Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].N.[Cl:17][CH2:18][C:19](Cl)=O>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:13]=[C:19]([CH2:18][Cl:17])[O:15][N:14]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reactant: O=C(Cl)CCl
Agent: N
Product: O=C(CCl)Nc1ccc(-c2noc(CCl)n2)nc1
Temperature: 0 °C

Procedure:
Compound of example 4 (0.500 g, 2.18 mmol) was heated in chloroacetyl chloride (2 mL) at a temperature in the range of 100-110° C. for 4 hours. The reaction mixture was cooled, poured over ice water, basified With ammonia solution, and extracted with ethyl acetate (3×60 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product obtained was purified over silica gel using ethyl acetate/petroleum ether (35%-50%) as eluent, and the pure fractions were concentrated and crystallized using chloroform/ petroleum ether, to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:12]([O-])([O-:15])(=[O:14])=[O:13].[Na+].[Na+].Cl>O.C(O)C>[CH2:5]([O:4][CH2:3][CH2:2][S:12]([OH:15])(=[O:14])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCOCc1ccccc1
Yield: 75.8 %

Procedure:
A mixture of [(2-bromoethoxy)methyl]benzene (6.0 g) and sodium sulfate (3.9 g) in water (12 ml) and ethanol (36 ml) was refluxed overnight. The mixture was acidified with conc. hydrochloric acid under ice-cooling. The mixture was evaporated under reduced pressure. The residue was suspended in dichloromethane/methanol (4/1) and filtered off through Celite pad. The filtrate was evaporated to give 2-(benzyloxy)ethanesulfonic acid (4.5 g).
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)CC3)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 7-(6-oxo-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (550 mg, 1.133 mmol) in methanol (10 ml) was treated with 1M sodium hydroxide (3.40 ml, 3.40 mmol) and the resultant solution was stirred at 50° C. for 1 hour. The solution was cooled to room temperature and concentrated under vacuum. The residue was diluted with water, acidified to pH ˜2 with 1N HCl, giving a white solid which was extracted with DCM (×3). The extracts were dried (MgSO4) and evaporated under vacuum to afford the title compound as a white solid;
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](Cl)=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:3]3[C:2]([F:1])=[CH:13][C:6]4[B:7]([OH:12])[O:8][C:9]([CH3:11])([CH3:10])[C:5]=4[CH:4]=3)[CH2:26]2)[CH:22]=[C:21]([Cl:31])[CH:20]=1
Reactant: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a solution of the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydro benzo[c][1,2]oxaborole-5-carbimidoyl chloride (300 mg, 0.92 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (222 mg, 0.92 mmol) in DMF (5 mL) at rt was added TEA (152 μL, 1.1 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (108 mg; yield 29% over 3 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.379 (s, 1H), 7.815-7.848 (m, 2H), 7.660 (s, 2H), 7.513 (d, J=10.0 Hz, 1H), 4.401 (d, J=18.4 Hz, 1H), 4.254 (d, J=18.8 Hz, 1H), 1.485 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1>>[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:19][CH:18]=1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Product: CNc1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1

Procedure:
N-Methyl-4-(4-nitroquinolin-2-yl)aniline T466P was prepared using general procedure A from 2-bromo-4-nitroquinoline (50 mg, 0.2 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (46 mg, 0.2 mmol). The product T466P was obtained as a brown solid (37 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 8.34 (m, 1H), 8.32 (s, 1H), 8.19 (m, 1H), 8.09 (m, 2H), 7.79 (m, 1H), 7.63 (m, 1H), 6.72 (m, 2H), 2.93 (s, 3H); MS (ESI): 280 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)c(CBr)c1
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxy-3-methylbenzoate (10.0 g, 55.6 mmol) dissolved in CCl4 (500 mL) was added N-bromosuccinimide (10.8 g, 61.1 mmol) and benzoyl perioxide (1.30 g, 5.56 mol). The mixture was irradiated with a sunlamp (250 W) to create a gentle reflux. After 2 hours of exposure the reaction was complete by TLC. The reaction mixture was cooled, filtered through celite, and concentrated to yield a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:25])[C@H:12]([CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:25])[C@H:12]([CH2:14][CH2:15][CH2:16][NH2:17])[NH:13][CH2:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCCc1ccccc1
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NCCC[C@H](NCCc1ccccc1)C(=O)NCCCc1ccccc1
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A cold solution (0° C.) of the above amine (3 g, 8.6 mmol), in methanol (20 ml), was treated sequentially with acetic acid (345 μl, 6 mmol) and phenylacetaldehyde (1.2 ml, 10 mmol). Then a solution of sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (10 ml) was added to the mixture slowly. The reaction was stirred for additional 30 minutes and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate, and purified by chromatography (silica gel, hexane/ethyl acetate) to afford Nα-(phenethyl)ornithine 3-phenylpropylamide (2.64 g): 1H NMR (400 MHz, CD3OD) δ1.4 (s, 9H), 1.45-1.8 (m, 6H), 2.6 (t, J=6.4 Hz, 2H), 2.65-2.8 (m, 4H), 3.02-3.2 (m, 5H), and 7.1-7.3 (m, 10H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(OCC)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1cccc(F)c1F
Solvent: CCOCC
Product: O=C(CBr)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Bromine (4.96 g, 31.1 mmol) was slowly added dropwise to a solution of 1-(2,3-difluorophenyl)ethanone (4.85 g, 31.1 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was distilled off under reduced pressure to give 7.29 g (99.9%) of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])[C:2]#[CH:3].Br[C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][C:2]#[C:3][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCOCCCCCCCBr
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(C#CCOCCCCCCCBr)c1
Yield: 46.1 %

Procedure:
7-Bromoheptyl prop-2-ynyl ether (55.1 g) in THF (250 ml) was added dropwise over ca 8 h to a stirred mixture of 3-bromobenzenesulfonamide (43.5 g), PdCl2(PPh3)2 (6.48 g), PPh3 (1.45 g), CuI (1.4 g) and Et3N (52 ml) in THF (250 ml) at 55±5° C. under nitrogen then the mixture heated for a further ca 15 hrs. The reaction was cooled, filtered through Celite and the solids washed with THF. The solution was concentrated and the product purified by chromatography on flash silica gel (600 g) eluting with petroleum ether:ethyl acetate (ratios ranging successively from 19:1 to 7:3) to give the title compound (33 g)—LC RT=5.85 min.
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7])(=[O:15])[CH3:14]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)CBr
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O

Procedure:
29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 17 g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred at 40° C. in 300 ml of acetonitrile for 16 h. The mixture was concentrated under reduced pressure, and the water was added to the residue. The product was extracted with ethyl acetate, the organic phase was washed with water and the solvent was removed completely under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(CO)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1CO
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
To a solution (2 mL) of 2-chloro-4-fluoro-3-(hydroxymethyl)benzonitrile (150 mg) in dimethyl sulfoxide were added (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (167 mg) and lithium carbonate (66 mg), and the mixture was stirred at 140° C. for 10 min in a microwave reaction apparatus. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) and recrystallized from ethyl acetate-isopropyl ether to give the compound as a pale-yellow solid (yield: 85 mg).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[NH:16]([C:23]1[S:24][C:25]2[CH:31]=[C:30]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:28][C:26]=2[N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:16]([C:23]1[S:24][C:25]2[CH:31]=[C:30]([CH2:32][C:33]([NH:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:15])[CH:13]=3)=[O:34])[CH:29]=[CH:28][C:26]=2[N:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc2nc(Nc3ccccc3)sc2c1
Reactant: COC(=O)CCCOc1cccc(N)c1
Product: O=C(O)CCCOc1cccc(NC(=O)Cc2ccc3nc(Nc4ccccc4)sc3c2)c1

Procedure:
Methyl4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with 2-anilino-6-carboxymethylbenzothiazole according to the method described in example 7 to produce the methyl ester of 2-anilino-6-{3-[3-carboxypropoxy]anilino carbonyl methyl}benzothiazole
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[SH:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:8]=1[C:9]#[N:10].C[O-].[Na+]>CO>[NH2:10][C:9]1[C:8]2[C:7](=[N:14][C:13]([CH3:15])=[CH:12][C:11]=2[CH3:16])[S:6][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)CBr
Reactant: Cc1cc(C)c(C#N)c(S)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c2c(N)c(C(N)=O)sc2n1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
α-Bromoacetamide (388 mg, 2.81 mmol) was added to a solution of 2-mercapto-4,6-dimethyl-nicotinonitrile (420 mg, 2.56 mmol) in MeOH (25 mL) at room temperature. This was followed by addition of sodium methoxide (1.76 mL, 25% NaOMe in MeOH, 7.7 mmol). The reaction mixture was heated to reflux. Heating at reflux was continued overnight, after which time the reaction mixture was cooled and filtered. The product was dried overnight providing 450 mg (80%) of the title compound, m.p. 238-40° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C>C1COCC1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([B:12]([OH:17])[OH:13])=[CH:4][CH:5]=1)[CH3:11]
Reactant: CCOc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A one-necked, 25-mL, round-bottomed flask equipped with a reflux condenser fitted with an argon inlet adapter was charged with magnesium powder (0.255 g, 10.5 mmol, -50 mesh), 7 mL THF, and 4-bromophenetol (1.41 g, 1.00 mL, 7.00 mmol). The resulting mixture was heated to reflux for 3 h. A second one-necked, 25-mL, round- bottomed flask equipped with a rubber septum and an argon inlet needle was charged with triisopropyl borate (3.95 g, 4.85 mL, 21.00 mmol) and cooled to -78° C. while the Grignard reagent prepared above was added dropwise via cannula over ca. 5 min. The cooling bath was removed and the reaction mixture was stirred for 3 h at room temperature. A mixture of ether (50 mL) and a 10% HCl solution (59 mL) was added and the resulting organic phase was washed with a 100-mL portion of water. The organic phase was dried over MgSO4, filtered, and concentrated to provide a yellow solid which was recrystallized from ether-hexanes to provide 0.783 g (67%) of a white solid:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](O)=[O:30])=[CH:21]1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>CN(C=O)C>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:30])=[CH:21]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1c[nH]c2ccccc12
Reaction time: 18 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (49.2 mg, 0.196 mmol), indole-3-carboxylic acid (37.9 mg, 0.235 mmol) and 1M DCC in CH2C2 solution (0.235 ml, 0.235 mmol) were mixed in DMF (2 ml) and the pH adjusted to 9.0 with triethylamine (32.7 μl, 0.235 mmol). The reaction was stirred 18 hrs. at 25° C., the DMF removed in vacuo, and the residue chromatographed on a Waters Semi-Prep C-18 30×0.9 cm column (gradient elution of 5 to 95% CH3CN in H2O) to give the title compound as a white solid from MeOH/ether: (m.p. 265°-268°).
Reaction SMILES: Br[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]2[CH2:8][CH2:7][N:6]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5](=[O:24])[C:4]=2[C:3]=1[CH3:25].[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[C:9]2[CH2:8][CH2:7][N:6]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:5](=[O:24])[C:4]=2[C:3]([CH3:25])=[C:2]1[C:30]1[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Temperature: 60 °C
Yield: 55.1 %

Procedure:
2-Bromo-1-(2-chlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (0.92 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.35 g, 2.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (350 mg) were dissolved in DME (46 ml) and 1 M Na2CO3 (12 ml)). The resulting solution was degassed and heated at 60° C. under nitrogen overnight. Water and EtOAc were added after cooling and the aqueous phase extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give a crude product that was purified by flash chromatography (heptane:EtOAc gradient) to afford 0.54 g (55%) of the product as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cccc(Nc2cccc(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(Nc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 3-(3-cyanophenylamino)benzoate (0.050 g; 0.187 mmol) in dioxane (1 ml) was added a solution of sodium hydroxide (0.022 g; 0.563 mmol) in water (0.6 ml). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to remove the dioxane. The aqueous solution was acidified with 6N hydrochloric acid, extracted with ethyl acetate (2×100 mL), dried and concentrated under reduced pressure to give quantitatively 3-(3-cyanophenylamino)benzoic acid which was directly used in the next step.
Reaction SMILES: [C:1]([CH:3]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C:4]1([CH3:11])[CH3:10])#[N:2].[OH2:12]>[OH-].[Na+].CO>[CH3:8][C:7]1([CH3:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[CH:3]1[C:1]([NH2:2])=[O:12]
Reactant: O
Reactant: CC1(C)CCC(C)(C)C1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)C1C(N)=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
760 mg of 1-cyano-2,2,5,5-tetramethylcyclopentane was dissolved in 5 ml of aqueous 3N sodium hydroxide solution and 10 ml of MeOH, and the solution was stirred at room temperature for 10 hours. Then, 10 ml of water was added thereto, and the mixture was twice extracted with 30 ml of chloroform. The organic layers were combined, washed with 50 ml of water and concentrated under reduced pressure. The thus obtained residue was recrystallized from n-hexane, whereby 640 mg of (2,2,5,5-tetramethylcyclopentane-1-yl) carboxamide was obtained (m.p. 97.7° C.).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[N:4]([CH3:22])[C:3]1=[O:23].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]=1[CH3:39])=[C:25]=[S:26]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:5]2[N:4]([CH3:22])[C:3](=[O:23])[CH:2]([NH:1][C:25]([NH:24][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][C:28]=3[CH3:39])=[S:26])[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=3)[C:6]=2[CH:17]=1
Reactant: Cc1cc(N2CCOCC2)ccc1N=C=S
Reactant: COc1cccc(C2=NC(N)C(=O)N(C)c3ccc(Cl)cc32)n1
Product: COc1cccc(C2=NC(NC(=S)Nc3ccc(N4CCOCC4)cc3C)C(=O)N(C)c3ccc(Cl)cc32)n1
Temperature: 70 °C
Yield: 89.5 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl-2H-1,4-benzodiazepin-2-one (0.0113 g, 0.0342 mmol) and 4-(4-isothiocyanato-3-methylphenyl)morpholine (0.0080 g, 0.034 mmol) in (CH2Cl)2 (0.9 mL) was heated at 70° C. for 20 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (2:1 CH2Cl2:EtOAc) to provide the title compound (0.0172 g, 89%) as a slightly yellow solid. 1H-NMR (CDCl3): δ 7.79 (dd, J=0.8 Hz, J=7.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.42 (br s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.28-7.25 (m partially hidden under CHCl3, 2H), 6.85-6.80 (m, 3H), 6.14 (m, 1H), 3.88-3.85 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H), 3.22-3.18 (m, 4H), 2.36 (s, 3H). MS (M+H+=565.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)([CH3:30])([CH3:29])[CH3:28]>O.ClCCl>[C:27]([O:31][C:32](=[O:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)CCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (2.10 g, 30.9 mmol), triphenylphosphine (8.10 g, 30.9 mmol), and iodine (6.27 g, 24.7 mmol) were successively added to a dichloromethane solution (100 mL) of t-butyl-8-hydroxyoctanoate (4) (4.45 g, 20.6 mmol) at 0° C. under the argon atmosphere, and the temperature of the reaction solution was raised to room temperature, followed by stirring for 2 hours. Thereafter, water (5 mL) was added to the reaction solution, and the mixture was washed successively with a 0.1 N aqueous sodium periodate solution (50 mL), 30% aqueous hydrogen peroxide (50 mL), and saturated brine (50 mL), dried over magnesium sulfate, and concentrated. The resulting brown oily crude product (21 g) was separated and purified by silica gel column chromatography (hexane:ethyl acetate 50:1) to obtain t-butyl-8-iodooctanoate (5) as a colorless liquid substance (5.53 g, 77%).