Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][N:7]=2.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][N:7]=2
Reactant: COCc1nc2cc(C(=O)OC)cnc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc2cc(C(=O)O)cnc2s1

Procedure:
A mixture of 1.1 g (4.62 mMol) of methyl 2-methoxymethyl-thiazolo[5,4-b]pyridine-6-carboxylate and 9.2 ml of 2N sodium hydroxide solution were stirred into 50 ml of ethanol for one hour at room temperature. Then 9.2 ml of 2N hydrochloric acid were added, the alcohol was distilled off, and it was diluted with 20 ml of water. The aqueous phase was acidified with concentrated hydrochloric acid whilst cooling with ice, the beige precipitate formed was filtered off, then washed with water and dried. Yield: 1.03 g (100% of theory), Rf value: 0.10 (silica gel; ethyl acetate/petroleum ether=3:7)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([Cl:17])=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Br)=[O:8])=[CH:5][CH:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([Cl:17])=[C:11]([CH2:12][C:20]#[N:21])[CH:14]=[CH:15][CH:16]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccc(CBr)c2Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)c2cccc(CC#N)c2Cl)cc1
Yield: 97.6 %

Procedure:
3-(4-Methoxybenzoyl)-2-chlorotoluene (4.55 g, 17.45 mmol) [prepared by the method described in Example 1(a)]was dissolved in benzene (150 ml), and the solution was purged with nitrogen. N-Bromosuccinimide (3.10 g, 1 eq.) and benzoyl peroxide (0.42 g, 0.1 eq.) were added and the reaction mixture was heated at reflux overnight. Since there was an appreciable amount of unreacted starting material still present in the reaction mixture, additional amounts of N-bromosuccinimide (1.55 g, 0.5 eq.) and benzoyl peroxide (0.21 g, 0.05 eq.) were added, and the heating was continued. After 3 h the reaction mixture was cooled to room temperature, and diluted with ether. The organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed in vacuo to give 7.6 g of an orange oil. Purification by flash chromatography (10/90 EtOAc/hexanes) gave 3-(4-methoxybenzoyl)-2-chlorobenzyl bromide as an oil that slowly crystallized to a solid (5.13 g, 87% yield). 1H NMR showed it was approximately 90% pure 3-(4-methoxybenzoyl)-2-chlorobenzyl bromide (4.97 g, 1 eq.) [prepared as described above] was added to a solution of KCN (1.05 g, 1.1 eq.) in dry DMSO (40 ml) under a nitrogen atmosphere. After 30 min the reaction mixture was poured into water (1 L) and the product was extracted into ethyl acetate. The organic extract was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 2-[3-(4-methoxy-benzoyl)-2-chlorophenyl]acetonitrile (4.08 g, 98% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH:26]=[CH2:27]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][CH2:27][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5]2[C@H:16]3[NH:17][C@@H:12]([CH2:11][C:6]1=2)[CH2:13][CH2:14][CH2:15]3
Reactant: C=Cc1cc(C)ccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc(C)c(CCn2c3c(c4cc(C)ccc42)[C@@H]2CCC[C@H](C3)N2)c1

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1,4-dimethyl-2-vinylbenzene (129 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.07-1.35 (m, 3H), 1.60-1.96 (m, 4H), 1.99 (s, 3H), 2.15 (s, 3H), 2.41 (s, 3H), 2.82 (dd, J=17, 7 Hz, 1H), 2.94-3.16 (m, 2H), 3.38-3.45 (m, 1H), 4.19 (ddd, J=15, 9, 5 Hz, 1H), 4.30-4.41 (m, 2H), 6.69 (s, 1H), 6.84-6.99 (m, 3H), 7.14 (s, 1H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CO
Solvent: CC#N
Product: CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 74.3 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.159 g of ethyl isocyanate according to the general procedure of Example 37 to give 0.86 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido-[2,3-d]pyrimidin-7-yl}-3-ethyl-urea, MS (ES+20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=517; mp 82°-90° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>CO>[OH:9][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([NH:16][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC(O)CCN1CCOCC1
Solvent: CO
Solvent: O
Product: OC(CCN1CCOCC1)CNC(c1ccccc1)C(O)c1ccccc1
Yield: 88.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 4-(4-amino-3-hydroxybutyl)morpholine (3.48 g, 0.020 mol) was heated on a steam bath for 18 hours. The resulting viscous oil was dissolved in methanol (20 mL) and the solution poured into water (150 mL). The aqueous mixture was extracted twice with 100 mL portions of methylene chloride. The extract was dried (MgSO4) and concentrated to obtain 3.29 g of the impure product as an oil. The material was chromatographed on silica gel (60 g) using increasing portions of acetone in ethyl acetate to elute the product. After combining the desired fractions and concentration under vacuum, 2.21 g (67%) of the product was obtained. The product was purified and characterized as the cyclohexyl sulfamic acid salt, mp 159°-160° C. (methanol/isopropyl ether).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18][C:19](=[O:29])[O:20][C@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.Br[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18][C:19](=[O:29])[O:20][C@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)[CH2:16][CH2:17]3)=[CH:11][CH:10]=2)=[N:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(C3(NC(=O)O[C@@H]4CN5CCC4CC5)CC3)cc2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Product: O=C(NC1(c2ccc(-c3ccc(F)cn3)cc2)CC1)O[C@@H]1CN2CCC1CC2
Yield: 34 %

Procedure:
Using general procedure E, (S)-quinuclidin-3-yl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl)cyclopropyl)carbamate, 2-bromo-5-fluoropyridine and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (34%). 1H NMR (500 MHz, CDCl3) δ 8.51-8.52 (d, J=3.5 Hz, 1H), 7.87-7.85 (d, J=10.5 Hz, 2H), 7.69-7.67 (m, 1H), 7.47-7.42 (m, 1H), 7.32-7.27 (m, 2H), 5.79-5.66 (d, 1H), 4.73-4.71 (t, J=5.0 Hz, 1H), 3.22-3.19 (m, 1H), 2.87-2.61 (m, 5H), 2.01-1.22 (m, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ 160.8, 157.4, 156.1, 153.5, 144.4, 137.8, 136.3, 126.7, 125.7, 124.9, 123.6, 121.1, 71.6, 55.7, 47.4, 46.5, 35.3, 29.7, 25.4, 24.8, 19.4, 18.2 ppm. Purity: >99% LCMS (214 nm & 254 nm); retention time 1.41 min; (M+1) 382.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH:52]1[CH2:64][OH:65])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH:52]1[CH2:64][O:65][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=[C:14]([F:13])[C:19]=1[F:20])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6043.8 %

Procedure:
(1Ba) A solution of 4.7 g (27 mmol) of diethyl azodicarboxylate in 15 ml of THF was added dropwise at 15° C. while stirring to a solution of 3.9 g (22.5 mmol) of 2,3-difluoro-5-nitrophenol, 7.1 g (27 mmol) of triphenylphosphine and 8 g (0.27 mmol) of 1,4-dibenzyl-2-hydroxymethylpiperazine in 250 ml of THF. The yellow reaction solution was then stirred at room temperature for an additional 3 hours. After concentrating the reaction solution, the oily residue was stirred with a total of 2 l of hot n-hexane in several portions. The hexane solution was separated and cooled. The separated triphenylphosphine oxide was removed by filtration under suction, and the filtrate was concentrated. Chromatography on silica gel with ether/n-hexane (1:1) as the eluent gave 7.4 g of 1,4-dibenzyl-2-[(6-nitro-2,3-difluorophenoxy)methyl]piperazine as a brown oil.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)CCCI
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)CCCOc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
464.5 g (1.95 mol) of 4-iodo-1,1,1-trifluorobutane, 390.4 g (1.95 mol) of 4-(benzyloxy)phenol and 539.5 g (3.90 mol) of potassium carbonate are dissolved in 3 L of NMP. The mixture is heated to 80° C. overnight. The solution is cooled to room temperature and the reaction mixture is extracted with ethyl acetate and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure to give 580 g of
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10]>C1C=CC=CC=1>[Cl:14][C:13]([Cl:16])([Cl:15])[CH2:12][O:11][C:9]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1

Procedure:
N-methylpiperazine (2 g) is dissolved in 20 ml benzene and reacted with a solution of 4.5 g 2,2,2-trichloroethyl chloroformate in 20 ml benzene, with stirring and cooling in an ice bath. After stirring for 2 hours the resulting crystals are collected by vacuum filtration, washed with ether and dried under water-pump vacuum at room temperature, to give the hydrochloride of the title compound, m.p. 238°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2CC3C(=CC=CC=3)C2)[C:15](=[O:30])[CH2:14]1.O.NN>CCO>[NH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14][C:15]1=[O:30]
Reactant: COc1ccc2nccc(N3CCN(CCN4Cc5ccccc5C4)C(=O)C3)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2nccc(N3CCN(CCN)C(=O)C3)c2n1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)-1H-isoindole-1,3(2H-dione (100 mg, 0.232 mmol) in EtOH (2 mL) was added hydrazine hydrate (120 μL, 3.85 mmol). After 2 h at 85° C., the solution was concentrated and the residue purified by column chromatography (silica, 5-10% MeOH in DCM (1% NH4OH)) yielding the title compound (46 mg, 66%) as a yellow oil: LCMS (ES) m/e 302 (M+H)+.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:39])=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[N:32][CH:33]=2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>ClCCl>[Cl:15][C:16]1[C:17]([CH3:39])=[C:18]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])=[N:32][CH:33]=2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Cyanuric chloride (0.43 g, 2.3 mmol) was added to N,N-dimethylformamide (0.18 mL, 2.3 mmol) at room temperature. After the formation of a white solid (10 minutes), methylene chloride (10 mL) was added, followed by 5-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (0.6 g, 2 mmol). After addition, the mixture was stirred at room temperature overnight, then diluted with dichloromethane and washed with sat. NaHCO3 solution. The organic layers were dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (0.58, 90%). LCMS calculated for C19H23Cl2NO2 (M+H)+: m/z=381.1; Found: 381.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][N:7]=1)=[O:5])[CH3:2].O1CCCC1.[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH2:12][Br:19])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: [Br-]
Reactant: CCOC(=O)c1cc(C(C)=O)[nH]n1
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.7 %

Procedure:
A 100ml flask was charged with 27.8 g of 5-acetylpyrazole-3-carboxylic acid ethyl ester and 40 ml of tetrahydrofuran. To this mixture, 56.4 g of phenyltrimethylammonium tribromide were added. The resulting red mixture was stirred at room temperature for 1 hour and poured into 600 ml of water. The resulting mixture was filtered and the solids were washed with more water. The solids were collected, air-dried and recrystallized from 1:1 mixture of disopropyl ether and hexanes (300ml) to afford 33.1 g of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester as white solids, mp 174°-176° C. NMR: 1.42 (t, 3H), 4.44 (q, 2H), 4.57 (s, 2H), 7.4 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=2[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[CH3:9].B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=2[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(CCNCc2ccccc2C(=O)NCCCCc2ccccc2)ccc1C
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(CCNCc2ccccc2C(=O)NCCCCc2ccccc2)cc1O
Yield: 14.5 %

Procedure:
Crude 2-{[2-(3-methoxy-4-methyl-phenyl)-ethylamino]-methyl}-N-(4-phenyl-butyl)-benzamide (derived via Procedure C from 200 mg resin) is dissolved in 3 mL of dichloromethane and treated with 0.5 mL of 1 M of boron tribromide in dichloromethane for 16 h. Methanol (3 mL) is carefully added and the volatiles are removed. The crude residue is purified via semi-preparative HPLC to give 2-{[2-(3-hydroxy-4-methyl-phenyl)-ethylamino]-methyl}-N-(4-phenyl-butyl)-benzamide (28 mg). MS: m/z 417 (m+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC(c1ccccc1)c1ccccc1)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol) in dry CH2Cl2 (20 ml)was added 3,3-diphenylpropionic acid (0.19 g, 0.82 mmol) under nitrogen. To the reaction was added EDC (0.18 g, 0.9 mmol) and DMAP (cat), and the reaction mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give the desired product in 70% yield
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[CH:11](O)=O.O.N>Cl>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]2[N:9]=[CH:11][NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)cc(N)c1N
Reactant: O=CO
Agent: Cl
Agent: N
Solvent: O
Product: Nc1cc(Br)cc2[nH]cnc12
Yield: 96.3 %

Procedure:
To a stirred suspension of 5-bromobenzene-1,2,3-triamine (81.5 g, 403 mmol) in HCl conc (2400 mL) at rt was added formic acid (46 mL, 1210 mmol, 3 eq). After stirring at reflux for 90 min, water (500 mL) was added to the suspension, and the pH was adjusted to 8 using ammonia (33% aqueous solution). After extraction with ethyl acetate (3×1000 mL), the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vaccuo. The crude product was trituarated with diethyl ether (200 mL), filtered and dried to yield 82.3 g (96.3%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]3[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][C:15]([F:23])=[CH:14][C:13]=3[N:12]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:11]=23)=[CH2:9])=[CH:4][CH:3]=1>CCO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[C:18]3[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:16][C:15]([F:23])=[CH:14][C:13]=3[N:12]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:11]=23)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(Cl)cc1)c1c2n(c3cc(F)cc(S(C)(=O)=O)c13)CCC2CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccc(Cl)cc1)c1c2n(c3cc(F)cc(S(C)(=O)=O)c13)CCC2CC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of the compound of Step 3 (78 mg) and 20 mg of Pd/C (10% w/w) in EtOH (3 mL) was stirred under H2 (balloon) for 1 h. The mixture was then filtered through a silica gel pad eluted with EtOAc and the filtrate was concentrated to give 75 mg of the title compound used as such.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([NH:21][CH2:22][CH2:23][N:24]3[CH:28]=[CH:27][NH:26][C:25]3=[O:29])=[N:12][C:11]1=2)[CH3:14]
Reactant: NCCN1CCNC1=O
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(NCCn3cc[nH]c3=O)nc21

Procedure:
The title compound, m.p.>300° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 1-(2-aminoethyl)-2-imidazolidone using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 250° C. for 30 min., and the product was crystallized from acetic acid.
Reaction SMILES: O=[C:2]([CH3:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([NH2:40])[CH3:39]>C(Cl)Cl>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([NH:40][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:39]
Reactant: CC(N)c1ccccn1
Reactant: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CCCN1C(=O)c2ccccc2C1=O)NC(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 2-(4-oxo-pentyl)-isoindole-1,3-dione (Abdel-Monem, M M et al. J. Med. Chem. 1974, 17, 447-451) in CH2Cl2 and 1-pyridin-2-yl-ethylamine with NaBH(OAc)3 gave 2-[4-(1-pyridin-2-yl-ethylamino)-pentyl]-isoindole-1,3-dione as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>CC(C)=O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[C:15]=3[CH:16]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenol (0.419 g, 1.185 mmol) was reacted with K2CO3 (0.213 g, 1.541 mmol) and methyl bromoacetate (0.236 g, 1.541 mmol) in acetone to give the product (0.362 g, 0.851 mmol, 72%) as a white solid, mp 109-112° C. 1H NMR (DMSO-d6) δ 1.77-1.87 (m, 4H), 2.65 (t, J=5.3 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 3.71 (s, 3H), 4.81 (s, 2H), 5.33 (s, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.3 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.25-7.30 (m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.58 (d, J=1.1 Hz, 1H); [ESI(+)], m/z 426 (M+H)+.