Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH:33]([CH3:37])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:38][C:39]1[CH:44]=[C:43]([NH2:45])[N:42]=[C:41]([NH2:46])[CH:40]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]([C:34](=[O:36])[NH:46][C:41]1[CH:40]=[C:39]([Cl:38])[CH:44]=[C:43]([NH2:45])[N:42]=1)[CH3:37])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(Cl)cc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HATU (2.7 g, 7.1 mmol) is added to a mixture of 2-{[(tert-butoxy)carbonyl]amino}-propanoic acid (850 mg, 4.5 mmol), 4-chloropyridine-2,6-diamine (1 g, 7.0 mmol), DIPEA (4.6 ml, 26.5 mmol) and NMP (7 ml) and the mixture is stirred at RT for 18 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 770 mg (55%). HPLC-MS: M+H=315 (Method—2).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[C:14]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[S:18][CH:17]=3)[CH:13]=[CH:12][C:11]=2[OH:25])=[CH:2]1.C(Cl)Cl.C(N(CC)CC)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>O>[C:36]([O:25][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][CH:17]=2)=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(-c2csc3ccccc23)cc1-c1csc2ccccc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(-c2csc3ccccc23)cc1-c1csc2ccccc12
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1.96 g of the thus obtained 2,4-bis(3-benzothiophenyl)phenol is placed in a round bottom flask; 10 mL of methylene chloride is added to form a transparent solution; after ice cooling the flask, 0.66 g of triethylamine is added; 0.59 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=90/10 (volume ratio)) to concentrate a component having an Rf of 0.20, thereby obtaining 1.43 g (yield: 63%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.78 (dd=1.2 & 10.8 Hz, 1H), 6.01 (dd=10.8 & 17.2 Hz, 1H), 6.26 (dd=1.2 & 17.2 Hz, 1H), 7.38 to 7.47 (m, 7H), 7.65 to 7.75 (m, 3H), 7.88 to 7.96 (m, 3H)
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([NH:24][C:25](=[O:36])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1CCCC1.C(O)(=[O:50])C>CN(C=O)C.O>[Si:1]([O:8][C@H:9]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@H:10]([NH:24][C:25](=[O:36])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:11][CH2:12][C:13](=[O:50])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: COc1ccc(COC(=O)N[C@H](CCC#Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNC1
Product: COc1ccc(COC(=O)N[C@H](CCC(=O)Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of nitrophenyl acetylene (from Step F, 41 g, 65.5 mmol) in DMF (40 ml) was added pyrrolidine (14 mL, 196.5 mmol) and the resulting mixture heated at 80° C. for 3 h. The mixture was cooled to room temperature and a 10% solution of acetic acid in water (110 ml) was added, and the resulting solution stirred at room temperature for another 3 h. The mixture was poured into water (300 ml) and extracted with EtOAc (3×250 ml); combined EtOAc layers were washed with water (2×250 ml), sat. NaCl (100 ml), dried over MgSO4, filtered and evaporated. The residue was purified by Horizon Flash 75 eluting with a gradient rising from 100% Hexanes to 50% EtOAc in Hexanes to give 34 g (81%) as a dark orange oil. 1H NMR (500 MHz, CDCl3): 8.17-8.14 (m, 2H), 7.32-7.23 (m, 9H), 6.87 (d, J=8.4 Hz, 2H), 4.96 (d, J=12.2 Hz, 1H), 4.90 (d, J=12.1 Hz, 1H), 4.72 (d, J=3 Hz, 1H), 4.16-4.13 (m, 1H), 3.81 (s, 3H), 3.71-3.77 (m, 2H), 2.65-2.52 (m, 2H), 1.97-1.92 (m, 1H), 1.72-1.60 (m, 1H), 0.93 (s, 9H), 0.05 (s, 3H), −0.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (3.95 g), N,N-diisopropylethylamine (1.79 mL), and morpholine (0.96 mL) in anhydrous DMF (149 mL) is heated at 65° C. for 1-2 h. The reaction is allowed to cool to room temperature, then poured into H2O (300 mL) to precipitate the product. The solid is filtered, adsorbed onto silica, and chromatographed (eluent 100% CH2Cl2 (0.5% CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1 L), 2% MeOH in CH2Cl2 (1L), 2.5% MeOH in CH2Cl2 (2L)). Product-containing fractions are combined and condensed to afford 3.17 g (73%) of the desired product as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:57][CH2:58][CH3:59])=O.CC(O)=O>C1COCC1>[C:58]([O:23][C@@H:21]1[CH2:20][N:19]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[C@@H:18]([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:22]1)(=[O:57])[CH3:59]
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a mixture of benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (1.50 g) and triphenylphosphine (1.43 g) in THF (15 mL) was added diethyl azodicarboxylate (0.86 mL) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added AcOH (0.29 mL) at 5° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in EtOAc, washed with saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 2:1 elution) to give benzyl (2R, 4S)-4-acetoxy-2-(4,5-diphenyloxazol-2-yl)pyrrolidine-1-carboxylate (1.88 g).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:13]([NH:25][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
18 g of glucose were stirred in 50 ml of ethanol at 70° C., 18.5 g of dodecylamine were then added, the mixture was heated again until a clear solution was obtained, the solution was allowed to cool to room temperature and, after 20 hours, the crystals which had precipitated were filtered off with suction. The product was washed with ethanol and ether and dried in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].[NH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(O)CN
Solvent: CC#N
Product: CC(C)(O)CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 4, 250 mg, 0.44 mmol) in acetonitrile (5.0 mL) is treated with 1-amino-2-methylpropan-2-ol (80 mg, 0.90 mmol), and the mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 179 mg; ESI mass spectrum [M+H]+=513; Retention time HPLC: 0.86 min (Z011_803).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:8]=1.BrC1C=C(S(Cl)(=O)=O)C=C([C:25]([F:28])([F:27])[F:26])C=1>>[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(CN)ccc1F
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Product: CC(C)(C)NS(=O)(=O)c1cc(CN)cc(C(F)(F)F)c1

Procedure:
3-Aminomethyl-N-tert-butyl-5-trifluoromethyl-benzenesulfonamide was synthesized in a manner analogous to 5-aminomethyl-N-tert-butyl-2-fluoro-benzenesulfonamide in Example 3, using 3-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride in place of 5-chloro-2-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 337 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: CN1CCc2ccc(F)cc2N(N)CC1
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCO
Product: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 20.3 %

Procedure:
To a solution of 9-fluoro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (4.0 g, 19.1 mmole) in 1-propanol (300 mL) was added cyclopentanone (14.3 ml, 169.6 mmole), followed by p-toluenesulfonic acid monohydrate (10.3 g, 53.3 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (350 mL), saturated aqueous sodium chloride (350 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 1.0 g of the title compound. 70.5 mg of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 168-170° C. MS (ES) m/z 259.12 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.Br[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:19][C:20]([OH:22])=[O:21])=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: FC(F)(F)CNc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CN(CC(F)(F)F)c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a slurry of hexanes-washed NaH (0.492 g of a 60% w/w suspension in mineral oil, 12.3 mmol) in dry DMF (10 mL) at 0° C. was added a solution of 4-bromo-N-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)aniline (1.96 g, 6.13 mmol) in DMF (2 mL), dropwise over 5 min. The mixture was stirred 15 min and tert-butyl bromoacetate (1.82 mL, 12.3 mmol) was added dropwise over 1 min. The mixture was stirred overnight, slowly warming to rt. The mixture was poured into water and the whole was extracted with Et2O (×3). Combined organic portions were washed (water, brine), dried over Na2SO4, filtered and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and to this solution was added Et3SiH (4.9 mL, 31 mmol) and TFA (20 mL). The mixture was stirred 1.5 h at rt and concentrated in vacuo. The residue was partitioned between water/Et2O and the layers were separated. The organic layer was concentrated in vacuo. The residue was purified by filtration through a pad of silica gel (10% EtOAc/hexanes, then EtOAc to elute carboxylic acid) affording 1.50 g of the title compound as a pale yellow solid: MS (APCI) m/z 380 ([M−H]−, 81Br), 378 ([M−H]−, 79Br).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:4]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])=[CH:26][CH:25]=2)[CH:3]=1.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[C:4]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(-c2ccccc2F)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(-c2ccccc2F)cc1

Procedure:
1 ml of developed Raney nickel was added to a methanol (5 ml) solution of 410 mg of t-butyl 2-(4-amino-2-((2′-fluorobiphenyl-4-yl)oxy)-5-nitrophenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred in a hydrogen atmosphere at room temperature for 1 day. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: F[C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@@H:14]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]2)[CH:9]=[N:8][CH:7]=1)=O.[NH2:33][NH2:34]>C1COCC1>[CH2:25]([C@@H:14]1[NH:15][CH2:16][CH2:17][N:12]([C:10]2[N:11]=[C:6]([C:4]3[C:3]4[C:2](=[N:32][CH:31]=[CH:30][CH:29]=4)[NH:34][N:33]=3)[CH:7]=[N:8][CH:9]=2)[CH2:13]1)[CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)C[C@H]1CN(c2cncc(C(=O)c3cccnc3F)n2)CCN1C(=O)OC(C)(C)C
Reactant: NN
Solvent: C1CCOC1
Product: CC(C)C[C@H]1CN(c2cncc(-c3n[nH]c4ncccc34)n2)CCN1
Temperature: 75 °C

Procedure:
To a solution of (S)-tert-butyl 4-(6-(2-fluoronicotinoyl)pyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate (160 mg, 0.3608 mmol) in THF (3 mL) was added hydrazine (1M in THF) (360.8 μL of 1 M, 0.3608 mmol) and the solution heated to 75° C. for 2 hrs. The reaction was allowed to cool and concentrated to give a yellow solid. This was columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-3-(6-(3-isobutylpiperazin-1-yl)pyrazin-2-yl)-1H-pyrazolo[3,4-b]pyridine as a pale yellow solid. The Boc intermediate was dissolved in DCM (6 mL) and TFA (3 mL, 38.94 mmol) was added and the solution stirred at rt for 1 hr. Reaction was concentrated and partitioned between EtOAc and Sat. Na2CO3 and the organic washed with brine, dried (MgSO4) and concentrated to give a yellow solid. It was columned on silica gel eluting with 10% MeOH in DCM (1% NH4OH) to give (S)-3-(6-(3-isobutylpiperazin-1-yl)pyrazin-2-yl)-1H-pyrazolo[3,4-b]pyridine as an off white solid (52 mg, 42% 2 steps). ES+ 338. 1HNMR (DMSO) 0.92-0.94 (6H, dd), 1.24-1.35 (2H, m), 1.79-1.88 (1H, m), 2.56-2.61 (1H, m), 2.67-2.80 (2H, m), 2.92-3.05 (2H, m), 4.25 (1H, d), 4.33 (1H, d), 7.32 (1H, dd), 8.30 (1H, s), 8.57-8.61 (2H, m), 8.73 (1H, d), 14.14 (1H, brs).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26](O)=[O:27].[N-]1C=CN=C1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:26]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=3)=[N:4]2)=[O:27])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: Cc1cc(C2=NN(C(=O)O)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: c1c[n-]cn1
Product: Cc1cc(C2=NN(C(=O)NC3CC3)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
4.33 g (10.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxylic acid-imidazolide are heated to boiling in 30 ml of cyclopropyl amine for 6 hours, whereupon the amine is distilled off in vacuo. The residue is taken up in 75 ml of dichloro methane, washed three times with 30 ml of water each, dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is recrystallized from 40 ml of ethanol and washed with 10 ml of diethyl ether. Thus 3.00 g of the desired compound are obtained, yield 71%, mp.: 171–175° C.
Reaction SMILES: CC(C([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)C([O-])=O)(C)C.Cl.[C:33](NN)([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([N:10]1[C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:12][CH:13]=[N:9]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)NN
Agent: Cl
Product: CC(C)(C)n1nccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the major isomer (80%). ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) 8.32 (d, 2H), 7.7 (d, 2H), 7.48 (d, 1H), 6.25 (d, 1H), 1.42 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][C:5]2([CH3:13])[CH3:12].[C:14]1([C@H:20]([CH2:22][OH:23])[NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH:21][C@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:22][OH:23])[CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)CC(=O)c2ccc(Cl)cc21
Reactant: N[C@@H](CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C[C@H](N[C@@H](CO)c2ccccc2)c2ccc(Cl)cc21
Temperature: 140 °C
Yield: 89.1 %

Procedure:
To a mixture of 5-chloro-3,3-dimethylindan-1-one (4.33 g, 0.0222 mol) and (R)-(−)-2-phenylglycinol (3.2 g, 0.0234 mol) in toluene (200 mL) was added p-toluenesulfonic acid monohydrate (241 mg, 0.00127 mol). The reaction was stirred at reflux (140° C.) under an atmosphere of nitrogen overnight, cooled and diluted with toluene. The mixture was washed with saturated aqueous NaHCO3 and water and the organic phase was concentrated. The residue was dissolved in THF (200 mL) under an atmosphere of nitrogen and cooled at 0° C. To this was added acetic acid (3.79 mL, 0.0667 mol) and sodium borohydride (1.26 g, 0.0334 mol). The reaction was stirred under at atmosphere of nitrogen overnight. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution, separated, and the organic phase was evaporated. The residue was purified by flash chromatography (20 to 100% EtOAc/hexanes) to afford the title compound (6.25 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13][C@H:12]2[CH2:21][NH:22][S:23](=[O:26])(=[O:25])[NH2:24])=[O:10])=[CH:5][CH:4]=1.[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:31][C:29](=[O:32])[CH3:30])[CH2:13][C@H:12]2[CH2:21][NH:22][S:23](=[O:25])(=[O:26])[NH2:24])=[O:10])=[CH:27][CH:28]=1
Reactant: CC([O-])=S
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CNS(N)(=O)=O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(C)=O)C[C@H]2CNS(N)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
To a solution of crude (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxy-2-sulfamoylaminomethylpyrrolidine (2.26 g) obtained in Step 5 in dimethylformamide (12 ml), potassium thioacetate (1.7 g) is added. The mixture is stirred at 60° C. for 5 hours. The reaction mixture is diluted with ethyl acetate, successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-acetylthio-2-sulfamoylaminomethylpyrrolidine (971 mg). NMR δ(CDCl3) ppm: 1.8(br s, 1H), 2.33(s, 3H), 2.4 to 2.7(m, 1H), 3.1 to 3.5(m), 3.81(s, 3H), 3.9 to 4.2(m, 2H), 5.05(s, 2H), 6.89(d, J=8.8 Hz, 2H), 7.30(d, J=8.8 Hz, 2H). IR ν (CHCl3) cm-1 : 3414, 3276, 1688.