Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:45]=[N:46][CH:47]=[C:42]([F:41])[CH:43]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cncc(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (132 mg) and a solution of 5-fluoropyridine-3-sulfonyl chloride (127 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:3) to give the title compound as a colorless oil (yield 224 mg, 93%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[Cl:18].[C:19](=[O:21])=[O:20]>CCOCC>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[C:19]([OH:21])=[O:20]
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a mixture of 65.2 ml of n-butyllithium (1.61M in hexane) and 100 ml of anhydrous ether was added dropwise 29.3 g of 4-bromo-3,5-dichlorobenzotrifluoride (3) in 30 ml of anhydrous ether at -78° C., followed by stirring for 20 minutes. Subsequently, 10 g of dry ice crashed into small pieces was added in small portions to the reaction mixture, followed by stirring at room temperature for 1.5 hours. Ice water was added to the reaction mixture, the mixture was thereafter extracted with ether, and the combined extract was subjected to reverse extraction with 10% aqueous sodium carbonate solution. The aqueous layer was acidified with 6N hydrochloric acid, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 20.4 g of the desired product in the form of white crystals (crude yield 79.1%). mp 117°~118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a mixture of 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]-acetate, 1 ml of acetonitrile, and 31 mg of potassium carbonate was added 32 mg of methyl iodide, and the mixture was stirred at room temperature for 1.5 hours. Then, 64 mg of methyl iodide was added, and the mixture was stirred at 50° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 97 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[C:15](=[O:18])(O)[O-:16].[Na+].O>O1CCOCC1.O>[C:4]([O:16][C:15]([N:2]1[CH2:5][CH:4]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1)=[O:18])([CH3:6])([CH3:5])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C1CNC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc(Cl)cc2)C1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A solution of azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride (50 g, 210 mmol) in dioxan:water 1:1 (800 ml) is added powdered sodium bicarbonate (61.7 g, 730 mmol) and the reaction mixture cooled to 10° C. Di-tbutyl-dicarbonate (52.6 g, 240 mmol) is added portion wise and the reaction mixture allowed to warm to room temperature with stirring for 1.5 hours. The reaction mixture is poured into water (1500 ml) and the resulting white precipitate filtered off and dried under vacuum to afford 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.45 (9H), 4.10 (1H), 4.20 (4H), 7.47 (2H), 7.80 (2H)
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)cc1
Yield: 36.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (150 mg. 0.42 mmol), acetic acid (24 μL, 0.42 mmol), 4-aminomethyl-benzoic acid methyl ester (170 mg, 0.84 mmol) and sodium triacetoxyborohydride (268 mg, 1.27 mmol) to afford 74 mg (36%) of the desired product after purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1C2C(=CC=CC=2B(O)O)[CH:18]=[CH:17][CH:16]=1>>[N:15]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][C:1]=2[C:7]2[N:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: OB(O)c1cccc2cccnc12
Product: O=Cc1cccc(-c2cccc3cccnc23)n1

Procedure:
Precursor (F) was prepared following the same procedure as that used to prepare precursor (A) except that 216 mg (1.2 mmol) of 8-quinolineboronic acid were used as reagent. 232 mg of precursor (F) were obtained as pale yellow solid with a yield of 99%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][Si:11]([CH3:27])([CH3:26])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C:17]1=[O:25].Br[CH2:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[N+:39]([C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][C:18]3([C:32]2=[O:33])[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:27])([CH3:26])[CH3:10])[C:17]3=[O:25])=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (3.64 mL, 22 mmol) is added to a stirred solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902) (2.64 g, 10 mmol) in THF (75 mL) at ambient temperature. To the stirred mixture is added dropwise a solution of 2-(bromomethyl)-5-nitrobenzoyl chloride (3.06 g, 11 mmol) [Pifferi et al. (1966) Tetrahedron 22, 2107] in THF (75 mL) and the mixture is then stirred at ambient temperature for 18 h. The mixture is then partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the aqueous layer further extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][C:45]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:51][S:48]([C:45]3([CH3:44])[CH2:47][CH2:46]3)(=[O:50])=[O:49])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: CC1(S(N)(=O)=O)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 58.1 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (105 mg, 0.177 mmol) and 1-methyl-cyclopropanesulfonic acid amide (31 mg, 0.23 mmol, prepared as described above). Flash chromatography (2% methanol/methylene chloride) gave 73 mg (58%) of [18-(isoquinolin-1-yloxy)-4-(1-methyl-cyclopropanesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: LC-MS (Method A, retention time: 3.50 min), MS m/z 710 (M++1).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C@@H:3]([NH2:5])[CH3:4].[F:7][C:8]1[C:13]([F:14])=[C:12]([C:15](O)=[O:16])[C:11]([F:18])=[C:10]([F:19])[C:9]=1[CH3:20]>>[F:14][C:13]1[C:8]([F:7])=[C:9]([CH3:20])[C:10]([F:19])=[C:11]([F:18])[C:12]=1[C:15]([NH:5][C@H:3]([CH:2]([CH3:6])[CH3:1])[CH3:4])=[O:16]
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC(C)[C@H](C)N
Product: Cc1c(F)c(F)c(C(=O)N[C@@H](C)C(C)C)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using (S)-3-methylbutan-2-amine and 2,3,5,6-tetrafluoro-p-toluic acid acid (93%). 1H NMR (CDCl3) δ 0.98 (d, J=6.9 Hz, 6H) 1.18 (d, J=6.8 Hz, 3H), 2.29 (m, 3H), 4.09 (m, 1H), 5.72 (bs, 1H). MS (304.1, M+H) m.p. 146-147° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:7]([F:10])([F:9])[F:8]>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:12]=[C:11]([C:6]([F:5])([F:18])[C:7]([F:9])([F:10])[F:8])[CH:16]=[CH:15][C:14]=1[CH3:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of concentrated nitric acid (1 ml) and concentrated sulphuric acid (2 ml) was added to a cooled stirred suspension of 4-pentafluoroethyltoluene (2.1 g) in concentrated sulphuric acid (5 ml) whilst maintaining the temperature below 5° C. The mixture was stirred at 0° C. for 10 minutes, allowed to warm to room temperature and stirred for 1.5 hours. It was poured onto ice (30 ml) and extracted with ether (2×25 ml). The combined organic extracts were washed with aqueous sodium carbonate (2M, 2×25 ml), water (25 ml), saturated aqueous sodium chloride solution (25 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-nitro-4-pentafluoroethyltoluene (2.04 g) as a pale yellow oil NMR (CDCl3) 2.7(s,3H), 7.45(d, 1H), 7.7(d, 1H), 8.1(s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(Ethoxycarbonylmethyl)piperazine (5.1 g) was dissolved in tetrahydrofuran (300 ml) under a nitrogen atmosphere, and then triethylamine (8.25 ml) and benzoyl chloride (3.44 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), water (100 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (8.19 g, quant.) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:35])[NH:12][C:13]1[C:14]([CH3:34])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[NH:33])[NH2:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:35])[NH:12][C:13]1[C:14]([CH3:34])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([NH:32][C:45](=[O:47])[CH3:46])=[NH:33])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1noc(-c2ccc(-c3ccc(CC(=N)N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(=N)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1
Temperature: 25 °C

Procedure:
To [5-(4′-carbamimidoylmethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.055 g, 0.12 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (0.052 mL, 0.3 mmol), followed by acetyl chloride (0.009 mL, 0.126 mmol), and the reaction was stirred at room temperature. Additional acetyl chloride (0.009 mL, 0.126 mmol) was added, and the reaction was stirred at room temperature. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][C:16]1[C:17]([NH:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[CH:18][C:19]([NH:22][C:23]2[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=2)=[N:20][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:19]2[N:20]=[CH:21][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[C:17]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:18]=2)=[N:24][CH:25]=1)#[N:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 2 h
Yield: 29.7 %

Procedure:
Triethylamine (11 μL, 0.082 mmol) and acetic anhydride (8 μL, 0.082 mmol) were added to a solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (29 mg, 0.068 mmol) in DMF (1 mL) at 0° C. After 2 hours, the mixture was loaded onto a MP-TsOH SPE cartridge, and eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated. Purified by preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)acetamide (7.4 mg, 32%).
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.C(Cl)(=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:6]([NH:8][CH:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:5])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)OC(C)(C)C)CC2c2ccccc2)CC1
Product: C=CCN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as Example 16, Step A and B, 1-(RS)-((t-butoxycarbonyl)amino)-3-(SR)-((4-(N-(4-nitrobenzylaminocarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane from Example 22 (derived from the lower isomer from Example 20, Step E) was deblocked and acylated with benzoyl chloride to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].CO>O1CCCC1>[OH:14][CH2:13][C@H:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 25.0 g of N-α-t-BOC-D-proline in 250 ml of tetrahydrofuran which is cooled to 0° C. is added dropwise 15 ml of 10M borane-methyl sulfide complex. The reaction is kept at around -20° C. during the addition followed by warming to room temperature and then is gently refluxed for one hour. The mixture is cooled to 0° C., 250 ml of methanol is added carefully and the reaction is evaporated in vacuo to give 23.3 g of a colorless oil which crystallizes on standing to a colorless solid, mp 50°-53° C., [α]D26° =+47°±1 (C=1.162%, methylene chloride).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH:3]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][O:9][C:4]2[CH:3]=[C:2]([NH:1][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(OCCc2ccc(C#N)cc2)c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a cold solution (ice:water temperature) of amino-[3-2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.13 g; 0.50 mmol; from step (iii) above) in pyridine (5 mL) was added benzenesulfonyl chloride (71 μL; 0.55 mmol). After 2 hours stirring, NaHCO3/aq (sat.) was added, and the solution extracted with EtOAc. The combined organic phases were dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; EtOAc:heptane (1:1)) to give 0.19 g (97%) of the sub-title compound.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:6])[CH:4]=[O:5].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)C(=O)NC=[CH:11]2.CI>O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:4](=[O:5])[N:3]([CH3:6])[CH:2]=[CH:11]2
Reactant: CN(C)C=O
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [Na]
Solvent: O
Solvent: CI
Product: Cn1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 60% sodium hydrogenate (18 mg) was added at 0° C. to 2 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. Then, 0.03 ml of methyl iodide was added at 0° C., stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by preparative thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 24 mg of the above compound as a white solid.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:30]([O:34][C:35](=[O:60])[NH:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48](=[NH:51])[NH:49]O)[CH:46]=2)[NH:41][C:40]=1[C:52]1[CH:57]=[C:56]([CH3:58])[CH:55]=[C:54]([CH3:59])[CH:53]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:60])[NH:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[N:51]=[C:1]([CH2:2][CH:3]([CH3:5])[CH3:4])[O:7][N:49]=3)[CH:46]=2)[NH:41][C:40]=1[C:52]1[CH:53]=[C:54]([CH3:59])[CH:55]=[C:56]([CH3:58])[CH:57]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=N)NO)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-c4noc(CC(C)C)n4)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of isovaleric acid (0.025 mL in 4 mL methylene chloride) was added 1-hydroxybenzotriazole (37.8 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.6 mg) and the reagents allowed to mix for 30 minutes. At this time a solution of {2-[2-(3,5-dimethylphenyl)-5-(N-hydroxycarbamimidoyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (81 mg in 3 mL methylene chloride) was added and the reaction stirred at room temperature. After 2 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to give the title compound (81 mg).
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][C@H:12]3[N:8]4[C:9]5[C:4](=[CH:3][CH:2]=[CH:1][C:10]=5[C@H:11]3[CH2:16]2)[CH2:5][CH2:6][CH2:7]4)=[CH:23][CH:24]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCCN2CC[C@@H]3[C@H](C2)c2cccc4c2N3CCC4)cc1
Yield: 31.8 %

Procedure:
The title compound (0.14 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 1-(3-chloropropoxy)-4-fluorobezene (0.37 g, 2.0 mmol), KI (catalytic) and K2CO3(0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.78–2.08 (m, 7H), 2.10–2.30 (m, 1H), 2.32–2.50 (m, 3H), 2.51–2.72 (m, 3H), 2.75–2.82 (m, 1H), 3.00–3.12 (m, 1H), 3.12–3.25 (m, 2H), 3.89 (t, J=6.3 Hz, 2H), 6.55 (t, J=7.5 Hz, 1H), 6.70–6.92 (m, 6H) ppm.