenzyloxy)phenyl)-1-(methylthio)-3-oxoprop-1-enylamino)pyrazine-2-carbonitrile (196 g, 423.8 mmol) and absolute ethanol (3 L). To the stirred suspension under nitrogen is added hydrazine hydrate (41.0 mL, 838.7 mmol) and glacial acetic acid (66.0 mL, 1.15 moles). A small exotherm is noted. The yellow suspension is warmed up to 65° C. Heating is then discontinued and the reaction mixture is allowed to cool to room temperature. The mixture is allowed to stand overnight under a nitrogen atmosphere. The solid is collected by filtration, washed with fresh ethanol, and dried in vacuo at 45° C. to give 140 g (87% yield for two steps) of a bright yellow solid. The product is used in the next step without further purification. LC-ES/MS m/z 429.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[O-:17][C:18]#[N:19].[K+]>C(O)(=O)C.O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][NH:1][C:18]([NH2:19])=[O:17])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: N#C[O-]
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NCc1ccc2c(c1)Nc1nccnc1S2
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of 420 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in acetic acid (2 ml)/water (4 ml) was heated to 70° C. and potassium cyanate (1 g in total) was added thereto over 2 hours. Then the reaction mixture was brought back to room temperature and diluted with water. The solid thus precipitated was filtered, washed well with water and recrystallized from dimethyl sulfoxide/ethyl acetate to thereby give 70 mg of the title compound as yellow crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2.B(Br)(Br)Br.[Cl:22]CCl>>[ClH:22].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2
Reactant: COc1cccc2nc3c(c(N)c12)CCCC3
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cl
Product: Nc1c2c(nc3cccc(O)c13)CCCC2
Reaction time: 1 h
Yield: 61 %

Procedure:
8-Methoxy-1,2,3,4-tetrahydro-9-acridinamine (4.0 g) was dissolved in dichloromethane (76 ml). Boron tribromide in dichloromethane (15.0 ml of a 1.0M solution) was added, and the reaction mixture was stirred 1 hr and then concentrated under reduced pressure. The residue was dissolved in warm water (100 ml), concentrated hydrochloric acid (400 ml) was added and the solution was chilled overnight in the refrigerator. The salt was collected and recrystallized from methanol-ether to give 2.68 g (61%) of product, mp 270° C. (dec).
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([Cl:10])=[CH:5][C:4]=1[C:11]([CH:13]=O)=[O:12].[NH2:15][C:16]([CH3:29])([CH3:28])[CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1.[BH4-].[Na+]>CO>[ClH:2].[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([Cl:10])=[CH:5][C:4]=1[CH:11]([OH:12])[CH2:13][NH:15][C:16]([CH3:29])([CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1)[CH3:28]
Reactant: CC(C)(N)CCn1cnc2ccccc21
Reactant: O=CC(=O)c1cc(Cl)c(O)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CCn1cnc2ccccc21)NCC(O)c1cc(Cl)c(O)cc1Cl
Product: Cl
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 9.3 gm of 2,5-dichloro-4-hydroxyphenylglyoxal hydrate, 7.25 gm of 1-(3-amino-3-methylbutyl)-benzimidazole and 100 ml of alcohol was stirred for 3 hours at 40°-45° C. The resulting solution was subsequently cooled, admixed in portions with 8 gm of sodium borohydride, and the mixture was stirred for 3 hours at room temperature. After the addition of 100 ml of methanol for decomposition of the sodium borohydride, the mixture was allowed to stand for 10 hours, the solvent was distilled off under reduced pressure, the residue was dissolved in 200 ml of water, and the solution was acidified with concentrated hydrochloric acid. 9.5 gm of 1-(2,5-dichloro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol dihydrochloride×1 H2O, m.p. 180°-183° C., of the formula ##STR33## were obtained. The yield was 50.4% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+]([O-])=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:17][O-:18].[Na+].[Na]>CO>[CH3:17][O:18][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Five (5) g (22 mmol) methyl 3,5-dinitrobenzoate (Aldrich) were suspended in 80 mL methanol (A.C.S. grade) and heated to reflux for app. 1 h under nitrogen, until a clear brown solution had formed. A simultaneously prepared sodium methoxide solution (prepared by portionwise addition of 0.76 g (33 mmol, 1.5 eq.) sodium to 10 mL methanol, the reaction flask was purged with nitrogen until all sodium had reacted) was added dropwise to the hot solution by syringe, each drop causing a deep red color. The reaction mixture was refluxed for an additional 15 h. After cooling to r.t., it was concentrated to dryness, the remaining brown-purple solid was taken up in 30 mL distilled water and acidified with 2 N HCl. The addition of ethyl acetate caused the present light orange solid to dissolve, phases were separated and extraction with ethyl acetate was repeated twice. The combined organic layers were washed with sat. aq. NaHCO3, with brine, then dried with MgSO4 and concentrated, leaving 3.7 g of a pale yellow solid. The crude product was purified by column chromatography (7:3 hexanes/ethyl acetate, Rf=0.6, UV; note: starting material coelutes but should be gone after the reaction time given) to afford 2.3 g (50%) of a light yellow solid. The procedure can be scaled up to 30 g starting material: depending on the course of the reaction, crude product material might be sufficiently pure to be carried on into the next step without further purification. mp 88-89° C. 2; 1H NMR (CDCl3) δ 8.46 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 7.92 (t, J1=2.4 Hz, J2=2.4 Hz, 1H), 7.88 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 3.99 (s, 3H, OCH3), 3.95 (s, 3H, OCH3); 13C NMR (CDCl3) δ 164.59, 160.00, 148.95, 132.37, 120.84, 116.36, 112.65, 56.02, 52.60.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH:14]2[C:20]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=3[N:18]([C:26](=[O:45])[C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[CH:29][C:28]=3[O:43][CH3:44])[CH2:17][CH2:16][CH2:15]2)(=O)=O)=CC=1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.[I-].[Na+]>CN(C)C=O>[CH3:47][N:48]1[CH2:53][CH2:52][N:51]([CH2:11][CH2:12][O:13][CH:14]2[C:20]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=3[N:18]([C:26](=[O:45])[C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[CH:29][C:28]=3[O:43][CH3:44])[CH2:17][CH2:16][CH2:15]2)[CH2:50][CH2:49]1
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OCCOS(=O)(=O)c2ccc(C)cc2)c2cc(F)ccc21
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OCCN2CCN(C)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 10 ml of dimethylformamide were dispersed 0.4 g of 5-[2-(p-toluenesulfonyloxy)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine, 0.38 ml of N-methylpiperazine and 0.3 g of sodium iodide. The dispersion was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was mixed with water and the mixture was subjected to extraction with ethyl acetate. The extract was dried over sodium carbonate and purified by silica gel column chromatography (elutant: dichloromethane/-methanol=10/1) to obtain 1.15 g of 5-[2-(4-methyl-1-piperazinyl)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[C:10]([Cl:12])[S:9][C:8]=1[Cl:13].C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.Cl>CCCCCC.CCOCC>[Cl:13][C:8]1[S:9][C:10]([Cl:12])=[CH:11][C:7]=1[B:18]([OH:19])[OH:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1cc(Br)c(Cl)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(Cl)sc1Cl
Reaction time: 1 h

Procedure:
n-Butyllithium in hexane (1.66M solution, 5.2 ml) was added dropwise to a solution of 3-bromo-2,5-dichlorothiophene (2.0 g) and triisopropoxyborane (2.4 ml) in ether (20.0 ml) at -75-65° C. for 10 minutes and the mixture was stirred at same temperature for 1 hour. The reaction mixture was poured onto 1N-hydrochloric acid (30 ml) and the mixture was extracted with ether. The separated extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (2,5-dichlorothiophen-3-yl)-dihydroxyborane (1.13 g).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:18])([CH3:17])[CH2:9]1.C(N(CC)CC)C>C1COCC1>[CH3:17][C:10]1([CH3:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:9]1
Reactant: CC1(C)CC(N)c2ccccc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC1CC(C)(C)c2ccccc21
Reaction time: 2 h
Yield: 79.9 %

Procedure:
With ice-cooling, 4.44 g (34.7 mmol) of ethanesulfonyl chloride were added dropwise to a solution of 5.1 g (31.6 mmol) of 1-amino-3,3-dimethylindan (Example 1a) and 12.8 g (126 mmol) of triethylamine in 100 ml of THF. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was taken up in water and EA. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, giving 6.4 g of 3,3-dimethyl-1-ethylsulfonylaminoindan.