Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:33][C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]2
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1ccncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1ccc2c(c1)CC(NS(=O)(=O)C(C)C)C2
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
A mixture of Intermediate 3 (80 mg, 0.22 mmol), 3-bromo-4-methylpyridine (1 eq, 38 mg, 0.22 mmol) and cesium carbonate (1.5 eq, 108 mg, 0.33 mmol) in a 3:1 mixture of 1,4-dioxan:water (4 ml) was degassed with argon for 5 minutes. Palladium acetate (2 mg, 0.01 mmol), followed by triphenylphosphine (12 mg, 0.04 mmol) were then added and the whole mixture stirred at 160° C. for 20 mins in a microwave reactor. The reaction mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated and evaporated under reduced pressure. The resulting product was purified on a 5 g Isolute™ Flash silica-gel column, eluting from 0-40% ethyl acetate in petroleum ether to give the title compound as a yellow oil (38 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[C@H:4]([CH2:42][CH2:43][S:44][CH3:45])[N:5](C(OC(C)(C)C)=O)[C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:17][CH:18]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH3:19])[S:14][CH2:15][CH3:16])=[CH:9][C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].Cl>O1CCOCC1>[CH2:15]([S:14][CH:13]([NH:17][CH:18]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:19])[C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:46])[CH2:42][CH2:43][S:44][CH3:45])=[O:34])=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:9]=1)[CH3:16]
Reactant: CCSC(NC(C)CC1CCCCC1)c1ccc(C(=O)N(C(=O)OC(C)(C)C)[C@@H](CCSC)C(=O)OC)c(-c2ccccc2C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCSC(NC(C)CC1CCCCC1)c1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2C)c1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of N-tert-butoxycarbonyl-N-[4-(1-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester (200 mg) in dioxane (1 mL) chilled to its melting point, was added HCl (0.75 mL, 4M in dioxane). After 1 h, the reaction was quenched with excess aqueous sodium bicarbonate, and extracted into dichloromethane. The solution was concentrated, and the residue was purified by silica gel chromatography eluting with 5% methanol/dichloromethane to afford the title compound as a colorless oil (72 mg, 42%). MS (APCI(+)) 587 (M+H)+. MS (APCI(−)) 621 (M+CI)−.
Reaction SMILES: NC1C=C(P(O)(=O)O)C=CC=1.[OH-].[Na+].C(=O)(O)[O-].N[C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[C:22](Br)=[CH:21][CH:20]=1>[Cu](Cl)Cl.O>[CH:26]1[C:25]2[C:24](=[O:34])[C:23]3[C:32](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:31](=[O:33])[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: Cl[Cu]Cl
Agent: Nc1cccc(P(=O)(O)O)c1
Agent: O=C([O-])O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 240.1 %

Procedure:
First of all, 17.3 g (0.1 mol) of 3-aminobenzenephosphonic acid was dispersed in a solution of 70 ml of water and 8 g of sodium hydroxide and mixed throughout. To the mixture, 8 g of sodim bicarbonate and 16 g (0.04 mol) of 1-amino-4-bromoanthraquinone were added and 0.6 g of copper chloride was then added and mixed at 70° to 75° C. until the reaction was terminated. The resultant mixture was filtered and the filtrate was made acidic to remove excess 3-aminobenzenephophonic acid. Sodium chloride was added to the filtrate and salted out, filtered and dried. It was then purified with alcohol to obtain a blue anthraquinone compound (20 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:32][C:14]2[CH2:15][C@@:16]3([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[CH:25]=4)[C@H:21]([CH2:22][C:13]=2[C:12]=1[CH3:33])[CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[ClH:38].CCOCC>CO>[ClH:38].[CH2:1]([NH:8][C:9]([C:11]1[NH:32][C:14]2[CH2:15][C@@:16]3([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)[C@H:21]([CH2:22][C:13]=2[C:12]=1[CH3:33])[CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]3)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@]23CCN(C)C[C@H]2Cc2c([nH]c(C(=O)NCc4ccccc4)c2C)C3)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1c(C(=O)NCc2ccccc2)[nH]c2c1C[C@@H]1CN(C)CC[C@@]1(c1cccc(O)c1)C2

Procedure:
0.38 g of (±)-trans-2-benzylaminocarbonyl-3,6-dimethyl-8a-(3-methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline were treated with 0.55 ml (5.7 mmol) of boron tribromide as described in example 2. The residue was dissolved in MeOH and the solution brought to acidic pH with HCl/Et2O. The solvent was evaporated in vacuo and the solid crystallised from a mixture of acetone/MeOH=1:1, yielding 0.15 g of the title compound. M.p.=297°-299° C. C27H31N3 O2.HCl I.R. (KBr): 3290, 2910, 1650, 1540, 1320cm-1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH:5]=[O:6].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][OH:6]
Reactant: CN(C)S(=O)(=O)c1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a solution of OBS02001 (6.0 g, 19.47 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.81 g, 21.42 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the filtrates gave OBS02002 as a pale yellow oil (5.54 g, 92%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.47; 1H-NMR (270 MHz, CDCl3)=2.97 (6H, s), 3.14 (1H, bs, OH), 4.51 (2H, s), 7.19 (1H, dd, J=1.5, 8.1), 7.37 (1H, d, J=8.4), 7.52 (1H, d, J=1.8).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]([N:49]=[C:50]=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CO.[NH4+].[OH-]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:50](=[O:51])[NH:49][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:29][CH:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(OCc3ccc(F)cc3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reactant: O=C=NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)NCc1ccccc1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 121 %

Procedure:
Bicyclic amine 49 (300 mg, 0.53 mmol) and TEA (150 μL) were dissolved in DCM (5 mL) at ambient temperature and benzyl isocyanate (135 μL, 1.06 mmol) was added. After 3 h, MeOH (20 mL) and 30% NH4OH (1 mL) were added and the solution was stirred for 15 min before being concentrated in vacuo. The residue was dissolved in EtOAc and washed successively with 1N HCl, water, aqueous NaHCO3, water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 450 mg of 50 as an amorphous solid which was used without further purification. Mass spectrum, m/z [702.3] (M+Na)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:32][O-:33].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:33][CH3:32])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C[O-]
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)c2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 105 °C

Procedure:
A mixture of (2,4-dichloro-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1 g, 2.085 mmol, Intermediate 41: step c) and solid sodium methoxide (0.56 g, 10.42 mmol) in toluene (10 mL) was heated in a sealed tube at 105° C. for 12 hours, cooled to room temperature, diluted with DCM and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (heptane/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15](Cl)=[O:16].Cl>CN(C=O)C.C(Cl)Cl.O>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:16]
Reactant: Nc1ccnc(Cl)c1F
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Cl)c2F)c(Cl)c1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
2-Chloro-3-fluoropyridin-4-ylamine (146 mg, 10 mmol) was added to a suspension of sodium hydride (60% dispersed in mineral oil, 80 mg, 2.0 mmol) in DMF (5 mL). The mixture was stirred for 30 minutes then 2,6-dichloro-4-cyano-benzoyl chloride (250 mg, 1.1 mmol) was added and stirring continued for 18 hours. Water (10 mL) and DCM (20 mL) were added to the reaction, and the resultant mixture was acidified with 1M HCl. The organic phase was separated, washed with brine (10 mL), dried over MgSO4, and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM. The crude product was triturated with diethyl ether to give the desired compound as a white solid (230 mg, 67% yield). 1H NMR (400 MHz, CDCl3): δ 8.46 (t, J=5.3 Hz, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.88 (br s, 1H), 7.72 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)[CH:2]=[CH2:3].C(O)CO.NN.[OH-].[K+]>>[CH2:1]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccccc2)CCCCC1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: C=CCC1(c2ccccc2)CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 2-allyl-2-phenylcyclohexanone (1.97 g, 9.19 mmol) in ethylene glycol (8 mL, 143 mmol) were added hydrazine (0.8 mL, 25 5 mmol) and potassium hydroxide (1.547 g, 27 6 mmol), and the mixture was stirred at 100° C. for 1 hr and refluxed in a 180° C. oil bath for 2.5 hrs. TLC showed that the hydrazone formation nearly complete. Then the excess hydrazine and water were distilled out in a 200° C. oil bath, and it was continued to heat at the same temperature for 4 hrs. After cooling to room temperature, the mixture was added to ether and washed with water and brine. The combined aqueous layers were back-extracted with ether (2×), combined, dried over Na2SO4, and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with hexane followed by 5:95 EtOAc-hexane to give product (825 mg).
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][N:18]([C:20]([C:22]3[CH:23]=[N:24][C:25]([NH:28][C:29]4[N:30]=[CH:31][C:32]5[CH:37]=[C:36]([C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[N:35]([CH:43]6[CH2:47][CH2:46][CH2:45][CH2:44]6)[C:33]=5[N:34]=4)=[CH:26][CH:27]=3)=[O:21])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.C(CC(OC)=O)C.C1COCC1.[H][H]>[Pd].CO>[CH3:40][N:39]([CH3:41])[C:38]([C:36]1[N:35]([CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[C:33]2[N:34]=[C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:20]([N:18]4[CH2:17][CH:16]5[NH:11][CH:12]([CH2:13][O:14][CH2:15]5)[CH2:19]4)=[O:21])=[CH:23][N:24]=3)[N:30]=[CH:31][C:32]=2[CH:37]=1)=[O:42]
Reactant: [H][H]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5COCC(C4)N5C(=O)OCc4ccccc4)cn3)nc2n1C1CCCC1
Agent: [Pd]
Solvent: CCCC(=O)OC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5COCC(C4)N5)cn3)nc2n1C1CCCC1
Yield: 92.8 %

Procedure:
To a round bottom flask was combined 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (0.461 g, 0.722 mmol), methanol ethyl acetate (12 ml), THF (3 ml), methanol (3 ml), and Pd on C/10%. The mixture was put under a balloon of hydrogen and stirred over night. The mixture was purged with nitrogen followed by addition of methylene chloride. The resultant mixture was filtered through a pad of celite. The celite was washed with additional methylene chloride. The organics were combined and concentrated to a residue. The residue was purified by silica gel chromotography which gave 7-Cyclopentyl-2-[5-(3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (338 mg, 0.67 mmol) in 93% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1H), 8.63 (d, J=8.6 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.87 (dd, J1=8.78 Hz, J2=2.26 Hz, 1H), 6.51 (s, 1H), 4.83 (m, 1H), 4.47 (s, 1H), 4.09 (m, 4H), 3.77 (s, 1H), 3.45-3.21 (m, 4H), 3.19 (s, 6H), 2.59 (m, 2H), 2.11 (m, 5H), 1.77 (m, 2H); HRMS m/z 505.2665 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:40]=[C:39]([CH2:41][N:42]3[CH:46]=[CH:45][CH:44]=[N:43]3)[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:40]=[C:39]([CH2:41][N:42]6[CH:46]=[CH:45][CH:44]=[N:43]6)[C:33]6[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(Cn3cccn3)c21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(Cn5cccn5)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
140 mg (0.508 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 210 mg (0.284 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-4-pyrazol-1-ylmethyl-3H-benzoxazol-2-one and 0.100 mL (0.581 mmol) DIPEA were combined in 1.0 mL DMF and stirred for 48 h at RT. Then the reaction mixture was purified several times by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([F:13])[N:5]=1)[CH3:2]>C1COCC1.[OH-].[OH-].[Pd+2]>[NH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([F:13])=[CH:7][CH:8]=1
Reactant: CCNc1nc(F)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNc1nc(F)ccc1N
Yield: 101.7 %

Procedure:
A solution of 2-(ethylamino)-6-fluoro-3-nitropyridine (43.2 g, 230 mmol) in THF (1 L) was stirred overnight at room temperature under hydrogen (1 atm.) in the presence of 20% Pd(OH)2/C (4.35 g). The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound (36.3 g, 95% yield) as a black solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C@@:10]2([CH3:17])[CH2:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH:21]=[CH:20]1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:6]1[C:5]([C@@:10]2([CH3:17])[CH2:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:4][CH:3]=[C:2]([C:25]2[CH:26]=[C:27]3[C:22]([CH:21]=[CH:20][N:19]3[CH3:18])=[CH:23][CH:24]=2)[N:7]=1
Reactant: COc1nc(Cl)ccc1[C@@]1(C)CCCNC1=O
Reactant: Cn1ccc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1nc(-c2ccc3ccn(C)c3c2)ccc1[C@@]1(C)CCCNC1=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a vessel containing (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (80 mg, 0.31 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (105 mg, 0.41 mmol), dioxane (3 mL), and 2 M Na2CO3 (0.31 mL, 0.63 mmol) was added Pd(dppf)Cl2 (23 mg, 0.031 mmol). The reaction was stirred for 18 h at 110° C. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to provide a crude product. Purification by preparative TLC (100% Ethyl Acetate) provided the title compound (80 mg, 76%). 1H NMR (400 MHz, CDCl3) δ: 1.65-1.70 (m, 1H); 1.72 (s, 3H), 1.78-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.40 (td, 1H), 3.35-3.41 (m, 1H), 3.52 (td, 1H), 3.87 (s, 3H), 4.11 (s, 3H), 5.83 (br. s., 1H), 6.49 (d, 1H), 7.10 (d, 1H), 7.41 (d, 1H), 7.64-7.67 (m, 2H), 7.77 (dd, 1H), 8.03 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(Br)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccnc1Nc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Compound 1 (4.9 g, 16.6 mmol) was dissolved in ethanol (20 ml). Tin (II) Chloride dihydrate (7.5 g, 33.3 mmol) was added and the solution stirred at 70° C. for 4 hours to provide the title compound. The product was confirmed by LC-MS. Addition of excess triethylamine caused a solid to form. The solid was filtered and the solution evaporated to leave an off white solid. The solid as recrystallized from ethanol to leave the title compound (3.8 g, 86%). [M+H] calc'd for C11H10BrN3, 265; found 265.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([OH:23])=O)=[O:15])[CH2:7][CH2:6]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[O:15])[CH2:7][CH2:6]2
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CCC(CC(=O)C1SCN[C@@H]1C(=O)O)C2
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: COc1ccc2c(c1)CCC(CC(=O)C1SCN[C@@H]1C(=O)N1CCCC1)C2
Yield: 52 %

Procedure:
A colorless oil of 1-[3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline prepared in Reference Example 23 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH3:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1c[nH]c2ccccc12
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Product: Cc1c(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)[nH]c2ccccc12

Procedure:
is obtained as described in Example 10 (a) from 10.0 g 4-chloro-3-sulfamoylbenzoyl chloride and 5.1 g 3-methylindole in the presence of 10.4 g aluminum chloride. Colorless crystals from isopropanol, m.p. 205° C.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:16]1[C:17]2[C:18]3[C:19](=[N:30][N:31]([CH2:33][C:34]4[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=4)[N:32]=2)[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[C:22]=3[CH2:23][S:24][N:25]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O1CCCC1.ClC(OCC(C)C)=O>O>[OH:28][CH2:27][CH2:26][C:21]1[C:22]2[CH2:23][S:24][N:25]=[C:16]([N:15]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[C:17]3=[N:32][N:31]([CH2:33][C:34]4[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=4)[N:30]=[C:19]([C:18]=23)[CH:20]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CC(=O)O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2nc3cc(CCO)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
N-Methylmorpholine (22 μl) was added to a mixture composed of the above {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetic acid (60 mg) and tetrahydrofuran (2 ml). Then, isobutyl chloroformate (39 μl) was added and the mixture was stirred at 0° C. for one hour. N-Methylmorpholine (44 μl) and isobutyl chloroformate (39 μl) were added to the reaction mixture, and the mixture was further stirred at 0° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Tetrahydrofuran (2 ml) and water (0.4 ml) were added to the resulting residue. Then, sodium borohydride (15 mg) was added under ice-cooling, and the mixture was stirred at 0° C. for one hour. Methanol (2 ml) was added dropwise to the reaction mixture. Then, the mixture was returned to room temperature and stirred for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (hexane-ethyl acetate) to obtain the title compound (16 mg, 27%) as an oil.